Experience with a hybrid recruitment approach of patient-facing web portal screening and subsequent phone and medical record review for a neurosurgical intervention trial for chronic ischemic stroke disability (PISCES III).

BACKGROUND: Recruitment of participants is the greatest risk to completion of most clinical trials, with 20-40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier 1), followed by phone screening and medical records review (tier 2) prior to a final in-person visit to confirm eligibility and consent. METHODS: Two tiers of screening were established: an initial screen of general eligibility using a patient-facing web portal (tier 1), followed by a more detailed screen that included phone survey and medical record review (tier 2). If potential participants passed the tier 2 screen, they were referred directly to visit 1 at a study site, where final in-person screening and consent were performed. Rates of screening were tracked during the period of trial recruitment and sources of referrals were noted. RESULTS: The approach to screening and recruitment resulted in 6125 tier 1 screens, leading to 1121 referrals to tier 2. The tier 2 screening resulted in 224 medical record requests and identification of 86 qualifying participants for referral to sites. The study attained a viable recruitment rate of 6 enrolled per month prior to being disrupted by COVID 19. CONCLUSIONS: A tiered approach to eligibility screening using a hybrid of web-based portals to self-identify and screen for general eligibility followed by a more detailed phone and medical record review allowed the study to use fewer sites and reduce cost. Despite the difficult and narrow population of patients suffering moderate chronic disability from stroke, this strategy produced a viable recruitment rate for this invasive study of intracranially injected neural stem cells. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03629275.

Optimization of a translational murine model of closed-head traumatic brain injury.

Traumatic brain injury (TBI) from closed-head trauma is a leading cause of disability, with limited effective interventions. Many TBI models impact brain parenchyma directly, and are limited by the fact that these forces do not recapitulate clinically relevant closed head injury. However, applying clinically relevant injury mechanics to the intact skull may lead to variability and as a result, preclinical modeling TBI remains a challenge. Current models often do not explore sex differences in TBI, which is critically important for translation to clinical practice. We systematically investigated sources of variability in a murine model of closed-head TBI and developed a framework to reduce variability across severity and sex. We manipulated pressure, dwell time, and displacement to determine effects on motor coordination, spatial learning, and neuronal damage in 10-week-old male and female mice. Increasing pressure beyond 70 psi had a ceiling effect on cellular and behavioral outcomes, while manipulating dwell time only affected behavioral performance. Increasing displacement precisely graded injury severity in both sexes across all outcomes. Physical signs of trauma occurred more frequently at higher displacements. Stratifying severity based on day-1 rotarod performance retained histological relationships and separated both sexes into injury severity cohorts with distinct patterns of behavioral recovery. Utilizing this stratification strategy, within-group rotarod variability over 6 days post-injury was reduced by 50%. These results have important implications for translational research in TBI and provide a framework for using this clinically relevant translational injury model in both male and female mice.

Regionalization of stroke systems of care in the stroke belt states: The IMPROVE stroke care quality improvement program.

BACKGROUND: Despite guidelines and strong evidence supporting intravenous thrombolysis and endovascular thrombectomy for acute stroke, access to these interventions remains a challenge. The objective of the IMPROVE stroke care program was to accelerate acute stroke care delivery by implementing best practices and improving the regional systems of care within comprehensive stroke networks. METHODS: The IMPROVE Stroke Care program was a prospective quality improvement program based on established models used in acute coronary care. Nine hub hospitals (comprehensive stroke centers), 52 regional/community referral hospitals (spokes), and over 100 emergency medical service agencies participated. Through 6 regional meetings, 49 best practices were chosen for improvement by the participating sites. Over 2 years, progress was tracked and discussed weekly and performance reviews were disseminated quarterly. RESULTS: Data were collected on 21,647 stroke code activations of which 8,502 (39.3%) activations had a final diagnosis of stroke. There were 7,226 (85.0%) ischemic strokes, and thrombolytic therapy was administered 2,814 times (38.9%). There was significant overall improvement in the proportion that received lytic therapy within 45 minutes (baseline of 44.6%-60.4%). The hubs were more frequently achieving this at baseline, but both site types improved. A total of 1,455 (17.1%) thrombectomies were included in the data of which 401 (27.6%) were transferred from a spoke. There was no clinically significant change in door-to-groin times for hub-presenting thrombectomy patients, however, significant improvement occurred for transferred cases, 46 minutes (interquartile range [IQR] 36, 115.5) at baseline to 27 minutes (IQR 10, 59). CONCLUSIONS: The IMPROVE program approach was successful at improving the delivery of thrombolytic intervention across the consortium at both spoke and hub sites through collaborative efforts to operationalize guideline-based care through iterative sharing of performance and best practices for implementation. Our approach allowed identification of both opportunities for improvement and operational best practices providing guidance on how best to create a regional stroke care network and operationalize the published acute stroke care guidelines.

Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.

The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box-binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulated) in the brain, including several GABAA receptor genes that are notably downregulated. Finally, whole-cell patch clamp analysis reveals a significant reduction in both spontaneous and tonic GABAergic inhibitory responses in Xbp1s-expressing neurons. Taken together, our findings unravel a link between XBP1s signaling and seizure occurrence.

Using the ICH score during acute telestroke consults to triage transfer to tertiary centers.

OBJECTIVE: Constrained resources at tertiary centers indicate a need for re-exploration of the practice of routinely transferring all community hospital patients with complex conditions such as hemorrhagic stroke (ICH). We addressed the clinical question of whether information available during acute care telestroke consults could identify ICH patients not requiring specialty services or neurosurgical intervention who could safely remain at the local center for care. DESIGN: Retrospective cohort analysis abstracting clinical factors to identify ICH patients associated with need for tertiary care or neurosurgical intervention. SETTING: The Duke Telestroke Network (DTN) in Central NC and Southern Virginia. PATIENTS: All DTN transferred ICH patients January 1, 2017 to December 31, 2018. INTERVENTIONS: We defined neurosurgical intervention as craniotomy, digital subtraction angiography, or external ventricular drain placement. MEASUREMENTS AND RESULTS: We identified 116 transferred ICH patients. Sixty-two were female, the median Glasgow coma score (GCS) was 13, and the median ICU and hospital length of stay were 2 and 7 days respectively. Thirty of the patients were offered and 27 ultimately received neurosurgical intervention. Using inclusion/exclusion criteria from two ICH surgical trials would have increased the intervention group to 35 patients (30%). Components of the ICH score differentiated surgical from non-surgical patients; patients with an ICH score of <2 and GCS ≥13 received no interventions. Nearly 50% of patients could receive medical management locally. CONCLUSIONS: Coupling the ICH score and GCS can provide triage guidance identifying patients for retention at the referring center. This retained population is distinct from patients eligible for current or novel surgical interventions. This approach provides a framework for assessment of transfers across specialty areas and furthers the value of telehealth networks.

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial.

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). Design, Setting, and Participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. Main Outcomes and Measures: Major or clinically relevant nonmajor (CRNM) bleeding. Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). Conclusions and Relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. Trial Registration: ClinicalTrials.gov Identifier: NCT02415400.

Machine Learning for Predicting In-Hospital Mortality After Traumatic Brain Injury in Both High-Income and Low- and Middle-Income Countries.

BACKGROUND: Machine learning (ML) holds promise as a tool to guide clinical decision making by predicting in-hospital mortality for patients with traumatic brain injury (TBI). Previous models such as the international mission for prognosis and clinical trials in TBI (IMPACT) and the corticosteroid randomization after significant head injury (CRASH) prognosis calculators can potentially be improved with expanded clinical features and newer ML approaches. OBJECTIVE: To develop ML models to predict in-hospital mortality for both the high-income country (HIC) and the low- and middle-income country (LMIC) settings. METHODS: We used the Duke University Medical Center National Trauma Data Bank and Mulago National Referral Hospital (MNRH) registry to predict in-hospital mortality for the HIC and LMIC settings, respectively. Six ML models were built on each data set, and the best model was chosen through nested cross-validation. The CRASH and IMPACT models were externally validated on the MNRH database. RESULTS: ML models built on National Trauma Data Bank (n = 5393, 84 predictors) demonstrated an area under the receiver operating curve (AUROC) of 0.91 (95% CI: 0.85-0.97) while models constructed on MNRH (n = 877, 31 predictors) demonstrated an AUROC of 0.89 (95% CI: 0.81-0.97). Direct comparison with CRASH and IMPACT models showed significant improvement of the proposed LMIC models regarding AUROC (P = .038). CONCLUSION: We developed high-performing well-calibrated ML models for predicting in-hospital mortality for both the HIC and LMIC settings that have the potential to influence clinical management and traumatic brain injury patient trajectories.

Machine Learning for Predicting Discharge Disposition After Traumatic Brain Injury.

BACKGROUND: Current traumatic brain injury (TBI) prognostic calculators are commonly used to predict the mortality and Glasgow Outcome Scale, but these outcomes are most relevant for severe TBI. Because mild and moderate TBI rarely reaches severe outcomes, there is a need for novel prognostic endpoints. OBJECTIVE: To generate machine learning (ML) models with a strong predictive capacity for trichotomized discharge disposition, an outcome not previously used in TBI prognostic models. The outcome can serve as a proxy for patients' functional status, even in mild and moderate patients with TBI. METHODS: Using a large data set (n = 5292) of patients with TBI from a quaternary care center and 84 predictors, including vitals, demographics, mechanism of injury, initial Glasgow Coma Scale, and comorbidities, we trained 6 different ML algorithms using a nested-stratified-cross-validation protocol. After optimizing hyperparameters and performing model selection, isotonic regression was applied to calibrate models. RESULTS: When maximizing the microaveraged area under the receiver operating characteristic curve during hyperparameter optimization, a random forest model exhibited top performance. A random forest model was also selected when maximizing the microaveraged area under the precision-recall curve. For both models, the weighted average area under the receiver operating characteristic curves was 0.84 (95% CI 0.81-0.87) and the weighted average area under the precision-recall curves was 0.85 (95% CI 0.82-0.88). CONCLUSION: Our group presents high-performing ML models to predict trichotomized discharge disposition. These models can assist in optimization of patient triage and treatment, especially in cases of mild and moderate TBI.

Toward Generalizable Trajectory Planning for Human Intracerebral Trials and Therapy.

INTRODUCTION: Stereotactic neurosurgical techniques are increasingly used to deliver biologics, such as cells and viruses, although standardized procedures are necessary to ensure consistency and reproducibility. OBJECTIVE: We provide an instructional guide to help plan for complex image-guided trajectories; this may be of particular benefit to surgeons new to biologic trials and companies planning such trials. METHODS: We show how nuclei can be segmented and multiple trajectories with multiple injection points can be created through a single or multiple burr hole(s) based on preoperative images. Screenshots similar to those shown in this article can be used for planning purposes and for quality control in clinical trials. RESULTS: This method enables the precise definition of 3-D target structures, such as the putamen, and efficient planning trajectories for biologic injections. The technique is generalizable and largely independent of procedural format, and thus can be integrated with frame-based or frameless platforms to streamline reproducible therapeutic delivery. CONCLUSIONS: We describe an easy-to-use and generalizable protocol for intracerebral trajectory planning for stereotactic delivery of biologics. Although we highlight intracerebral stem cell delivery to the putamen using a frame-based stereotactic delivery system, similar strategies may be employed for different brain nuclei using different platforms. We anticipate this will inform future advanced and fully automated neurosurgical procedures to help unify the field and decrease inherent variability seen with manual trajectory planning.

Socioeconomic Influence on Emergency Medical Services Utilization for Acute Stroke: Think Nationally, Act Locally.

BACKGROUND AND PURPOSE: Rates of emergency medical services (EMS) utilization for acute stroke remain low nationwide, despite the time-sensitive nature of the disease. Prior research suggests several demographic and social factors are associated with EMS use. We sought to evaluate which demographic or socioeconomic factors are associated with EMS utilization in our region, thereby informing future education efforts. METHODS: We performed a retrospective analysis of patients for whom the stroke code system was activated at 2 hospitals in our region. Univariate and logistic regression analysis was performed to identify factors associated with use of EMS versus private vehicle. RESULTS: EMS use was lower in patients who were younger, had higher income, were married, more educated and in those who identified as Hispanic. Those arriving by EMS had significantly faster arrival to code, arrival to imaging, and arrival to thrombolytic treatment times. CONCLUSION: Analysis of regional data can identify specific populations underutilizing EMS services for acute stroke symptoms. Factors effecting EMS utilization varies by region and this information may be useful for targeted education programs promoting EMS use for acute stroke symptoms. EMS use results in more rapid evaluation and treatment of stroke patients.

Surgical intervention and patient factors associated with poor outcomes in patients with traumatic brain injury at a tertiary care hospital in Uganda.

OBJECTIVE: The purpose of this study was to investigate whether neurosurgical intervention for traumatic brain injury (TBI) is associated with reduced risks of death and clinical deterioration in a low-income country with a relatively high neurosurgical capacity. The authors further aimed to assess whether the association between surgical intervention and acute poor outcomes differs according to TBI severity and various patient factors. METHODS: Using TBI registry data collected from a national referral hospital in Uganda between July 2016 and April 2020, the authors performed Cox regression analyses of poor outcomes in admitted patients who did and did not undergo surgery for TBI, with surgery as a time-varying treatment variable. Patients were further stratified by TBI severity using the admission Glasgow Coma Scale (GCS) score: mild TBI (mTBI; GCS scores 13-15), moderate TBI (moTBI; GCS scores 9-12), and severe TBI (sTBI; GCS scores 3-8). Poor outcomes constituted Glasgow Outcome Scale scores 2-3, deterioration in TBI severity between admission and discharge (e.g., mTBI to sTBI), and death. Several clinical and demographic variables were included as covariates. Patients were observed for outcomes from admission through hospital day 10. RESULTS: Of 1544 patients included in the cohort, 369 (24%) had undergone surgery. Rates of poor outcomes were 4% (n = 13) for surgical patients and 12% (n = 144) among nonsurgical patients (n = 1175). Surgery was associated with a 59% reduction in the hazard for a poor outcome (HR 0.41, 95% CI 0.23-0.72). Age, pupillary nonreactivity, fall injury, and TBI severity at admission were significant covariates. In models stratifying by TBI severity at admission, patients with mTBI had an 80% reduction in the hazard for a poor outcome with surgery (HR 0.20, 95% CI 0.04-0.90), whereas those with sTBI had a 65% reduction (HR 0.35, 95% CI 0.14-0.89). Patients with moTBI had a statistically nonsignificant 56% reduction in hazard (HR 0.44, 95% CI 0.17-1.17). CONCLUSIONS: In this setting, the association between surgery and rates of poor outcomes varied with TBI severity and was influenced by several factors. Patients presenting with mTBI had the greatest reduction in the hazard for a poor outcome, followed by those presenting with sTBI. However, patients with moTBI had a nonsignificant reduction in the hazard, indicating greater variability in outcomes and underscoring the need for closer monitoring of this population. These results highlight the importance of accurate, timely clinical evaluation throughout a patient's admission and can inform decisions about whether and when to perform surgery for TBI when resources are limited.

Barriers to biomedical care for people with epilepsy in Uganda: A cross-sectional study.

OBJECTIVE: Epilepsy, a neurological disorder with effective biomedical treatment, remains largely untreated in Uganda. Potential reasons for this treatment gap (TG) include limited access to trained providers and clinics, social stigmata of seizures, cultural beliefs, or lack of public understanding of epilepsy as a treatable condition. The current study aimed to formally evaluate barriers faced by people with epilepsy (PWE) in Uganda when seeking biomedical care. METHODS: In a cross-sectional study, 435 participants drawn from a community prevalence study were enrolled. We included participants reporting a history of recurrent seizures suggestive of epilepsy, who completed a survey about barriers to obtaining care for their symptoms. Principal axis factor analysis (PFA) using a promax rotation was conducted for data reduction. Frequencies of barrier factors were compared across those who did not seek care for epilepsy (n = 228), those who sought care from biomedical facilities (n = 166), and those who sought care from a traditional or pastoral healer (n = 41). RESULTS: The PFA yielded a five-factor solution: 1) logistical and actual costs; 2) treatment effectiveness; 3) influence of the opinion of others; 4) doctors' care; and 5) contextual factors impacting decision-making. Variables related to logistical and actual costs were most endorsed. Comparison of groups by care sought did not reveal a difference in endorsement of factors, with the exception that those who sought biomedical care were more likely to endorse factors related to doctors' care compared with those that sought care from traditional or pastoral healers (P = .005). CONCLUSIONS: People with repetitive seizures in Uganda report several barriers to obtaining biomedical care in Uganda, with those related to practical and actual costs endorsed the most. It is imperative that interventions developed to reduce the TG in Uganda consider these practical issues to improve access to effective epilepsy care. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda.

Hospital-based epilepsy care in Uganda: A prospective study of three major public referral hospitals.

OBJECTIVE: This study sets out to describe the current demographics of people with epilepsy (PWE) attending hospital-based care in Uganda and the epilepsy treatment practices within three of the largest Ugandan public referral hospitals. METHODS: In a six-month prospective cohort study, 626 children and adults attending epilepsy clinics at Mulago National Referral Hospital, Butabika National Referral Mental Hospital and Mbarara Regional Referral Hospital were enrolled. Using a study questionnaire, data were collected at baseline and at 3 weeks, 3 months, and 6 months following enrollment. Specific data surrounding individual patient demographics, clinical characteristics and severity of epilepsy, and treatment of epilepsy with antiepileptic drugs (AEDs) were collected. RESULTS: Female patients totaled to 50.8%, with a nearly equal gender distribution at each hospital. There was no statistical difference in gender or age between sites. The majority of PWE had completed primary school, with less than 15% of patients completing more than a secondary education. Seizure severity was high, with most patients having multiple seizures per week at the initial onset of epilepsy, and greater than 90% of patients reporting a loss of consciousness with seizures. The majority of patients (54.95%) also reported a developmental or learning delay. Most patients were on 1 AED (46.01%) or 2 AEDs (36.90%), with carbamazepine being the most frequently prescribed AED. There was a trend towards improved seizure severity over the follow-up period, as assessed by the corresponding Personal Impact of Epilepsy Scale (PIES) subscale. CONCLUSIONS: People with epilepsy attending hospital-based care in Uganda tend to have severe forms of epilepsy requiring management with AEDs. Current hospital-based practices show a positive trend for seizure burden and quality of life of PWE in Uganda. Further interventions to improve overall access to biomedical care are required to continue to advance the management of PWE across all communities. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".

Leveraging the lessons learned from studies on the cultural context of epilepsy care in Uganda: Opportunities and future directions.

In this summary paper, we review the body of research contained in this special issue, The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda, and corollary recommendations for a way forward. We review key findings and conclusions for the studies, which tell a story of culture and care-seeking through discussions and data gleaned from a rich research landscape traversing community village dwellings, shared communal areas, churches, and urban hospitals. The voices and perspectives of over 16,000 study participants inclusive of people living with epilepsy, their neighbors and healthcare workers, traditional healers, and faith leaders are reported. From this, we synthesize findings and prioritize a set of recommendations to advance epilepsy care in Uganda. Progress will require infrastructure strengthening, multilevel educational investments, and an ambitious, extensive program of community sensitization. These proposed priorities and actions outline a way forward through formidable but surmountable challenges but require harmonized efforts by government and other relevant stakeholders, scholars, clinicians, and community leaders. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".

Sociocultural determinants and patterns of healthcare utilization for epilepsy care in Uganda.

OBJECTIVE: Epilepsy is a global public health concern, with the majority of cases occurring in lower- and middle-income countries where the treatment gap remains formidable. In this study, we simultaneously explore how beliefs about epilepsy causation, perceived barriers to care, seizure disorder characteristics, and demographics influence the initial choice of healthcare for epilepsy and its impact on attaining biomedical care (BMC). METHODS: This study utilized the baseline sample (n = 626) from a prospective cohort study of people with epilepsy (PWE) attending three public hospitals in Uganda (Mulago National Referral Hospital, Butabika National Referral Mental Hospital, and Mbarara Regional Referral Hospital) for epilepsy care. Patient and household demographics, clinical seizure disorder characteristics, and sociocultural questionnaires were administered. Logistic regression and principal component analyses (PCA) were conducted to examine associations with the choice of primary seizure treatment. RESULTS: The sample was 49% female, and 24% lived in rural settings. A biomedical health facility was the first point of care for 355 (56.7%) participants, while 229 (36.6%) first sought care from a traditional healer and 42 (6.7%) from a pastoral healer. Preliminary inspection of candidate predictors using relaxed criteria for significance (p < 0.20) identified several factors potentially associated with a greater odds of seeking BMC first. Demographic predictors included older caredriver (decision-maker for the participant) age (odds ratio [OR]: 1.01, 95% confidence interval [CI]: [0.99, 1.02], p-value: 0.09), greater caredriver education level (OR = 1.21, 95% CI: [1.07, 1.37], p-value = 0.003), and lower ratio of sick to healthy family members (OR = 0.77 [0.56, 1.05], P = 0.097). For clinical predictors, none of the proposed predictors associated significantly with seeking BMC first. Self-report causation predictors associated with a greater odds of seeking BMC first included higher belief in biological causes of epilepsy (OR = 1.31 [0.92, 1.88], P = 0.133) and lower belief in socio-spiritual causes of epilepsy (OR = 0.68 [0.56, 0.84], P < 0.001). In the multivariate model, only higher caredriver education (OR = 1.19 [1.04, 1.36], P = 0.009) and lower belief in socio-spiritual causes of epilepsy (OR = 0.69 [0.56, 0.86], P < 0.01) remained as predictors of seeking BMC first. Additionally, PCA revealed a pattern which included high income with low beliefs in nonbiological causes of epilepsy as being associated with seeking BMC first (OR = 1.32 [1.12, 1.55], p = 0.001). Despite reaching some form of care faster, individuals seeking care from traditional or pastoral healers experienced a significant delay to eventual BMC (P < 0.001), with an average delay of more than two years (traditional healer: 2.53 years [1.98, 3.24]; pastoral care: 2.18 [1.21, 3.91]). CONCLUSIONS: Coupled with low economic and educational status, belief in spiritual causation of epilepsy is a dominant determinant of opting for traditional or pastoral healing over BMC, regardless of concurrent belief in biological etiologies. There is a prolonged delay to eventual BMC for PWE who begin their treatment seeking with nonallopathic providers, and although nonallopathic healers provide PWE with benefits not provided by BMC, this notable delay likely prevents earlier administration of evidence-based care with known efficacy. Based on these findings, initiatives to increase public awareness of neurobiological causes of epilepsy and effectiveness of biomedical drug treatments may be effective in preventing delays to care, as would programs designed to facilitate cooperation and referral among traditional, faith-based, and biomedical providers. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".

COVID-19-Associated Guillain-Barre Syndrome: Atypical Para-infectious Profile, Symptom Overlap, and Increased Risk of Severe Neurological Complications.

The concurrence of COVID-19 with Guillain-Barre syndrome (GBS) can increase the likelihood of neuromuscular respiratory failure, autonomic dysfunction, and other life-threatening symptoms. Currently, very little is known about the underlying mechanisms, clinical course, and prognostic implications of comorbid COVID-19 in patients with GBS. We reviewed COVID-19-associated GBS case reports published since the outbreak of the pandemic, with a database search up to August 2020, including a manual search of the reference lists for additional relevant cases. Fifty-one (51) case reports of COVID-19 patients (aged 23-84 years) diagnosed with GBS in 11 different countries were included in this review. The results revealed atypical manifestations of GBS, including para-infectious profiles and onset of GBS without antecedent COVID-19 symptoms. Although all tested patients had signs of neuroinflammation, none had SARS-CoV-2 in the cerebrospinal fluid (CSF), and only four (4) patients had antiganglioside antibodies. The majority had a 1- to 10-day time interval between the onset of COVID-19 and GBS symptoms, and many had a poor outcome, with 20 out of the 51 (39.2%) requiring mechanical ventilation, and two deaths within 12 to 24 h. The atypical manifestations of COVID-19-associated GBS, especially the para-infectious profile and short time interval between the onset of the COVID-19 and GBS symptoms, increase the likelihood of symptom overlap, which can complicate the treatment and result in worsened disease progression and/or higher mortality rates. Inclusion of a neurological assessment during diagnosis of COVID-19 might facilitate timely identification and effective management of the GBS symptoms and improve treatment outcome.

Autoimmune Encephalitis: NMDA Receptor Encephalitis as an Example of Translational Neuroscience.

Autoimmune encephalitis (AE) is a group of disorders causing synaptic receptor dysfunction with a broad range of neurological symptoms that has been historically difficult to differentiate clinically. Today, AE represents an excellent example of the rapid determination of the cause of a disease and the ability to identify potential treatments using relatively simple basic science techniques of investigation. Of the number of autoimmune encephalitides identified thus far, one of the best examples of the impact of basic science studies on disease management is NMDA receptor mediated autoimmune encephalitis (NMDAr-AE). In this review, we will provide an overview of the epidemiology of NMDAr-AE, clinical features and treatments, and the basic science tools and techniques that were used to identify the cause, correlate symptoms to underlying pathophysiology, and to understand the mechanism of disease pathology.

Implementation of Best Practices-Developing and Optimizing Regional Systems of Stroke Care: Design and Methodology.

The AHA Guidelines recommend developing multi-tiered systems for the care of patients with acute stroke.1 An ideal stroke system of care should ensure that all patients receive the most efficient and timely care, regardless of how they first enter or access the medical care system. Coordination among the components of a stroke system is the most challenging but most essential aspect of any system of care. The Implementation of Best Practices For Acute Stroke Care-Developing and Optimizing Regional Systems of Stroke Care (IMPROVE Stroke Care) project, is designed to implement existing guidelines and systematically improve the acute stroke system of care in the Southeastern United States. Project participation includes 9 hub hospitals, approximately 80 spoke hospitals, numerous pre-hospital agencies (911, fire, and emergency medical services) and communities within the region. The goal of the IMPROVE Stroke program is to develop a regional integrated stroke care system that identifies, classifies, and treats acute ischemic stroke patients more rapidly and effectively with reperfusion therapy. The project will identify gaps and barriers to implementation of stroke systems of care, leverage existing resources within the regions, aid in designing strategies to improve care processes, bring regional representatives together to agree on and implement best practices, protocols, and plans based on guidelines, and establish methods to monitor quality of care. The impact of implementation of stroke systems of care on mortality and long-term functional outcomes will be measured.

Stroke in Patients With Peripheral Artery Disease.

Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.