GPR56 Promotes Diabetic Kidney Disease Through eNOS Regulation in Glomerular Endothelial Cells.

Although glomerular endothelial dysfunction is well recognized as contributing to the pathogenesis of diabetic kidney disease (DKD), the molecular pathways contributing to DKD pathogenesis in glomerular endothelial cells (GECs) are only partially understood. To uncover pathways that are differentially regulated in early DKD that may contribute to disease pathogenesis, we recently conducted a transcriptomic analysis of isolated GECs from diabetic NOS3-null mice. The analysis identified several potential mediators of early DKD pathogenesis, one of which encoded an adhesion G protein-coupled receptor-56 (GPR56), also known as ADGRG1. Enhanced glomerular expression of GPR56 was observed in human diabetic kidneys, which was negatively associated with kidney function. Using cultured mouse GECs, we observed that GPR56 expression was induced with exposure to advanced glycation end products, as well as in high-glucose conditions, and its overexpression resulted in decreased phosphorylation and expression of endothelial nitric oxide synthase (eNOS). This effect on eNOS by GPR56 was mediated by coupling of Gα12/13-RhoA pathway activation and Gαi-mediated cAMP/PKA pathway inhibition. The loss of GPR56 in mice led to a significant reduction in diabetes-induced albuminuria and glomerular injury, which was associated with reduced oxidative stress and restoration of eNOS expression in GECs. These findings suggest that GPR56 promotes DKD progression mediated, in part, through enhancing glomerular endothelial injury and dysfunction.

Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.

Classical Regression and Predictive Modeling.

BACKGROUND: With the advent of personalized and stratified medicine, there has been much discussion about predictive modeling and the role of classical regression in modern medical research. We describe and distinguish the goals in these 2 frameworks for analysis. METHODS: The assumptions underlying and utility of classical regression are reviewed for continuous and binary outcomes. The tenets of predictive modeling are then discussed and contrasted. Principles are illustrated by simulation and through application of methods to a neurosurgical study. RESULTS: Classical regression can be used for insights into causal mechanisms if careful thought is given to the role of variables of interest and potential confounders. In predictive modeling, interest lies more in accuracy of predictions and so alternative metrics are used to judge adequacy of models and methods; methods which average predictions over several contending models can improve predictive performance but these do not admit a single risk score. CONCLUSIONS: Both classical regression and predictive modeling have important roles in modern medical research. Understanding the distinction between the 2 frameworks for analysis is important to place them in their appropriate context and interpreting findings from published studies appropriately.

Rescue therapy for vasospasm following aneurysmal subarachnoid hemorrhage: a propensity score-matched analysis with machine learning.

OBJECTIVE: Rescue therapies have been recommended for patients with angiographic vasospasm (aVSP) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). However, there is little evidence from randomized clinical trials that these therapies are safe and effective. The primary aim of this study was to apply game theory-based methods in explainable machine learning (ML) and propensity score matching to determine if rescue therapy was associated with better 3-month outcomes following post-SAH aVSP and DCI. The authors also sought to use these explainable ML methods to identify patient populations that were more likely to receive rescue therapy and factors associated with better outcomes after rescue therapy. METHODS: Data for patients with aVSP or DCI after SAH were obtained from 8 clinical trials and 1 observational study in the Subarachnoid Hemorrhage International Trialists repository. Gradient boosting ML models were constructed for each patient to predict the probability of receiving rescue therapy and the 3-month Glasgow Outcome Scale (GOS) score. Favorable outcome was defined as a 3-month GOS score of 4 or 5. Shapley Additive Explanation (SHAP) values were calculated for each patient-derived model to quantify feature importance and interaction effects. Variables with high SHAP importance in predicting rescue therapy administration were used in a propensity score-matched analysis of rescue therapy and 3-month GOS scores. RESULTS: The authors identified 1532 patients with aVSP or DCI. Predictive, explainable ML models revealed that aneurysm characteristics and neurological complications, but not admission neurological scores, carried the highest relative importance rankings in predicting whether rescue therapy was administered. Younger age and absence of cerebral ischemia/infarction were invariably linked to better rescue outcomes, whereas the other important predictors of outcome varied by rescue type (interventional or noninterventional). In a propensity score-matched analysis guided by SHAP-based variable selection, rescue therapy was associated with higher odds of 3-month GOS scores of 4-5 (OR 1.63, 95% CI 1.22-2.17). CONCLUSIONS: Rescue therapy may increase the odds of good outcome in patients with aVSP or DCI after SAH. Given the strong association between cerebral ischemia/infarction and poor outcome, trials focusing on preventative or therapeutic interventions in these patients may be most able to demonstrate improvements in clinical outcomes. Insights developed from these models may be helpful for improving patient selection and trial design.

Impact of subcallosal artery origin and A1 asymmetry on surgical outcomes of anterior communicating artery aneurysms.

BACKGROUND: Surgical clipping of anterior communicating artery (ACoA) aneurysms remains challenging due to their complex anatomy. Anatomical risk factors for ACoA aneurysm surgery require further elucidation. The aim of this study is to investigate whether proximity of the midline perforating artery, subcallosal artery (SubCA), and associated anomaly of the ACoA complex affect functional outcomes of ACoA aneurysm surgery. METHODS: A total of 92 patients with both unruptured and ruptured ACoA aneurysms, who underwent surgical clipping, were retrospectively analyzed from a multicenter, observational cohort database. Association of ACoA anatomy with SubCA origin at the aneurysmal neck under microsurgical observation was analyzed in the interhemispheric approach subgroup (n = 56). Then, we evaluated whether anatomical factors associated with SubCA neck origin affected surgical outcomes in the entire cohort (both interhemispheric and pterional approaches, n = 92). RESULTS: In the interhemispheric approach cohort, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was stratified to have the highest probability of the SubCA neck origin by a decision tree analysis. Then, among the entire cohort using either interhemispheric or pterional approach, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was significantly associated with poor functional outcomes by multivariable logistic regression analysis (OR 6.76; 95% CI 1.19-38.5; p = 0.03) as compared with A1 symmetry group in the acute subarachnoid hemorrhage settings. CONCLUSION: Combination of A1 asymmetry and larger aneurysmal size was significantly associated with SubCA aneurysmal neck origin and poor functional outcomes in ACoA aneurysm surgery. Interhemispheric approach may be proposed to provide a wider and unobstructed view of SubCA for ACoA aneurysms with this high-risk anatomical variant.

Commentary on Post, et al. Ultra-early tranexamic acid after subarachnoid hemorrhage: A randomized controlled trial. Lancet 2021.

BACKGROUND: Tranexamic acid (TA) administration in aneurysmal subarachnoid hemorrhage (SAH) within the first 24 hours may reduce the incidence of early aneurysmal rebleeding. However, this is also the potential for an increased risk of delayed cerebral ischemia if TA is administered for more than 72 hours following the initial aneurysmal rupture. METHODS: In the ultra-early tranexamic acid after subarachnoid hemorrhage randomized controlled trial by Post et al., patients were randomized to receive TA within the first 24 hours, or until start of aneurysm treatment. These results were compared to a matched control group. RESULTS: Ultra-early administration (≤24 h) of TA reduced the incidence of rebleeding, and did not alter the incidence of delayed cerebral ischemia and/or extracranial thrombosis. Further, no significant differences were noted between the TA group and control arm in the incidence of good (modified Rankin scores 0-3) clinical outcomes at 6 months. CONCLUSION: Ultra-early administration of TA (≤24 h) resulted in a lower rate of recurrent hemorrhage, without increasing the incidence of delayed cerebral ischemia in SAH patients.

Phase 1b Study to Evaluate Safety, Tolerability, and Maximum Tolerated Dose of PF-05230907 for Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: This study aimed to determine the maximum tolerated dose and to evaluate the overall safety and tolerability of single doses of PF-05230907 in subjects with acute intracerebral hemorrhage. METHODS: Individuals presenting with intracerebral hemorrhage were enrolled in a phase 1, multicenter, open-label clinical trial. A Bayesian modified continual reassessment method design based on treatment-emergent thromboembolic or ischemic events was adopted. Sequential dosing, an external data monitoring committee, and prespecified stopping rules were incorporated as safeguards. RESULTS: Twenty-one subjects received PF-05230907. The mean (±SD) age in years and intracerebral hemorrhage volume in mL at baseline were 62 (±9) and 18 (±11), respectively. Two treatment-emergent thromboembolic or ischemic events occurred (deep vein thrombosis and cerebral ischemia), in the 30 µg/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 µg/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 µg/kg, with a mean fitted dose-toxicity estimate of 11.9% (95% CI, 1.2%-27.4%). CONCLUSIONS: Single doses of PF-05230907 appeared to be tolerated across a range of doses in the intracerebral hemorrhage population, with thrombotic events observed only at the highest dose level tested. Recruitment within the recommended therapeutic window of opportunity remains a challenge. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02687191.

Review of Toyoda K, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischemic stroke in Japan. Lancet Neurol. 2019 Jun;18(6):539-548.

BACKGROUND: Prior meta-analyses showed that treatment with cilostazol, with or without aspirin, significantly reduced the incidence of recurrent ischemic stroke, occurrence of hemorrhagic stroke, and frequency of other serious vascular adverse events. METHODS: This review highlights the value of the randomized controlled trial (RCT) by Toyoda et al. entitled, "Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischemic stroke in Japan: a multicenter, open-label, randomized controlled trial." Here, dual therapy consisting of cilostazol and another antiplatelet agent was used to prevent secondary ischemic stroke in high-risk Japanese patients. RESULTS: Patients on dual therapy consisting of cilostazol/aspirin or cilostazol/clopidogrel had significantly lower frequencies of recurrent stroke. However, there were significant differences in the incidence of attendant hemorrhagic complications utilizing mono or dual therapy. CONCLUSION: This RCT demonstrated the safety of dual therapy, consisting of cilostazol/aspirin or cilostazol/ clopidogrel, in preventing secondary ischemic stroke in a high-risk Japanese population. Further studies are required to generalize these findings to other patient populations worldwide.

"Clip Anchor-Assisted Coil Embolization" for Endovascular Parent Artery Occlusion of Intracranial Traumatic Aneurysm.

Traumatic cerebral aneurysms are histologically dissecting aneurysms or pseudoaneurysms, thus requiring parent artery occlusion for cure. Combination of endovascular parent artery occlusion and extracranial-intracranial bypass is considered optimal to obtain complete obliteration of the aneurysm and to avoid hemodynamic hypoperfusion. However, endovascular parent artery occlusion of the supraclinoid internal carotid artery (ICA) is at risk of ischemic complications due to distal coil protrusion to adjacent perforating arteries or distal embolism of the thrombi generated in the coil mass. A 20-year-old man presented with progressive left optic neuropathy following motor vehicle accident. Radiological examination revealed left supraclinoid ICA aneurysmal formation with dissecting change. We treated this traumatic supraclinoid ICA aneurysm by combination of endovascular parent artery occlusion and high-flow bypass in the hybrid operating room. An aneurysmal clip was applied on the ICA just distal to the aneurysm prior to coil embolization, and worked as a scaffold for subsequent filling coils and as a blockade for the distal emboli. This "clip anchor-assisted coil embolization" technique resulted in optimal parent artery occlusion for the traumatic aneurysm of the supraclinoid ICA with minimal risks of residual blood flow, intraoperative rupture, and thromboembolic complications.

Between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository.

OBJECTIVE: Differences in clinical outcomes between centers and countries may reflect variation in patient characteristics, diagnostic and therapeutic policies, or quality of care. The purpose of this study was to investigate the presence and magnitude of between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The authors analyzed data from 5972 aSAH patients enrolled in randomized clinical trials of 3 different treatments from the Subarachnoid Hemorrhage International Trialists (SAHIT) repository, including data from 179 centers and 20 countries. They used random effects logistic regression adjusted for patient characteristics and timing of aneurysm treatment to estimate between-center and between-country differences in unfavorable outcome, defined as a Glasgow Outcome Scale score of 1-3 (severe disability, vegetative state, or death) or modified Rankin Scale score of 4-6 (moderately severe disability, severe disability, or death) at 3 months. Between-center and between-country differences were quantified with the median odds ratio (MOR), which can be interpreted as the ratio of odds of unfavorable outcome between a typical high-risk and a typical low-risk center or country. RESULTS: The proportion of patients with unfavorable outcome was 27% (n = 1599). The authors found substantial between-center differences (MOR 1.26, 95% CI 1.16-1.52), which could not be explained by patient characteristics and timing of aneurysm treatment (adjusted MOR 1.21, 95% CI 1.11-1.44). They observed no between-country differences (adjusted MOR 1.13, 95% CI 1.00-1.40). CONCLUSIONS: Clinical outcomes after aSAH differ between centers. These differences could not be explained by patient characteristics or timing of aneurysm treatment. Further research is needed to confirm the presence of differences in outcome after aSAH between hospitals in more recent data and to investigate potential causes.

Impact of temperature decline from the previous day as a trigger of spontaneous subarachnoid hemorrhage: case-crossover study of prefectural stroke database.

OBJECTIVE: Several environmental factors have been reported to correlate with incidence of spontaneous subarachnoid hemorrhage (SAH). However, because of different patient selection and study designs among these studies, meteorological factors that trigger the incidence of SAH in a short hazard period remain unknown. Among meteorological factors, daily temperature changes may disrupt and violate homeostasis and predispose to cerebrovascular circulatory disturbances and strokes. The authors aimed to investigate whether a decline in the temperature from the highest of the previous day to the lowest of the event day (temperature decline from the previous day [TDP]) triggers SAH in the prefecture-wide stroke database. METHODS: All 28 participating institutions with primary or comprehensive stroke centers located throughout Kochi Prefecture, Japan, were included in the study. Data collected between January 2012 and December 2016 were analyzed, and 715 consecutive SAH patients with a defined date of onset were enrolled. Meteorological data in this period were obtained from the Kochi Local Meteorological Observatory. A case-crossover study was performed to investigate association of TDP and other environmental factors with onset of SAH. RESULTS: The increasing TDP in 1°C on the day of the SAH event was associated with an increased incidence of SAH (OR 1.041, 95% CI 1.007-1.077) after adjustment for other environmental factors. According to the stratified analysis, a significant association between TDP and SAH was observed in women, patients < 65 years old, and patients with weekday onset. Among these factors, increasing TDP had a great impact on SAH onset in patients < 65 years old (p = 0.028, Mann-Whitney U-test). CONCLUSIONS: TDP, temperature decline from the highest of the previous day to the lowest of the day, was correlated with the incidence of spontaneous SAH, particularly in younger patients < 65 years old.

Antithrombotic agents and traumatic brain injury in the elderly population: hemorrhage patterns and outcomes.

OBJECTIVE: Among the elderly, use of antithrombotics (ATs), antiplatelets (APs; aspirin, clopidogrel), and/or anticoagulants (ACs; warfarin, direct oral ACs [DOACs; dabigatran, rivaroxaban, apixaban]) to prevent thromboembolic events must be carefully weighed against the risk of intracranial hemorrhage (ICH) with trauma. The goal of this study was to assess the risk of sustaining a traumatic brain injury (TBI), ICH, and poorer outcomes in relation to AT use among all patients 65 years or older presenting to a single institution with head trauma. METHODS: Data were collected from all head trauma patients 65 years or older presenting to the authors' supraregional tertiary trauma center over a 24-month period and included age, sex, injury mechanism, medical history, international normalized ratio, Glasgow Coma Scale (GCS) score, ICH presence and type, hospital admission, reversal therapy, surgery, discharge destination, Extended Glasgow Outcome Scale (GOSE) score at discharge, and mortality. RESULTS: A total of 1365 head trauma patients 65 years or older were included; 724 were on AT therapy (413 on APs, 151 on ACs, 59 on DOACs, 48 on 2 APs, 38 on AP+AC, and 15 on AP+DOAC) and 641 were not. Among all head trauma patients, the risk of sustaining a TBI was associated with AP use after adjusting for covariates. Of the 731 TBI patients, those using ATs had higher rates of ICH (p <0.0001), functional dependency at discharge (GOSE score ≤ 4; p < 0.0001), and mortality (p < 0.0001). Elevated rates of ICH progression on follow-up CT scanning were observed in patients in the warfarin monotherapy (OR 5.30, p < 0.0001) and warfarin + AP (OR 6.15, p = 0.0011). Risk of mortality was not associated with single antiplatelet use but was notably high with 2 APs (OR 4.66, p = 0.0056), warfarin (OR 5.18, p = 0.0003), and DOAC use (OR 5.09, p = 0.0149). CONCLUSIONS: Elderly trauma patients on ATs, especially combination therapy, are at elevated risk of ICH and poor outcomes compared with those not on AT therapy. While both AP and warfarin use alone and in combination were associated with significantly elevated odds of sustaining an ICH among TBI patients, only warfarin use was a predictor of hemorrhage progression on follow-up scans. The use of a single AP was not associated with mortality; however, the combination of both aspirin and clopidogrel was. Warfarin and DOAC users had comparable mortality rates; however, DOAC users had lower rates of ICH progression, and fewer survivors were functionally dependent at discharge than were warfarin users. DOACs are an overall safer alternative to warfarin for patients at high risk of falls.

Determining blood flow direction from short neurovascular surgical microscope videos.

Neurovascular surgery aims to repair diseased or damaged blood vessels in the brain or spine. There are numerous procedures that fall under this category, and in all of them, the direction of blood flow through these vessels is crucial information. Current methods to determine this information intraoperatively include static pre-operative images combined with augmented reality, Doppler ultrasound, and injectable fluorescent dyes. Each of these systems has inherent limitations. This study includes the proposal and preliminary validation of a technique to identify the direction of blood flow through vessels using only video segments of a few seconds acquired from routinely used surgical microscopes. The video is enhanced to reveal subtle colour fluctuations related to blood pulsation, and these rhythmic signals are further analysed in Fourier space to reveal the direction of blood flow. The proposed method was validated using a novel physical phantom and retrospective analysis of surgical videos and demonstrated high accuracy in identifying the direction of blood flow.

Augmented reality guidance in cerebrovascular surgery using microscopic video enhancement.

Cerebrovascular surgery treats vessel abnormalities in the brain and spinal cord, including arteriovenous malformations (AVMs) and aneurysms. These procedures often involve clipping the vessels feeding blood to these abnormalities, making accurate classification of blood vessel types (feeding versus draining) important during surgery. Previous work to guide the intraoperative identification of the vessels included augmented reality (AR) using pre-operative images, injected dyes, and Doppler ultrasound, but each with their drawbacks. The authors propose and demonstrate a novel technique to help differentiate vessels by enhancing short videos of a few seconds from the surgical microscope using motion magnification and spectral analysis, and constructing AR views that fuse the analysis results as intuitive colourmaps and the surgical microscopic view. They demonstrated the proposed technique retrospectively with two real cerebrovascular surgical cases: one AVM and one aneurysm. The results showed that the proposed technique can help characterise different vessel types (feeding and draining the abnormality), which agree with those identified by the operating surgeon.

Effect of choice of treatment modality on the incidence of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Shunt-dependent hydrocephalus (SDHC) may arise after aneurysmal subarachnoid hemorrhage (aSAH) as CSF resorptive mechanisms are disrupted. Using propensity score analysis, the authors aimed to investigate which treatment modality, surgical clipping or endovascular treatment, is superior in reducing rates of SDHC after aSAH. METHODS: The authors' multicenter SAH database, comprising 3 stroke centers affiliated with Kyoto University, Japan, was used to identify patients treated between January 2009 and July 2016. Univariate and multivariate analyses were performed to characterize risk factors for SDHC after aSAH. A propensity score model was generated for both treatment groups, incorporating relevant patient covariates to detect any superiority for prevention of SDHC after aSAH. RESULTS: A total of 566 patients were enrolled in this study. SDHC developed in 127 patients (22%). On multivariate analysis, age older than 53 years, the presence of intraventricular hematoma, and surgical clipping as opposed to endovascular coiling were independently associated with SDHC after aSAH. After propensity score matching, 136 patients treated with surgical clipping and 136 with endovascular treatment were matched. Propensity score-matched cohorts exhibited a significantly lower incidence of SDHC after endovascular treatment than after surgical clipping (16% vs 30%, p = 0.009; OR 2.2, 95% CI 1.2-4.2). SDHC was independently associated with poor neurological outcomes (modified Rankin Scale score 3-6) at discharge (OR 4.3, 95% CI 2.6-7.3; p < 0.001). CONCLUSIONS: SDHC after aSAH occurred significantly more frequently in patients who underwent surgical clipping. Strategies for treatment of ruptured aneurysms should be used to mitigate SDHC and minimize poor outcomes.