Endovascular therapy versus best medical management in distal medium middle cerebral artery acute ischaemic stroke: a multinational multicentre propensity score-matched study.

BACKGROUND: The efficacy of endovascular treatment (EVT) in acute ischaemic stroke due to distal medium vessel occlusion (DMVO) remains uncertain. Our study aimed to evaluate the safety and efficacy of EVT compared with the best medical management (BMM) in DMVO. METHODS: In this prospectively collected, retrospectively reviewed, multicentre cohort study, we analysed data from the Multicentre Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy registry. Patients with acute ischaemic stroke due to DMVO in the M2, M3 and M4 segments who underwent EVT or received BMM were included. Primary outcome measures comprised 10 co-primary endpoints, including functional independence (mRS 0-2), excellent outcome (mRS 0-1), mortality (mRS 6) and haemorrhagic complications. Propensity score matching was employed to balance the cohorts. RESULTS: Among 2125 patients included in the primary analysis, 1713 received EVT and 412 received BMM. After propensity score matching, each group comprised 391 patients. At 90 days, no significant difference was observed in achieving mRS 0-2 between EVT and BMM (adjusted OR 1.00, 95% CI 0.67 to 1.50, p>0.99). However, EVT was associated with higher rates of symptomatic intracerebral haemorrhage (8.4% vs 3.0%, adjusted OR 3.56, 95% CI 1.69 to 7.48, p<0.001) and any intracranial haemorrhage (37% vs 19%, adjusted OR 2.61, 95% CI 1.81 to 3.78, p<0.001). Mortality rates were similar between groups (13% in both, adjusted OR 1.48, 95% CI 0.87 to 2.51, p=0.15). CONCLUSION: Our findings suggest that while EVT does not significantly improve functional outcomes compared with BMM in DMVO, it is associated with higher risks of haemorrhagic complications. These results support a cautious approach to the use of EVT in DMVO and highlight the need for further prospective randomised trials to refine treatment strategies.

Compositional Deep Probabilistic Models of DNA-Encoded Libraries.

DNA-encoded library (DEL) has proven to be a powerful tool that utilizes combinatorially constructed small molecules to facilitate highly efficient screening experiments. These selection experiments, involving multiple stages of washing, elution, and identification of potent binders via unique DNA barcodes, often generate complex data. This complexity can potentially mask the underlying signals, necessitating the application of computational tools, such as machine learning, to uncover valuable insights. We introduce a compositional deep probabilistic model of DEL data, DEL-Compose, which decomposes molecular representations into their monosynthon, disynthon, and trisynthon building blocks and capitalizes on the inherent hierarchical structure of these molecules by modeling latent reactions between embedded synthons. Additionally, we investigate methods to improve the observation models for DEL count data, such as integrating covariate factors to more effectively account for data noise. Across two popular public benchmark data sets (CA-IX and HRP), our model demonstrates strong performance compared to count baselines, enriches the correct pharmacophores, and offers valuable insights via its intrinsic interpretable structure, thereby providing a robust tool for the analysis of DEL data.

Correlation between Physical Activity and Depression in Community-Dwelling Older Adult Palestinians.

OBJECTIVE: Investigating the relationship between physical activity (PA) and depressive symptoms is a vital field of research globally. Nonetheless, this association remains unexplored in the context of older Palestinian adults, highlighting the need for additional research on this population. Therefore, this study aimed to examine the association between PA and depressive symptoms among older Palestinian adults. SUBJECTS AND METHODS: A cross-sectional study was conducted in the West Bank/Palestine with 266 participants. Data were collected using a PA socio-cultural adapted questionnaire (PA-SCAQ), the EuroQuol-5Dimensions-5Levels measure, and the Geriatric depression scale (GDS-15). Independent sample t tests and ANOVA tests were used to investigate mean differences in PA and GDS-15 scores between groups. Furthermore, multiple linear regression analysis was used to examine the relationship between study variables and the impact of the independent variable (PA level) on depressive symptoms. RESULTS: The mean age of the participants was 65.01 ± 8.02 years (range: 55-86), women 51.9%. Lower levels of PA and higher depressive symptoms were recorded among women, participants ≥65 years, and with recorded diagnosed disease (p < 0.05). The regression analysis showed a negative significant correlation between PA and GDS-15 scores (ß = -0.235, p < 0.001), when controlling for age (model 2), and for age and sex (model 3), significant associations were recorded, respectively (ß = 0.192, p = 0.002), and (ß = 0.14, p = 0.015). CONCLUSION: Participants who recorded higher depressive symptoms had a lower level of PA; regular moderate-intensity aerobic exercises can contribute to prevent depression symptoms in older adults.

DEL-Dock: Molecular Docking-Enabled Modeling of DNA-Encoded Libraries.

DNA-encoded library (DEL) technology has enabled significant advances in hit identification by enabling efficient testing of combinatorially generated molecular libraries. DEL screens measure protein binding affinity though sequencing reads of molecules tagged with unique DNA barcodes that survive a series of selection experiments. Computational models have been deployed to learn the latent binding affinities that are correlated to the sequenced count data; however, this correlation is often obfuscated by various sources of noise introduced in its complicated data-generation process. In order to denoise DEL count data and screen for molecules with good binding affinity, computational models require the correct assumptions in their modeling structure to capture the correct signals underlying the data. Recent advances in DEL models have focused on probabilistic formulations of count data, but existing approaches have thus far been limited to only utilizing 2-D molecule-level representations. We introduce a new paradigm, DEL-Dock, that combines ligand-based descriptors with 3-D spatial information from docked protein-ligand complexes. 3-D spatial information allows our model to learn over the actual binding modality rather than using only structure-based information of the ligand. We show that our model is capable of effectively denoising DEL count data to predict molecule enrichment scores that are better correlated with experimental binding affinity measurements compared to prior works. Moreover, by learning over a collection of docked poses we demonstrate that our model, trained only on DEL data, implicitly learns to perform good docking pose selection without requiring external supervision from expensive-to-source protein crystal structures.

Posterior Cerebral Artery Aneurysm Re-Rupture Following Revascularization for Moyamoya Disease.

OBJECTIVES: Aneurysms associated with hemorrhagic moyamoya disease (MMD) are reported to stabilize or recede following revascularization. CASE REPORT/RESULTS: A 29 year-old male with no past medical history presented obtunded with diffuse intraventricular hemorrhage and vascular imaging demonstrating bilateral MMD without any associated aneurysms. He underwent a delayed right-sided STA-MCA bypass and pial synangiosis, and was subsequently discharged on hospital day 24 with a modified Rankin Scale score (mRS) of 2. He returned eleven days later from a rehabilitation facility with recurrent IVH. A saccular 5 mm right P4 segment posterior cerebral artery aneurysm was seen on a diagnostic angiogram and embolized with Onyx glue. CONCLUSIONS: Distal posterior circulation artery aneurysmal rupture is a rare cause of hemorrhagic MMD. This case demonstrates the capacity of these aneurysms to re-rupture following revascularization and underscores the importance of treating the aneurysms directly.

Computed Tomography Angiography Versus Digital Subtraction Angiography for Postclipping Aneurysm Obliteration Detection.

Background and Purpose- Digital subtraction angiography has been used as the gold standard to confirm successful aneurysmal obliteration after aneurysm clipping procedures using titanium or cobalt alloy clips. Computed tomographic angiography is a newer, less invasive imaging technique also used to confirm successful aneurysmal obliteration; however, its use compared with digital subtraction angiography remains controversial. Methods- A comprehensive literature search was conducted on Pubmed, EMBASE, and Cochrane databases through November 6, 2017, for studies that evaluated postclipping aneurysm obliteration with both computed tomographic angiography and digital subtraction angiography. Pooled sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated using the bivariate random-effects model. Results- Out of 6916 studies, 13 studies met inclusion criteria for this meta-analysis. A total of 510 patients with 613 aneurysms were included. Compared with digital subtraction angiography, which detected 87 residual aneurysms, computed tomographic angiography detected 58 resulting in a pooled sensitivity of 69% (95% CI, 54%-81%) and a pooled specificity of 99% (95% CI, 97%-99%). This corresponded to LR+ of 55.5 (95% CI, 23.6-130.9) and LR- of 0.31 (95% CI, 0.20-0.48). Univariate meta-regression revealed that the pooled sensitivity was worse in prospective designs ( P interaction <0.05), and the pooled specificity was better in higher-quality studies and for postoperative aneurysm diameters of <2 mm ( P interaction <0.001 for both). Conclusions- This meta-analysis revealed that computed tomographic angiography had a favorable LR+ but not a favorable LR-. Thus, this imaging modality may be applicable to rule in, but not rule out, residual aneurysms after clipping.

Impact of Balloon Guide Catheter Use on Clinical and Angiographic Outcomes in the STRATIS Stroke Thrombectomy Registry.

Background and Purpose- Mechanical thrombectomy has been shown to improve clinical outcomes in patients with acute ischemic stroke. However, the impact of balloon guide catheter (BGC) use is not well established. Methods- STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter study of patients with large vessel occlusion treated with the Solitaire stent retriever as first-line therapy. In this study, an independent core laboratory, blinded to the clinical outcomes, reviewed all procedures and angiographic data to classify procedural technique, target clot location, recanalization after each pass, and determine the number of stent retriever passes. The primary clinical end point was functional independence (modified Rankin Scale, 0-2) at 3 months as determined on-site, and the angiographic end point was first-pass effect (FPE) success rate from a single device attempt (modified Thrombolysis in Cerebral Infarction, ≥2c) as determined by a core laboratory. Achieving modified FPE (modified Thrombolysis in Cerebral Infarction, ≥2b) was also assessed. Comparisons of clinical outcomes were made between groups and adjusted for baseline and procedural characteristics. All participating centers received institutional review board approval from their respective institutions. Results- Adjunctive technique groups included BGC (n=445), distal access catheter (n=238), and conventional guide catheter (n=62). The BGC group had a higher rate of FPE following first pass (212/443 [48%]) versus conventional guide catheter (16/62 [26%]; P=0.001) and distal access catheter (83/235 [35%]; P=0.002). Similarly, the BGC group had a higher rate of modified FPE (294/443 [66%]) versus conventional guide catheter (26/62 [42%]; P<0.001) and distal access catheter (129/234 [55%]; P=0.003). The BGC group achieved the highest rate of functional independence (253/415 [61%]) versus conventional guide catheter (23/55 [42%]; P=0.007) and distal access catheter (113/218 [52%]; P=0.027). Final revascularization and mortality rates did not differ across the groups. Conclusions- BGC use was an independent predictor of FPE, modified FPE, and functional independence, suggesting that its routine use may improve the rates of early revascularization success and good clinical outcomes. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02239640.

Epigenetic Silencing of TAP1 in Aldefluor+ Breast Cancer Stem Cells Contributes to Their Enhanced Immune Evasion.

Avoiding detection and destruction by immune cells is key for tumor initiation and progression. The important role of cancer stem cells (CSCs) in tumor initiation has been well established, yet their ability to evade immune detection and targeting is only partly understood. To investigate the ability of breast CSCs to evade immune detection, we identified a highly tumorigenic population in a spontaneous murine mammary tumor based on increased aldehyde dehydrogenase activity. We performed tumor growth studies in immunocompetent and immunocompromised mice. In immunocompetent mice, growth of the spontaneous mammary tumor was restricted; however, the Aldefluor+ population was expanded, suggesting inherent resistance mechanisms. Gene expression analysis of the sorted tumor cells revealed that the Aldefluor+ tumor cells has decreased expression of transporter associated with antigen processing (TAP) genes and co-stimulatory molecule CD80, which would decrease susceptibility to T cells. Similarly, the Aldefluor+ population of patient tumors and 4T1 murine mammary cells had decreased expression of TAP and co-stimulatory molecule genes. In contrast, breast CSCs identified by CD44+ CD24- do not have decreased expression of these genes, but do have increased expression of C-X-C chemokine receptor type 4. Decitabine treatment and bisulfite pyrosequencing suggests that DNA hypermethylation contributes to decreased TAP gene expression in Aldefluor+ CSCs. TAP1 knockdown resulted in increased tumor growth of 4T1 cells in immunocompetent mice. Together, this suggests immune evasion mechanisms in breast CSCs are marker specific and epigenetic silencing of TAP1 in Aldefluor+ breast CSCs contributes to their enhanced survival under immune pressure. Stem Cells 2018;36:641-654.

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke).

BACKGROUND: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. METHODS: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. RESULTS: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients (P<0.001). Clinical outcomes were better in the direct group, with 60.0% (299/498) achieving functional independence compared with 52.2% (213/408) in the transfer group (odds ratio, 1.38; 95% confidence interval, 1.06-1.79; P=0.02). Likewise, excellent outcome (modified Rankin Score 0-1) was achieved in 47.4% (236/498) of direct patients versus 38.0% (155/408) of transfer patients (odds ratio, 1.47; 95% confidence interval, 1.13-1.92; P=0.005). Mortality did not differ between the 2 groups (15.1% for direct, 13.7% for transfer; P=0.55). Intravenous tissue plasminogen activator did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that intravenous tissue plasminogen activator would be delayed by 12 minutes, but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then intravenous tissue plasminogen activator would be delayed by 7 minutes and MT performed 94 minutes earlier. CONCLUSIONS: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640.

Automated design of collective variables using supervised machine learning.

Selection of appropriate collective variables (CVs) for enhancing sampling of molecular simulations remains an unsolved problem in computational modeling. In particular, picking initial CVs is particularly challenging in higher dimensions. Which atomic coordinates or transforms there of from a list of thousands should one pick for enhanced sampling runs? How does a modeler even begin to pick starting coordinates for investigation? This remains true even in the case of simple two state systems and only increases in difficulty for multi-state systems. In this work, we solve the "initial" CV problem using a data-driven approach inspired by the field of supervised machine learning (SML). In particular, we show how the decision functions in SML algorithms can be used as initial CVs (SMLcv ) for accelerated sampling. Using solvated alanine dipeptide and Chignolin mini-protein as our test cases, we illustrate how the distance to the support vector machines' decision hyperplane, the output probability estimates from logistic regression, the outputs from shallow or deep neural network classifiers, and other classifiers may be used to reversibly sample slow structural transitions. We discuss the utility of other SML algorithms that might be useful for identifying CVs for accelerating molecular simulations.

MSMBuilder: Statistical Models for Biomolecular Dynamics.

MSMBuilder is a software package for building statistical models of high-dimensional time-series data. It is designed with a particular focus on the analysis of atomistic simulations of biomolecular dynamics such as protein folding and conformational change. MSMBuilder is named for its ability to construct Markov state models (MSMs), a class of models that has gained favor among computational biophysicists. In addition to both well-established and newer MSM methods, the package includes complementary algorithms for understanding time-series data such as hidden Markov models and time-structure based independent component analysis. MSMBuilder boasts an easy to use command-line interface, as well as clear and consistent abstractions through its Python application programming interface. MSMBuilder was developed with careful consideration for compatibility with the broader machine learning community by following the design of scikit-learn. The package is used primarily by practitioners of molecular dynamics, but is just as applicable to other computational or experimental time-series measurements.

Hide-and-seek: the interplay between cancer stem cells and the immune system.

The enhanced ability of cancer stem cells (CSCs) to give rise to new tumors suggests that these cells may also have an advantage in evading immune detection and elimination. This tumor-forming ability, combined with the known plasticity of the immune system, which can play both protumorigenic and antitumorigenic roles, has motivated investigations into the interaction between CSCs and the immune system. Herein, we review the interplay between host immunity and CSCs by examining the immune-related mechanisms that favor CSCs and the CSC-mediated expansion of protumorigenic immune cells. Furthermore, we discuss immune cells, such as natural killer cells, that preferentially target CSCs and the strategies used by CSCs to evade immune detection and destruction. An increased understanding of these interactions and the pathways that regulate them may allow us to harness immune system components to create new adjuvant therapies that eradicate CSCs and improve patient survival.

Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke: Primary Results of the STRATIS Registry.

BACKGROUND AND PURPOSE: Mechanical thrombectomy with stent retrievers has become standard of care for treatment of acute ischemic stroke patients because of large vessel occlusion. The STRATIS registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) aimed to assess whether similar process timelines, technical, and functional outcomes could be achieved in a large real world cohort as in the randomized trials. METHODS: STRATIS was designed to prospectively enroll patients treated in the United States with a Solitaire Revascularization Device and Mindframe Capture Low Profile Revascularization Device within 8 hours from symptom onset. The STRATIS cohort was compared with the interventional cohort of a previously published SEER patient-level meta-analysis. RESULTS: A total of 984 patients treated at 55 sites were analyzed. The mean National Institutes of Health Stroke Scale score was 17.3. Intravenous tissue-type plasminogen activator was administered in 64.0%. The median time from onset to arrival in the enrolling hospital, door to puncture, and puncture to reperfusion were 138, 72, and 36 minutes, respectively. The Core lab-adjudicated modified Thrombolysis in Cerebral Infarction ≥2b was achieved in 87.9% of patients. At 90 days, 56.5% achieved a modified Rankin Scale score of 0 to 2, all-cause mortality was 14.4%, and 1.4% suffered a symptomatic intracranial hemorrhage. The median time from emergency medical services scene arrival to puncture was 152 minutes, and each hour delay in this interval was associated with a 5.5% absolute decline in the likelihood of achieving modified Rankin Scale score 0 to 2. CONCLUSIONS: This largest-to-date Solitaire registry documents that the results of the randomized trials can be reproduced in the community. The decrease of clinical benefit over time warrants optimization of the system of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02239640.

Vision outcomes in patients with paraclinoid aneurysms treated with clipping, coiling, or flow diversion: a systematic review and meta-analysis.

OBJECTIVE Patients with paraclinoid aneurysms commonly present with visual impairment. They have traditionally been treated with clipping or coiling, but flow diversion (FD) has recently been introduced as an alternative treatment modality. Although there is still initial aneurysm thrombosis, FD is hypothesized to reduce mass effect, which may decompress the optic nerve when treating patients with visually symptomatic paraclinoid aneurysms. The authors performed a meta-analysis to compare vision outcomes following clipping, coiling, or FD of paraclinoid aneurysms in patients who presented with visual impairment. METHODS A systematic literature review was performed using the PubMed and Web of Science databases. Studies published in English between 1980 and 2016 were included if they reported preoperative and postoperative visual function in at least 5 patients with visually symptomatic paraclinoid aneurysms (cavernous segment through ophthalmic segment) treated with clipping, coiling, or FD. Neuroophthalmological assessment was used when reported, but subjective patient reports or objective visual examination findings were also acceptable. RESULTS Thirty-nine studies that included a total of 2458 patients (520 of whom presented with visual symptoms) met the inclusion criteria, including 307 visually symptomatic cases treated with clipping (mean follow-up 26 months), 149 treated with coiling (mean follow-up 17 months), and 64 treated with FD (mean follow-up 11 months). Postoperative vision in these patients was classified as improved, unchanged, or worsened compared with preoperative vision. A pooled analysis showed preoperative visual symptoms in 38% (95% CI 28%-50%) of patients with paraclinoid aneurysms. The authors found that vision improved in 58% (95% CI 48%-68%) of patients after clipping, 49% (95% CI 38%-59%) after coiling, and 71% (95% CI 55%-84%) after FD. Vision worsened in 11% (95% CI 7%-17%) of patients after clipping, 9% (95% CI 2%-18%) after coiling, and 5% (95% CI 0%-20%) after FD. New visual deficits were found in patients with intact baseline vision at a rate of 1% (95% CI 0%-3%) for clipping, 0% (95% CI 0%-2%) for coiling, and 0% (95% CI 0%-2%) for FD. CONCLUSIONS To the authors' knowledge, this is the first meta-analysis to assess vision outcomes after treatment for paraclinoid aneurysms. The authors found that 38% of patients with these aneurysms presented with visual impairment. These data also demonstrated a high rate of visual improvement after FD without a significant difference in the rate of worsened vision or iatrogenic visual impairment compared with clipping and coiling. These findings suggest that FD is an effective option for treatment of visually symptomatic paraclinoid aneurysms.

Optimized parameter selection reveals trends in Markov state models for protein folding.

As molecular dynamics simulations access increasingly longer time scales, complementary advances in the analysis of biomolecular time-series data are necessary. Markov state models offer a powerful framework for this analysis by describing a system's states and the transitions between them. A recently established variational theorem for Markov state models now enables modelers to systematically determine the best way to describe a system's dynamics. In the context of the variational theorem, we analyze ultra-long folding simulations for a canonical set of twelve proteins [K. Lindorff-Larsen et al., Science 334, 517 (2011)] by creating and evaluating many types of Markov state models. We present a set of guidelines for constructing Markov state models of protein folding; namely, we recommend the use of cross-validation and a kinetically motivated dimensionality reduction step for improved descriptions of folding dynamics. We also warn that precise kinetics predictions rely on the features chosen to describe the system and pose the description of kinetic uncertainty across ensembles of models as an open issue.

Allosteric pathways in imidazole glycerol phosphate synthase.

Protein allosteric pathways are investigated in the imidazole glycerol phosphate synthase heterodimer in an effort to elucidate how the effector (PRFAR, N'-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide) activates glutaminase catalysis at a distance of 25 Å from the glutamine-binding site. We apply solution NMR techniques and community analysis of dynamical networks, based on mutual information of correlated protein motions in the active and inactive enzymes. We find evidence that the allosteric pathways in the PRFAR bound enzyme involve conserved residues that correlate motion of the PRFAR binding loop to motion at the protein-protein interface, and ultimately at the glutaminase active site. The imidazole glycerol phosphate synthase bienzyme is an important branch point for the histidine and nucleotide biosynthetic pathways and represents a potential therapeutic target against microbes. The proposed allosteric mechanism and the underlying allosteric pathways provide fundamental insights for the design of new allosteric drugs and/or alternative herbicides.

The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma.

Glioblastoma multiforme (GBM) is an aggressive tumor with poor survival outcomes and limited treatment options. We conducted a literature review to compare the survival outcomes of intra-arterial (IA) and intravenous (IV) chemotherapy delivery for GBM. Nine studies of IA chemotherapy infusion with 301 total patients met our criteria for inclusion and three studies contained IV treatment groups for comparison (n = 230 for IA, n = 71 for IV). The studies were grouped by either using newly diagnosed or recurrent GBM patients. In the newly diagnosed group, IV chemotherapy produced a statistically higher median overall survival (MOS; 16.3 months) compared with IA treatment (14.02 months). However, the total number of adverse events in IA chemotherapy was 1.08 per patient whereas for IV it was higher at 1.54 events per patient. Our recurrent GBM group includes only patients treated with IA chemotherapy which resulted in an average MOS of 10.84 months. This group had 2.7 adverse events per patient but no IV group is available for comparison. Historically, the survival of patients with recurrent GBM ranges from 3 to 9 months (Gil-Gil et al. Bevacizumab for the treatment of glioblastoma. Clin Med Insights Oncol 2013;7:123-35). For this reason, we believe IA chemotherapy to be a viable methodology in recurrent GBM patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications.

A 16-year-old boy presented with triple-A syndrome associated with neuromuscular disorders: a case report.

Introduction and importance: Allgrove syndrome (AS) (AAA syndrome) is a rare autosomal recessive disease caused by mutations in the AAAS gene located on chromosome 12q13. The AAAS gene encodes for the ALADIN protein (alacrima, achalasia, adrenal insufficiency, neurologic disorder). AS can manifest with a plethora of symptoms. Early recognition of the syndrome remains challenging due to its rarity and progressive nature. This report presents an unusual case of triple-A syndrome (TAS) with concurrent neuromuscular manifestations. Understanding the atypical presentation of this syndrome is vital for early diagnosis and appropriate management. Case presentation: We report a 16-year-old boy with severe malnutrition presented with painful swallowing, fatigue, and bilateral congenital ptosis. Barium swallow, upper gastrointestinal endoscopy, and Shimmer test were performed, which led to the diagnosis of TAS. Treatment included laparoscopic Heller's procedure, artificial tears, hydrocortisone. Clinical discussion: TAS, also known as AS, is a rare multisystem disorder characterized by achalasia, Addison's disease, and alacrima. This syndrome is occasionally referred to as 4A syndrome due to the inclusion of autonomic dysfunction. There is no treatment for AS. Management includes artificial tears for alacrima, glucocorticoid replacement therapy to treat adrenal insufficiency, and treatment of achalasia. Conclusion: This case emphasizes the importance of considering atypical presentations of TAS. Early diagnosis and treatment are paramount in addressing the varied components of this rare disorder. Understanding the clinical complexities of this syndrome aids in improved patient care and underscores the necessity for comprehensive evaluation and management in similar cases.

Randomized Clinical Trials in Cerebrovascular Neurosurgery From 2018 to 2022.

There has been an exponential increase in randomized controlled trials (RCTs) on cerebrovascular disease within neurosurgery. The goal of this study was to review, outline the scope, and summarize all phase 2b and phase 3 RCTs impacting cerebrovascular neurosurgery practice since 2018. We searched PubMed, MEDLINE, Embase, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases for relevant RCTs published between January 1, 2018, and July 1, 2022. We searched for studies related to eight major cerebrovascular disorders relevant to neurosurgery, including acute ischemic stroke, cerebral aneurysms and subarachnoid hemorrhage, intracerebral hemorrhage, subdural hematomas, cerebral venous thrombosis, arteriovenous malformations, Moyamoya disease and extracranial-intracranial bypass, and carotid and intracranial atherosclerosis. We limited our search to phase 2b or 3 RCTs related to cerebrovascular disorders published during the study period. The titles and abstracts of all relevant studies meeting our search criteria were included. Pediatric studies, stroke studies related to rehabilitation or cardiovascular disease, study protocols without published results, prospective cohort studies, registry studies, cluster randomized trials, and nonrandomized pivotal trials were excluded.  From an initial total of 2,797 records retrieved from the database searches, 1,641 records were screened after duplicates and studies outside of our time period were removed. After screening, 511 available reports within our time period of interest were assessed for eligibility. Pediatric studies, stroke studies related to rehabilitation or cardiovascular disease, study protocols without published results, prospective cohort studies, registry studies, cluster randomized trials, and nonrandomized pivotal trials were excluded. We found 80 unique phase 2b or 3 RCTs that fit our criteria, with 165 topic-relevant articles published within the study period.  Numerous RCTs in cerebrovascular neurosurgery have been published since 2018. Ischemic stroke, including mechanical thrombectomy and thrombolysis, accounted for a majority of publications, but there were large trials in intracerebral hemorrhage, subdural hemorrhage, aneurysms, subarachnoid hemorrhage, and cerebral venous thrombosis, among others. This review helps define the scope of the large RCTs published in the last four years to guide future research and clinical care.

Detecting Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder Using Multimodal Time-Frequency Analysis with Machine Learning Using the Electroretinogram from Two Flash Strengths.

PURPOSE: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are conditions that similarly alter cognitive functioning ability and challenge the social interaction, attention, and communication skills of affected individuals. Yet these are distinct neurological conditions that can exhibit diverse characteristics which require different management strategies. It is desirable to develop tools to assist with early distinction so that appropriate early interventions and support may be tailored to an individual's specific requirements. The current diagnostic procedures for ASD and ADHD require a multidisciplinary approach and can be lengthy. This study investigated the potential of electroretinogram (ERG), an eye test measuring retinal responses to light, for rapid screening of ASD and ADHD. METHODS: Previous studies identified differences in ERG amplitude between ASD and ADHD, but this study explored time-frequency analysis (TFS) to capture dynamic changes in the signal. ERG data from 286 subjects (146 control, 94 ASD, 46 ADHD) was analyzed using two TFS techniques. RESULTS: Key features were selected, and machine learning models were trained to classify individuals based on their ERG response. The best model achieved 70% overall accuracy in distinguishing control, ASD, and ADHD groups. CONCLUSION: The ERG to the stronger flash strength provided better separation and the high frequency dynamics (80-300 Hz) were more informative features than lower frequency components. To further improve classification a greater number of different flash strengths may be required along with a discrimination comparison to participants who meet both ASD and ADHD classifications and carry both diagnoses.