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The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type-specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues., Competing Interests: EB, KV, LZ, CG, SE, MS, JS, FD No competing interests declared, (© 2024, Bomba-Warczak, Velez et al.)

Primary central nervous system vasculitis (PCNSV) is a rare and complex disease that poses formidable diagnostic and therapeutic challenges. Since its initial recognition as a distinct clinical entity in the 1950s, there has been considerable advancement in our understanding of PCNSV histopathology, specific clinical subsets, and their response to treatment. However, PCNSV is one of the rarest vasculitides, and still remains a challenging diagnosis with many unanswered questions regarding optimal management. In this review, we intend to provide a detailed outline of approaches that are currently being employed for the treatment of PCNSV. We exhaustively review available cohort series of PCNSV and critically appraise the data for study definitions, treatment approaches, and predictors of treatment outcomes. Finally, we also propose a treatment approach for PCNSV., Competing Interests: Dr Rula Hajj-Ali reports personal fees from GSK, personal fees from Amgen, personal fees from UptoDate, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2024 Kesav et al.)

Primary Angiitis of the Central Nervous System (PACNS) is an uncommon disease with kaleidoscopic clinical manifestations. Ischemic strokes are commoner than their hemorrhagic counterpart. Intracranial pseudoaneurysms are rarely reported in PACNS cohorts. We hereby describe the case of a 39-year-old female, who presented for evaluation of acute onset of left middle cerebral artery (MCA) ischemic stroke, with cerebral angiogram showing multifocal stenosis and irregularities in intracranial blood vessels with an aneurysm arising from the lenticulostriate branch of the left MCA M1 segment. A diagnosis of probable PACNS was made and patient initiated on immunomodulatory treatment with corticosteroids. 12 weeks follow up neuroimaging studies revealed resolution of the previously described intracranial aneurysm, thereby postulating the possibility of a pseudoaneurysm related to the underlying angiitis.

Atrial fibrillation (AFib) is the most common cardiac rhythm disturbance, often treated via electrical cardioversion. Following rhythm restoration, a period of depressed mechanical function known as atrial stunning occurs, suggesting that defects in contractility occur in AFib and are revealed upon restoration of rhythm. This project aims to define the contractile remodeling that occurs in AFib. To assess contractile function, we used a canine atrial tachypacing model of induced AFib. Mass spectrometry analysis showed dysregulation of contractile proteins in samples from AFib compared with sinus rhythm atria. Atrial cardiomyocytes show reduced force of contraction, decreased resting tension, and increased calcium sensitivity in skinned single cardiomyocyte studies. These alterations correlated with degradation of myofilament proteins including myosin heavy chain altering force of contraction, titin altering resting tension, and troponin I altering calcium sensitivity. We measured degradation of other myofilament proteins, including cardiac myosin binding protein C and actinin, that show degradation products in the AFib samples that are absent in the sinus rhythm atria. Many of the degradation products appeared as discrete cleavage products that are generated by calpain proteolysis. We assessed calpain activity and found it to be significantly increased. These results provide an understanding of the contractile remodeling that occurs in AFib and provide insight into the molecular explanation for atrial stunning and the increased risk of atrial thrombus and stroke in AFib. NEW & NOTEWORTHY Atrial fibrillation is the most common cardiac rhythm disorder, and remodeling during atrial fibrillation is highly variable between patients. This study has defined the biophysical changes in contractility that occur in atrial fibrillation along with identifying potential molecular mechanisms that may drive this remodeling. This includes proteolysis of several myofilament proteins including titin, troponin I, myosin heavy chain, myosin binding protein C, and actinin, which is consistent with the observed contractile deficits.

The mechanisms contributing to age-related deterioration of the female reproductive system are complex, but aberrant protein homeostasis is a major contributor. We elucidated the exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, both ovaries and oocytes harbor a panel of exceptionally long-lived proteins, including cytoskeletal components, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules might play a critical role in both lifelong maintenance and age-dependent deterioration of reproductive tissues.

Background: Data on P2Y12 inhibitors responsiveness from the middle east is scarce. We sought to investigate patient responsiveness to P2Y12 inhibitors within a cohort of major races that characterize the UAE population. The secondary objective was to assess risk factors for hyper and hypo-responsiveness in this population., Methods: We conducted a cross-sectional study on adults who received either clopidogrel or ticagrelor treatments and had platelet responsiveness testing before undergoing neuro-endovascular interventions at our quaternary care hospital between March 2015 and April 2019., Results: During the study period, 249 subjects met the inclusion criteria. Overall, 17.3 % were hyper-responsive and 25.7 % were hypo-responsive to P2Y12 inhibitors. When comparing between the P2Y12 inhibitors, rates of hyper-responsiveness were significantly higher to ticagrelor when compared to clopidogrel (11 versus 6 %, p = 0.02 respectively). Contrarily, hypo-responsiveness rates were significantly higher in clopidogrel treated patients compared to their ticagrelor treated counterparts (23 versus 2 %, p < .001 respectively). Patients of Middle-Eastern origin showed a significantly higher rate of hypo-responsiveness to both clopidogrel and ticagrelor when compared to other races (41.1 % and 26.7 %, P < 0.001 respectively). Asians showed the highest rates of hyper-responsiveness for both agents. Multivariate logistic regression analysis showed that proton pump inhibitors and statin combination, (OR: 6.39, 95 %CI [1.60, 25.392]), and Middle East vs. Indian subcontinent patients (OR: 4.67, 95 %CI [1.79-12.14]) were independent predictors of hypo-responsiveness to both P2Y12 inhibitors., Conclusion: This study demonstrated a high rate of hypo-responsiveness to P2Y12 inhibitors in a UAE cohort of patients undergoing neuro-endovascular procedures. In addition, therapeutic responsiveness to P2Y12 inhibitors varied markedly based on the racial background. Future larger studies are needed to evaluate genetic variations that may contribute to this rate of hypo-responsiveness in our population., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Accurate dose measurements are difficult in small fields due to charge particle disequilibrium, partial source occlusion, steep dose gradient, and the finite size of the detector., Aim: The study aims to determine the output factor using various detectors oriented in parallel and perpendicular orientations for three different tertiary collimating systems using 15 MV photon beams. In addition, this study analyzes how the output factor could be affected by different configurations of X and Y jaws above the tertiary collimators., Materials and Methods: Small field output factor measurements were carried out with three detectors for different tertiary collimating systems such as BrainLab stereotactic cones, BrainLab mMLC and Millennium MLC namely. To analyze the effect of jaw position on output factor, measurements have been carried out by positioning the jaws at the edge, 0.25, 0.5, and 1.0 cm away from the tertiary collimated field., Results: The data acquired with 15 MV photon beams show significant differences in output factor obtained with different detectors for all collimating systems. For smaller fields when compared to microDiamond, the SRS diode underestimates the output by up to -1.7% ± 0.8% and -2.1% ± 0.3%, and the pinpoint ion chamber underestimates the output by up to -8.1% ± 1.4% and -11.9% ± 1.9% in their parallel and perpendicular orientation respectively. A large increase in output factor was observed in the small field when the jaw was moved 0.25 cm symmetrically away from the tertiary collimated field., Conclusion: The investigated data on the effect of jaw position inferred that the position of the X and Y jaw highly influences the output factors of the small field. It also confirms that the output factor highly depends on the configuration of X and Y jaw settings, the tertiary collimating system as well as the orientation of the detectors in small fields., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Medical Physics.)

Background: Endovascular mechanical thrombectomy (EMT) for acute ischemic stroke can be conducted under conscious sedation (CS) or general anesthesia (GA). Emergency conversion from CS to GA during the procedure can occur, but its predictors and impact on clinical outcomes are not fully understood., Methods: A single centre retrospective analysis was conducted on 226 patients who underwent EMT for anterior circulation stroke. Two groups were identified: patients who completed the procedure under CS and those requiring emergency conversion to GA. The predictors of emergency conversion to GA and its impact on clinical outcomes were analyzed., Results: Forty-five patients (19.9%) required conversion to GA. Atrial fibrillation (OR 2.38; CI 1.09-5.22; p = 0.03) and prolonged duration of procedure (OR 1.02; CI 1.01-1.04; p < 0.001) were identified as the independent predictors of emergency conversion to GA., Conclusion: Patients with atrial fibrillation and prolonged duration of procedure especially when utilizing combined aspiration-stent retriever or angioplasty/stenting techniques, had a higher likelihood of requiring emergency conversion to general anesthesia (GA)., 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 © 2023 Elsevier Ltd. All rights reserved.)

Fibromuscular dysplasia (FMD) is a rare idiopathic, segmental, noninflammatory and nonatherosclerotic arteriopathy of medium-sized arteries. It is classically considered to be a disease of young and middle adulthood, with females more commonly affected than males. FMD is a systemic disease. Although historically considered to be rare, cerebrovascular FMD (C-FMD) has now been recognized to be as common as the renovascular counterpart. Extracranial carotid and vertebral arteries are the most commonly involved vascular territories in C-FMD with the clinical presentation determined by vessels affected. Common symptoms include headaches and pulsatile tinnitus, with transient ischemic attacks, ischemic stroke and subarachnoid or intracerebral hemorrhage constituting the more severe clinical manifestations. Cervical artery dissection involving carotids more often than vertebral arteries and intracranial aneurysms account for the cerebrovascular pathologies detected in C-FMD. Our understanding regarding C-FMD has been augmented in the recent past on account of dedicated C-FMD data from North American, European and other international FMD cohorts. In this review article, we provide an updated and comprehensive overview on epidemiology, clinical presentation, etiology, diagnosis and management of C-FMD., Competing Interests: Dr. Kesav reports no disclosures. Dr. Raj reports no disclosures. Dr. John reports no disclosures., (© 2023 Kesav et al.)

Background: To assess and compare the local control and toxicities between HDR Intracavitary Brachytherapy with 7.5 Gy and 9 Gy per fraction after EBRT in treatment of carcinoma cervix., Methodology: A total of 180 patients were randomly assigned to 2 arms. Arm A received HDR intracavitary brachytherapy with a dose of 7.5 Gy per fraction, 1 fraction per week for 3 fractions and Arm B received 9 Gy per fraction, 1 fraction per week for 2 fractions. Patients were evaluated on follow up for assessment of local control and toxicities., Results: The median follow up was 12 months (6-18 months). In arm A 89% of the patient had complete response and 11% had recurrence or metastasis. In arm B 93% of the patient had complete response and 7% had recurrence or metastasis. Grade 2/3 diarrhoea was seen in 4.4% of patients in Arm A and in 7.7% in Arm B. Grade 2/3 proctitis was seen in 3.3% of patients in 7.5 Gy arm and in 6.6% in 9 Gy arm. One patient in each arm had grade 1 haematuria. The overall duration of treatment was significant lower in Arm B compared to Arm A (59 days vs 68 days, p = 0.01)., Conclusion: The result of this clinical study shows that Intracavitary brachytherapy with a dose of 9 Gy per fraction is non inferior to other schedules in term of local control and does not result in increased toxicity., (© 2023. The Author(s).)

Hearing depends on precise synaptic transmission between cochlear inner hair cells and spiral ganglion neurons through afferent ribbon synapses. Neuroligins (Nlgns) facilitate synapse maturation in the brain, but they have gone unstudied in the cochlea. We report Nlgn3 and Nlgn1 knockout (KO) cochleae have fewer ribbon synapses and have impaired hearing. Nlgn3 KO is more vulnerable to noise trauma with limited activity at high frequencies one day after noise. Furthermore, Nlgn3 KO cochleae have a 5-fold reduction in synapse number compared to wild type after two weeks of recovery. Double KO cochlear phenotypes are more prominent than the KOs, for example, 5-fold smaller synapses, 25% reduction in synapse density, and 30% less synaptic output. These observations indicate Nlgn3 and Nlgn1 are essential to cochlear ribbon synapse maturation and function., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Many tobacco smokers consume nicotine intermittently, but the underlying mechanisms and neurobiological changes associated with intermittent nicotine intake are unclear. Understanding intermittent nicotine intake is a high priority, as it could promote therapeutic strategies to attenuate tobacco consumption. We examined nicotine intake behavior and neurobiological changes in male rats that were trained to self-administer nicotine during brief (5 min) trials interspersed with longer (15 min) drug-free periods. Rats readily adapted to intermittent access (IntA) SA following acquisition on a continuous access (ContA) schedule. Probabilistic analysis of IntA nicotine SA suggested reduced nicotine loading behavior compared to ContA, and nicotine pharmacokinetic modeling revealed that rats taking nicotine intermittently may have increased intake to maintain blood levels of nicotine that are comparable to ContA SA. After IntA nicotine SA, rats exhibited an increase in unreinforced responses for nicotine-associated cues (incubation of craving) and specific alterations in the striatal proteome after 7 days without nicotine. IntA nicotine SA also induced nAChR functional upregulation in the interpeduncular nucleus (IPN), and it enhanced nicotine binding in the brain as determined via [ 11 C]nicotine positron emission tomography. Reducing the saliency of the cue conditions during the 5 min access periods attenuated nicotine intake, but incubation of craving was preserved. Together, these results indicate that IntA conditions promote nicotine SA and nicotine seeking after a nicotine-free period., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Competing Interests: None

Background and Purpose: Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year., Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020)., Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths., Conclusions: During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

Abstract: Guillain-Barre Syndrome (GBS) is an acute inflammatory polyradiculoneuropathy which can lead to rapid neuromuscular respiratory failure, with an estimated annual incidence of 1-2 per 100,000 person-years. Even though cranial nerve involvement is known to occur in GBS, radiological correlation on neuroimaging studies are less frequently reported in pediatric population. We hereby report the case of a 14-year-old boy with acute motor axonal neuropathy variant of GBS, who had extensive contrast enhancement of multiple cranial nerves on Magnetic Resonance Imaging brain, associated with clinicoradiological dissociation on presentation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: COVID-19 pandemic has negatively impacted stroke care services at multiple levels. There was a decline in acute stroke admissions. Fewer interventions have been performed. Increased "door-to-needle times and "door-to-groin puncture" during this pandemic. These factors combined have led to declining in the favoured outcomes of stroke patients' globally. Yet this pandemic permits an opportunity for higher preparedness for future pandemics., Objectives and Methods: This paper aims to shed light on the main lessons learned in the field of stroke care during the first wave of COVID-19 pandemic. Here we are presenting proposals and initiatives for better preparedness in future similar emergencies. These proposals are based primarily on literature review of COVID-19 publications, as well as the first-hand experience gained during the first wave at the regional level. In addition to the consensus and collective ride of stroke experts in the Middle East North Africa Stroke and Interventional Neurotherapies Organization (MENA+-SINO) and interaction and collaboration with international stroke specialists from the Stroke World Organization (WSO), European Stroke Organization (ESO) and stroke and COVID-19 papers authors., Conclusion: Stroke care is very complex, particularly in the initial hours after onset of symptoms. A successful outcome requires very close collaboration between clinical personnel from multiple specialties. Preparedness for future pandemics requires the improvement of care plans that allow for rapid assessment of stroke patients and ensuring that regular 'mock exercises' familiarize quintessential services that care for the stroke patients., (Copyright © 2021. Published by Elsevier B.V.)

Background: The experimental determination of relative output factors presents the greatest challenge, especially for small fields with different detectors. The aim of this study is to evaluate the influence of jaw positions on small-field output factors for the fields defined by micro-multileaf collimator and circular cones with different detectors., Materials and Methods: The stereotactic output factors were measured on Primus linear accelerator with BrainLab micro-multileaf collimator (mMLC) and circular cones as add-on tertiary collimators. Square field sizes ranging from 0.6 cm × 0.6 cm to 9.8 cm × 9.8 cm and circular fields of diameter ranging from 1.0 cm to 4.0 cm were defined by mMLC and circular cones, respectively. The influence of jaw position on output factor was assessed for different geometric configurations with three different detectors., Results: The values obtained with PinPoint ion chamber were consistent with microDiamond detector for fields greater than 24 mm × 24 mm, but an underestimation of 23.9% was noticed in 6 mm x 6 mm field size. For the mMLC defined field size of 6 mm × 6 mm, when the X-Y jaw was moved from 8 mm × 8 mm to 80 mm × 80 mm, an increase in the output by a factor of 1.7 was observed with both microDiamond and stereotactic radiosurgery diode, whereas an increase in output by a factor of 1.9 was noticed with PinPoint ion chamber., Conclusion: Output factors obtained with different detectors show high differences in the smallest field size for all collimating systems. This study confirms that the position of X and Y jaw above the tertiary collimator significantly influences the small-field output factor., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Medical Physics.)

Background: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study's objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines., Methods: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation., Findings: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p<0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p<0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile., Interpretation: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction., Competing Interests: Competing interests: TNN: PI CLEAR study (Medtronic). DCH: Stryker, Vesalio, Cerenovus consultant. AEH: consultant and speaker for Medtronic, Stryker, Microvention, Penumbra, Balt, Scientia, Genentech and GE Healthcare. PJ: Medtronic, Microvention, Balt, Cerenovus consultant. SO-G: Medtronic, Stryker consultant. DSL: Cerenovus, Genentech, Stryker, Medtronic consultant. TGJ: advisor/investor for Anaconda, Route92, FreeOx, and Blockade Medical; Medtronic grants, DAWN, AURORA PI (Stryker). WJM: consultant: Rebound Therapeutics, Viseon Imperative Care, Q’Apel, Stryker, Stream Biomedical, Spartan Micro; Investor: Cerebrotech, Endostream, Q’Apel, Viseon, Rebound, and Spartan Micro. RGN: Stryker; Cerenovus/Neuravi; Anaconda, Cerebrotech, Ceretrieve, Vesalio (Advisory Board); Imperative Care., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cell-based therapies cure some hematologic malignancies, although little information exists on solid cancer cell responses. The study objective was to test the hypothesis that xenogeneic fibroblasts can inhibit the growth of human cancer cell lines in vitro. Seven human cell lines (pancreatic cancer HPAF II; brain cancer U-87 MG; fibrosarcoma; ovarian cancer OVCAR3 and SKOV3; and breast cancer MCF7 and MDA-MB231) were co-cultured with two xenogeneic fibroblast cell lines (CV-1; monkey, Cercopithecus aethiops and DF-1; chicken, Gallus gallus) in a Transwell culture system. Cancer cell proliferation was assessed colorimetrically. Different concentrations of breast and ovarian cancer cells were tested. Gene expression induced by DF-1 xenogeneic fibroblasts was assessed by RNAseq of MCF7 breast cancer cells. The proliferation of the majority of the cancer cell lines was altered by co-culture with xenogeneic fibroblasts. Cell proliferation was increased (4-17%) by CV-1; DF-1 increased brain cancer cell proliferation (16%), decreased breast and ovarian cancer cell growth (15 and 26% respectively) but did not affect fibrosarcoma and pancreatic cancer cells. When the initial cancer cell concentrations were lowered 4-fold, growth inhibition of breast and ovarian cancer increased more than 2-fold. DF-1 fibroblasts induced significant differential expression of 484 genes in MCF7 breast cancer cells; 285 genes were downregulated and 199 genes were upregulated compared to control. Genes involved in the immune response were the major downregulated entities. RNAseq results were validated by qRT-PCR of 12 genes. The results show that xenogeneic fibroblasts can alter the growth and gene expression of cancer cells in vitro. This suggests a potentially novel investigational approach to the control of cancer cell growth.

Background: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide., Aims: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior)., Methods: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers., Results: The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, -19.7 to -18.7), 11.5% (95%CI, -12.6 to -10.6), and 12.7% (95%CI, -13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (-20.5%) had greater declines in mechanical thrombectomy volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions., Conclusion: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.

Background: Endovascular mechanical thrombectomy (EMT) is the standard of care for acute ischemic stroke (AIS) caused by proximal large vessel occlusions. There is conflicting evidence on outcome of patients undergoing EMT under procedural sedation (PS) or general anesthesia (GA). In this retrospective study we analyze the effect of GA and PS on the functional outcome of patients undergoing EMT., Methods: Patients who have been admitted at our institute AIS and were treated with EMT under GA or PS between January 2015 and September 2018 were included in the study. Primary end point was the proportion of patients with good functional outcome as defined by a modified Rankin score (mRS) 0-2 at discharge., Results: A total of 155 patients were analyzed in this study including 45 (29.03 %) patients who received 97 GA, 110 (70.9 %) PS and 31 of these received Dexmedetomidine/Remifentanil. The median (IQR) 98 mRS at discharge was 4.0 (1.0-4.0) in the GA group Vs 3.00, (1.00-4.00) in the PS group. Among the secondary outcomes the lowest MAP recorded was significantly less in GA group (64.56 100 ± 18.70) compared to PS group (70.86 ± 16.30); p = 0.03. The PS group had a lower odd of mRS 3-5 (after adjustment), however, this finding was statistically not significant (OR 0.52 [0.07-3.5] 102 p = 0.5)., Conclusions: Our retrospective analysis did not find any influence of GA compared to PS whenever this was delivered by target controlled infusion (TCI) of propofol or by remifentanil/dexmedetomidine (REX) on early functional outcome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To compare ischemic and hemorrhagic stroke patients with COVID-19 to non-COVID-19 controls, and to describe changes in stroke admission patterns during the pandemic., Methods: This is a single center, retrospective, observational study. All consecutive patients admitted with primary diagnosis of ischemic/ hemorrhagic stroke between March1st -May10th 2020 were included and compared with the same time period in 2019., Results: There was a 41.9% increase in stroke admissions in 2020 (148 vs 210,P = .001). When comparing all ischemic strokes, higher rate of large vessel occlusion (LVO) (18.3% vs 33.8%,P = .008) and significant delay in initiation of mechanical thrombectomy after hospital arrival (67.75 vs 104.30 minutes,P = .001) was observed in 2020. When comparing all hemorrhagic strokes, there were no differences between the two years. Among 591 COVID-19 admissions, 31 (5.24%) patients with stroke including 19 with ischemic (3.21%) and 12 with hemorrhagic stroke (2.03%) were identified. Patients with COVID-19 and ischemic stroke were significantly younger (58.74 vs 48.11 years,P = .002), predominantly male (68.18% vs 94.74%,P = .016), had lesser vascular risk factors, had more severe clinical presentation (NIHSS 7.01 vs 17.05,P < .001), and higher rate of LVO (23.6% vs. 63.1%,P = .006). There was no difference in the rate of endovascular thrombectomy, but time to groin puncture was significantly longer in COVID-19 patients (83.41 vs 129.50 minutes,P = .003). For hemorrhagic stroke, COVID-19 patients did not differ from non-COVID-19 patients., Conclusions: Stroke continues to occur during this pandemic and stroke pathways have been affected by the pandemic. Stroke occurs in approximately 5% of patients with COVID-19. COVID-19 associated ischemic stroke occurs in predominantly male patients who are younger, with fewer vascular risk factors, can be more severe, and have higher rates of LVO. Despite an increase in LVO during the pandemic, treatment with mechanical thrombectomy has not increased. COVID-19 associated hemorrhagic stroke does not differ from non-COVID-19 hemorrhagic stroke patients., (Copyright © 2020. Published by Elsevier B.V.)

The mechanisms and phenotype of ischemic stroke associated with coronavirus disease 2019 (COVID-19) remain uncertain. A retrospective study was conducted in patients with COVID-19 presenting with ischemic stroke from March 1 to May 25, 2020, and cases with large-vessel occlusion were identified. To provide baseline institutional stroke data within and outside the COVID-19 pandemic, all consecutive ischemic stroke and TIA admissions (COVID and non-COVID) to the hospital during a 10-week period from March 1 to May 10, 2020, were collected and compared with data from the same time period in 2019. Among 20 patients with COVID-19 and acute ischemic stroke, 15 (75%) had large-vessel occlusion. These patients were young (mean age, 46.5 years), male (93%), without major burden of traditional cardiovascular risk factors, and had a severe stroke presentation. Large-vessel occlusions were observed in multiple vessels (40%), uncommonly affected vessels, and atypical locations with a large thrombus burden. Systemic thrombosis separate from large-vessel occlusion was not uncommon (26%). At short-term follow-up, stroke etiology remained undetermined in 46% of patients and functional outcome was poor. The above findings raise the possibility of stroke related to mechanisms induced by the COVID-19 infection itself, including a hypercoagulable state and/or endothelial damage. In addition, they document the severe presentation and poor outcomes of large-vessel occlusion in COVID-19 ischemic stroke., (© 2020 by American Journal of Neuroradiology.)

Exposure to excessive sound causes noise-induced hearing loss through complex mechanisms and represents a common and unmet neurological condition. We investigate how noise insults affect the cochlea with proteomics and functional assays. Quantitative proteomics reveals that exposure to loud noise causes proteotoxicity. We identify and confirm hundreds of proteins that accumulate, including cytoskeletal proteins, and several nodes of the proteostasis network. Transcriptomic analysis reveals that a subset of the genes encoding these proteins also increases acutely after noise exposure, including numerous proteasome subunits. Global cochlear protein ubiquitylation levels build up after exposure to excess noise, and we map numerous posttranslationally modified lysines residues. Several collagen proteins decrease in abundance, and Col9a1 specifically localizes to pillar cell heads. After two weeks of recovery, the cochlea selectively elevates the abundance of the protein synthesis machinery. We report that overstimulation of the auditory system drives a robust cochlear proteotoxic stress response., Competing Interests: Declaration of Interests A.F.R. is a co-founder of Otonomy; is a scientific advisory board member; and holds an equity position. UCSD has approved this relationship. Otonomy played no part in this research., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

COVID-19 pandemic has led to a change in the way we manage acute medical illnesses. This pandemic had a negative impact on stroke care worldwide. The World Stroke Organization (WSO) has raised concerns due to the lack of available care and compromised acute stroke services globally. The numbers of thrombolysis and thrombectomy therapies are declining. As well as, the rates and door-to treatment times for thrombolysis and thrombectomy therapies are increasing. The stroke units are being reallocated to serve COVID-19 patients, and stroke teams are being redeployed to COVID-19 centers. Covid 19 confirmed cases and deaths are rising day by day. This pandemic clearly threatened and threatening all stroke care achievements regionally. Managing stroke patients during this pandemic is even more challenging at our region. The Middle East and North Africa Stroke and Interventional Neurotherapies Organization (MENA-SINO) is the main stroke organization regionally. MENA-SINO urges the need to developing new strategies and recommendations for stroke care during this pandemic. This will require multiple channels of interventions and create a protective code stroke with fast triaging path. Developing and expanding the tele-stroke programs are urgently required. There is an urgent need for enhancing collaboration and cooperation between stroke expertise regionally and internationally. Integrating such measures will inevitably lead to an improvement and upgrading of the services to a satisfactory level., (Copyright © 2020. Published by Elsevier Inc.)

Human papilloma virus (HPV) causes a subset of head and neck squamous cell carcinomas (HNSCC) of the oropharynx. We combined targeted DNA- and genome-wide RNA-sequencing to identify genetic variants and gene expression signatures respectively from patients with HNSCC including oropharyngeal squamous cell carcinomas (OPSCC). DNA and RNA were purified from 35- formalin fixed and paraffin embedded (FFPE) HNSCC tumor samples. Immuno-histochemical evaluation of tumors was performed to determine the expression levels of p16INK4A and classified tumor samples either p16+ or p16-. Using ClearSeq Comprehensive Cancer panel, we examined the distribution of somatic mutations. Somatic single-nucleotide variants (SNV) were called using GATK-Mutect2 ("tumor-only" mode) approach. Using RNA-seq, we identified a catalog of 1,044 and 8 genes as significantly expressed between p16+ and p16-, respectively at FDR 0.05 (5%) and 0.1 (10%). The clinicopathological characteristics of the patients including anatomical site, smoking and survival were analyzed when comparing p16+ and p16- tumors. The majority of tumors (65%) were p16+. Population sequence variant databases, including gnomAD, ExAC, COSMIC and dbSNP, were used to identify the mutational landscape of somatic sequence variants within sequenced genes. Hierarchical clustering of The Cancer Genome Atlas (TCGA) samples based on HPV-status was observed using differentially expressed genes. Using RNA-seq in parallel with targeted DNA-seq, we identified mutational and gene expression signatures characteristic of p16+ and p16- HNSCC. Our gene signatures are consistent with previously published data including TCGA and support the need to further explore the biologic relevance of these alterations in HNSCC., Competing Interests: No Authors have competing interests.

In the unprecedented current era of the COVID-19 pandemic, challenges have arisen in the management and interventional care of patients with acute stroke and large vessel occlusion, aneurysmal subarachnoid hemorrhage, and ruptured vascular malformations. There are several challenges facing endovascular therapy for stroke, including shortages of medical staff who may be deployed for COVID-19 coverage or who may have contracted the infection and are thus quarantined, patients avoiding early medical care, a lack of personal protective equipment, delays in door-to-puncture time, anesthesia challenges, and a lack of high-intensity intensive care unit and stroke ward beds. As a leading regional neurovascular organization, the Middle East North Africa Stroke and Interventional Neurotherapies Organization (MENA-SINO) has established a task force composed of medical staff and physicians from different disciplines to establish guiding recommendations for the implementation of acute care pathways for various neurovascular emergencies during the current COVID-19 pandemic. This consensus recommendation was achieved through a series of meetings to finalize the recommendation., (Copyright © 2020 Al-Jehani, John, Hussain, Al Hashmi, Alhamid, Amr, Ozdemir, Shuaib, Alhazzani, Ghorbani, Mansour and Saqqur.)

Background: The number of cases of gonorrhoea in the USA and worldwide caused by Neisseria gonorrhoeae is increasing (555 608 reported US cases in 2017, and 87 million cases worldwide in 2016). Many countries report declining in vitro susceptibility of azithromycin, which is a concern because azithromycin and ceftriaxone are the recommended dual treatment in many countries. We aimed to identify strain types associated with decreased susceptibility to azithromycin., Methods: We did a genomic analysis of N gonorrhoeae isolates obtained by the US Gonococcal Isolate Surveillance Project. Isolates were whole-genome sequenced based on decreased susceptibility to azithromycin (minimal inhibitory concentration [MIC] ≥2 μg/mL, using agar dilution antibiotic susceptibility testing) and geographical representation. Bioinformatic analyses established genomic diversity, strain population dynamics, and antimicrobial resistance profiles., Findings: 410 isolates were sorted into more than 20 unique phylogenetic clades. One predominant persistent clade (consisting of 97 isolates) included the most isolates with azithromycin MICs of 2 μg/mL or higher (61 of 97 [63%] vs 59 of 311 [19%]; p<0·0001) and carried a mosaic mtr (multiple transferable resistance) locus (68 of 97 [70%] vs two of 313 [1%]; p<0·0001). Of the remaining 313 isolates, 57 (18%) had decreased susceptibility to azithromycin (MIC ≥4 μg/mL), which was attributed to 23S rRNA variants (56 of 57 [98%]) and formed phylogenetically diverse clades, showing various levels of clonal expansion., Interpretation: Reduced azithromycin susceptibility was associated with expanding and persistent clades harbouring two well described resistance mechanisms, mosaic mtr locus and 23S rRNA variants. Understanding the role of recombination, particularly within the mtr locus, on the fitness and expansion of strains with decreased susceptibility has important implications for the public health response to minimise gonorrhoea transmission., Funding: US Centers for Disease Control and Prevention (CDC), CDC Combating Antibiotic Resistant Bacteria initiative, Oak Ridge Institute for Science Education, US Department of Energy/CDC/Emory University, National Institutes of Health, and Biomedical Laboratory Research and Development Service of the US Department of Veterans Affairs., Competing Interests: Declaration of interests We declare no competing interests.

Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely underexplored in invasion and metastasis. Here, we investigated heterogeneity within collective cancer invasion by integrating DNA methylation and gene expression analysis in rare purified lung cancer leader and follower cells. Our results showed global DNA methylation rewiring in leader cells and revealed the filopodial motor MYO10 as a critical gene at the intersection of epigenetic heterogeneity and three-dimensional (3D) collective invasion. We further identified JAG1 signaling as a previously unknown upstream activator of MYO10 expression in leader cells. Using live-cell imaging, we found that MYO10 drives filopodial persistence necessary for micropatterning extracellular fibronectin into linear tracks at the edge of 3D collective invasion exclusively in leaders. Our data fit a model where epigenetic heterogeneity and JAG1 signaling jointly drive collective cancer invasion through MYO10 up-regulation in epigenetically permissive leader cells, which induces filopodia dynamics necessary for linearized fibronectin micropatterning., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

In 2016, the proportion of Neisseria gonorrhoeae isolates with reduced susceptibility to azithromycin rose to 3.6%. A phylogenetic analysis of 334 N. gonorrhoeae isolates collected in 2016 revealed a single, geographically diverse lineage of isolates with MICs of 2 to 16 μg/ml that carried a mosaic-like mtr locus, whereas the majority of isolates with MICs of ≥16 μg/ml appeared sporadically and carried 23S rRNA mutations. Continued molecular surveillance of N. gonorrhoeae isolates will identify new resistance mechanisms., (Copyright © 2020 American Society for Microbiology.)

Objective: Mechanical thrombectomy (MT) is now an established treatment for acute ischemic stroke (AIS) with large vessel occlusion (LVO) within 6 hours. Since 2018, MT is also recommended from 6-24 hours after selecting with additional multimodal imaging including perfusion imaging. We sought to investigate patients with significant discrepancy in core infarct between computed tomography (CT) and CT perfusion (CTP)., Methods: In this retrospective study, patients with AIS who were evaluated for MT using the RAPID software (IschemaView, Redwood City, CA, USA) from February 2018 to March 2019 were included. Cases with discrepancy between infarct volume on non-contrast CT and core volume (cerebral blood flow <30%) as analyzed by RAPID on CTP were analyzed., Results: In the study period, 635 patients were evaluated for acute stroke symptoms. Non-contrast head CT was performed in 635 patients, and CTP with RAPID software post processing was performed in 134 patients. Among the 134 patients, 8 (5.9%) patients had gross discrepancy in core infarct between CT and CTP, with underestimation of infarct by CTP. Evaluation of these cases shows that the likely reason for this discrepancy is recanalization of a LVO, which then leads to erroneously normal or gross underestimate of the core infarct volume determined from CTP post processing analysis., Conclusions: Recanalization of a LVO can lead to erroneously normal or gross underestimation of the core infarct as determined by post processing software analysis of CTP data. The whole composite of hyperacute CT imaging should be examined while making decisions. This caveat of perfusion imaging interpretation has not been reported previously., Competing Interests: Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper., (Copyright © 2020 by KSCVS and KoNES.)

Background: Intrasaccular flow disruption has emerged as a useful modality for treatment of wide-necked saccular aneurysm at vessel bifurcations. The Woven EndoBridge (WEB) device is one such device that has been evaluated in several series with excellent safety and good midterm efficacy. Bailout techniques to retrieve or reposition a dislocated WEB device are sparse and associated with significant risks. We describe a case of a dislocated WEB device that was repositioned with a microcatheter alone., Methods: We describe a case of a WEB device that inadvertently detached in the parent vessel and the technique we used to reposition it. A number of bailout techniques are discussed with pros and cons associated with each maneuver., Results: An unruptured middle cerebral artery (MCA) aneurysm was treated by endovascular embolization with a WEB device. The WEB was deployed within the aneurysm without incident. However, the device failed to detach. While attempting to resheath the device, it extruded out of the aneurysm and then inadvertently detached in the MCA. After many options were considered, a microcatheter alone was used to push the device back into the aneurysm., Conclusion: Caution should be exercised, especially when detaching the WEB device. Microcatheter repositioning by pushing the dislocated device may be attempted, especially if part of the device is within the aneurysm. This is the first description of the described microcatheter repositioning rescue maneuver., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Given the lack of new antimicrobials or a vaccine, understanding the evolutionary dynamics of Neisseria gonorrhoeae is a significant public and global health priority. We investigated the emergence and spread of gonococcal strains with decreased susceptibility to cephalosporins and azithromycin using detailed genomic analyses of gonococcal isolates collected in the United States, 2014-2016., Methods: We sequenced genomes of 649 isolates collected through the Gonococcal Isolate Surveillance Project. We examined the genetic relatedness of isolates and assessed associations between clades and various genotypic and phenotypic combinations., Results: We identified a large and clonal lineage of strains (MLST ST9363) associated with elevated azithromycin minimum inhibitory concentration (AZIem), characterized by a mosaic mtr locus (C substitution in the mtrR promoter, mosaic mtrR and mtrD). Mutations in 23S rRNA were sporadically distributed among AZIem strains. Another clonal group (MLST ST1901) possessed 7 unique PBP2 patterns, and it shared common mutations in other genes associated with cephalosporin resistance., Conclusions: Whole-genome sequencing methods can enhance monitoring of antimicrobial resistant gonococcal strains by identifying gonococcal populations containing mutations of concern. These methods could inform the development of point-of-care diagnostic tests designed to determine the specific antibiotic susceptibility profile of a gonococcal infection in a patient., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)