Predictors of recurrence after surgical resection of parafalcine and parasagittal meningiomas.

PURPOSE: Owing to their vicinity near the superior sagittal sinus, parasagittal and parafalcine meningiomas are challenging tumors to surgically resect. In this study, we investigate key factors that portend increased risk of recurrence after surgery. METHODS: This is a retrospective study of patients who underwent resection of parasagittal and parafalcine meningiomas at our institution between 2012 and 2018. Relevant clinical, radiographic, and histopathological variables were selected for analysis as predictors of tumor recurrence. RESULTS: A total of 110 consecutive subjects (mean age: 59.4 ± 15.2 years, 67.3% female) with 74 parasagittal and 36 parafalcine meningiomas (92 WHO grade 1, 18 WHO grade 2/3), are included in the study. A total of 37 patients (33.6%) exhibited recurrence with median follow-up of 42 months (IQR: 10-71). In the overall cohort, parasagittal meningiomas exhibited shorter progression-free survival compared to parafalcine meningiomas (Kaplan-Meier log-rank p = 0.045). On univariate analysis, predictors of recurrence include WHO grade 2/3 vs. grade 1 tumors (p < 0.001), higher Ki-67 indices (p < 0.001), partial (p = 0.04) or complete sinus invasion (p < 0.001), and subtotal resection (p < 0.001). Multivariable Cox regression analysis revealed high-grade meningiomas (HR: 3.62, 95% CI: 1.60-8.22; p = 0.002), complete sinus invasion (HR: 3.00, 95% CI: 1.16-7.79; p = 0.024), and subtotal resection (HR: 3.10, 95% CI: 1.38-6.96; p = 0.006) as independent factors that portend shorter time to recurrence. CONCLUSION: This study identifies several pertinent factors that confer increased risk of recurrence after resection of parasagittal and parafalcine meningiomas, which can be used to devise appropriate surgical strategy to achieve improved patient outcomes.

Clinical Outcomes After Ultra-Early Cranioplasty Using Craniectomy Contour Classification as a Patient Selection Criterion.

BACKGROUND: Although not a technically difficult operation, cranioplasty is associated with high rates of complications. The optimal timing of cranioplasty to mitigate complications remains the subject of debate. OBJECTIVE: To report outcomes between patients undergoing cranioplasty at ultra-early (0-6 weeks), intermediate (6 weeks to 6 months), and late (>6 months) time frames. We report a novel craniectomy contour classification (CCC) as a radiographic parameter to assess readiness for cranioplasty. METHODS: A single-institution retrospective analysis of patients undergoing cranioplasty was performed. Patients were stratified into ultra-early (within 6 weeks of index craniectomy), intermediate (6 weeks to 6 months), and late (>6 months) cranioplasty cohorts. We have devised CCC scores, A, B, and C, based on radiographic criteria, where A represents those with a sunken brain/flap, B with a normal parenchymal contour, and C with "full" parenchyma. RESULTS: A total of 119 patients were included. There was no significant difference in postcranioplasty complications, including return to operating room ( P = .212), seizures ( P = .556), infection ( P = .140), need for shunting ( P = .204), and deep venous thrombosis ( P = .066), between the cohorts. Univariate logistic regression revealed that ultra-early cranioplasty was significantly associated with higher rate of functional independence at >6 months (odds ratio 4.32, 95% CI 1.39-15.13, P = .015) although this did not persist when adjusting for patient selection features (odds ratio 2.90, 95% CI 0.53-19.03, P = .234). CONCLUSION: In appropriately selected patients, ultra-early cranioplasty is not associated with increased rate of postoperative complications and is a viable option. The CCC may help guide decision-making on timing of cranioplasty.

Impact of neurovascular comorbidities and complications on outcomes after procedural management of arteriovenous malformations.

OBJECTIVE: Cerebral arteriovenous malformations (AVMs) are complex vascular lesions at perpetual risk for rupture, which can lead to significant morbidity and mortality. This study sought to evaluate the dynamic relationship between comorbidities and post-procedure complications to quantify the risk of poor discharge outcomes to create a predictive outcomes model. METHODS: The National Inpatient Sample (NIS) data from 2012 to 2015 was queried for AVM treatment using International Classification of Diseases, Ninth Revision codes. The Neurovascular Comorbidities Index (NCI) quantified patient comorbidity burden. In-hospital complications included surgical and medical complications or seizures. The primary outcome was the NIS Subarachnoid Hemorrhage Outcome Measure (NIS-SOM). RESULTS: A total of 1363 patients were included. A total of 1330 patients (98%) underwent embolization, 28 (2%) underwent resection, and 9 (0.7%) underwent radiosurgery. A higher NCI was associated with the occurrence of any complication (odds ratio [OR], 1.30 if NCI = 2; P < 0.001). Higher NCI was also significantly associated with a poor NIS-SOM outcome (OR, 2.45 if NCI = 2 and no complications; P < 0.001). A ruptured AVM with intracranial hemorrhage (ICH) increased the risk of in-hospital complications (OR, 2.16; P = 0.007) and a poor NIS-SOM outcome (OR, 3.18; P < 0.001). Various hypothetical patient scenarios and the predicted outcomes are also presented. CONCLUSION: Neurovascular comorbidities have a significant impact on poor functional outcomes at discharge in patients with and without complications following procedural management of AVMs. At the time of initial patient assessment, risk stratification strategies should take into account neurovascular comorbidities and potential complications. Such an approach would ultimately optimize patient outcomes and increase the value of care provided.

CYP2C19 Loss-of-Function Associated with First-Time Ischemic Stroke in Non-surgical Asymptomatic Carotid Artery Stenosis During Clopidogrel Therapy.

This study measures effect of CYP2C19 genotype on ischemic stroke risk during clopidogrel therapy for asymptomatic, extracranial carotid stenosis patients. Using deidentified electronic health records, patients were selected for retrospective cohort using administrative code for carotid stenosis, availability of CYP2C19 genotype result, clopidogrel exposure, and established patient care. Patients with intracranial atherosclerosis, aneurysm, arteriovenous malformation, prior ischemic stroke, or observation time <1 month were excluded. Dual antiplatelet therapy patients were included. Patients with carotid endarterectomy or stenting were analyzed in a separate subgroup. Time-to-event analysis using Cox regression was conducted to model ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted with the most predictive covariates from univariate analysis. Covariates included age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. A total of 1110 patients met selection criteria for medical therapy cohort (median age 68 [interquartile range (IQR) 60-75] years, 64.9% male, 91.9% Caucasian). Median study period was 2.8 [0.8-5.3] years. A total of 47 patients (4.2%) had an ischemic stroke event during study period. CYP2C19 loss-of-function allele was strongly associated with ischemic stroke events (one allele: HR 2.3, 95% CI 1.1-4.7, p=0.020; two alleles: HR 10.2, 95% CI 2.8-36.8, p<0.001) after adjustment. For asymptomatic carotid stenosis patients receiving clopidogrel to prevent ischemic stroke, CYP2C19 loss-of-function allele is associated with 2- to 10-fold increased risk of ischemic stroke. CYP2C19 genotype may be considered when selecting antiplatelet therapy for stroke prophylaxis in non-procedural, asymptomatic carotid stenosis.

Socioeconomic health disparities in pediatric traumatic brain injury on a national level.

OBJECTIVE: Low socioeconomic status is a determinant of pediatric traumatic brain injury (TBI) incidence and severity. In this study, the authors used National (Nationwide) Inpatient Sample (NIS) data to evaluate socioeconomic and health disparities among children hospitalized after TBI. METHODS: This retrospective study identified pediatric patients aged 0 to 19 years with ICD-9 codes for TBI in the NIS database from 2012 to 2015. Socioeconomic variables included race, sex, age, census region, and median income of the patient residential zip code. Outcomes included mechanism of injury, hospital length of stay (LOS), cost, disposition at discharge, death, and inpatient complications. Multivariate linear regressions in log scale were built for LOS and cost. Logistic regressions were built for death, disposition, and inpatient complications. RESULTS: African American, Hispanic, and Native American patients experienced longer LOSs (ß 0.06, p < 0.001; ß 0.03, p = 0.03; ß 0.13, p = 0.02, respectively) and increased inpatient costs (ß 0.13, p < 0.001; ß 0.09, p < 0.001; ß 0.14, p = 0.03, respectively). Females showed increased rates of medical complications (OR 1.57, p < 0.001), LOS (ß 0.025, p = 0.02), and inpatient costs (p = 0.04). Children aged 15 to 19 years were less likely to be discharged home (OR 3.99, p < 0.001), had increased mortality (OR 1.32, p = 0.03) and medical complications (OR 1.84, p < 0.001), and generated increased costs (p < 0.001). CONCLUSIONS: The study results have demonstrated that racial minorities, females, older children, and children in lower socioeconomic groups were at increased risk of poor outcomes following TBI, including increased LOS, medical complications, mortality, inpatient costs, and worse hospital disposition. Public education and targeted funding for these groups will ensure that all children have equal opportunity for optimal clinical outcomes following TBI.

Measuring the effects of institutional pediatric traumatic brain injury volume on outcomes for rural-dwelling children.

OBJECTIVE: Rural-dwelling children may suffer worse pediatric traumatic brain injury (TBI) outcomes due to distance from and accessibility to high-volume trauma centers. This study aimed to compare the impacts of institutional TBI volume and sociodemographics on outcomes between rural- and urban-dwelling children. METHODS: This retrospective study identified patients 0-19 years of age with ICD-9 codes for TBI in the 2012-2015 National Inpatient Sample database. Patients were characterized as rural- or urban-dwelling using United States Census classification. Logistic and linear (in log scale) regressions were performed to measure the effects of institutional characteristics, patient sociodemographics, and mechanism/severity of injury on occurrence of medical complications, mortality, length of stay (LOS), and costs. Separate models were built for rural- and urban-dwelling patients. RESULTS: A total of 19,736 patients were identified (median age 11 years, interquartile range [IQR] 2-16 years, 66% male, 55% Caucasian). Overall, rural-dwelling patients had higher All Patient Refined Diagnosis Related Groups injury severity (median 2 [IQR 1-3] vs 1 [IQR 1-2], p < 0.001) and more intracranial monitoring (6% vs 4%, p < 0.001). Univariate analysis showed that overall, rural-dwelling patients suffered increased medical complications (6% vs 4%, p < 0.001), mortality (6% vs 4%, p < 0.001), and LOS (median 2 days [IQR 1-4 days ] vs 2 days [IQR 1-3 days], p < 0.001), but multivariate analysis showed rural-dwelling status was not associated with these outcomes after adjusting for injury severity, mechanism, and hospital characteristics. Institutional TBI volume was not associated with medical complications, disposition, or mortality for either population but was associated with LOS for urban-dwelling patients (nonlinear beta, p = 0.008) and cost for both rural-dwelling (nonlinear beta, p < 0.001) and urban-dwelling (nonlinear beta, p < 0.001) patients. CONCLUSIONS: Overall, rural-dwelling pediatric patients with TBI have worsened injury severity, mortality, and in-hospital complications, but these disparities disappear after adjusting for injury severity and mechanism. Institutional TBI volume does not impact clinical outcomes for rural- or urban-dwelling children after adjusting for these covariates. Addressing the root causes of the increased injury severity at hospital arrival may be a useful path to improve TBI outcomes for rural-dwelling children.

The value of simplicity: externally validating the Baylor cranial gunshot wound prognosis score.

OBJECTIVE: Gunshot wounds to the head (GSWH) are devastating injuries with a grim prognosis. Several prognostic scores have been created to estimate mortality and functional outcome, including the so-called Baylor score, an uncomplicated scoring method based on bullet trajectory, patient age, and neurological status on admission. This study aimed to validate the Baylor score within a temporally, institutionally, and geographically distinct patient population. METHODS: Data were obtained from the trauma registry at a level I trauma center in the southeastern US. Patients with a GSWH in which dural penetration occurred were identified from data collected between January 1, 2009, and June 30, 2019. Patient demographics, medical history, bullet trajectory, intent of GSWH (e.g., suicide), admission vital signs, Glasgow Coma Scale score, pupillary response, laboratory studies, and imaging reports were collected. The Baylor score was calculated directly by using its clinical components. The ability of the Baylor score to predict mortality and good functional outcome (Glasgow Outcome Scale score 4 or 5) was assessed using the receiver operating characteristic curve and the area under the curve (AUC) as a measure of performance. RESULTS: A total of 297 patients met inclusion criteria (mean age 38.0 [SD 15.7] years, 73.4% White, 85.2% male). A total of 205 (69.0%) patients died, whereas 69 (23.2%) patients had good functional outcome. Overall, the Baylor score showed excellent discrimination of mortality (AUC = 0.88) and good functional outcome (AUC = 0.90). Baylor scores of 3-5 underestimated mortality. Baylor scores of 0, 1, and 2 underestimated good functional outcome. CONCLUSIONS: The Baylor score is an accurate and easy-to-use prognostic scoring tool that demonstrated relatively stable performance in a distinct cohort between 2009 and 2019. In the current era of trauma management, providers may continue to use the score at the point of admission to guide family counseling and to direct investment of healthcare resources.

Incorporating conditional survival into prognostication for gunshot wounds to the head.

OBJECTIVE: Several scores estimate the prognosis for gunshot wounds to the head (GSWH) at the point of hospital admission. However, prognosis may change over the course of the hospital stay. This study measures the accuracy of the Baylor score among patients who have already survived the acute phase of hospitalization and generates conditional outcome curves for the duration of hospital stay for patients with GSWH. METHODS: Patients in whom GSWH with dural penetration occurred between January 2009 and June 2019 were identified from a trauma registry at a level I trauma center in the southeastern US. The Baylor score was calculated using component variables. Conditional overall survival and good functional outcome (Glasgow Outcome Scale score of 4 or 5) curves were generated. The accuracy of the Baylor score in predicting mortality and functional outcome among acute-phase survivors (survival > 48 hours) was assessed using receiver operating characteristic curves and the area under the curve (AUC). RESULTS: A total of 297 patients were included (mean age 38.0 [SD 15.7] years, 73.4% White, 85.2% male), and 129 patients survived the initial 48 hours of admission. These acute-phase survivors had a decreased mortality rate of 32.6% (n = 42) compared to 68.4% (n = 203) for all patients, and an increased rate of good functional outcome (48.1%; n = 62) compared to the rate for all patients (23.2%; n = 69). Among acute-phase survivors, the Baylor score accurately predicted mortality (AUC = 0.807) and functional outcome (AUC = 0.837). However, the Baylor score generally overestimated true mortality rates and underestimated good functional outcome. Additionally, hospital day 18 represented an inflection point of decreasing probability of good functional outcome. CONCLUSIONS: During admission for GSWH, surviving beyond the acute phase of 48 hours doubles the rates of survival and good functional outcome. The Baylor score maintains reasonable accuracy in predicting these outcomes for acute-phase survivors, but generally overestimates mortality and underestimates good functional outcome. Future prognostic models should incorporate conditional survival to improve the accuracy of prognostication after the acute phase.

Creation and Validation of a Stroke Scale to Increase Utility of National Inpatient Sample Administrative Data for Clinical Stroke Research.

INTRODUCTION: The National Inpatient Sample (NIS) has led to several breakthroughs via large sample size. However, utility of NIS is limited by the lack of admission NIHSS and 90-day modified Rankin score (mRS). This study creates estimates for stroke severity at admission and 90-day mRS using NIS data for acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). METHODS: Three patient cohorts undergoing MT for AIS were utilized: Cohort 1 (N = 3729) and Cohort 3 (N = 1642) were derived from NIS data. Cohort 2 (N=293) was derived from a prospectively-maintained clinical registry. Using Cohort 1, Administrative Stroke Outcome Variable (ASOV) was created using disposition and mortality. Factors reflective of stroke severity were entered into a stepwise logistic regression predicting poor ASOV. Odds ratios were used to create the Administrative Data Stroke Scale (ADSS). Performances of ADSS and ASOV were tested using Cohort 2 and compared with admission NIHSS and 90-day mRS, respectively. ADSS performance was compared with All Patient Refined-Diagnosis Related Group (APR-DRG) severity score using Cohort 3. RESULTS: Agreement of ASOV with 90-day mRS > 2 was fair (κ = 0.473). Agreement with 90-day mRS > 3 was substantial (κ = 0.687). ADSS significantly correlated (p < 0.001) with clinically-significant admission NIHSS > 15. ADSS performed comparably (AUC = 0.749) to admission NIHSS (AUC = 0.697) in predicting 90-day mRS > 2 and mRS > 3 (AUC = 0.767, 0.685, respectively). ADSS outperformed APR-DRG severity score in predicting poor ASOV (AUC = 0.698, 0.682, respectively). CONCLUSION: We developed and validated measures of stroke severity at admission (ADSS) and outcome (ASOV, estimate for 90-day mRS > 3) to increase utility of NIS data in stroke research.

Impact of Neurovascular Comorbidities and Complications on Outcomes After Procedural Management of Intracranial Aneurysm: Part 2, Ruptured Intracranial Aneurysm.

OBJECTIVE: We aim to define the dynamic interplay between neurovascular-specific comorbidities and in-hospital complications on outcomes (functional outcome and mortality), length of stay (LOS), and cost of hospital stay. METHODS: The 2012-2015 National Inpatient Sample (NIS) was queried for intracranial aneurysm treatment after subarachnoid hemorrhage using International Classification of Diseases, Ninth Revision codes. Neurovascular comorbidity index (NCI) was aggregated. NIS-Subarachnoid Hemorrhage Severity Score (NIS-SSS) was used as a Hunt-Hess grade proxy. In-hospital complications were medical complications, surgical complications, seizures, and cerebral vasospasm. Outcomes were functional outcome (modified Rankin Scale [mRS]-equivalent measure), in-hospital mortality, LOS, and cost. Multivariable logistic regression models were built for mRS equivalent and in-hospital mortality. Multivariable linear regression models in log scale were built for LOS and cost. RESULTS: A total of 5353 patients were included. The median NCI was 4.00 (interquartile range [IQR], 0.00-7.00) and 2882 patients (54%) had in-hospital complication. Higher NCI (odds ratio [OR], 1.13 if NCI = 1; OR, 2.05 if NCI = 7; P < 0.001) was associated with any complication, seizure (OR, 1.11, NCI = 1; OR, 1.60, NCI = 7; P < 0.001), medical complication (OR, 1.18, NCI = 1; OR, 2.50, NCI = 7; P < 0.001), surgical complication (OR, 1.13, NCI = 1; OR, 1.91, NCI = 7; P < 0.001), and cerebral vasospasm (OR, 1.09, NCI = 1; OR, 1.49, NCI = 7; P < 0.001). Patients with higher NCI (OR, 1.06, NCI = 1; OR, 1.95, NCI = 7; P < 0.001) or with in-hospital complication (P < 0.001) had poorer mRS equivalent outcome. Similar trends were observed for other outcomes including in-hospital mortality, LOS, and cost. CONCLUSIONS: Neurovascular comorbidities are the primary driver of poor mRS equivalent outcome, in-hospital mortality, higher LOS, and higher cost after ruptured intracranial aneurysm procedural treatment. The conditional event of complication influences patients with moderate comorbidities more so than those with low or high comorbidities.

Impact of insurance type on national variation in cost of endovascular treatment for unruptured cerebral aneurysms.

BACKGROUND: Identifying drivers of nationwide variation in healthcare costs could help reduce overall cost. Endovascular treatment for unruptured cerebral aneurysms (ETUCR) is an elective neurointerventional procedure that allows for detailed analysis of cost variation. This study aimed to investigate the role of insurance type in cost variation of ETUCR. METHODS: A retrospective analysis of patients undergoing ETUCR was done. Demographic and hospital data were obtained from the National Inpatient Sample 2012-2015. Multivariate analysis was done using a generalized linear model. Oaxaca-Blinder decomposition was performed to identify factors driving cost variation. RESULTS: There was a significant difference in median cost ($25 331.82 vs $25 825.25, respectively, P<0.001) as well as length of stay (P<0.001) and complications (P<0.001) between patients with private insurance and Medicare. In multivariate analysis, insurance type was not predictive of increased cost. Among patients aged 65-75 years there was a higher median cost with private insurance compared to Medicare ($28 373.85 vs $25 558.25, respectively, P<0.001) but no difference in complications or length of stay. Oaxaca-Blinder decomposition showed higher marginal costs associated with private insurance patients at hospitals with greater endovascular operative volume (P=0.015). CONCLUSIONS: In patients aged 65-75 years, private insurance is associated with higher costs compared to Medicare; however, insurance type is not predictive of increased cost in multivariate analysis. Differential treatment of private insurance and Medicare patients at hospitals with greater operative volume seems to influence this difference, likely due to differential reimbursement schemes that lead to weaker cost controls.

Neighborhood Socioeconomic Status and Mechanical Thrombectomy Outcomes.

BACKGROUND/PURPOSE: Our study aimed to assess the impacts of neighborhood socioeconomic status on mechanical thrombectomy (MT) outcomes for acute ischemic stroke (AIS). METHODS: We conducted a prospective observational study of consecutive adult AIS patients treated with MT at one US comprehensive stroke center from 2012 to 2018. A composite neighborhood socioeconomic score (nSES) was created using patient home address, median household income, percentage of households with interest, dividend, or rental income, median value of housing units, percentage of persons 25 or older with high school degrees, college degrees or holding executive, managerial or professional specialty occupations. Using this score, patients were divided into low, middle and high nSES tertiles. Outcomes included 90-day functional independence, in-hospital mortality, length of hospital stay, discharge location, time to recanalization, successful recanalization, and symptomatic intracranial hemorrhage (sICH). RESULTS: 328 patients were included. Between the three nSES groups, proportion of White patients, time-to-recanalization and admission NIH stroke scale differed significantly (p<0.05). Patients in the high nSES tertile were more likely to be functionally dependent at 90 days (unadjusted OR, 95% CI, 1.91 [1.10, 3.36]) and were less likely to die in the hospital (unadjusted OR, 95% CI, 0.46, [0.20, 0.98]). Further, patients in the high nSES tertile had decreased times to recanalization (median time in minutes, low=335, mid=368, high=297, p=0.04). However, after adjusting for variance in race and severity of stroke, the differences in clinical outcomes were not significant. CONCLUSION: This study highlights how unadjusted neighborhood socioeconomic status is significantly associated with functional outcome, mortality, and time-to-recanalization following MT for AIS. Since adjustment modifies the significant association, the socioeconomic differences may be influenced by differences in pre-hospital factors that drive severity of stroke and time to recanalization. Better understanding of the interplay of these factors may lead to timelier evaluation and improvement in patient outcomes.

CYP2C19 Loss-of-Function is Associated with Increased Risk of Ischemic Stroke after Transient Ischemic Attack in Intracranial Atherosclerotic Disease.

OBJECTIVES: Intracranial atherosclerotic disease (ICAD) is responsible for 8-10% of acute ischemic strokes, and resistance to antiplatelet therapy is prevalent. CYP2C19 gene loss-of-function (up to 45% of patients) causes clopidogrel resistance. For patients with asymptomatic ICAD and ICAD characterized by transient ischemic attack (TIA), this study measures the effect of CYP2C19 loss-of-function on ischemic stroke risk during clopidogrel therapy. MATERIALS AND METHODS: From a deidentified database of medical records, patients were selected with ICD-9/10 code for ICAD, availability of CYP2C19 genotype, clopidogrel exposure, and established patient care. Dual-antiplatelet therapy patients were included. Patients with prior ischemic stroke, other neurovascular condition, intracranial angioplasty/stenting, or observation time <1 month were excluded. Time-to-event analysis using Cox regression was conducted to model first-time ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted for age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. Subset analyses were performed for asymptomatic and post-TIA subtypes of ICAD. RESULTS: A total of 337 patients were included (median age 68, 58% male, 88% Caucasian, 26% CYP2C19 loss-of-function). A total of 161 (47.8%) patients had TIA at time of ICAD diagnosis, while 176 (52.2%) were asymptomatic. First-time ischemic stroke was observed among 20 (12.4%) post-TIA ICAD patients and 17 (9.7%) asymptomatic ICAD patients. Median observation time was 2.82 [IQR 1.13-5.17] years. CYP2C19 loss-of-function allele was associated with ischemic stroke event (HR 2.2, 95% CI 1.1-4.3, p=0.020) after adjustment. Post-TIA ICAD patients had a higher risk of ischemic stroke from CYP2C19 loss-of-function (HR 3.4, 95% CI 1.4-8.2, p=0.006). CONCLUSIONS: CYP2C19 loss-of-function was associated with 3-fold increased risk of first-time ischemic stroke for ICAD patients treated with clopidogrel after TIA. This effect was not observed for asymptomatic ICAD. CYP2C19-guided antiplatelet selection may improve stroke prevention in ICAD after TIA.

Impact of Neurovascular Comorbidities and Complications on Outcomes After Procedural Management of Intracranial Aneurysm: Part 1, Unruptured Intracranial Aneurysm.

OBJECTIVE: This study investigates the relationship between neurovascular comorbidities and in-hospital complications in determining functional outcome, mortality, length of stay (LOS), and cost of stay. METHODS: Patients were identified from the 2012-2015 National Inpatient Sample (NIS) using International Classification of Diseases, Ninth Revision codes for unruptured intracranial aneurysm (UIA) treatment in patients without subarachnoid hemorrhage. In-hospital complications were divided into medical complications, surgical complications, and seizures. Primary outcomes were functional outcome measured by modified Rankin Scale (mRS)-equivalent measure, in-hospital mortality, LOS, and cost. Multivariable logistic regression models were built for mRS-equivalent and in-hospital mortality. Multivariable linear regression models in log scale were built for LOS and cost. RESULTS: A total of 7398 procedurally managed patients with UIA were included (median age, 58 years; 75% female; 66% white; 43% private insurance). Higher Neurovascular Comorbidities Index (NCI) was associated with seizure (odds ratio [OR], 1.11 if NCI = 1; OR, 2.49 if NCI = 7; P < 0.001), medical complication (OR, 1.21, NCI = 1; OR, 3.46, NCI = 7; P < 0.001), and surgical complication (OR, 1.25, NCI = 1; OR, 3.47, NCI = 7; P < 0.001). NCI remained significantly predictive of poor mRS-equivalent outcome (OR, 1.20, NCI = 1; OR, 5.79, NCI = 7; P < 0.001), in-hospital mortality (OR, 1.98, NCI = 1; OR, 10.9, NCI = 7; P < 0.001), LOS (coefficient dependent on multiple variables, P < 0.001), and cost (coefficient dependent on multiple variables, P < 0.001) after adjustment. CONCLUSIONS: Neurovascular comorbidities are the primary driver of poor mRS-equivalent outcome, in-hospital mortality, higher LOS, and higher cost after procedural treatment of UIA. The conditional event of complication influences patients with fewer comorbidities more so than those with no comorbidities or high comorbidities. It is imperative to precisely account for these factors to optimize targeted resource allocation and increase the value of care for patients with UIA.

Aligning patient and physician views on educational pelvic examinations under anaesthesia: the medical student perspective.

Recent media articles have stirred controversy over anecdotal reports of medical students practising educational pelvic examinations on women under anaesthesia without explicit consent. The understandable public outrage that followed merits a substantive response from the medical community. As medical students, we offer a unique perspective on consent for trainee involvement informed by the transitional stage we occupy between patient and physician. We start by contextualising the role of educational pelvic examinations under anaesthesia (EUAs) within general clinical skill development in medical education. Then we analyse two main barriers to achieving explicit consent for educational pelvic EUAs: ambiguity within professional guidelines on how to operationalize 'explicit consent' and divergent patient and physician perspectives on harm which prevent physicians from understanding what a reasonable patient would want to know before a procedure. To overcome these barriers, we advocate for more research on patient perspectives to empower the reasonable patient standard. Next, we call for minimum disclosure standards informed by this research and created in conjunction with students, physicians and patients to improve the informed consent process and relieve medical student moral injury caused by performing 'unconsented' educational pelvic exams.

Tracking the Volume of Neurosurgical Care During the Coronavirus Disease 2019 Pandemic.

OBJECTIVE: In the present study, we quantified the effect of the coronavirus disease 2019 (COVID-19) on the volume of adult and pediatric neurosurgical procedures, inpatient consultations, and clinic visits at an academic medical center. METHODS: Neurosurgical procedures, inpatient consultations, and outpatient appointments at Vanderbilt University Medical Center were identified from March 23, 2020 through May 8, 2020 (during COVID-19) and March 25, 2019 through May 10, 2019 (before COVID-19). The neurosurgical volume was compared between the 2 periods. RESULTS: A 40% reduction in weekly procedural volume was demonstrated during COVID-19 (median before, 75; interquartile range [IQR], 72-80; median during, 45; IQR, 43-47; P < 0.001). A 42% reduction occurred in weekly adult procedures (median before, 62; IQR, 54-70; median during, 36; IQR, 34-39; P < 0.001), and a 31% reduction occurred in weekly pediatric procedures (median before, 13; IQR, 12-14; median during, 9; IQR, 8-10; P = 0.004). Among adult procedures, the most significant decreases were seen for spine (P < 0.001) and endovascular (P < 0.001) procedures and cranioplasty (P < 0.001). A significant change was not found in the adult open vascular (P = 0.291), functional (P = 0.263), cranial tumor (P = 0.143), or hydrocephalus (P = 0.173) procedural volume. Weekly inpatient consultations to neurosurgery decreased by 24% (median before, 99; IQR, 94-114; median during, 75; IQR, 68-84; P = 0.008) for adults. Weekly in-person adult and pediatric outpatient clinic visits witnessed a 91% decrease (median before, 329; IQR, 326-374; median during, 29; IQR, 26-39; P < 0.001). In contrast, weekly telehealth encounters increased from a median of 0 (IQR, 0-0) before to a median of 151 (IQR, 126-156) during COVID-19 (P < 0.001). CONCLUSIONS: Significant reductions occurred in neurosurgical operations, clinic visits, and inpatient consultations during COVID-19. Telehealth was increasingly used for assessments. The long-term effects of the reduced neurosurgical volume and increased telehealth usage on patient outcomes should be explored.

Rapid development of telehealth capabilities within pediatric patient portal infrastructure for COVID-19 care: barriers, solutions, results.

The COVID-19 national emergency has led to surging care demand and the need for unprecedented telehealth expansion. Rapid telehealth expansion can be especially complex for pediatric patients. From the experience of a large academic medical center, this report describes a pathway for efficiently increasing capacity of remote pediatric enrollment for telehealth while fulfilling privacy, security, and convenience concerns. The design and implementation of the process took 2 days. Five process requirements were identified: efficient enrollment, remote ability to establish parentage, minimal additional work for application processing, compliance with guidelines for adolescent autonomy, and compliance with institutional privacy and security policies. Weekly enrollment subsequently increased 10-fold for children (age 0-12 years) and 1.2-fold for adolescents (age 13-17 years). Weekly telehealth visits increased 200-fold for children and 90-fold for adolescents. The obstacles and solutions presented in this report can provide guidance to health systems for similar challenges during the COVID-19 response and future disasters.

Discoordinate surface expression of IFN-gamma-induced HLA class II proteins in nonprofessional antigen-presenting cells with absence of DM and class II colocalization.

We compared HLA class II expression in a human melanoma line (a nonprofessional APC), induced by IFN-gamma or by stable transfection with CIITA, with constitutive class II expression in an EBV-transformed B lymphoblastoid cell line (a professional APC) from the same donor. IFN-gamma-induced and CIITA-transfected melanoma cells expressed DR, DP, and DQ at levels similar to those expressed by the professional APC; however, DP and DQ proteins and DM-dependent DR epitopes were delayed in appearing on the cell surface when induced by IFN-gamma. The delay in cell surface expression of some IFN-gamma-induced class II epitopes was observed even though Northern blots demonstrated class II and DM genes to be coordinately transcribed and their mRNA levels to be equivalent to that in B lymphoblastoid cells. Confocal microscopy suggests that discoordinate cell surface expression of class II results from different intracellular trafficking for IFN-gamma-induced class II proteins in the melanoma line compared with that in professional APCs. Specifically, although DR and DM proteins were present 2 days after IFN-gamma induction, colocalization of DR and DM proteins intracellularly was not apparent in cells at any time after induction. Failure of DR and DM proteins to colocalize suggests that IFN-gamma-induced cells lack an intracellular MIIC-like compartment. The absence of a compartment containing DR and DM to facilitate interaction between the two proteins may account for the delayed surface expression of class II epitopes whose formation requires both class II and DM.

Novel mutants define genes required for the expression of human histocompatibility leukocyte antigen DM: evidence for loci on human chromosome 6p.

We and others have shown that the products of the HLA-DM locus are required for the intracellular assembly of major histocompatibility complex class II molecules with cognate peptides for antigen presentation. HLA-DM heterodimers mediate the dissociation of invariant chain (Ii)-derived class II-associated Ii peptides (CLIP) from class II molecules and facilitate the loading of class II molecules with antigenic peptides. Here we describe novel APC mutants with defects in the formation of class II-peptide complexes. These mutants express class II molecules which are conformationally altered, and an aberrantly high percentage of these class II molecules are associated with Ii-derived CLIP. This phenotype resembles that of DM null mutants. However, we show that the defects in two of these new mutants do not map to the DM locus. Nevertheless, our evidence suggests that the antigen processing defective phenotype in these mutants results from deficient DM expression. These mutants thus appear to define genes in which mutations have differential effects on the expression of conventional class II molecules and DM molecules. Our data are most consistent with these factors mapping to human chromosome 6p. Previous data have suggested that the expression of DM and class II genes are coordinately regulated. The results reported here suggest that DM and class II can also be differentially regulated, and that this differential regulation has significant effects on class II-restricted antigen processing.

Exogenously provided peptides fail to complex with intracellular class II molecules for presentation by antigen-presenting cells.

Exogenously supplied antigenic peptides can bind to and be presented by cell surface class II molecules of APCs without prior processing. However, it has been unclear whether peptide Ags exogenously supplied to APCs can also form complexes with nascent intracellular class II molecules that contribute to Ag presentation. We found that exogenously provided peptide Ags, unlike whole protein Ags, are presented as efficiently by fixed as by unfixed B lymphoblastoid APCs, suggesting that intracellular processes do not contribute to the presentation of exogenously supplied peptides by unfixed APCs. Consistent with this finding, exogenously provided peptides do not bind detectably to nascent intracellular class II molecules. We studied the basis for this failure. First, as compared with whole proteins, exogenously supplied peptides accumulate very poorly intracellularly. Second, peptides are more rapidly exocytosed. The limited ability of APCs to accumulate exogenously supplied peptides intracellularly provides a likely explanation for the failure of these peptides to associate with nascent intracellular class II molecules. Exogenously supplied peptides probably never reach the intracellular vesicles in which peptide loading of class II molecules occurs. These findings have implications for the use of peptides therapeutically to block presentation of autoantigens in autoimmune disease.