An interpretable framework to identify responsive subgroups from clinical trials regarding treatment effects: Application to treatment of intracerebral hemorrhage.

Randomized Clinical trials (RCT) suffer from a high failure rate which could be caused by heterogeneous responses to treatment. Despite many models being developed to estimate heterogeneous treatment effects (HTE), there remains a lack of interpretable methods to identify responsive subgroups. This work aims to develop a framework to identify subgroups based on treatment effects that prioritize model interpretability. The proposed framework leverages an ensemble uplift tree method to generate descriptive decision rules that separate samples given estimated responses to the treatment. Subsequently, we select a complementary set of these decision rules and rank them using a sparse linear model. To address the trial's limited sample size problem, we proposed a data augmentation strategy by borrowing control patients from external studies and generating synthetic data. We apply the proposed framework to a failed randomized clinical trial for investigating an intracerebral hemorrhage therapy plan. The Qini-scores show that the proposed data augmentation strategy plan can boost the model's performance and the framework achieves greater interpretability by selecting complementary descriptive rules without compromising estimation quality. Our model derives clinically meaningful subgroups. Specifically, we find those patients with Diastolic Blood Pressure≥70 mm hg and Systolic Blood Pressure<215 mm hg benefit more from intensive blood pressure reduction therapy. The proposed interpretable HTE analysis framework offers a promising potential for extracting meaningful insight from RCTs with neutral treatment effects. By identifying responsive subgroups, our framework can contribute to developing personalized treatment strategies for patients more efficiently.

Clinical manifestations and outcome of patients with primary amoebic meningoencephalitis in Pakistan. A single-center experience.

Primary amoebic meningoencephalitis (PAM) is a rapidly progressing central nervous system (CNS) infection caused by Naegleria fowleri, a free-living amoeba found in warm freshwater. The disease progression is very rapid, and the outcome is nearly always fatal. We aim to describe the disease course in patients admitted with PAM in a tertiary care center in Karachi, Pakistan between the periods of 2010 to 2021. A total of 39 patients were included in the study, 33 males (84.6%). The median age of the patients was 34 years. The most frequent presenting complaint was fever, which was found in 37 patients (94.9%) followed by headache in 28 patients (71.8%), nausea and vomiting in 27 patients (69.2%), and seizures in 10 patients (25.6%). Overall, 39 patients underwent lumbar puncture, 27 patients (69.2%) had a positive motile trophozoites on CSF wet preparation microscopy, 18 patients (46.2%) had a positive culture, and 10 patients had a positive PCR. CSF analysis resembled bacterial meningitis with elevated white blood cell counts with predominantly neutrophils (median, 3000 [range, 1350-7500] cells/µL), low glucose levels median, 14 [range, 1-92] mg/dL), and elevated protein levels (median, 344 [range, 289-405] mg/dL). Imaging results were abnormal in approximately three-fourths of the patients which included cerebral edema (66.7%), hydrocephalus (25.6%), and cerebral infarctions (12.8%). Only one patient survived. PAM is a fatal illness with limited treatment success. Early diagnosis and prompt initiation of treatment can improve the survival of the patients and reduce mortality.

Automated Large Vessel Occlusion Detection Software and Thrombectomy Treatment Times: A Cluster Randomized Clinical Trial.

Importance: The benefit of endovascular stroke therapy (EVT) in large vessel occlusion (LVO) ischemic stroke is highly time dependent. Process improvements to accelerate in-hospital workflows are critical. Objective: To determine whether automated computed tomography (CT) angiogram interpretation coupled with secure group messaging can improve in-hospital EVT workflows. Design, Setting, and Participants: This cluster randomized stepped-wedge clinical trial took place from January 1, 2021, through February 27, 2022, at 4 comprehensive stroke centers (CSCs) in the greater Houston, Texas, area. All 443 participants with LVO stroke who presented through the emergency department were treated with EVT at the 4 CSCs. Exclusion criteria included patients presenting as transfers from an outside hospital (n = 158), in-hospital stroke (n = 39), and patients treated with EVT through randomization in a large core clinical trial (n = 3). Intervention: Artificial intelligence (AI)-enabled automated LVO detection from CT angiogram coupled with secure messaging was activated at the 4 CSCs in a random-stepped fashion. Once activated, clinicians and radiologists received real-time alerts to their mobile phones notifying them of possible LVO within minutes of CT imaging completion. Main Outcomes and Measures: Primary outcome was the effect of AI-enabled LVO detection on door-to-groin (DTG) time and was measured using a mixed-effects linear regression model, which included a random effect for cluster (CSC) and a fixed effect for exposure status (pre-AI vs post-AI). Secondary outcomes included time from hospital arrival to intravenous tissue plasminogen activator (IV tPA) bolus in eligible patients, time from initiation of CT scan to start of EVT, and hospital length of stay. In exploratory analysis, the study team evaluated the impact of AI implementation on 90-day modified Rankin Scale disability outcomes. Results: Among 243 patients who met inclusion criteria, 140 were treated during the unexposed period and 103 during the exposed period. Median age for the complete cohort was 70 (IQR, 58-79) years and 122 were female (50%). Median National Institutes of Health Stroke Scale score at presentation was 17 (IQR, 11-22) and the median DTG preexposure was 100 (IQR, 81-116) minutes. In mixed-effects linear regression, implementation of the AI algorithm was associated with a reduction in DTG time by 11.2 minutes (95% CI, -18.22 to -4.2). Time from CT scan initiation to EVT start fell by 9.8 minutes (95% CI, -16.9 to -2.6). There were no differences in IV tPA treatment times nor hospital length of stay. In multivariable logistic regression adjusted for age, National Institutes of Health Stroke scale score, and the Alberta Stroke Program Early CT Score, there was no difference in likelihood of functional independence (modified Rankin Scale score, 0-2; odds ratio, 1.3; 95% CI, 0.42-4.0). Conclusions and Relevance: Automated LVO detection coupled with secure mobile phone application-based communication improved in-hospital acute ischemic stroke workflows. Software implementation was associated with clinically meaningful reductions in EVT treatment times. Trial Registration: ClinicalTrials.gov Identifier: NCT05838456.

Women With Large Vessel Occlusion Acute Ischemic Stroke Are Less Likely to Be Routed to Comprehensive Stroke Centers.

Background Prehospital routing of patients with large vessel occlusion (LVO) acute ischemic stroke (AIS) to centers capable of performing endovascular therapy may improve clinical outcomes. Here, we explore whether distance to comprehensive stroke centers (CSCs), stroke severity, and sex are associated with direct-to-CSC prehospital routing in patients with LVO AIS. Methods and Results In this cross-sectional study, we identified consecutive patients with LVO AIS from a prospectively collected multihospital registry throughout the greater Houston area from January 2019 to June 2020. Primary outcome was prehospital routing to CSC and was compared between men and women using modified Poisson regression including age, sex, race or ethnicity, first in-hospital National Institutes of Health Stroke Scale score, travel time, and distances to the closest primary stroke center and CSC. Among 503 patients with LVO AIS, 413 (82%) were routed to CSCs, and women comprised 46% of the study participants. Women with LVO AIS compared with men were older (73 versus 65, P<0.01) and presented with greater National Institutes of Health Stroke Scale score (14 versus 12, P=0.01). In modified Poisson regression, women were 9% less likely to be routed to CSCs compared with men (adjusted relative risk [aRR], 0.91 [0.84-0.99], P=0.024) and distance to nearest CSC ≤10 miles was associated with 38% increased chance of routing to CSC (aRR, 1.38 [1.26-1.52], P<0.001). Conclusions Despite presenting with more significant stroke syndromes and living within comparable distance to CSCs, women with LVO AIS were less likely to be routed to CSCs compared with men. Further study of the mechanisms behind this disparity is needed.

Sex differences in the inflammatory response to stroke.

Ischemic stroke is a leading cause of morbidity and mortality and disproportionally affects women, in part due to their higher longevity. Older women have poorer outcomes after stroke with high rates of cognitive deficits, depression, and reduced quality of life. Post-stroke inflammatory responses are also sexually dimorphic and drive differences in infarct size and recovery. Factors that influence sex-specific immune responses can be both intrinsic and extrinsic. Differences in gonadal hormone exposure, sex chromosome compliment, and environmental/social factors can drive changes in transcriptional and metabolic profiles. In addition, how these variables interact, changes across the lifespan. After the onset of ischemic injury, necrosis and apoptosis occur, which activate microglia and other glial cells within the central nervous system, promoting the release of cytokines and chemokines and neuroinflammation. Cells involved in innate and adaptive immune responses also have dual functions after stroke as they can enhance inflammation acutely, but also contribute to suppression of the inflammatory cascade and later repair. In this review, we provide an overview of the current literature on sex-specific inflammatory responses to ischemic stroke. Understanding these differences is critical to identifying therapeutic options for both men and women.

Heart Brain Clinic: An Integrated Approach to Stroke Care.

Background and Objectives: Multidisciplinary clinics have been shown to improve care. Patients with patent foramen ovale (PFO)-associated stroke need evaluation by cardiology and neurology specialists. We report our experience creating a multidisciplinary Structural Heart Brain Clinic (HBC) with a focus on patients with PFO-associated stroke. Methods: Demographic and clinical data were retrospectively collected for patients with PFO-associated ischemic stroke. Patients with PFO-associated stroke were divided into a standard care group and Heart Brain Clinic group for analysis. Outcome measures included time from stroke to PFO closure and number of clinic visits before decision regarding closure. Nonparametric analysis evaluated differences in median time to visit and clinical decision, while the chi square analysis compared differences in categorical variables between groups. Results: From February 2017 to December 2021, 120 patients were evaluated for PFO-associated stroke. The Structural HBC began in 12/2018 with coordination between Departments of Neurology and Cardiology. For this analysis, 41 patients were considered in the standard care group and 79 patients in the HBC group. During data analysis, 107 patients had received recommendations about PFO closure. HBC patients required fewer clinic visits (p = 0.001) before decision about closure; however, among patients who underwent PFO closure, there was no significant difference in weeks from stroke to PFO closure. Clinicians were more likely to recommend against PFO closure among patients seen in HBC compared with those seen in standard care (p = 0.021). Discussion: Our data demonstrate that a multidisciplinary, patient-centered approach to management of patients with PFO-associated ischemic stroke is feasible and may improve the quality of care in this younger patient population. The difference in recommendation to not pursue PFO closure between groups may reflect selection and referral bias. Additional work is needed to determine whether this approach improves other aspects of care and outcomes.

AKU Giant Pituitary Adenoma Score: A Novel Scoring System to Predict the Outcomes of Surgery for Giant Pituitary Adenomas.

Background No scoring system is available to predict the extent of resection of giant pituitary adenomas (GPAs) based on magnetic resonance imaging (MRI) parameters. We developed a novel AKU Giant Pituitary Adenoma (AGPA) score and assessed the predictive ability of the scoring system concerning the extent of resection of GPAs. Methodology We retrospectively collected data of patients presenting with GPAs and used our scoring system to assess the surgical resection of these tumors. The Lundin-Pederson (ABC/2) method was used to calculate the pre- and post-resection tumor volume. The relationship between the extent of resection and the AGPA score was assessed using linear regression. The AGPA score considered the tumor's extension into various planes. The maximum total score was 9. Results The scoring system was applied to 45 patients with GPA who underwent surgical resection. The mean resected tumor volume (%) was 82.0 ± 16.7, and the overall mean AGPA score was 4.2 ± 0.8. The pairwise correlation between the resected tumor volume and the overall AGPA scores showed a strong inverse association (r = -0.633, p < 0.001). A significant difference was detected between the estimated scores of 3 and 5 and 4 and 5 (p < 0.001). Conclusions AGPA score is inversely related to the extent of the tumor to be resected, which would help surgeons predict the amount of tumor resection possible as well as predict the difficulty of surgery and plan optimal preoperative patient counseling. In addition, it can predict if staging and a transcranial approach are required.

Prognostic implication of size on outcomes of pituitary macroadenoma: a comparative analysis of giant adenoma with non-giant macroadenoma.

BACKGROUND: Due to the differences in size and invasiveness when compared to non-giant macroadenomas (nGPAs), giant pituitary adenomas (GPAs) are considerably harder to resect. This study aimed to differentiate GPAs from nGPAs, based on the presenting complaints, surgical approaches, peri- and postoperative outcomes. METHODS: We retrospectively analyzed cases of pituitary macroadenomas that underwent surgical resection at a tertiary care hospital. GPAs were tumors greater than 4 cm in the largest dimension, while nGPAs were tumors smaller than 4 cm. 55 GPA patients and 70 nGPA patients from 2006 to 2017 were included. Demographic, perioperative, and post-operative outcomes were evaluated. Group comparisons for continuous variables were made using an independent t-test/Mann Whitney U test and categorical data was analyzed on Chi-square/Fisher exact test; a p-value of < 0.05 was considered significant. RESULTS: Visual deterioration was the most common complaint, reported by 61.4% of nGPA patients and 81.8% of GPA patients. The mean extent of gross total resection was 47.1% in nGPA patients and 18.2% in GPA patients (p = 0.001). After surgery, tumor recurrence was seen in 1.4% of nGPA patients and 18.2% of GPA patients (p = 0.001). First re-do surgery was required in 5.7% of nGPA patients and 25.5% of GPA patients (p = 0.004). CONCLUSION: Compared to nGPAs, GPAs are more likely to present with a higher number of preoperative symptoms, and lesser chances of gross total tumor resection. GPAs are also associated with a higher rate of recurrence, which results in more follow-up procedures. Larger, multi-center longitudinal studies need to be done to validate these findings.

Mobile Stroke Units: Current Evidence and Impact.

PURPOSE OF REVIEW: Several approaches have been developed to optimize prehospital systems for acute stroke given poor access and significant delays to timely treatment. Specially equipped ambulances that directly initiate treatment, known as Mobile Stroke Units (MSUs), have rapidly proliferated across the world. This review provides a comprehensive summary on the efficacy of MSUs in acute stroke, its various applications beyond thrombolysis, as well as the establishment, optimal setting and cost-effectiveness of incorporating an MSU into healthcare systems. RECENT FINDINGS: MSUs speed stroke treatment into the first "golden hour" when better outcomes from thrombolysis are achieved. While evidence for the positive impact of MSUs on outcomes was previously unavailable, two recent landmark controlled trials, B_PROUD and BEST-MSU, show that MSUs result in significantly lesser disability compared to conventional ambulance care. Emerging literature prove the significant impact of MSUs. Adaptability however remains limited by significant upfront financial investment, challenges with reimbursements and pending evidence on their cost-effectiveness.

Value of Routine Preoperative Tests for Coagulation Before Elective Cranial Surgery. Results of an Institutional Audit and a Nationwide Survey of Neurosurgical Centers in Pakistan.

BACKGROUND: Routine preoperative blood testing has become a dogma. The general practice is to order preoperative workup as a knee-jerk response rather than individualize it for each patient. The fact that the bleeding brain tends to swell, which coupled with limited options for proximal control, packing, and overall hemostasis, leads to an overemphasis on the preoperative coagulation profile. MATERIAL AND METHODS: This is a retrospective review of the medical records of patients admitted at Aga Khan University Hospital from January 2010 to December 2015 for an elective craniotomy. The hospital registry was used to identify files for review. Data were collected on a predefined proforma. A nationwide survey was performed, and 30 neurosurgery centers were contacted across Pakistan to confirm the practice of preoperative workup. RESULTS: The survey revealed that all centers had a similar practice of preoperative workup. This included complete blood count, serum electrolytes, and coagulation profile, including prothrombin time, activated partial thromboplastin time (aPTT), and international normalized ratio (INR). A total of 1800 files were reviewed. Nine (0.5%) patients were found to have deranged clotting profile without any predictive history of clotting derangement; 56% were male and 44% were female. Median age was 32 years with an interquartile range of 27 years. Median aPTT was (40.8 with 20.8 IQR). Median INR was (1.59 with 0.48 IQR). Median blood loss was (400 with 50 IQR). No significant association between coagulation profile (aPTT, INR) and blood loss was found (P = 0.85, r = -0.07). CONCLUSIONS: We conclude that patients without a history of coagulopathy and normal physical examination do not require routine coagulation screening before elective craniotomy.