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Numerous variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have evolved. Viral variants may evolve with harmful susceptibility to the immunity established with the existing COVID-19 vaccination. These variants are more transmissible, induce relatively extreme illness, have evasive immunological features, decrease neutralization using antibodies from vaccinated persons, and are more susceptible to re-infection. The Centers for Disease Control and Prevention (CDC) has categorized SARS-CoV-2 mutations as variants of interest (VOI), variants of concern (VOC), and variants of high consequence (VOHC). At the moment, four VOC and many variants of interest have been defined and require constant observation. This review article summarizes various variants of SARS-CoV-2 surfaced with special emphasis on VOCs that are spreading across the world, as well as several viral mutational impacts and how these modifications alter the properties of the virus., (© 2022 Wiley Periodicals LLC.)

Background: Randomized trials have not demonstrated benefit from intravenous thrombolysis among patients undergoing endovascular thrombectomy (EVT). However, these trials included primarily patients presenting directly to an EVT capable hub center. We sought to study outcomes for EVT candidates who presented to spoke hospitals and were subsequently transferred for EVT consideration, comparing those administered alteplase at spokes (i.e., 'drip-and-ship' model) versus those not., Methods: Consecutive EVT candidates presenting to 25 spokes from 2018 to 2020 with pre-transfer CT angiography defined emergent large vessel occlusion and Alberta Stroke Program CT score ≥6 were identified from a prospectively maintained Telestroke database. Outcomes of interest included adequate reperfusion (Thrombolysis in Cerebral Infarction (TICI) 2b-3), intracerebral hemorrhage (ICH), discharge functional independence (modified Rankin Scale (mRS) ≤2), and 90 day functional independence., Results: Among 258 patients, median age was 70 years (IQR 60-81), median National Institutes of Health Stroke Scale (NIHSS) score was 13 (6-19), and 50% were women. Ninety-eight (38%) were treated with alteplase at spokes and 113 (44%) underwent EVT at the hub. Spoke alteplase use independently increased the odds of discharge mRS ≤2 (adjusted OR 2.43, 95% CI 1.08 to 5.46, p=0.03) and 90 day mRS ≤2 (adjusted OR 3.45, 95% CI 1.65 to 7.22, p=0.001), even when controlling for last known well, NIHSS, and EVT; it was not associated with an increased risk of ICH (OR 1.04, 95% CI 0.39 to 2.78, p=0.94), and there was a trend toward association with greater TICI 2b-3 (OR 3.59, 95% CI 0.94 to 13.70, p=0.06)., Conclusions: Intravenous alteplase at spoke hospitals may improve discharge and 90 day mRS and should not be withheld from EVT eligible patients who first present at alteplase capable spoke hospitals that do not perform EVT. Additional studies are warranted to confirm and further explore these benefits., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflicts of interest None disclosed.

Objective: To assess the clinical, racial, and social characteristics of victims of Gunshot wounds (GSWs) to the head and assess for associations between these factors and outcomes., Summary Background Data: Previous literature has not focused on the association of race and socioeconomic factors with these specific injuries., Methods: We identified patients with GSWs to the head who presented to 2 urban academic medical centers between 1998 and 2020, and extracted patient-level demographic data, information about the clinical and surgical course, and outcomes at discharge and follow-up., Results: The cohort included 250 patients, 90% (n = 226) of whom were male, with a mean age of 28 years. Forty-five percent were white (n = 112), 19% Black (n = 48), 18% Latinx (n = 45), with 6% "other" (n = 16), and 12% "unknown" (n = 29). The majority of patients presented with assault-related trauma (n = 153, 61%) as compared to self-inflicted injuries (n = 97, 39%). Across the entire cohort, sex, age, race, and median income by ZIP code were not significant predictors of outcome. Victims of assault by GSW to the head were more likely to be age 18 or younger (OR 5.26, P = 0.01), between the ages of 19 and 33 years (OR 4.7, P = 0.001), Black (OR 6.66, P < .001), and Latinx (OR 2.65, P = 0.03). Most patients (n = 155, 63%) had a poor functional outcome (modified Rankin Score 3-6) at discharge., Conclusion: Age, race, and income status were not independent predictors of mortality or functional outcome at discharge in our population. Assault-related GSWs to the head mostly involved young Black or Latinx men of lower socioeconomic status, while self-inflicted injuries were largely seen in older white men., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

The expectation of family members and society towards students has increased in recent years to perform well or achieve success in their life. But lack of job opportunities and increased competition among students has depressed the student community. The expectation without support has negatively impacted students which has catalysed suicide among the students in India. Students are committing suicide in Indian society due to failure in achieving families' expectations which is a matter of grave concern for social scientists. The current study has applied content analysis as a method to evaluate the cases of student suicide. The cases of student suicide have been collected from different newspapers, magazines, and news portals from July 2020 and April 2021. The study finds that most students are committed suicide due to depression. The study points out that students committed suicide due to failure to fulfil the expectations of a family member., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Alzheimer's disease (AD) is a neurodegenerative disorder leading to memory loss and impaired cognition. Despite several decades of research, AD therapeutic is not available. In this study, we have investigated the impact of a chronic intervention of riluzole on memory and neurometabolism in the AβPP-PS1 mouse model of AD. The 10-month-old AβPP-PS1 mice were administered 30 doses of riluzole (6 mg/kg, intragastrically) on an alternate day for two months. The memory was assessed using Morris Water Maze, while neurometabolism was evaluated by 1 H-[ 13 C]-NMR spectroscopy together with an intravenous infusion of [1,6- 13 C 2 ]glucose. The normal saline-treated AβPP-PS1 mice exhibited a decrease in learning and memory that were restored to the control level following riluzole treatment. Most interestingly, the reduced 13 C labeling of Glu C4 and Asp C3 from [1,6- 13 C]glucose in the AβPP-PS1 mice was restored to the control level following riluzole intervention. As a consequence, chronic riluzole treatment improved metabolic activity of glutamatergic neurons in AβPP-PS1 mice. Together these data suggest that riluzole may be useful for improving cognition in AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rural Canadians have high health care needs due to high prevalence of osteoarthritis (OA) but lack access to care. Examining realized access to three types of providers (general practitioners (GPs), orthopedic surgeons (Ortho), and physiotherapists (PTs)) simultaneously helps identify gaps in access to needed OA care, inform accessibility assessment, and support health care resource allocation. Travel time from a patient's postal code to the physician's postal code was calculated using origin-destination network analysis. We applied descriptive statistics to summarize differences in travel time, hotspot analysis to explore geospatial patterns, and distance decay function to examine the travel pattern of health care utilization by urbanicity. The median travel time in Alberta was 11.6 min (IQR = 4.3-25.7) to GPs, 28.9 (IQR = 14.8-65.0) to Ortho, and 33.7 (IQR = 23.1-47.3) to PTs. We observed significant rural-urban disparities in realized access to GPs (2.9 and IQR = 0.0-92.1 in rural remote areas vs. 12.6 and IQR = 6.4-21.0 in metropolitan areas), Ortho (233.3 and IQR = 171.3-363.7 in rural remote areas vs. 21.3 and IQR = 14.0-29.3 in metropolitan areas), and PTs (62.4 and IQR = 0.0-232.1 in rural remote areas vs. 32.1 and IQR = 25.2-39.9 in metropolitan areas). We identified hotspots of realized access to all three types of providers in rural remote areas, where patients with OA tend to travel longer for health care. This study may provide insight on the choice of catchment size and the distance decay pattern of health care utilization for further studies on spatial accessibility.

Objective: This study was conducted to determine the safety and efficacy of the Esperance ® Distal Access Catheter (0.071"), a novel large bore aspiration catheter in treating acute ischemic stroke (AIS) with large vessel occlusion (LVO)., Methods: A prospective multicenter clinical trial involving 15 stroke centers was performed. Baseline characteristics, procedural data, and angiographic and clinical outcomes of all acute stroke procedures (from May 2020 to March 2021) using the novel large bore aspiration catheter were analyzed., Results: During the study period, 160 consecutive patients were recruited. The mean age and median baseline NIHSS were 65.4 years and 16, respectively. Successful reperfusion was achieved in 147 (91.9%) cases [at least modified Thrombolysis in Cerebral Infarction (mTICI) 2b] with aspiration alone, with complete reperfusion (mTICI 3) in 94 (58.8%) cases. Successful/complete first pass reperfusion was achieved in 104 (64.60%) cases, including mTICI 2b in 34 (21.1%) cases and mTICI 3 in 70 (43.5%) cases. The time from groin puncture to successful reperfusion was 44 (33, 62) min. There were 16 (9.9%) cases requiring rescue therapy using stent-retriever. Procedure-related complications included 2 (1.3%) cases of arterial perforation, 2 (1.3%) cases of arterial dissection, 12 (7.5%) cases of distal embolization, and 1(0.6%) case of puncture site infection. The rate of symptomatic intracranial hemorrhage (sICH) was 3.8% and mortality rate was 13.8%. A total of 99 (62.3%) cases had a favorable outcome (mRS 0-2) at 90 days., Conclusions: In current practice, the first-line aspiration approach with the Esperance ® Distal Access Catheter is safe and efficacious. This device may achieve high reperfusion rates with lower instances of rescue stent retriever therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Bai, Hu, Guo, Chen, Zhou, Chen, Gao, Liu, Yang, Liu, Xu, Chen, Wang, Yang, Dmytriw, Patel, Ma and Jiao.)

Background: M2 segment occlusions represent approximately one-third of non-lacunar ischemic stroke and can lead to permanent neurological deficits. Various techniques are available for mechanical thrombectomy beyond the circle of Willis, but data evaluating their effectiveness and safety are lacking., Methods: A retrospective review of patients with ischemic stroke undergoing mechanical thrombectomy for M2 occlusions from 13 centers in North American and Europe was performed. Tandem or multiple-territory occlusions were excluded. The primary outcome was 90-day modified Rankin Scale and reperfusion rates across stent-retriever, direct aspiration and combined techniques., Results: There were 465 patients (mean age 71.48±14.03 years, 53.1% female) with M2 occlusions who underwent mechanical thrombectomy. Stent-retriever alone was used in 133 (28.6%), direct aspiration alone in 93 (20.0%) and the combined technique in 239 (51.4%) patients. Successful reperfusion was achieved with the combined technique in 198 (82.2%; OR 2.6 (1.1-6.9)), with stent-retriever alone in 112 (84.2%; OR 9.2 (1.9-44.6)) and with direct aspiration alone in 62 (66.7%; referencecategory). Intraprocedural subarachnoid hemorrhages (iSAH) were 36 (7.7%) and were more likely to occur in patients treated with the stent-retrievers (OR 5.0 (1.1-24.3)) and combined technique (OR 4.6 (1.1-20.9)). Good clinical outcome was achieved in 260 (61.8%) patients, while 59 (14.0%) patients died. Older age, higher baseline NIHSS (National Institutes of Health Stroke Scale), parenchymal hemorrhage and iSAH were associated with poor outcome while successful recanalization and higher baseline ASPECTS (Alberta Stroke Program Early CT Score) were associated with good outcome. No differences were found among the three techniques in terms of clinical outcome., Conclusion: Stent-retrievers and a combined approach for M2 occlusions seem more effective than direct aspiration, but with higher rates of iSAH. This leads to no detectable difference in clinical outcome at 3 months., Competing Interests: Competing interests: MC is a member of the JNIS editorial board., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The mechanisms and outcomes in coronavirus disease (COVID-19)-associated stroke are unique from those of non-COVID-19 stroke., Objective: To describe the efficacy and outcomes of acute revascularization of large vessel occlusion (LVO) in the setting of COVID-19 in an international cohort., Methods: We conducted an international multicenter retrospective study of consecutively admitted patients with COVID-19 with concomitant acute LVO across 50 comprehensive stroke centers. Our control group constituted historical controls of patients presenting with LVO and receiving a mechanical thrombectomy between January 2018 and December 2020., Results: The total cohort was 575 patients with acute LVO; 194 patients had COVID-19 while 381 patients did not. Patients in the COVID-19 group were younger (62.5 vs 71.2; P < .001) and lacked vascular risk factors (49, 25.3% vs 54, 14.2%; P = .001). Modified thrombolysis in cerebral infarction 3 revascularization was less common in the COVID-19 group (74, 39.2% vs 252, 67.2%; P < .001). Poor functional outcome at discharge (defined as modified Ranklin Scale 3-6) was more common in the COVID-19 group (150, 79.8% vs 132, 66.7%; P = .004). COVID-19 was independently associated with a lower likelihood of achieving modified thrombolysis in cerebral infarction 3 (odds ratio [OR]: 0.4, 95% CI: 0.2-0.7; P < .001) and unfavorable outcomes (OR: 2.5, 95% CI: 1.4-4.5; P = .002)., Conclusion: COVID-19 was an independent predictor of incomplete revascularization and poor outcomes in patients with stroke due to LVO. Patients with COVID-19 with LVO were younger, had fewer cerebrovascular risk factors, and suffered from higher morbidity/mortality rates., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Background: Spreading depolarizations (SDs) are associated with worse outcome following subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI), but gold standard detection requires electrocorticography with a subdural strip electrode. Electroencephalography (EEG) ictal-interictal continuum abnormalities are associated with poor outcomes after TBI and with both delayed cerebral ischemia (DCI) and poor outcomes after SAH. We examined rates of SD detection in patients with SAH and TBI with intraparenchymal and subdural strip electrodes and assessed which continuous EEG (cEEG) measures were associated with intracranially quantified SDs., Methods: In this single-center cohort, we included patients with SAH and TBI undergoing ≥ 24 h of interpretable intracranial monitoring via eight-contact intraparenchymal or six-contact subdural strip platinum electrodes or both. SDs were rated according to established consensus criteria and compared with cEEG findings rated according to the American Clinical Neurophysiology Society critical care EEG monitoring consensus criteria: lateralized rhythmic delta activity, generalized rhythmic delta activity, lateralized periodic discharges, generalized periodic discharges, any ictal-interictal continuum, or a composite scalp EEG tool for seizure risk estimation: the 2HELPS2B score. Among patients with SAH, cEEG was assessed for validated DCI biomarkers: new or worsening epileptiform abnormalities and new background deterioration., Results: Over 6 years, SDs were recorded in 5 (18%) of 28 patients recorded with intraparenchymal electrodes and 4 (40%) of 10 patients recorded with subdural strip electrodes. There was no significant association between occurrence of SDs and day 1 cEEG findings (American Clinical Neurophysiology Society main terms lateralized periodic discharges, generalized periodic discharges, lateralized rhythmic delta activity, or seizures, individually or in combination). After SAH, established cEEG DCI predictors were not associated with SDs., Conclusions: Intraparenchymal recordings yielded low rates of SD, and documented SDs were not associated with ictal-interictal continuum abnormalities or other cEEG DCI predictors. Identifying scalp EEG correlates of SD may require training computational EEG analytics and use of gold standard subdural strip electrocorticography recordings., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Patients with aneurysmal subarachnoid hemorrhage (aSAH) with electroencephalographic epileptiform activity (seizures, periodic and rhythmic patterns, and sporadic discharges) are frequently treated with antiseizure medications (ASMs). However, the safety and effectiveness of ASM treatment for epileptiform activity has not been established. We used observational data to investigate the effectiveness of ASM treatment in patients with aSAH undergoing continuous electroencephalography (cEEG) to develop a causal hypothesis for testing in prospective trials., Methods: This was a retrospective single-center cohort study of patients with aSAH admitted between 2011 and 2016. Patients underwent ≥ 24 h of cEEG within 4 days of admission. All patients received primary ASM prophylaxis until aneurysm treatment (typically within 24 h of admission). Treatment exposure was defined as reinitiation of ASMs after aneurysm treatment and cEEG initiation. We excluded patients with non-cEEG indications for ASMs (e.g., epilepsy, acute symptomatic seizures). Outcomes measures were 90-day mortality and good functional outcome (modified Rankin Scale scores 0-3). Propensity scores were used to adjust for baseline covariates and disease severity., Results: Ninety-four patients were eligible (40 continued ASM treatment; 54 received prophylaxis only). ASM continuation was not significantly associated with higher 90-day mortality (propensity-adjusted hazard ratio [HR] = 2.01 [95% confidence interval (CI) 0.57-7.02]). ASM continuation was associated with lower likelihood for 90-day good functional outcome (propensity-adjusted HR = 0.39 [95% CI 0.18-0.81]). In a secondary analysis, low-intensity treatment (low-dose single ASM) was not significantly associated with mortality (propensity-adjusted HR = 0.60 [95% CI 0.10-3.59]), although it was associated with a lower likelihood of good outcome (propensity-adjusted HR = 0.37 [95% CI 0.15-0.91]), compared with prophylaxis. High-intensity treatment (high-dose single ASM, multiple ASMs, or anesthetics) was associated with higher mortality (propensity-adjusted HR = 6.80 [95% CI 1.67-27.65]) and lower likelihood for good outcomes (propensity-adjusted HR = 0.30 [95% CI 0.10-0.94]) compared with prophylaxis only., Conclusions: Our findings suggest the testable hypothesis that continuing ASMs in patients with aSAH with cEEG abnormalities does not improve functional outcomes. This hypothesis should be tested in prospective randomized studies., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with selective degeneration of motor neurons in the central nervous system. The pathophysiology of ALS is not well understood. We have used 1 H-[ 13 C]-NMR spectroscopy together with an administration of [1,6- 13 C 2 ]glucose and [2- 13 C]acetate in female and male SOD1 G37R mice to assess neuronal and astroglial metabolic activity, respectively, in the central nervous system in ALS condition. The female (p = 0.0008) and male (p < 0.0001) SOD1 G37R mice exhibited decreased forelimb strength when compared with wild-type mice. There was a reduction in N-acetylaspartylglutamate level, and elevation in myo-inositol in the spinal cord of female and male SOD1 G37R mice. The transgenic male mice exhibited increased acetate oxidation in the spinal cord (p = 0.05) and cerebral cortex (p = 0.03), while females showed an increase in the spinal cord (p = 0.02) only. As acetate is transported and preferentially metabolized in the astrocytes, the finding of increased rate of acetate oxidation in the transgenic mice is suggestive of astrocytic involvement in the pathogenesis of ALS. The rates of glucose oxidation in glutamatergic (p = 0.0004) and GABAergic neurons (p = 0.0052) were increased in the cerebral cortex of male SOD1 G37R mice when compared with the controls. The female mice showed an increase in glutamatergic (p = 0.039) neurometabolic activity only. The neurometabolic activity was unperturbed in the spinal cord of either sex. These data suggest differential changes in neurometabolic activity across the central nervous system in SOD1 G37R mice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The utilization of non-local primary care physicians (PCP) is a key primary care indicator identified by Alberta Health to support evidence-based healthcare planning. This study aims to identify area-level factors that are significantly associated with non-local PCP utilization and to examine if these associations vary between rural and urban areas. We examined rural-urban differences in the associations between non-local PCP utilization and area-level factors using multivariate linear regression and geographically weighted regression (GWR) models. Global Moran's I and Gi* hot spot analyses were applied to identify spatial autocorrelation and hot spots/cold spots of non-local PCP utilization. We observed significant rural-urban differences in the non-local PCP utilization. Both GWR and multivariate linear regression model identified two significant factors (median travel time and percentage of low-income families) with non-local PCP utilization in both rural and urban areas. Discontinuity of care was significantly associated with non-local PCP in the southwest, while the percentage of people having university degree was significant in the north of Alberta. This research will help identify gaps in the utilization of local primary care and provide evidence for health care planning by targeting policies at associated factors to reduce gaps in OA primary care provision.

Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding and residues at the mouth of the pocket to mimic interactions made by phospholipids. Here, we unite these two designs into one molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep versus surface polar regions in the pocket. While deep pocket contacts convey high affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.

Understanding the learning dynamics and inductive bias of neural networks (NNs) is hindered by the opacity of the relationship between NN parameters and the function represented. Partially, this is due to symmetries inherent within the NN parameterization, allowing multiple different parameter settings to result in an identical output function, resulting in both an unclear relationship and redundant degrees of freedom. The NN parameterization is invariant under two symmetries: permutation of the neurons and a continuous family of transformations of the scale of weight and bias parameters. We propose taking a quotient with respect to the second symmetry group and reparametrizing ReLU NNs as continuous piecewise linear splines. Using this spline lens, we study learning dynamics in shallow univariate ReLU NNs, finding unexpected insights and explanations for several perplexing phenomena. We develop a surprisingly simple and transparent view of the structure of the loss surface, including its critical and fixed points, Hessian, and Hessian spectrum. We also show that standard weight initializations yield very flat initial functions, and that this flatness, together with overparametrization and the initial weight scale, is responsible for the strength and type of implicit regularization, consistent with previous work. Our implicit regularization results are complementary to recent work, showing that initialization scale critically controls implicit regularization via a kernel-based argument. Overall, removing the weight scale symmetry enables us to prove these results more simply and enables us to prove new results and gain new insights while offering a far more transparent and intuitive picture. Looking forward, our quotiented spline-based approach will extend naturally to the multivariate and deep settings, and alongside the kernel-based view, we believe it will play a foundational role in efforts to understand neural networks. Videos of learning dynamics using a spline-based visualization are available at http://shorturl.at/tFWZ2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sahs, Pyle, Damaraju, Caro, Tavaslioglu, Lu, Anselmi and Patel.)

Two-dimensional (2D) transition metal dichalcogenide (TMDC) heterostructure is a new age strategy to achieve high electrocatalytic activity and ion storage capacity. The less complex and cost-effective applicability of the large-area TMDC heterostructure (HS) for energy applications require more research. Herein, we report the MoSe 2 @WSe 2 nanohybrid HS electrocatalyst prepared using liquid exfoliated nanocrystals, followed by direct electrophoretic deposition (EPD). The improved catalytic activity is attributed to the exposure of catalytic active sites on the edge of nanocrystals after liquid exfoliation and the synergistic effect arises at HS interfaces between the MoSe 2 and WSe 2 nanocrystals. As predicted, the HS catalyst achieves a lower overpotential of 158 mV, a smaller Tafel slope of 46 mV dec -1 for a current density of 10 mA cm -2 , and is stable for a long time. The flexible symmetric supercapacitor (FSSC) based on the HS catalyst demonstrates the excellent specific capacitance ( C sp ) of 401 F g -1 at 1 A g -1 , 97.20% capacitance retention after 5000 cycles and high flexible stability over 1000 bending cycles. This work presents a less complex and solution-processed efficient catalyst for future electrochemical energy applications.

A stroke volume of arterial blood that arrives to the brain housed in the rigid cranium must be matched over the cardiac cycle by an equivalent volume of ejected venous blood. We hypothesize that the brain maintains this equilibrium by organizing coherent arterial and venous pulse waves. To test this hypothesis, we applied wavelet computational methods to diagnostic cerebral angiograms in four human patients, permitting the capture and analysis of cardiac frequency phenomena from fluoroscopic images acquired at faster than cardiac rate. We found that the cardiac frequency reciprocal phase of a small region of interest (ROI) in a named artery predicts venous anatomy pixel-wise and that the predicted pixels reconstitute venous bolus passage timing. Likewise, a small ROI in a named vein predicts arterial anatomy and arterial bolus passage timing. The predicted arterial and venous pixel groups maintain phase complementarity across the bolus travel. We thus establish a novel computational method to analyze vascular pulse waves from minimally invasive cerebral angiograms and provide the first direct evidence of arteriovenous coupling in the intact human brain. This phenomenon of arteriovenous coupling may be a physiologic mechanism for how the brain precisely maintains mechanical equilibrium against volume displacement and kinetic energy transfer resulting from cyclical deformations with each heartbeat. The study also paves the way to study deranged arteriovenous coupling as an underappreciated pathophysiologic disturbance in a myriad of neurological pathologies linked by mechanical disequilibrium., Competing Interests: The wavelet angiography methods are described in United States patents 10,123,761, 10,653,379, and 11,123,035. Massachusetts General Hospital and W.E.B. Have assigned rights to these to Angiowave Imaging, Inc., in return for shares. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Koch, Duy, Grannan, Patel, Raymond, Agarwalla, Kahle and Butler.)

Objective: The natural history of asymptomatic adult moyamoya disease (MMD) is unclear, and the benefit of treatment remains controversial. This study aimed to investigate the natural history of asymptomatic MMD in a North American cohort and to evaluate risk factors associated with and the effects of treatment on disease progression., Methods: Medical records from 3 institutions of consecutive adult patients with MMD diagnosed between 1984 and 2018 were retrospectively reviewed. Patients with unilateral or bilateral asymptomatic MMD were evaluated for subsequent development of infarction or hemorrhage. Multivariate Cox proportional hazards regression assessed risk factors associated with infarction or hemorrhage, adjusting for age, sex, race, initial Suzuki grade, hypertension, hyperlipidemia, diabetes, obesity, presence of aneurysms, smoking status, aspirin, and statin use at diagnosis., Results: We identified 106 hemispheres with asymptomatic MMD in 97 patients with mean 5.1 years (interquartile range, 1.0-7.9 years) of follow-up. Of 106 hemispheres, 59 were treated medically, and 47 were treated with revascularization with direct or indirect bypasses. The medical and surgical cohorts had a 1.9% and 1.3% annual rate of radiographic infarction or hemorrhage per hemisphere, respectively. Cox regression for radiographic events, including early postoperative events, showed no significant difference between the treatment groups (adjusted hazard ratio 0.34 [95% confidence interval 0.05-2.5])., Conclusions: We found an overall 1.7% annual rate of radiographic infarction or hemorrhage in asymptomatic MMD hemispheres. Although we did not find a benefit to surgical treatment within the study period, asymptomatic patients with expected long-term survival may benefit from surgery given the sustained long-term benefits after surgery despite an initial postoperative risk., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The Woven EndoBridge (WEB) device (Terumno Corp. [parent company of Microvention]) was approved by the U.S. Food and Drug Administration as the first intrasaccular device for intracranial aneurysm treatment in December 2018. Its use has become more common since then, but both trial results and postmarket experiences have raised questions about the efficacy in achieving complete aneurysm obliteration. Retreatment after WEB embolization has not been extensively discussed., Objective: To discuss the incidence and retreatment of aneurysms after initial WEB embolization., Methods: Retrospective review across 13 institutions identified all occurrences of WEB retreatment within neurovascular databases. Details regarding demographics, aneurysm characteristics, treatment considerations, clinical outcomes, and aneurysm occlusion were obtained and analyzed., Results: Thirty aneurysms were retreated in 30 patients in a cohort of 342 WEB-treated aneurysms. The retreatment rate was 8.8%. Endovascular methods were used for 23 cases, and 7 were treated surgically. Two aneurysms presented with rehemorrhage after initial WEB embolization. Endovascular treatments included stent-assisted coiling (12), flow diversion (7), coiling (2), PulseRider (Johnson & Johnson)-assisted coiling (1), and additional WEB placement (1). Surgical treatments included primary clipping (6) and Hunterian ligation (1). There were no major complications within the study group., Conclusion: WEB retreatments were successfully performed by a variety of techniques, including stent-assisted coiling, clipping, and flow diversion as the most common. These procedures were performed safely with subsequent obliteration of most aneurysms. The potential need for retreatment of aneurysms should be considered during primary WEB treatments., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Advances in robotic technology have been adopted in various subspecialties of both open and minimally invasive surgery, offering benefits such as enhanced surgical precision and accuracy with reduced fatigue of the surgeon. Despite the advantages, robotic applications to endovascular neurosurgery have remained largely unexplored because of technical challenges such as the miniaturization of robotic devices that can reach the complex and tortuous vasculature of the brain. Although some commercial systems enable robotic manipulation of conventional guidewires for coronary and peripheral vascular interventions, they remain unsuited for neurovascular applications because of the considerably smaller and more tortuous anatomy of cerebral arteries. Here, we present a teleoperated robotic neurointerventional platform based on magnetic manipulation. Our system consists of a magnetically controlled guidewire, a robot arm with an actuating magnet to steer the guidewire, a set of motorized linear drives to advance or retract the guidewire and a microcatheter, and a remote-control console to operate the system under real-time fluoroscopy. We demonstrate our system's capability to navigate narrow and winding pathways both in vitro with realistic neurovascular phantoms representing the human anatomy and in vivo in the porcine brachial artery with accentuated tortuosity for preclinical evaluation. We further demonstrate telerobotically assisted therapeutic procedures including coil embolization and clot retrieval thrombectomy for treating cerebral aneurysms and ischemic stroke, respectively. Our system could enable safer and quicker access to hard-to-reach lesions while minimizing the radiation exposure to physicians and open the possibility of remote procedural services to address challenges in current stroke systems of care.

Purpose: In recent years, metabolic syndrome has risen in prevalence and brought a heavy disease burden to modern society. As the representative aspect of metabolic syndrome, obesity has been shown to be related to an increased risk of stroke. Given that visceral adipose tissue (VAT) forms the fundamental basis of central obesity, we sought to explore a causal relationship between VAT and stroke by using mendelian randomization (MR) methods., Methods: Based on two large genome-wide association studies (GWAS) including 325,153 and 35,762 cases of VAT and stroke, respectively, we conducted a MR study which has the inherent advantage of reducing the noise of confounding and reverse causation., Results: VAT had a significant causal association with ischemic stroke (OR, per 1kg increase in VAT mass, 1.30; 95% CI, 1.18 ~ 1.45; P = 5.87E-07) as opposed to intracranial hemorrhage (ICH) (OR, 1.15; 95% CI, 0.70 ~ 1.88, P = 5.81E-01) as evaluated with inverse-variance weighting (IVW). Regarding subtypes of ischemic stroke, there was a significant causal effect for cardioembolic stroke (OR, 1.34; 95% CI, 1.13 ~ 1.58, P = 8.07E-04), and potential causal effect for small-vessel stroke (OR, 1.32; 95% CI, 1.06 ~ 1.65, P = 1.39E-02) and large-artery atherosclerotic stroke (OR, 1.33; 95% CI, 1.03 ~ 1.70, P = 2.59E-02)., Conclusions: This study provides potential evidence for a causal role of VAT in ischemic stroke and could suggest novel genetical therapeutic strategies for distinct subtypes of ischemic stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Hu, Wang, Yang, Jiang, Luo, Zhang, Patel, Dmytriw and Jiao.)

Background: Survivors of aneurysmal subarachnoid hemorrhage (SAH) face a protracted intensive care unit (ICU) course and are at risk for developing refractory hydrocephalus with the need for a permanent ventriculoperitoneal shunt (VPS). Management of the external ventricular drain (EVD) used to provide temporary cerebrospinal fluid diversion may influence the need for a VPS, ICU length of stay (LOS), and drain complications, but the optimal EVD management approach is unknown. Therefore, we sought to determine the effect of EVD discontinuation strategy on VPS rate., Methods: This was a prospective multicenter observational study at six neurocritical care units in the United States. The target population included adults with suspected aneurysmal SAH who required an EVD. Patients were preassigned to rapid or gradual EVD weans based on their treating center. The primary outcome was the rate of VPS placement. Secondary outcomes were EVD duration, ICU LOS, hospital LOS, and drain complications., Results: A rapid EVD wean protocol was associated with a lower rate of VPS placement, including a delayed posthospitalization shunt, in an adjusted Cox proportional analysis (hazard ratio 0.52 [p = 0.041]) and adjusted logistic regression model (odds ratio 0.43 [95% confidence interval 0.18-1.03], p = 0.057). A rapid wean was also associated with 2.1 fewer EVD days (p = 0.007) and saved an estimated 2.5 ICU days (p = 0.049), as compared with a gradual wean protocol. There were fewer nonfunctioning EVDs in the rapid group (odds ratio 0.32 [95% confidence interval 0.11-0.92]). Furthermore, we found that the time to first wean and the number of weaning attempts were important independent covariates that affected the likelihood of receiving a VPS and the duration of ICU admission., Conclusions: A rapid EVD wean was associated with decreased rates of VPS placement, decreased ICU LOS, and decreased drain complications in survivors of aneurysmal SAH. These findings suggest that a randomized multicentered controlled study comparing rapid vs. gradual EVD weaning protocols is justified., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Originating in ancient India, Ayurveda is an alternative medicinal approach that provides substantial evidence for a theoretical-level analysis of all aspects of life. Unlike modern medicine, Ayurveda is based upon tridoshas ( Vata, pitta, and Kapha ) and Prakriti. On the other hand, the research of all the genes involved at the proteomics, metabolomics, and transcriptome levels are referred to as genomics . Geoclimatic regions (deshanupatini), familial characteristics (kulanupatini), and ethnicity (jatiprasakta) have all been shown to affect phenotypic variability. The combination of genomics with Ayurveda known as ayurgenomics provided new insights into tridosha that may pave the way for precision medicine (personalized medicine). Through successful coordination of "omics," Prakriti -based treatments can help change the existing situation in health care. Prakriti refers to an individual's behavioral trait, which is established at the moment of birth and cannot be fully altered during one's existence. Ayurvedic methodologies are based on three Prakriti aspects: aushadhi (medication), vihara (lifestyle), and ahara (diet). A foundation of Prakriti -based medicine, preventative medicine, and improvement of life quality with longevity can be accomplished through these ayurvedic characteristics. In this perspective, we try to understand prakriti's use in personalized medicine, and how to integrate it with programs for drug development and discovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Chavda, Bezbaruah, Uversky, P., Patel and Chen.)

Background: To analyse the clinical characteristics of COVID-19 with acute ischaemic stroke (AIS) and identify factors predicting functional outcome., Methods: Multicentre retrospective cohort study of COVID-19 patients with AIS who presented to 30 stroke centres in the USA and Canada between 14 March and 30 August 2020. The primary endpoint was poor functional outcome, defined as a modified Rankin Scale (mRS) of 5 or 6 at discharge. Secondary endpoints include favourable outcome (mRS ≤2) and mortality at discharge, ordinal mRS (shift analysis), symptomatic intracranial haemorrhage (sICH) and occurrence of in-hospital complications., Results: A total of 216 COVID-19 patients with AIS were included. 68.1% (147/216) were older than 60 years, while 31.9% (69/216) were younger. Median [IQR] National Institutes of Health Stroke Scale (NIHSS) at presentation was 12.5 (15.8), and 44.2% (87/197) presented with large vessel occlusion (LVO). Approximately 51.3% (98/191) of the patients had poor outcomes with an observed mortality rate of 39.1% (81/207). Age >60 years (aOR: 5.11, 95% CI 2.08 to 12.56, p<0.001), diabetes mellitus (aOR: 2.66, 95% CI 1.16 to 6.09, p=0.021), higher NIHSS at admission (aOR: 1.08, 95% CI 1.02 to 1.14, p=0.006), LVO (aOR: 2.45, 95% CI 1.04 to 5.78, p=0.042), and higher NLR level (aOR: 1.06, 95% CI 1.01 to 1.11, p=0.028) were significantly associated with poor functional outcome., Conclusion: There is relationship between COVID-19-associated AIS and severe disability or death. We identified several factors which predict worse outcomes, and these outcomes were more frequent compared to global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-Dimer, predicted both morbidity and mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cancer is a prominent cause of mortality globally, and it becomes fatal and incurable if it is delayed in diagnosis. Chemotherapy is a type of treatment that is used to eliminate, diminish, or restrict tumor progression. Chemotherapeutic medicines are available in various formulations. Some tumors require just one type of chemotherapy medication, while others may require a combination of surgery and/or radiotherapy. Treatments might last from a few minutes to many hours to several days. Each medication has potential adverse effects associated with it. Researchers have recently become interested in the use of natural bioactive compounds in anticancer therapy. Some phytochemicals have effects on cellular processes and signaling pathways with potential antitumor properties. Beneficial anticancer effects of phytochemicals were observed in both in vivo and in vitro investigations. Encapsulating natural bioactive compounds in different drug delivery methods may improve their anticancer efficacy. Greater in vivo stability and bioavailability, as well as a reduction in undesirable effects and an enhancement in target-specific activity, will increase the effectiveness of bioactive compounds. This review work focuses on a novel drug delivery system that entraps natural bioactive substances. It also provides an idea of the bioavailability of phytochemicals, challenges and limitations of standard cancer therapy. It also encompasses recent patents on nanoparticle formulations containing a natural anti-cancer molecule., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chavda, Patel, Mistry, Suthar, Wu, Chen and Hou.)

Background and Objectives: The care of patients with large vessel occlusion (LVO) stroke has been revolutionized by endovascular thrombectomy (EVT). While EVT has a large effect size, most patients treated with EVT remain disabled or die within 90 days. A better understanding of outcomes may influence EVT selection criteria, novel therapies, and prognostication. We sought to identify associations between outcomes and brain regions involved in ischemic lesions., Methods: For this cohort study, consecutive patients with LVO who were treated with EVT and underwent post-EVT MRI were identified from a tertiary referral center (2011-2019). Acute ischemic lesions were manually segmented from diffusion-weighted imaging and spatially normalized. Individual lesions were parcellated (atlas-defined 94 cortical regions, 14 subcortical nuclei, 20 white matter tracts) and reduced to 10 essential lesion patterns with the use of unsupervised dimensionality reduction techniques. Ninety-day modified Rankin Scale (mRS) score (>2) was modeled via bayesian regression, taking the 10 lesion patterns as inputs and controlling for lesion size, age, sex, acute NIH Stroke Scale (NIHSS) score, alteplase, prior stroke, intracerebral hemorrhage, and good reperfusion (Thrombolysis in Cerebral Infarction 2b-3). In comparative analyses, 90-day mRS score was modeled considering covariates only, and compartment-wise relevances for acute stroke severity and 90-day mRS score were evaluated., Results: There were 151 patients with LVO identified (age 68 ± 15 years, 52% female). The median NIHSS score was 16 (interquartile range 13-20); 56% had mRS score >2. Lesion locations predictive of 90-day mRS score involved bilateral but left hemispherically more pronounced precentral and postcentral gyri, insular and opercular cortex, and left putamen and caudate (area under the curve 0.91, highest probability density interval [HPDI] covering 90% certainty 0.90-0.92). The lesion location model outperformed the simpler model relying on covariates only (bayesian model comparison of 97% weight to the model with vs 3% weight to the model without lesion location). While lesions affecting subcortical nuclei had the highest relevance for stroke severity (posterior distribution mean 0.75, 90% HPDI 0.256-1.31), lesions affecting white matter tracts had the highest relevance for 90-day mRS score (0.656, 90% HPDI 0.0864-1.12)., Discussion: These data describe the significance for outcomes of specific brain regions involved in ischemic lesions on MRI after EVT. Future work in additional datasets is needed to confirm these granular findings., (© 2022 American Academy of Neurology.)

Objective: Although the populations of patients with functional seizures (FS) and epileptic seizures (ES) are extremely heterogeneous with multiple etiologies and phenotypes, patients with FS have increased somatic sensitivity and report more positive complaints on review-of-systems questionnaires (ROSQs). We evaluated if data-driven clustering and projection analysis could identify symptom phenotypes that could differentiate between patients with FS and ES., Methods: The dataset included all adult patients admitted from January 2006 to March 2020 for video-electroencephalography with available ROSQs (N = 877). Latent clusters and axes of variation in ROSQ responses were evaluated using multiple well-established methods. Leave-one-out cross-validation was used to evaluate if logistic regression using information could differentiate patients with FS from ES., Results: When evaluating individual symptom response and proportion of positive responses, the area under the receiver operating curve (AUC) was 62% (95% CI, 53%-69%) and 72% (CI, 65%-78%), respectively. The best AUC achieved by phenotyping methods was 74%. The patterns of clusters and components reflected properties of each analysis and did not correlate with assigned "system" from the ROSQ or other interpretations., Discussion: The overall proportion of positive responses was the most informative metric to differentiate patients with FS compared to ES. While both FS and ES are heterogeneous populations with multiple subgroups, these subgroups were not meaningfully identified based on ROSQ symptoms. The limited overall predictive accuracy and AUC suggests that, in absence of other supporting data, ROSQ responses in patients with FS and ES were not clinically useful for screening., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Enfortumab vedotin is a first-in-class Nectin-4-directed antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) previously treated with a platinum-based chemotherapy and a programmed death receptor-1/programmed death-ligand 1 (PD-1/L1) inhibitor, or patients with la/mUC who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy. Enfortumab vedotin is the only drug to have demonstrated survival benefit versus chemotherapy in a randomized controlled trial in patients with la/mUC previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. The development of dermatologic events following the administration of enfortumab vedotin is anticipated given the expression of Nectin-4 in epidermal keratinocytes and skin appendages (eg, sweat glands and hair follicles). There is the potential for rare but severe and possibly fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis, as described in the boxed warning of the US prescribing information for enfortumab vedotin. This manuscript describes the presumed pathophysiology and manifestations of dermatologic reactions related to enfortumab vedotin, and presents recommendations for prevention and treatment, to provide oncologists and other healthcare providers with an awareness of these potential adverse events to best anticipate and manage them., (© The Author(s) 2022. Published by Oxford University Press.)

Background: In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response., Methods: Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT., Results: Eighty-one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0-341 days) and 50 days (range, 1-352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune-related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331-0.972; P = .039)., Conclusions: CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit., (© 2021 American Cancer Society.)

Background: Junctional ectopic tachycardia (JET) is a prevalent life-threatening arrhythmia in children with congenital heart disease (CHD), with marked resemblance to normal sinus rhythm (NSR) often leading to delay in diagnosis., Objective: To develop a novel automated arrhythmia detection tool to identify JET., Methods: A single-center retrospective cohort study of children with CHD was performed. Electrocardiographic (ECG) data produced by bedside monitors is captured automatically by the Sickbay platform. Based on the detection of R and P wave peaks, 2 interpretable ECG features are calculated: P prominence median and PR interval interquartile range (IQR). These features are used as input to a simple logistic regression classification model built to distinguish JET from NSR., Results: This study analyzed a total of 64.5 physician-labeled hours consisting of 509,833 cardiac cycles (R-R intervals), from 40 patients with CHD. The extracted P prominence median feature is much smaller in JET compared to NSR, whereas the PR interval IQR feature is larger in JET compared to NSR. The area under the receiver operating characteristic curve for the unseen patient test cohort was 93%. Selecting a threshold of 0.73 results in a true-positive rate of 90% and a false-positive rate of 17%., Conclusion: This novel arrhythmia detection tool identifies JET, using 2 distinctive features of JET in ECG-the loss of a normal P wave and PR relationship-allowing for early detection and timely intervention., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Currently, the world is facing a Coronavirus pandemic with a grave deficiency of specific therapy for Coronavirus Disease (COVID-19). Moreover, scientists attempt to discover the most refined approach to prevent this condition. Regarding COVID-19 infection, herbal medicines with immunomodulatory effects may offer patients a promising preventive treatment option. Several ayurvedic and Traditional Chinese Medicine (TCM) are effective during this worrisome Coronavirus pandemic i.e. Tinospora cordifolia (Willd.) Miers, Withania somnifera ( L. ) Dunal, Scutellaria baicalensis Georgi, Curcuma longa L. etc. TCM was shown to be utilized with over 90% efficacy when the COVID-19 pandemic broke out in early 2020. In addition to herbal treatments and nutraceutical drugs, dietary supplements such as vitamins and amino acid derivatives also play a significant part in COVID-19 management. Diet can assist in regulating inflammation, while nutraceuticals can aid in the prevention of viral invasion. Functional amino acids (e.g., arginine, cysteine, glutamate, glutamine, glycine, taurine, and tryptophan) and glutathione, which are all abundant in animal-sourced foodstuffs, are crucial for optimum immunity and health in humans and animals. The goal of this article is to thoroughly evaluate recent statistics on the effectiveness of herbal medicines in COVID-19, the antiviral activity of nutraceuticals, and the significance of these results in creating dietary supplements that would enhance innate immunity and contribute as preventive measures against severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2)., (© 2022 The Author(s).)

Purpose: Targeted therapies against non-small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a single-arm, open-label, phase II study., Patients and Methods: Patients with advanced HER2 exon 20 mutant NSCLC were enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The primary end point was objective response rate per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response., Results: Thirty patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed objective response rate was 27% (95% CI, 12 to 46). Responses were observed across HER2 exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI, 4.0 to not estimable). The median progression-free survival was 5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95% CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhea (20%). There was one possible treatment-related death because of pneumonitis., Conclusion: Poziotinib showed promising antitumor activity in patients with HER2 exon 20 mutant NSCLC including patients who had previously received platinum-based chemotherapy., Competing Interests: Yasir Y. ElaminConsulting or Advisory Role: Lilly, AstraZeneca, Turning Point TherapeuticsResearch Funding: Spectrum Pharmaceuticals, AstraZeneca, Takeda, Xcovery, Lilly, Elevation Oncology, Turning Point TherapeuticsTravel, Accommodations, Expenses: Lilly Jacqulyne P. RobichauxResearch Funding: Spectrum Pharmaceuticals, TakedaPatents, Royalties, Other Intellectual Property: Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations, Patent application Mehmet AltanConsulting or Advisory Role: GlaxoSmithKline, Shattuck LabsResearch Funding: Lilly, Bristol Myers Squibb, Novartis, GlaxoSmithKline, Jounce Therapeutics, Adaptimmune, Genentech, Nektar, Shattuck Labs Don L. GibbonsStock and Other Ownership Interests: Exact Sciences, NektarConsulting or Advisory Role: Sanofi, GlaxoSmithKline, Janssen Research & Development, Ribon Therapeutics, Mitobridge, Lilly, Menarini, Napa TherapeuticsResearch Funding: Janssen Research & Development, Takeda, AstraZeneca, Mitobridge, Ribon Therapeutics, Boehringer Ingelheim, Mirati Therapeutics, NGM BiopharmaceuticalsTravel, Accommodations, Expenses: AstraZeneca/MedImmune, BerGenBio, Takeda Vincent K. LamConsulting or Advisory Role: Takeda, Seattle Genetics, Bristol Myers SquibbResearch Funding: Guardant Health, Takeda, GlaxoSmithKline, Bristol Myers Squibb Anisha B. PatelConsulting or Advisory Role: OnQuality Pharmaceuticals, Novartis, Deciphera, NanOlogyResearch Funding: Lutris, Pfizer, OnQuality PharmaceuticalsTravel, Accommodations, Expenses: Novartis, OnQuality Pharmaceuticals Marcelo V. NegraoConsulting or Advisory Role: Mirati TherapeuticsResearch Funding: Mirati Therapeutics, AstraZeneca, Pfizer, Novartis, ZIOPHARM Oncology, Checkmate Pharmaceuticals Xiuning LeConsulting or Advisory Role: AstraZeneca, Lilly, EMD Serono, Spectrum Pharmaceuticals, Daiichi Sankyo/LillyResearch Funding: Lilly, Boehringer Ingelheim Jianjun ZhangHonoraria: Roche, Sino-USA Biomedical Platform, Geneplus, Origimed, Innovent Biologics, CancerNet, Zhejiang Cancer Hospital, Geneplus, Innovent Biologics, Zhejiang Cancer HospitalConsulting or Advisory Role: AstraZeneca, Geneplus, Capital Medical University, Johnson & Johnson/JanssenResearch Funding: MerckTravel, Accommodations, Expenses: Innovent Biologics, Zhejiang Cancer Hospital George Blumenschein JrEmployment: Janssen (I), Johnson & Johnson (I)Stock and Other Ownership Interests: Virogin BiotechConsulting or Advisory Role: Bristol Myers Squibb, Bayer, Celgene, Clovis Oncology, AbbVie, ARIAD, Genentech, Novartis, Xcovery, Adicet, Amgen, AstraZeneca, Roche, MedImmune, Maverick Therapeutics, Johnson & Johnson (I), Virogin Biotech, Gilead Sciences, Daiichi Sankyo Inc, Novartis, Tyme, Janssen Oncology, Lilly, InstilResearch Funding: Merck, Celgene, Genentech, Xcovery, Novartis, Bristol Myers Squibb, GlaxoSmithKline, Adaptimmune, Macrogenics, Kite Pharma, Immatics, Torque, Incyte, MedImmune, Exelixis, Immunocore, Roche, AstraZeneca, Bayer, Tmunity Therapeutics, Inc, Regeneron, BeiGene, Repertoire Immune Medicines, Daiichi Sankyo Inc, Verastem Anne S. TsaoConsulting or Advisory Role: Novartis, Boehringer Ingelheim, Genentech/Roche, Lilly, Bristol Myers Squibb, Epizyme, AstraZeneca/MedImmune, ARIAD, EMD Serono, Takeda, HERONResearch Funding: Merck, Genentech/Roche, Seattle Genetics, Millennium, Bristol Myers Squibb, Boehringer Ingelheim, Polaris, EMD Serono, Seattle Genetics, TakedaPatents, Royalties, Other Intellectual Property: UptoDate John V. HeymachStock and Other Ownership Interests: Cardinal Spine, Bio-TreeConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Lilly, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer Ingelheim, Catalyst Biotech, Foundation medicine, Novartis, Mirati Therapeutics, BrightPath Biotheraputics, Janssen, Nexus Health Systems, Pneuma Respiratory, Kairos Ventures, Roche, Leads BiolabsResearch Funding: AstraZeneca, Spectrum Pharmaceuticals, GlaxoSmithKlinePatents, Royalties, Other Intellectual Property: Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutationsNo other potential conflicts of interest were reported.

Objectives: This study aimed to better understand differences in the total days’ supply and fills of common opiates following urologic procedures. Materials and Methods: The Truven Health MarketScan® database was used to extract CPT codes from adults 18 years or older who underwent a urologic procedure with 90-day follow-up from 2012−2015 within the Austin−Round Rock, Texas metropolitan service area. A multivariate analysis and first hurdle modeling with a logistic outcome for any opiates was used to (1) assess differences in opioid prescribing patterns, (2) investigate opioid prescription outcomes, and (3) explore variability among opiate prescription patterns across seven urologic procedure categories. Results: Among the 2312 patients who met the inclusion criteria, 23.7% received an opiate, with an average total day’s supply of 6.20 (range 2.61−10.59). The proportion of patients receiving opiates varied significantly by procedure type (p = 0.028). Patients that had reconstructive procedures had the highest proportion of any opiates and the highest number of mean opiate prescriptions among the seven procedure categories (42% received opiates, p = 0.028, mean opiate prescriptions were 1.0 among all patients, p = 0.026). After adjustments, the multivariate analysis demonstrated that patients undergoing reconstructive procedures filled more opiate prescriptions (odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.00−3.50, p = 0.05) compared to other subcategories. Of those that received opiates, reconstructive patients had a shorter time to fills (mean −18.4 days, CI −8.40 to −28.50, p < 0.001). Conclusion: Patients undergoing reconstructive procedures are prescribed and fill more opiates compared to other common urological procedures. The standardization and implementation of postoperative pain regimens may help curtail this variability.

Transdermal drug delivery aims to create a safe and effective method of administering drugs through the skin that attracts a lot of attention and investment due to the constant progress in the field. Transferosomes are flexible or malleable vesicles (having almost the same structure as liposomes but with better skin penetration properties) discovered initially in the early 90s. The name transferosomes, which means "carrying bodies," is coined from the Latin phrase "Transferee," which means "to carry through," and the Greek term "soma," meaning "body." In comparison to typical herbal extracts, phytosomes (Transferosomes) are created by attaching specific herbal extracts to phosphatidylcholine, resulting in a formulation with increased solubility and, hence, better absorption, resulting in improved pharmacokinetic and pharmacodynamic features of the entrapped drugs. We are using the word phytosomes and transferosomes interchangeably as we have consolidated vesicular delivery of herbal drugs through skin. In this mini-review, we have demonstrated the enormous potential of developing nanotechnology to deliver bioactive phytochemicals, with a special emphasis on phytosomes (Transferosomes) as a unique lipid-based nanocarrier for transdermal drug delivery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Chavda, Patel and Chen.)

Nutritional supplements for patients with exocrine pancreatic insufficiency (EPI) typically utilize pancreatic enzyme replacement therapy (PERT) which is associated with gastrointestinal side effects. We evaluated serum triglyceride levels in patients with cystic fibrosis following consumption of an enzyme-modified oil oral nutritional supplement (EMO-ONS) versus a standard triacylglycerol-based ONS product (TAG-ONS) used concomitantly with PERT and patient tolerability between the two approaches. Ten subjects with CF and EPI taking PERT were enrolled in a single-center, double-blind, cross-over proof of concept trial. Five subjects randomized to Arm 1 were administered a PERT placebo and EMO-ONS and 5 subjects in Arm 2 were administered TAG-ONS+PERT. After 4 to 14 days, subjects received the opposite ONS. Serum triglyceride levels were measured at baseline and hourly for 6 h. Following the above, subjects were randomly assigned to receive 2 daily servings of EMO-ONS+PERT placebo or TAG-ONS+PERT at home for 7-days, self-reporting gastrointestinal symptoms daily. Mean change in peak serum triglyceride levels were similar for both groups (EMO-ONS = 41.9 ± 46.7 mg/dL vs. TAG-ONS+PERT = 46.4 ± 44.1 mg/L; p = 0.85). There was no difference in mean ratio of the serum triglyceride AUC between the two groups ( p = 0.58) or self-reported gastrointestinal tolerance. EMO-based products may provide a PERT-free alternative to traditional ONS products in patients with cystic fibrosis.

Objective: Transradial access (TRA) is commonly utilized in neurointerventional procedures. This study compared the technical and clinical outcomes of the use of TRA versus those of transfemoral access (TFA) for intracranial aneurysm embolization with the Woven EndoBridge (WEB) device., Methods: This is a secondary analysis of the Worldwide WEB Consortium, which comprises multicenter data related to adult patients with intracranial aneurysms who were managed with the WEB device. These aneurysms were categorized into two groups: those who were treated with TRA or TFA. Patient and aneurysm characteristics and technical and clinical outcomes were compared between groups. Propensity score matching (PSM) was used to match groups according to the following baseline characteristics: age, sex, subarachnoid hemorrhage, aneurysm location, bifurcation aneurysm, aneurysm with incorporated branch, neck width, aspect ratio, dome width, and elapsed time since the last follow-up imaging evaluation., Results: This study included 682 intracranial aneurysms (median [interquartile range] age 61.3 [53.0-68.0] years), of which 561 were treated with TFA and 121 with TRA. PSM resulted in 65 matched pairs. After PSM, both groups had similar characteristics, angiographic and functional outcomes, and rates of retreatment, thromboembolic and hemorrhagic complications, and death. TFA was associated with longer procedure length (median 96.5 minutes vs 72.0 minutes, p = 0.006) and fluoroscopy time (28.2 minutes vs 24.8 minutes, p = 0.037) as compared with TRA. On the other hand, deployment issues were more common in those treated with TRA, but none resulted in permanent complications., Conclusions: TRA has comparable outcomes, with shorter procedure and fluoroscopy time, to TFA for aneurysm embolization with the WEB device.

Purpose: Treatment options for corticosteroid-refractory and/or high-grade checkpoint inhibitor (CPI)-induced cutaneous adverse events (CAEs) are limited; however, anecdotal reports of biologic therapies have been successful. We aim to characterize the appropriate treatment scenarios and safety and efficacy profiles of biologics used to treat patients with CPI-induced CAEs at a single institution., Methods: This is a retrospective case series of patients from January 1st, 2015 to October 20th, 2020, with CPI-induced CAEs who were treated with biologics at a single cancer center. Patients were identified using institutional electronic medical record who underwent CPI therapy with subsequent CAEs that necessitated biologic therapy. Diagnostic criteria utilized for CAEs were based on documentation by four board-certified dermatologists, in combination with detailed chart reviews and pathology findings. Primary study outcome measurements include CAE response, tumor response, and adverse events during biologics treatment., Results: We identified 17 patients who fit study criteria. Sixteen patients experienced some degree of CAE improvement on biologics, with 10 of 10 patients reaching CAE resolution at 6 months post biologics. Eight patients needed new systemic treatment post biologics treatment, while 9 patients received no further treatment or stayed on the CPI. Thirteen patients tolerated biologics well with no significant adverse events or blood abnormalities, with only 2 patients experiencing biologic dose delays., Conclusion: In our cohort, biologics appear to be extremely efficacious in the treatment of severe-grade and/or steroid refractory CAEs. They also appeared to be well-tolerated without overtly negative effects on tumor response. In patients with limited cancer treatment options and good tumor response to CPIs, biologics should be considered for severe-grade and/or refractory CAEs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Basilar artery fenestration has been proposed as a contributor to ischemic stroke, as unique flow patterns induced by fenestration may be related to thrombus formation or insufficiency. This study aimed to evaluate the hemodynamics of basilar artery fenestration (BAF) using computational fluid dynamics (CFD). Methods: Patients with BAF and normal vertebrobasilar system were recruited and separately evaluated using CFD. Specific geometric vascular models were reconstructed based on 3D-rotational angiography (3D-RA). Patients were divided into the BAF group and control group (i.e., patients with the normal vertebrobasilar system). Hemodynamic and geometric variables were calculated and compared between groups using Student's t -test or Wilcoxon rank-sum test. Results: Overall, 24 patients were included, with 12 patients each in the BAF group and the control group. The BAF group had a significantly smaller basilar artery diameter than the control group (3.1 ± 0.51 vs. 3.76 ± 0.4, p = 0.002). Compared to the control group, the BAF group had higher values of maxOSI (median, 0.3 vs. 0.09, p = 0.028), TAWSSG (median, 983.42 vs. 565.39, p = 0.038) in the flow confluence, higher SAR-TAWSSG in bifurcation (median, 70.22 vs. 27.65, p = 0.002) and higher SAR-TAWSSG in basilar artery (median, 48.75 vs. 16.17, p < 0.001) of the vertebrobasilar artery. Conclusions: This pilot study suggested that hemodynamic differences between BAF and normal vertebrobasilar artery across multiple shear flow parameters. The disturbed flow in the BAF may increase the risk of thrombus formation, plaque instability, and subsequent ischemic cerebrovascular events. These should be confirmed by future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dong, Mei, Bai, Tong, Dmytriw, Yang, Wang, Patel, Yang, Li, Yang, Chen and Jiao.)

Alpelisib is an alpha isoform-specific phosphatidylinositol 3-kinase (PI3K) inhibitor approved for use in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative metastatic breast cancer in combination with fulvestrant. Hyperglycemia, rash, and gastrointestinal upset are the most commonly reported adverse events associated with alpelisib. Although rash is a known on-target effect of alpelisib, patients typically present with a morbilliform rash. We describe two cases of periorbital edema associated with alpelisib. We discuss the clinical findings, management, and prognosis of this unique reaction. These cases highlight the importance of early involvement of dermatology to manage adverse cutaneous events associated with alpelisib., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Mathematical modelling may aid in understanding the complex interactions between injury and immune response in critical illness., Methods: We utilize a system biology model of COVID-19 to analyze the effect of altering baseline patient characteristics on the outcome of immunomodulatory therapies. We create example parameter sets meant to mimic diverse patient types. For each patient type, we define the optimal treatment, identify biologic programs responsible for clinical responses, and predict biomarkers of those programs., Findings: Model states representing older and hyperinflamed patients respond better to immunomodulation than those representing obese and diabetic patients. The disparate clinical responses are driven by distinct biologic programs. Optimal treatment initiation time is determined by neutrophil recruitment, systemic cytokine expression, systemic microthrombosis and the renin-angiotensin system (RAS) in older patients, and by RAS, systemic microthrombosis and trans IL6 signalling for hyperinflamed patients. For older and hyperinflamed patients, IL6 modulating therapy is predicted to be optimal when initiated very early (<4 th day of infection) and broad immunosuppression therapy (corticosteroids) is predicted to be optimally initiated later in the disease (7 th - 9 th day of infection). We show that markers of biologic programs identified by the model correspond to clinically identified markers of disease severity., Interpretation: We demonstrate that modelling of COVID-19 pathobiology can suggest biomarkers that predict optimal response to a given immunomodulatory treatment. Mathematical modelling thus constitutes a novel adjunct to predictive enrichment and may aid in the reduction of heterogeneity in critical care trials., Funding: C.V. received a Marie Skłodowska Curie Actions Individual Fellowship (MSCA-IF-GF-2020-101028945). R.K.J.'s research is supported by R01-CA208205, and U01-CA 224348, R35-CA197743 and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Advanced Medical Research Foundation and Harvard Ludwig Cancer Center. No funder had a role in production or approval of this manuscript., Competing Interests: Declaration of interests LLM owns equity in Bayer AG and is a consultant for SimBiosys. R.K.J. received honorarium from Amgen; consultant fees from Chugai, Elpis, Merck, Ophthotech, Pfizer, SPARC, SynDevRx, XTuit; owns equity in Accurius, Enlight, Ophthotech, SynDevRx; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund; and received a grant from Boehringer Ingelheim. Neither any reagent nor any funding from these organizations was used in this study. Other coauthors have no conflict of interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Sex-specific differences in ischemic stroke outcomes are prevalent. We sought to investigate sex differences in the determinants of reperfusion and functional outcomes after endovascular thrombectomy (EVT) for emergent large vessel occlusion ischemic stroke (ELVO)., Methods: Patients presenting to a single referral center with an anterior circulation ELVO that underwent EVT from 2011 to 2019 were included in this retrospective analysis. Sex differences in history, presentation, adequate reperfusion (TICI 2b-3), and 90-day good outcome [delta modified Rankin Scale (mRS) ≤ 2 from pre-stroke] were examined. Multivariable logistic regression analyses were performed to assess sex-specific associations with outcomes., Results: Three hundred and eighty-one consecutive ELVO patients were identified. Women (N = 193) were older (75 vs 64 years, p < 0.0001), had more pre-stroke disability (17% vs 9%, p = 0.032), more atrial fibrillation (41% vs 30%, p = 0.033), but less carotid atherosclerosis (8% vs 16%, p = 0.027). Rates of TICI 2b-3 and good outcome were similar between sexes. Carotid atherosclerosis (OR 0.315, 95% CI 0.130, 0.762) and dissection (OR 0.124, 95% CI 0.027, 0.569) independently decreased the odds of TICI 2b-3 among men but not women. Older age, more severe stroke, and not achieving TICI 2b-3 independently decreased the odds of good outcome among both sexes, while prior stroke (OR 0.258, 95% CI 0.083, 0.797) and hemorrhagic transformation (OR 0.111, 0.021, 0.592) were determinants exclusive to men., Conclusion: In a real-world analysis of ELVO stroke patients treated with EVT, we found that despite advanced age and more pre-stroke disability, women have comparable reperfusion rates and functional outcomes compared to men. Sex-specific determinants of reperfusion and functional outcome were identified that require further study., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)