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OBJECTIVE: To assess the effectiveness of routine intensive care unit surveillance compared with frequent 12-lead electrocardiogram monitoring for detecting electrocardiogram evidence suggestive of prolonged myocardial ischemia in vascular surgery patients. DESIGN: Prospective cohort trial. SETTING: Intensive care unit. PARTICIPANTS: We studied 149 patients undergoing elective infrainguinal or aortic vascular surgery who were admitted to the intensive care unit postoperatively. INTERVENTIONS: Patients were simultaneously monitored with a 10-electrode/12-lead electrocardiogram obtained every 2 mins (criterion standard) and routine intensive care unit surveillance that included standard monitoring (five-electrode/two-lead electrocardiogram with ST segment trends and routine 12-lead electrocardiogram) and clinical assessment for detecting myocardial ischemia. The results of the criterion standard were not available to the caregivers. MEASUREMENTS AND MAIN RESULTS: We measured the ability of routine intensive care unit surveillance to detect the first 20 mins of electrocardiogram evidence suggestive of myocardial ischemia, defined as ST segment depression or elevation of >/=1 mm in two consecutive leads, during the first postoperative day. Seventeen patients (11%) had electrocardiogram evidence suggestive of prolonged myocardial ischemia, the majority of which occurred in leads V2-V4. The sensitivity of routine intensive care unit surveillance for detecting the first episode of electrocardiogram evidence suggestive of prolonged myocardial ischemia in a patient was 12% (95% confidence interval, 7-17%), and the specificity was 98% (95% confidence interval, 95-100%) with a positive predictive value of 40% (95% confidence interval, 32-48%), a negative predictive value of 90% (95% confidence interval, 85-94%), a positive likelihood ratio of 6, and a negative likelihood ratio of 1. The sensitivity of routine intensive care unit surveillance for detecting all episodes was 3% (95% confidence interval, 2-3%) and the specificity 99% (95% confidence interval, 99-100%) per 20-min monitoring interval, with a positive predictive value of 17% (95% confidence interval, 16-18%), negative predictive value of 95% (95% confidence interval, 95-96%), positive likelihood ratio of 3, and negative likelihood ratio of 1. CONCLUSIONS: Routine intensive care unit surveillance has low sensitivity for detecting electrocardiogram evidence suggestive of prolonged myocardial ischemia compared with frequent 12-lead electrocardiograms. Because detecting electrocardiogram evidence suggestive of prolonged postoperative myocardial ischemia is important, physicians should consider alternative strategies to detect myocardial ischemia. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study was to develop a convolutional neural network (CNN) for fracture detection, classification, and identification of greater tuberosity displacement ≥ 1 cm, neck-shaft angle (NSA) ≤ 100°, shaft translation, and articular fracture involvement, on plain radiographs., Methods: The CNN was trained and tested on radiographs sourced from 11 hospitals in Australia and externally validated on radiographs from the Netherlands. Each radiograph was paired with corresponding CT scans to serve as the reference standard based on dual independent evaluation by trained researchers and attending orthopaedic surgeons. Presence of a fracture, classification (non- to minimally displaced; two-part, multipart, and glenohumeral dislocation), and four characteristics were determined on 2D and 3D CT scans and subsequently allocated to each series of radiographs. Fracture characteristics included greater tuberosity displacement ≥ 1 cm, NSA ≤ 100°, shaft translation (0% to < 75%, 75% to 95%, > 95%), and the extent of articular involvement (0% to < 15%, 15% to 35%, or > 35%)., Results: For detection and classification, the algorithm was trained on 1,709 radiographs (n = 803), tested on 567 radiographs (n = 244), and subsequently externally validated on 535 radiographs (n = 227). For characterization, healthy shoulders and glenohumeral dislocation were excluded. The overall accuracy for fracture detection was 94% (area under the receiver operating characteristic curve (AUC) = 0.98) and for classification 78% (AUC 0.68 to 0.93). Accuracy to detect greater tuberosity fracture displacement ≥ 1 cm was 35.0% (AUC 0.57). The CNN did not recognize NSAs ≤ 100° (AUC 0.42), nor fractures with ≥ 75% shaft translation (AUC 0.51 to 0.53), or with ≥ 15% articular involvement (AUC 0.48 to 0.49). For all objectives, the model's performance on the external dataset showed similar accuracy levels., Conclusion: CNNs proficiently rule out proximal humerus fractures on plain radiographs. Despite rigorous training methodology based on CT imaging with multi-rater consensus to serve as the reference standard, artificial intelligence-driven classification is insufficient for clinical implementation. The CNN exhibited poor diagnostic ability to detect greater tuberosity displacement ≥ 1 cm and failed to identify NSAs ≤ 100°, shaft translations, or articular fractures., Competing Interests: R. W. A. Spek received payments of an amount between USD 10,000 and USD 100,000 from the Flinders Foundation (Adelaide, Australia) for the purpose of this study. During the study period, R. W. A. Spek received payments of an amount between USD 10,000 and USD 100,000 from Prins Bernhard Cultuurfonds (Amsterdam, the Netherlands), Stichting Zabawas (The Hague, The Netherlands), and with an amount of less than USD 10,000 from Michael van Vloten Foundation (Rotterdam, The Netherlands) and Anna Fonds NOREF (Mijdrecht, the Netherlands), all of which were unrelated to this specific study. B. Jadav provided paid consultations for Johnson & Johnson, unrelated to the current study. G. I. Bain received a Flinders Foundation grant for this study, paid to Flinders University, as well as royalties or licenses from Fusetec, stock or stock options in Fusetec, and speaker payments or honoraria from Depuy Synthes and Medartis, none of which are related to this study. G. I. Bain also holds fiduciary roles in the Australian Hand Surgery Society, the Shoulder and Elbow Society of Australia, the Asia Pacific Wrist Association, the International Federation for the Societies for Surgery of the Hand, and the Journal of Wrist Surgery. J. L. Jaarsma is an unpaid executive of the Australian Orthopaedic Association. B. Jadav received a one-off consultation payment and payment for teaching courses from Johnson & Johnson, unrelated to this study. M. P. J. van den Bekerom receives fellowship support from Smith & Nephew, which contributed to this study., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P) + metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD + metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD + precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD + precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy., (© 2024. The Author(s).)

The surge in RNA therapeutics has revolutionized treatments for infectious diseases like COVID-19 and shows the potential to expand into other therapeutic areas. However, the typical requirement for ultra-cold storage of mRNA-LNP formulations poses significant logistical challenges for global distribution. Lyophilization serves as a potential strategy to extend mRNA-LNP stability while eliminating the need for ultra-cold supply chain logistics. Although recent advancements have demonstrated the promise of lyophilization, the choice of lyoprotectant is predominately focused on sucrose, and there remains a gap in comprehensive evaluation and comparison of lyoprotectants and buffers. Here, we aim to systematically investigate the impact of a diverse range of excipients including oligosaccharides, polymers, amino acids, and various buffers, on the quality and performance of lyophilized mRNA-LNPs. From the screening of 45 mRNA-LNP formulations under various lyoprotectant and buffer conditions for lyophilization, we identified previously unexplored formulation compositions, e.g., polyvinylpyrrolidone (PVP) in Tris or acetate buffers, as promising alternatives to the commonly used oligosaccharides to maintain the physicochemical stability of lyophilized mRNA-LNPs. Further, we delved into how physicochemical and structural properties influence the functionality of lyophilized mRNA-LNPs. Leveraging high-throughput small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM), we showed that there is complex interplay between mRNA-LNP structural features and cellular translation efficacy. We also assessed innate immune responses of the screened mRNA-LNPs in human peripheral blood mononuclear cells (PBMCs), and showed minimal alterations of cytokine secretion profiles induced by lyophilized formulations. Our results provide valuable insights into the structure-activity relationship of lyophilized formulations of mRNA-LNP therapeutics, paving the way for rational design of these formulations. This work creates a foundation for a comprehensive understanding of mRNA-LNP properties and in vitro performance change resulting from lyophilization., Competing Interests: Declaration of competing interest Yuchen Fan, Diamanda Rigas, Nanzhi Zang, Kristina McKee, Christopher C. Kemball, Wan-Chih Su, Pierce Jessen, Tao Chen, Stefan G. Koenig, Karthik Nagapudi, Dennis Leung, and Chun-Wan Yen are employees of Genentech, Inc. Feng-Peng Chang, Zhixin Yu, and Pascal Winkler are former employees of Genentech, Inc. Lee Joon Kim and Greg L. Hura are employees of Lawrence Berkeley National Lab., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Flow diverting stents (FDS) are used to treat cerebral aneurysms, by promoting thrombosis and occlusion of the aneurysm sac. However, retreatment is required in some cases, and the biologic basis behind treatment outcome is not known. The goal of this study was to understand how changes in hemodynamic flow after FDS placement affect aneurysmal endothelial cell (EC) activity., Methods: Three-dimensional models of patient-specific aneurysms were created to quantify the EC response to FDS placement. Computational fluid dynamic simulations were used to determine the hemodynamic impact of FDS. Two identical models were created for each patient; into one a FDS was inserted. Each model was then populated with human carotid ECs and subjected to patient-specific pulsatile flow for 24 h. ECs were isolated from aneurysm dome from each model and bulk RNA sequencing was performed., Results: Paired untreated and treated models were created for four patients. Aneurysm dome EC analysis revealed 366 (2.6%) significant gene changes between the untreated and FDS conditions, out of 13909 total expressed genes. Gene set enrichment analysis of the untreated models demonstrated enriched gene ontology terms related to cell adhesion, growth/tensile activity, cytoskeletal organization, and calcium ion binding. In the FDS models, enriched terms were related to cellular proliferation, ribosomal activity, RNA splicing, and protein folding., Conclusion: Treatment of cerebral aneurysms with FDS induces significant EC gene transcription changes related to aneurysm hemodynamics in patient-specific in vitro 3D-printed models subjected to pulsatile flow. Further investigation is needed into the relationship between transcriptional change and treatment outcome., Competing Interests: Declarations Conflict of interest Dr. Levitt is the recipient of educational grants from Stryker and Medtronic. He reports equity interest in Synchron, Stroke Diagnostics, Proprio, Hyperion Surgical, Fluid Biomed, and Apertur. He is an advisor for Metis Innovative, and is a consultant for Medtronic, Aeaean Advisors and Stereotaxis. He is on the editorial board of Journal of NeuroInterventional Surgery and the Data Safety Monitoring Board of Arsenal Medical., (© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Background and Objectives: Advances in endovascular flow diverters have led to a secular shift in the management of brain aneurysms, causing debate on current bypass indications. We therefore sought to investigate the long-term results, current indications, and trends of bypasses for brain aneurysms., Methods: We retrospectively reviewed bypasses performed between 2005 and 2022 to treat brain aneurysms. Demographic, clinical, and radiological data were collected till the most recent follow-up. Aneurysm occlusion and graft patency was noted on cerebral angiogram in the immediate postoperative, 3-month, and most recent follow-up periods. Clinical outcomes (modified Rankin scores) and complications were assessed at 3 month and most recent follow-up. Trends in bypass volume and graft patency were assessed in 5-year epochs. Results were dichotomized based on aneurysm location to generate location-specific results and trends., Results: Overall, 203 patients (mean age 50 years, 57% female patients) with 207 cerebral aneurysms were treated with 233 cerebral bypasses with a mean follow-up of 2 years. Fusiform morphology was the most common bypass indication. Aneurysm occlusion on immediate postoperative and final follow-up angiogram was 89% (184/207) and 96% (198/207), respectively. Graft patency rate in the immediate postoperative period and most recent follow-up was 95% (222/233) and 92% (215/233), respectively. Of 207 aneurysms, 5 (2%) recurred. Of 203 patients, 81% (165) patients had modified Rankin scores of 0-2 at the 3-month follow-up and 11 patients died (mortality 5%). Although there was a steady decrease in the bypass volume over the study period, the proportion of bypasses for recurrent aneurysms increased serially. Posterior circulation aneurysms had lower rates of aneurysm occlusion and significantly higher incidence of postoperative strokes and deaths (P = .0035), with basilar artery aneurysms having the worst outcomes., Conclusion: Bypass indications have evolved with the inception of novel flow diverters. However, they remain relevant in the cerebrovascular surgeon's armamentarium, and long-term results are excellent., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Lipid nanoparticles (LNPs) are being intensively researched and developed to leverage their ability to safely and effectively deliver therapeutics. To achieve optimal therapeutic delivery, a comprehensive understanding of the relationship between formulation, structure, and efficacy is critical. However, the vast chemical space involved in the production of LNPs and the resulting structural complexity make the structure to function relationship challenging to assess and predict. New components and formulation procedures, which provide new opportunities for the use of LNPs, would be best identified and optimized using high-throughput characterization methods. Recently, a high-throughput workflow, consisting of automated mixing, small-angle X-ray scattering (SAXS), and cellular assays, demonstrated a link between formulation, internal structure, and efficacy for a library of LNPs. As SAXS data can be rapidly collected, the stage is set for the collection of thousands of SAXS profiles from a myriad of LNP formulations. In addition, correlated LNP small-angle neutron scattering (SANS) datasets, where components are systematically deuterated for additional contrast inside, provide complementary structural information. The centralization of SAXS and SANS datasets from LNPs, with appropriate, standardized metadata describing formulation parameters, into a data repository will provide valuable guidance for the formulation of LNPs with desired properties. To this end, we introduce Simple Scattering, an easy-to-use, open data repository for storing and sharing groups of correlated scattering profiles obtained from LNP screening experiments. Here, we discuss the current state of the repository, including limitations and upcoming changes, and our vision towards future usage in developing our collective knowledge base of LNPs., Competing Interests: Author DS is employed by David Shin Consulting. 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 © 2024 Kim, Shin, Leite, O’Neill, Ruebel, Tritt and Hura.)

Objective: Borden-Shucart type I dural arteriovenous fistulas (dAVFs) lack cortical venous drainage and occasionally necessitate intervention depending on patient symptoms. Conversion is the rare transformation of a low-grade dAVF to a higher grade. Factors associated with increased risk of dAVF conversion to a higher grade are poorly understood. The authors hypothesized that partial treatment of type I dAVFs is an independent risk factor for conversion., Methods: The multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research database was used to perform a retrospective analysis of all patients with type I dAVFs., Results: Three hundred fifty-eight (33.2%) of 1077 patients had type I dAVFs. Of those 358 patients, 206 received endovascular treatment and 131 were not treated. Two (2.2%) of 91 patients receiving partial endovascular treatment for a low-grade dAVF experienced conversion to a higher grade, 2 (1.5%) of 131 who were not treated experienced conversion, and none (0%) of 115 patients who received complete endovascular treatment experienced dAVF conversion. The majority of converted dAVFs localized to the transverse-sigmoid sinus and all received embolization as part of their treatment., Conclusions: Partial treatment of type I dAVFs does not appear to be significantly associated with conversion to a higher grade.

Background and Importance: Neurointervention is a very competitive specialty in the United States due to the limited number of training spots and the larger pool of applicants. The training standards are continuously updated to ensure solid training experiences. Factors affecting candidate(s) selection have not been fully established yet. Our study aims to investigate the factors influencing the selection process., Methods: A 52-question survey was distributed to 93 program directors (PDs). The survey consisted of six categories: (a) Program characteristics, (b) Candidate demographics, (c) Educational credentials, (d) Personal traits, (e) Research and extracurricular activities, and (f) Overall final set of characteristics. The response rate was 59.1%. As per the programs' characteristics, neurosurgery was the most involved specialty in running the training programs (69%). Regarding demographics, the need for visa sponsorship held the greatest prominence with a mean score of 5.9 [standard deviation (SD) 2.9]. For the educational credentials, being a graduate from a neurosurgical residency and the institution where the candidate's residency training is/was scored the highest [5.4 (SD = 2.9), 5.4 (SD = 2.5), respectively]. Regarding the personal traits, assessment by faculty members achieved the highest score [8.9 (SD = 1)]. In terms of research/extracurricular activities, fluency in English had the highest score [7.2 (SD = 1.9)] followed by peer-reviewed/PubMed-indexed publications [6.4 (SD = 2.2)]., Conclusion: Our survey investigated the factors influencing the final decision when choosing the future neurointerventional trainee, including demographic, educational, research, and extracurricular activities, which might serve as valuable guidance for both applicants and programs to refine the selection process., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Medium-sized rings (8-11-membered cycles) are often more challenging to synthesize than smaller rings (5-7-membered cycles) due to ring strain. Herein, we report a catalytic method for forming 8- and 9-membered rings that proceeds via the intramolecular Friedel-Crafts reactions of vinyl carbocation intermediates. These reactive species are generated catalytically through the ionization of vinyl toluenesulfonates by a Lewis acidic lithium cation-weakly coordinating anion salt.

Objective: In this research, the authors sought to characterize the incidence and extent of cerebrovascular lesions after penetrating brain injury in a civilian population and to compare the diagnostic value of head computed tomography angiography (CTA) and digital subtraction angiography (DSA) in their diagnosis., Methods: This was a prospective multicenter cohort study of patients with penetrating brain injury due to any mechanism presenting at two academic medical centers over a 3-year period (May 2020 to May 2023). All patients underwent both CTA and DSA. The sensitivity and specificity of CTA was calculated, with DSA considered the gold standard. The number of DSA studies needed to identify a lesion requiring treatment that had not been identified on CTA was also calculated., Results: A total of 73 patients were included in the study, 33 of whom had at least 1 penetrating cerebrovascular injury, for an incidence of 45.2%. The injuries included 13 pseudoaneurysms, 11 major arterial occlusions, 9 dural venous sinus occlusions, 8 dural arteriovenous fistulas, and 6 carotid cavernous fistulas. The sensitivity of CTA was 36.4%, and the specificity was 85.0%. Overall, 5.6 DSA studies were needed to identify a lesion requiring treatment that had not been identified with CTA., Conclusions: Cerebrovascular injury is common after penetrating brain injury, and CTA alone is insufficient to diagnosis these injuries. Patients with penetrating brain injuries should routinely undergo DSA.

The structural determination of natural products (NPs) can be arduous because of sample heterogeneity. This often demands iterative purification processes and characterization of complex molecules that may be available only in miniscule quantities. Microcrystal electron diffraction (microED) has recently shown promise as a method to solve crystal structures of NPs from nanogram quantities of analyte. However, its implementation in NP discovery remains hampered by sample throughput and purity requirements, akin to traditional NP-discovery workflows. In the methods described herein, we leverage the resolving power of transmission electron microscopy (TEM) and the miniaturization capabilities of deoxyribonucleic acid (DNA) microarray technology to address these challenges through the establishment of an NP screening platform, array electron diffraction (ArrayED). In this workflow, an array of high-performance liquid chromatography (HPLC) fractions taken from crude extracts was deposited onto TEM grids in picoliter-sized droplets. This multiplexing of analytes on TEM grids enables 1200 or more unique samples to be simultaneously inserted into a TEM instrument equipped with an autoloader. Selected area electron diffraction analysis of these microarrayed grids allows for the rapid identification of crystalline metabolites. In this study, ArrayED enabled structural characterization of 14 natural products, including four novel crystal structures and two novel polymorphs, from 20 crude extracts. Moreover, we identify several chemical species that would not be detected by standard mass spectrometry (MS) or ultraviolet-visible (UV/vis) spectroscopy and crystal forms that would not be characterized using traditional methods., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background and Objectives: Anecdotal cases of rapidly progressing dementia in patients with dural arteriovenous fistulas (dAVFs) have been reported in small series. However, large series have not characterized these dAVFs. We conducted an analysis of the largest cohort of dAVFs presenting with cognitive impairment (dAVFs-CI), aiming to provide a detailed characterization of this subset of dAVFs., Methods: Patients with dAVFs-CI were analyzed from the CONDOR Consortium, a multicenter repository comprising 1077 dAVFs. A propensity score matching analysis was conducted to compare dAVFs-CI with Borden type II and type III dAVFs without cognitive impairment (controls). Logistic regression was used to identify angiographic characteristics specific to dAVFs-CI. Furthermore, post-treatment outcomes were analyzed., Results: A total of 60 patients with dAVFs-CI and 60 control dAVFs were included. Outflow obstruction leading to venous hypertension was observed in all dAVFs-CI. Sinus stenosis was significantly associated with dAVFs-CI (OR 2.85, 95% CI: 1.16-7.55, P = .027). dAVFs-CI were more likely to have a higher number of arterial feeders (OR 1.56, 95% CI 1.22-2.05, P < .001) and draining veins (OR 2.05, 95% CI 1.05-4.46, P = .004). Venous ectasia increased the risk of dAVFs-CI (OR 2.38, 95% CI 1.13-5.11, P = .024). A trend toward achieving asymptomatic status at follow-up was observed in patients with successful closure of dAVFs (OR 2.86, 95% CI 0.85-9.56, P = .09)., Conclusion: Venous hypertension is a key angiographic feature of dAVFs-CI. Moreover, these fistulas present at a mean age of 58 years-old, and exhibit a complex angioarchitecture characterized by an increased number of arteriovenous connections and stenosed sinuses. The presence of venous ectasia further exacerbates the impaired drainage and contributes to the development of dAVFs-CI. Notably, in certain cases, closure of the dAVF has the potential to reverse symptoms., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Introduction: Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia. Methods: We hypothesized that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO) of both sexes. To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, breathing was recorded by barometric plethysmography in four experimental groups: obese male, obese female, lean male, and lean female following acute administration of IN leptin. Respiratory data were complemented with measures of arterial blood gas. Operant behavioral assays were used to determine the impact of IN leptin on the analgesic efficacy of morphine. Results: Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Blood gas measures confirmed the effectiveness of IN leptin for preventing respiratory acidosis in DIO male mice. However, IN leptin was not effective in lean mice of both sexes and appeared to exacerbate acid-base disturbances in DIO female mice. Additionally, morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. Discussion: IN leptin effectively treated OIRD in morphine-tolerant DIO male mice without impacting analgesia. In contrast, IN leptin had no effect in lean mice of either sex or DIO female mice. The arterial blood gas data were consistent with ventilatory findings showing that IN leptin reversed morphine-induced respiratory acidosis only in DIO male mice but not in other mouse groups. Finally, a hypercapnic sensitivity study revealed that IN leptin rescued minute ventilation under hypercapnic conditions only in DIO male mice, which suggests that differential responses to IN leptin are attributable to different leptin sensitivities depending on sex and the obesity status., 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 © 2023 Singer, Shin, Kim, Freire, Aung, Pho, East, Sgambati, Latremoliere, Pham and Polotsky.)

The NAD + -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role for sirtuin-2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under-expressed. Here, we sought to test whether SIRT2 over-expression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high-fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2-Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background and Importance: Giant intracranial aneurysms have a poor natural history with mortality rates of 68% and 80% over 2-year and 5-year, respectively. Cerebral revascularization can provide flow preservation while treating complex aneurysms requiring parent artery sacrifice. In this report, we describe the microsurgical clip trapping and high-flow bypass revascularization for a giant middle cerebral artery (MCA) aneurysm., Clinical Presentation: A 19-year-old man was diagnosed with a giant left MCA aneurysm after he suffered a left hemispheric capsular stroke 6 months ago. Since then, the patient recovered from the right hemiparesis and dysarthria with residual symptoms. Neuroimaging demonstrated a giant fusiform aneurysm encompassing the entire M1 segment. The bilobed aneurysm measured 37 × 16 × 15 mm. Endovascular treatment options included partial coiling of the aneurysm followed by deployment of flow-diverting stent spanning from the M2 branch-through the aneurysm neck-into the internal carotid artery. Because of the high risk of lenticulostriate artery stroke with endovascular treatment, the patient opted for microsurgical clip trapping and bypass. The patient consented to the procedure. High-flow bypass from internal carotid artery to M2 MCA was performed using radial artery graft, followed by aneurysm clip trapping using 3 clips., Conclusion: We demonstrate the successful microsurgical treatment for a complex case of giant M1 MCA aneurysm with fusiform morphology. High-flow revascularization using radial artery graft helped in achieving good clinical outcome with complete aneurysm occlusion with flow preservation despite the challenging morphology and location. Cerebral bypass continues to be a useful tool to tackle complex intracranial aneurysms., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

The nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age-related disease, whereby it is assumed that NMN is incorporated into NAD + through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD + metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD + metabolites, suggesting the microbiome could be in competition with the host for dietary NAD + precursors. These findings highlight new interactions between NMN and the gut microbiome., (© 2023 Federation of European Biochemical Societies.)

Background: Anterior cranial fossa dural arteriovenous fistulas (ACF-dAVFs) are aggressive vascular lesions. The pattern of venous drainage is the most important determinant of symptoms. Due to the absence of a venous sinus in the anterior cranial fossa, most ACF-dAVFs have some degree of drainage through small cortical veins. We describe the natural history, angiographic presentation and outcomes of the largest cohort of ACF-dAVFs., Methods: The CONDOR consortium includes data from 12 international centers. Patients included in the study were diagnosed with an arteriovenous fistula between 1990-2017. ACF-dAVFs were selected from a cohort of 1077 arteriovenous fistulas. The presentation, angioarchitecture and treatment outcomes of ACF-dAVF were extracted and analyzed., Results: 60 ACF-dAVFs were included in the analysis. Most ACF-dAVFs were symptomatic (38/60, 63%). The most common symptomatic presentation was intracranial hemorrhage (22/38, 57%). Most ACF-dAVFs drained through cortical veins (85%, 51/60), which in most instances drained into the superior sagittal sinus (63%, 32/51). The presence of cortical venous drainage predicted symptomatic presentation (OR 9.4, CI 1.98 to 69.1, p=0.01). Microsurgery was the most effective modality of treatment. 56% (19/34) of symptomatic patients who were treated had complete resolution of symptoms. Improvement of symptoms was not observed in untreated symptomatic ACF-dAVFs., Conclusion: Most ACF-dAVFs have a symptomatic presentation. Drainage through cortical veins is a key angiographic feature of ACF-dAVFs that accounts for their malignant course. Microsurgery is the most effective treatment. Due to the high risk of bleeding, closure of ACF-dAVFs is indicated regardless of presentation., Competing Interests: Competing interests: LJK is a co-founder of Spi Surgical and reports compensation for consultant services from Microvention. IJA reports stock options in Remedy Robotics and compensation from Remedy Robotics and InNeuroCo for consultant services. MRL reports equity interest in Propio, Cerebrotech and Synchron, and grants from Stryker, Volcano Philips and Medtronic. MRL is part of the editorial board of JNIS. APK reports compensation from Penumbra and Microvention for consultant services. WB reports compensation for consultant services from Johnson & Johnson, Stryker, Medtronic Vascular and Microvention; compensation from MIVI Neurovascular for data and safety monitoring services; stock holdings from Marblehead Medical LLC. AJP reports compensation from DePuy Synthes Spine for consultant services. BG reports compensation from Microvention and Medtronic for consultant services. AA reports compensation from Johnson & Johnson and Cerenovous for consultant services. RMS reports consulting and teaching agreements with Penumbra, Abbott, Medtronic, InNeuroCo and Cerenovous. RD reports compensation from Grand Rounds for consultant services and compensation from NIH for other services. CD reports stock options from Euphrates Vascular; compensation from noNO and Penumbra, Inc for data and safety monitoring services. EAS is a proctor with Microvention and reports compensation from Medtronic and Rapid Medical for consultant services., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Obesity and male sex are main risk factors for sleep-disordered breathing (SDB). We have shown that male diet-induced obesity (DIO) mice develop hypoventilation, sleep apnea, and sleep fragmentation. The effects of DIO on breathing and sleep architecture in females have not been investigated. We hypothesized that female mice are less susceptible to the detrimental effects of DIO on sleep and SDB compared to males. Female DIO-C57BL/6J and lean C57BL/6J mice underwent 24-hour metabolic studies and were exposed to 8% CO2 to measure the hypercapnic ventilatory response (HCVR), and sleep studies. Ventilatory response to arousals was calculated as ratio of the average and peak minute ventilation (VE) during each arousal relative to the baseline VE. Breathing stability was measured with Poincaré plots of VE. Female obesity was associated with decreased metabolism, indicated by reduced oxygen consumption (VO2) and CO2 production (VCO2). VE in 8% CO2 and HCVR were significantly attenuated during wakefulness. NREM sleep duration was reduced in DIO mice, but REM sleep was preserved. Ventilation during NREM and REM sleep was augmented compared to lean mice. Arousal frequency was similar between groups. Obesity increased the frequency of spontaneous arousals, whereas the apnea index was 4-fold reduced in DIO compared to lean mice. Obesity decreased pre- and post-apnea arousals. Obese mice had more stable breathing with reduced ventilatory response to arousals, compared to lean females. We conclude that obese female mice are protected against SDB, which appears to be related to an attenuated CO2 responsiveness, compared to the lean state., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The recent clinical and commercial success of lipid nanoparticles (LNPs) for nucleic acid delivery has incentivized the development of new technologies to manufacture LNPs. As new technologies emerge, researchers must determine which technologies to assess and how to perform comparative evaluations. In this article, we use a quality-by-design approach to systematically investigate how the mixer technology used to form LNPs influences LNPstructure. Specifically, a coaxial turbulent jet mixer and a staggered herringbone microfluidic mixer were systematically compared via matched formulation and process conditions. A full-factorial design-of-experiments study with three factors and three levels was executed for each mixer to compare process robustness in the production of antisense oligonucleotide (ASO) LNPs. ASO-LNPs generated with the coaxial turbulent jet mixer were consistently smaller, had a narrower particle size distribution, and had a higher ASO encapsulation as compared to the microfluidic mixer, but had a greater variation in internal structure with less ordered cores. A subset of the study was replicated for mRNA-LNPs with comparable trends in particle size and encapsulation, but more frequent bleb features for LNPs produced by the coaxial turbulent jet mixer. The study design used here provides a road map for how researchers may compare different mixer technologies (or process changes more broadly) and how such studies can inform process robustness and manufacturing control strategies.

Introduction: The purpose of this study was to examine the association with in-hospital mortality of 8 illness severity scores in patients with aneurysmal subarachnoid hemorrhage (aSAH)., Methods: In a retrospective cohort study, we investigated the association with in-hospital mortality of admission Hunt and Hess (HH) score, Fisher grade, severity of illness and risk of mortality scores, and serial Glasgow coma scale (GCS) score in patients with aSAH. We also explored the changes in GCS between admission and discharge using a multivariate model adjusting for age, clinical vasospasm, and external ventricular drain status., Results: Data from 480 patients with aSAH, of which 383 (79.8%) aneurysms were in the anterior circulation, were included in analysis. Patients were female (n=340, 70.8%) with a median age of 56 (interquartile range: 48 to 66) years. The majority (n=332, 69.2%) had admission HH score 3 to 5, Fisher grade 3 to 4 (n=437, 91%), median severity of illness 3 (range: 1 to 4), median risk of mortality 3 (range: 1 to 4), and median admission GCS of 13 (interquartile range: 7 to 15). Overall, 406 (84.6%) patients received an external ventricular drain, 469 (97.7%) underwent aneurysm repair, and 60 died (12.5%). Compared with admission HH score, GCS 24 hours after admission (area under the curve: 0.84, 95% confidence interval [CI]: 0.79-0.88) and 24 hours after aneurysm repair (area under the curve: 0.87, 95% CI: 0.82-0.90) were more likely to be associated with in-hospital mortality. Among those who died, the greatest decline in GCS was noted between 24 hours after aneurysm repair and discharge (-3.38 points, 95% CI: -4.17, -2.58)., Conclusions: Compared with admission HH score, GCS 24 hours after admission (or 24 h after aneurysm repair) is more likely to be associated with in-hospital mortality after aSAH., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Successful occlusion of cerebral aneurysms using coil embolization is contingent upon stable thrombus formation, and the quality of the thrombus depends upon the biomechanical environment. The goal of this study was to investigate how coil embolization alters the mechanical micro-environment within the aneurysm dome. Inertialess particles were injected in three-dimensional, computational simulations of flow inside patient aneurysms using patient-specific boundary conditions. Coil embolization was simulated as a homogenous porous medium of known permeability and inertial constant. Lagrangian particle tracking was used to calculate the residence time and shear stress history for particles in the flow before and after treatment. The percentage of particles entering the aneurysm dome correlated with the neck surface area before and after treatment (pretreatment: R2 = 0.831, P < 0.001; post-treatment: R2 = 0.638, P < 0.001). There was an inverse relationship between the change in particles entering the dome and coil packing density (R2 = 0.600, P < 0.001). Following treatment, the particles with the longest residence times tended to remain within the dome even longer while accumulating lower shear stress. A significant correlation was observed between the treatment effect on residence time and the ratio of the neck surface area to porosity (R2 = 0.390, P = 0.007). The results of this study suggest that coil embolization triggers clot formation within the aneurysm dome via a low shear stress-mediated pathway. This hypothesis links independently observed findings from several benchtop and clinical studies, furthering our understanding of this treatment strategy., (Copyright © 2023 by ASME.)

Glioblastoma is the most malignant primary brain tumor, the prognosis of which remains dismal even with aggressive surgical, medical, and radiation therapies. Glioblastoma stem cells (GSCs) promote therapeutic resistance and cellular heterogeneity due to their self-renewal properties and capacity for plasticity. To understand the molecular processes essential for maintaining GSCs, we performed an integrative analysis comparing active enhancer landscapes, transcriptional profiles, and functional genomics profiles of GSCs and non-neoplastic neural stem cells (NSCs). We identified sorting nexin 10 (SNX10), an endosomal protein sorting factor, as selectively expressed in GSCs compared with NSCs and essential for GSC survival. Targeting SNX10 impaired GSC viability and proliferation, induced apoptosis, and reduced self-renewal capacity. Mechanistically, GSCs utilized endosomal protein sorting to promote platelet-derived growth factor receptor β (PDGFRβ) proliferative and stem cell signaling pathways through posttranscriptional regulation of the PDGFR tyrosine kinase. Targeting SNX10 expression extended survival of orthotopic xenograft-bearing mice, and high SNX10 expression correlated with poor glioblastoma patient prognosis, suggesting its potential clinical importance. Thus, our study reveals an essential connection between endosomal protein sorting and oncogenic receptor tyrosine kinase signaling and suggests that targeting endosomal sorting may represent a promising therapeutic approach for glioblastoma treatment.

Hemodynamic factors have long been associated with clinical outcomes in the treatment of cerebral aneurysms. Computational studies of cerebral aneurysm hemodynamics have provided valuable estimates of the mechanical environment experienced by the endothelium in both the parent vessel and aneurysmal dome walls and have correlated them with disease state. These computational-clinical studies have recently been correlated with the response of endothelial cells (EC) using either idealized or patient-specific models. Here, we present a robust workflow for generating anatomic-scale aneurysm models, establishing luminal cultures of ECs at physiological relevant flow profiles, and comparing EC responses to curvature mediated flow. We show that flow patterns induced by parent vessel curvature produce changes in wall shear stress (WSS) and wall shear stress gradients (WSSG) that are correlated with differences in cell morphology and cellular protein localization. Cells in higher WSS regions align better with the flow and display strong Notch1-extracellular domain (ECD) polarization, while, under low WSS, differences in WSSG due to curvature change were associated with less alignment and attenuation of Notch1-ECD polarization in ECs of the corresponding regions. These proof-of-concept results highlight the use of engineered cellularized aneurysm models for connecting computational fluid dynamics to the underlying endothelial biology that mediates disease., (Copyright © 2023 by ASME.)

Background: Irregular pulsation of aneurysmal wall detected by four-dimensional CT angiography (4D-CTA) has been described as a novel imaging feature of aneurysm vulnerability. Our study aimed to investigate whether irregular pulsation is associated with symptomatic and ruptured intracranial aneurysms (IAs)., Methods: This retrospective study included consecutive patients with IAs who underwent 4D-CTA from January 2018 to July 2021. IAs were categorized as asymptomatic, symptomatic or ruptured. The presence of irregular pulsation (defined as a temporary focal protuberance ≥1 mm on more than three successive frames) was identified on 4D-CTA movies. Univariate and multivariate analyses were used to identify the parameters associated with aneurysm symptomatic or ruptured status., Results: Overall, 305 patients with 328 aneurysms (37 ruptured, 60 symptomatic, 231 asymptomatic) were included. Ruptured and symptomatic IAs were significantly larger in size compared with asymptomatic IAs (median (IQR) 6.5 (5.1-8.3) mm, 7.0 (5.5-9.7) mm vs 4.7 (3.8-6.3) mm, p=0.001 and p<0.001, respectively) and had more irregular pulsations (70.3%, 78.3% vs 28.1%, p<0.05). Irregular pulsation (OR 5.03, 95% CI 2.83 to 8.92; p<0.001) was independently associated with aneurysm symptomatic/ruptured status in the whole population. With unruptured IAs, both irregular pulsation (OR 6.31, 95% CI 3.02 to 13.20; p<0.001) and size (OR 1.17, 95% CI 1.03 to 1.32; p=0.015) were independently associated with the symptoms. The combination of irregular pulsation and size increased the accuracy over size alone in identifying symptomatic aneurysms (AUC 0.81 vs 0.77, p=0.007) in unruptured IAs., Conclusion: In a large cohort of patients with IAs detected by 4D-CTA, the presence of irregular pulsation was independently associated with aneurysm symptomatic and ruptured status., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Dural arteriovenous fistulas (dAVFs) located at craniocervical junction are extremely rare (1%-2% of intracranial/spinal dAVFs). Their angio-architectural complexity renders endovascular embolization to be challenging given multiple small feeders with risk of embolysate reflux into vertebral artery and limited transvenous access. The available literature discussing microsurgery for these lesions is limited to few case reports., Objective: To report a multicenter experience assessing microsurgery safety/efficacy., Methods: Prospectively maintained registries at 13 North American centers were queried to identify craniocervical junction dAVFs treated with microsurgery (2006-2021)., Results: Thirty-eight patients (median age 59.5 years, 44.7% female patients) were included. The most common presentation was subarachnoid/intracranial hemorrhage (47.4%) and myelopathy (36.8%) (92.1% of lesions Cognard type III-V). Direct meningeal branches from V3/4 vertebral artery segments supplied 84.2% of lesions. All lesions failed (n = 5, 13.2%) or were deemed inaccessible/unsafe to endovascular treatment. Far lateral craniotomy was the most used approach (94.7%). Intraoperative angiogram was performed in 39.5% of the cases, with angiographic cure in 94.7% of cases (median imaging follow-up of 9.2 months) and retreatment rate of 5.3%. Favorable last follow-up modified Rankin Scale of 0 to 2 was recorded in 81.6% of the patients with procedural complications of 2.6%., Conclusion: Craniocervical dAVFs represent rare entity of lesions presenting most commonly with hemorrhage or myelopathy because of venous congestion. Microsurgery using a far lateral approach provides robust exposure and visualization for these lesions and allows obliteration of the arterialized draining vein intradurally as close as possible to the fistula point. This approach was associated with a high rate of angiographic cure and favorable clinical outcomes., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

The global epidemic of obesity and type 2 diabetes parallels the rampant state of sleep deprivation in our society. Epidemiological studies consistently show an association between insufficient sleep and metabolic dysfunction. Mechanistically, sleep and circadian rhythm exert considerable influences on hormones involved in appetite regulation and energy metabolism. As such, data from experimental sleep deprivation in humans demonstrate that insufficient sleep induces a positive energy balance with resultant weight gain, due to increased energy intake that far exceeds the additional energy expenditure of nocturnal wakefulness, and adversely impacts glucose metabolism. Conversely, animal models have found that sleep loss-induced energy expenditure exceeds caloric intake resulting in net weight loss. However, animal models have significant limitations, which may diminish the clinical relevance of their metabolic findings. Clinically, insomnia disorder and insomnia symptoms are associated with adverse glucose outcomes, though it remains challenging to isolate the effects of insomnia on metabolic outcomes independent of comorbidities and insufficient sleep durations. Furthermore, both pharmacological and behavioral interventions for insomnia may have direct metabolic effects. The goal of this review is to establish an updated framework for the causal links between insufficient sleep and insomnia and risks for type 2 diabetes and obesity., (© 2022 New York Academy of Sciences.)

Rationale: Obesity hypoventilation syndrome (OHS) is often underdiagnosed, with significant morbidity and mortality. Bicarbonate, as a surrogate of arterial carbon dioxide, has been proposed as a screening tool for OHS. Understanding the predictors of serum bicarbonate could provide insights into risk factors for OHS. We hypothesized that the bicarbonate levels would increase with an increase in body mass index (BMI), since the prevalence of OHS increases with obesity., Methods: We used the TriNetX Research Network, an electronic health record database with de-identified clinical data from participating healthcare organizations across the United States, to identify 93,320 adults without pulmonary or advanced renal diseases who had serum bicarbonate and BMI measurements within 6 months of each other between 2017 and 2022. We used linear regression analysis to examine the associations between bicarbonate and BMI, age, and their interactions for the entire cohort and stratified by sex. We also applied a non-linear machine learning algorithm (XGBoost) to examine the relative importance of age, BMI, sex, race/ethnicity, and obstructive sleep apnea (OSA) status on bicarbonate., Results: This cohort population was 56% women and 72% white and 80% non-Hispanic individuals, with an average ( SD ) age of 49.4 (17.9) years and a BMI of 29.1 (6.1) kg/m 2 . The mean bicarbonate was 24.8 (2.8) mmol/L, with higher levels in men (mean 25.2 mmol/L) than in women (mean 24.4 mmol/L). We found a small negative association between bicarbonate and BMI, with an expected change of -0.03 mmol/L in bicarbonate for each 1 kg/m 2 increase in BMI ( p < 0.001), in the entire cohort and both sexes. We found sex differences in the bicarbonate trajectory with age, with women exhibiting lower bicarbonate values than men until age 50, after which the bicarbonate levels were modestly higher. The non-linear machine learning algorithm similarly revealed that age and sex played larger roles in determining bicarbonate levels than the BMI or OSA status., Conclusion: Contrary to our hypothesis, BMI is not associated with elevated bicarbonate levels, and age modifies the impact of sex on bicarbonate., Competing Interests: Conflict of interest LK and JJ declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. 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.

Sleep-disordered breathing (SDB) affects over 50% of obese individuals. Exaggerated hypoxic chemoreflex is a cardinal trait of SDB in obesity. We have shown that leptin acts in the carotid bodies (CB) to augment chemoreflex and that leptin activates the transient receptor potential melastatin 7 (TRPM7) channel. However, the effect of leptin-TRPM7 signalling in CB on breathing and SDB has not been characterized in diet-induced obesity (DIO). We hypothesized that leptin acts via TRPM7 in the CB to increase chemoreflex leading to SDB in obesity. DIO mice were implanted with EEG/EMG electrodes and transfected with Lepr b short hairpin RNA (shRNA) or Trpm7 shRNA vs. control shRNA in the CB area bilaterally. Mice underwent a full-polysomnography and metabolic studies at baseline and after transfection. Ventilatory responses to hypoxia and hypercapnia were assessed during wakefulness. Lepr b and Trpm7 were upregulated and their promoters were demethylated in the CB of DIO mice. Lepr b knockdown in the CB did not significantly affect ventilation. Trpm7 knockdown in the CB stimulated breathing during sleep in normoxia. These effects were not driven by changes in CB chemosensitivity or metabolism. Under sustained hypoxia, Trpm7 shRNA in the CB augmented ventilation during sleep, but decreased oxyhaemoglobin saturation. We conclude that the suppression of TRPM7 in the CB improved sleep-related hypoventilation and that the respiratory effects of CB TRPM7 channels in obesity are independent of leptin. TRPM7 signalling in the CB could be a therapeutic target for the treatment of obesity-related SDB. KEY POINTS: The leptin-TRPM7 axis in the carotid bodies may play an important role in the pathogenesis of sleep-disordered breathing. TRPM7 channels regulate breathing during sleep by acting peripherally in the carotid bodies. Suppression of TRPM7 signalling in the carotid bodies improves the obesity-induced hypoventilation in mice. Pharmacological blockade of TRPM7 channels in the carotid bodies could be a therapy for sleep-disordered breathing in obesity., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Obesity is associated with sleep-disordered breathing (SDB) and unrefreshing sleep. Residual daytime sleepiness and sleep impairments often persist after SDB treatment in patients with obesity, which suggests an independent effect of obesity on breathing and sleep. However, examining the relationship between sleep architecture and SDB in patients with obesity is complex and can be confounded by multiple factors. The main goal of this study was to examine the relationship between obesity-related changes in sleep architecture and SDB. Sleep recordings were performed in 15 lean C57BL/6J and 17 diet-induced obesity (DIO) mice of the same genetic background. Arousals from sleep and apneas were manually scored. Respiratory arousals were classified as events associated with ≥30% drops in minute ventilation (V E ) from baseline. We applied Poincaré analysis of V E during sleep to estimate breathing variability. Obesity augmented the frequency of arousals by 45% and this increase was independent of apneas. Respiratory arousals comprised only 15% of the arousals in both groups of mice. Breathing variability during non-rapid-eye-movment (NREM) sleep was significantly higher in DIO mice, but it was not associated with arousal frequency. Our results suggest that obesity induces sleep fragmentation independently of SDB severity. NEW & NOTEWORTHY Our diet-induced obesity (DIO) model reproduces sleep features of human obesity, including sleep fragmentation, increased apnea frequency, and larger breathing variability. DIO induces sleep fragmentation independently of apnea severity. Sleep fragmentation in DIO mice is mainly attributed to non-respiratory arousals. Increased breathing variability during sleep did not account for the higher arousal frequency in DIO. Our results provide a rationale to examine sleep in patients with obesity even when they are adequately treated for sleep-disordered breathing.

Objective: The objective is to examine the relationship between transcranial Doppler cerebral vasospasm (TCD-vasospasm), and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH)., Methods: In a retrospective cohort study, using univariate and multivariate analysis, we examined the association between TCD-vasospasm (defined as Lindegaard ratio >3) and patient's ability to ambulate without assistance, the need for tracheostomy and gastrostomy tube placement, and the likelihood of being discharged home from the hospital., Results: We studied 346 patients with aSAH; median age 55 years (Interquartile range IQR 46,64), median Hunt and Hess 3 [IQR 1-5]. Overall, 68.6% (n=238) had TCD-vasospasm, and 28% (n=97) had delayed cerebral ischemia. At hospital discharge, 54.3% (n=188) were able to walk without assistance, 5.8% (n=20) had received a tracheostomy, and 12% (n=42) had received a gastrostomy tube. Fifty-three percent (n=183) were discharged directly from the hospital to their home. TCD-vasospasm was not associated with ambulation without assistance at discharge (adjusted odds ratio, aOR 0.54, 95% 0.19,1.45), tracheostomy placement (aOR 2.04, 95% 0.23,18.43), gastrostomy tube placement (aOR 0.95, 95% CI 0.28,3.26), discharge to home (aOR 0.36, 95% CI 0.11,1.23)., Conclusion: This single-center retrospective study finds that TCD-vasospasm is not associated with clinical outcomes such as ambulation without assistance, discharge to home from the hospital, tracheostomy, and gastrostomy feeding tube placement. Routine screening for cerebral vasospasm and its impact on vasospasm diagnostic and therapeutic interventions and their associations with improved clinical outcomes warrant an evaluation in large, prospective, case-controlled, multi-center studies., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Lele et al.)

Clinical significance of increased clopidogrel response measured by VerifyNow P2Y12 assay is unclear; management guidelines are lacking in the context of neuroendovascular intervention. Our objective was to assess whether increased clopidogrel response predicts complications from endovascular aneurysm treatment requiring dual antiplatelet therapy. A single-institution, 9-year retrospective study of patients undergoing endovascular treatments for ruptured and unruptured aneurysms requiring aspirin and clopidogrel was conducted. Patients were grouped according to preoperative platelet inhibition in response to clopidogrel measured by the VerifyNow P2Y12 assay (VNP; P2Y12 reactivity units, PRU). Demographic and clinical features were compared across groups. Hemorrhagic complication rates (intracranial, major extracranial, minor extracranial) and thromboembolic complications (in-stent stenosis, stroke/transient ischemic attack) were compared, controlling for potential confounders and multiple comparisons. Data were collected from 284 patients across 317 procedures. Pre-operative VNP assays identified 9 % Extreme Responders (PRU ≤ 15), 13 % Hyper-Responders (PRU 16-60), 62 % Therapeutic Responders (PRU 61-214), 16 % Hypo-Responders (PRU ≥ 215). Increased response to clopidogrel was associated with increased risk of any hemorrhagic complication (≤60 PRU vs > 60 PRU; 39 % vs 24 %, P = 0.050); all intracranial hemorrhages occurred in patients with PRU > 60. Thromboembolic complications were similar between therapeutic and subtherapeutic patients (<215 PRU vs ≥ 215 PRU; 15 % vs 16 %, P = 0.835). Increased preoperative clopidogrel response is associated with increased rate of extracranial hemorrhagic complications in endovascular aneurysm treatments. Hyper-responders (16-60 PRU) and Extreme Responders (≤15 PRU) were not associated with intracranial hemorrhagic or thrombotic complications. Hypo-responders who underwent adjustment of antiplatelet therapy and neurointerventions did not experience higher rates of complications., Competing Interests: Declaration of Competing Interest Dr. Levitt is the recipient of unrestricted educational grants from Stryker and Medtronic, reports equity interest in Synchron, Cerebrotech, Proprio, Hyperion Surgical, and Fluid Biomed, is an advisor for Metis Innovative, and a consultant for Medtronic and Aeaean Advisers. The remaining 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 Ltd. All rights reserved.)

Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, hyperactivity, cranial features and lower FMRP protein expression, similar to what is typically observed in Fragile X Syndrome (FXS) in humans. We hypothesized that gut dysbiosis and inflammation during pregnancy influenced the prenatal uterine environment, leading to abnormal phenotypes in offspring. We found that oral in utero supplementation with a beneficial anti-inflammatory probiotic microbe, Lactobacillus reuteri , was sufficient to inhibit FXS-like phenotypes in offspring mice. Cytokine profiles in the pregnant WD females showed that their circulating levels of pro-inflammatory cytokine interleukin (Il)-17 were increased relative to matched gravid mice and to those given supplementary L. reuteri probiotic. To test our hypothesis of prenatal contributions to this neurodevelopmental phenotype, we performed Caesarian (C-section) births using dissimilar foster mothers to eliminate effects of maternal microbiota transferred during vaginal delivery or nursing after birth. We found that foster-reared offspring still displayed a high frequency of these FXS-like features, indicating significant in utero contributions. In contrast, matched foster-reared progeny of L. reuteri -treated mothers did not exhibit the FXS-like typical features, supporting a key role for microbiota during pregnancy. Our findings suggest that diet-induced dysbiosis in the prenatal uterine environment is strongly associated with the incidence of this neurological phenotype in progeny but can be alleviated by addressing gut dysbiosis through probiotic supplementation.

Objective: To determine the effectiveness of the modified Frailty Index-5 (mFI-5) in predicting postoperative functional outcome after microsurgical resection of ruptured brain arteriovenous malformations (bAVMs)., Methods: A retrospective review was performed of patients undergoing microsurgical resection of acutely ruptured bAVMs. Demographics, bAVM characteristics, mFI-5, Ruptured Arteriovenous Malformation Grading Scale (RAGS) score, and Spetzler-Martin (S-M) grade were recorded. Predictive ability of mFI-5 for postoperative functional outcome measured by modified Rankin Scale (mRS) was assessed with univariate and multivariate logistic and linear regression. RAGS score and S-M grade alone were compared with adding mFI-5 to either RAGS score or S-M grade using area under the curve (AUC) analysis., Results: In total, 109 patients were included. For every 1-point increase in mFI-5, there was a lower likelihood of good functional outcome (mRS score ≤2; odds ratio [OR], 0.33; confidence interval [CI], 0.15-0.60; P = 0.011). Healthy patients (mFI-5 = 0) were more likely to have good postoperative outcomes versus frail patients (mFI-5 ≥1) (OR, 3.32; CI, 1.24-8.97; P = 0.017). In multivariate analysis controlling for RAGS score, for every 1-point mFI-5 increase, there was a decreased likelihood of postoperative good functional outcome (OR, 0.32; CI, 0.14-0.63; P = 0.0026) and mFI-5 did not significantly predict secondary outcomes. S-M grade with mFI-5 showed better discrimination for postoperative good functional outcome (AUC 0.616), compared with S-M grade alone (AUC 0.544). RAGS score with mFI-5 showed the best discrimination for postoperative good functional outcome (AUC 0.798), compared with RAGS score alone (AUC 0.721)., Conclusions: Measuring frailty with mFI-5 additive to established bAVM grading systems may improve assessment of individual patient likelihood of postoperative good functional outcome after hemorrhagic bAVM resection., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Seizures are the second most common presenting symptom of brain arteriovenous malformations (bAVMs) after hemorrhage. Risk factors for preoperative seizures and subsequent seizure control outcomes have been well studied. There is a paucity of literature on postoperative, de novo seizures in initially seizure-naïve patients who undergo resection. Whereas this entity has been documented after craniotomy for a wide variety of neurosurgically treated pathologies including tumors, trauma, and aneurysms, de novo seizures after bAVM resection are poorly studied. Given the debilitating nature of epilepsy, the purpose of this study was to elucidate the incidence and risk factors associated with de novo epilepsy after bAVM resection., Methods: A retrospective review of patients who underwent resection of a bAVM over a 15-year period was performed. Patients who did not present with seizure were included, and the primary outcome was de novo epilepsy (i.e., a seizure disorder that only manifested after surgery). Demographic, clinical, and radiographic characteristics were compared between patients with and without postoperative epilepsy. Subgroup analysis was conducted on the ruptured bAVMs., Results: From a cohort of 198 patients who underwent resection of a bAVM during the study period, 111 supratentorial ruptured and unruptured bAVMs that did not present with seizure were included. Twenty-one patients (19%) developed de novo epilepsy. One-year cumulative rates of developing de novo epilepsy were 9% for the overall cohort and 8.5% for the cohort with ruptured bAVMs. There were no significant differences between the epilepsy and no-epilepsy groups overall; however, the de novo epilepsy group was younger in the cohort with ruptured bAVMs (28.7 ± 11.7 vs 35.1 ± 19.9 years; p = 0.04). The mean time between resection and first seizure was 26.0 ± 40.4 months, with the longest time being 14 years. Subgroup analysis of the ruptured and endovascular embolization cohorts did not reveal any significant differences. Of the patients who developed poorly controlled epilepsy (defined as Engel class III-IV), all had a history of hemorrhage and half had bAVMs located in the temporal lobe., Conclusions: De novo epilepsy after bAVM resection occurs at an annual cumulative risk of 9%, with potentially long-term onset. Younger age may be a risk factor in patients who present with rupture. The development of poorly controlled epilepsy may be associated with temporal lobe location and a delay between hemorrhage and resection.

Objectives: To determine the frequency of post-traumatic complaints and recovery rate of non-hospitalised patients with minor head injury (MHI) and their relationship with demographic and injury characteristics. We also evaluated the differences between patient groups in this least severe category of brain and head injury., Design: Prospective cohort follow-up study., Setting: Patients admitted to the emergency department (ED) of a tertiary hospital in the Netherlands., Participants: 242 patients with MHI (n=100 with head injury only and n=142 with mild traumatic brain injury (mTBI)) discharged home directly after evaluation at the ED., Outcome Measures: The primary outcome measure was incomplete recovery at 3 months measured by the Glasgow Outcome Scale-Extended score <8. Secondary outcome measures were number of post-traumatic complaints assessed 2 weeks and 3 months postinjury by a standardised questionnaire. Also the number of patients that visited their general practitioner because of persistent complaints was determined., Results: Three months postinjury 48% of patients reported more than one post-traumatic complaint. Half (51%) of patients showed incomplete recovery. Incomplete recovery was associated with headache directly postinjury (OR 3.27, 95% CI 1.28 to 8.34), age (OR 1.02, 95% CI 1.00 to 1.05) and the number of post-traumatic complaints (OR 1.24, 95% CI 1.09 to 1.40) and depression (OR 6.31, 95% CI 1.24 to 32.00) 2 weeks postinjury. Incomplete recovery was comparable between the head injury only and mTBI group (55% vs 50%, 95% CI -12.5 to -23.0). In total 36 MHI patients (28%) visited their general practitioner because of complaints related to their head injury., Conclusion: Half of the non-hospitalised patients with MHI experienced incomplete recovery after 3 months without differences between head injury only and mTBI patients. Therefore, early identification of patients at risk for incomplete recovery must be started at the ED to provide appropriate aftercare to avoid long-term post-traumatic complaints., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the safety and effectiveness of the Flow Redirection Endoluminal Device (FRED) flow diverter in support of an application for Food and Drug Administration approval in the USA., Methods: 145 patients were enrolled in a prospective, single-arm multicenter trial. Patients with aneurysms of unfavorable morphology for traditional endovascular therapies (large, wide-necked, fusiform, etc) were included. The trial was designed to demonstrate non-inferiority in both safety and effectiveness, comparing trial results with performance goals (PGs) established from peer-reviewed published literature. The primary safety endpoint was death or major stroke (National Institutes of Health Stroke Scale score ≥4 points) within 30 days of the procedure, or any major ipsilateral stroke or neurological death within the first year. The primary effectiveness endpoint was complete occlusion of the target aneurysm with ≤50% stenosis of the parent artery at 12 months after treatment, and in which an alternative treatment of the target intracranial aneurysm had not been performed., Results: 145 patients underwent attempted placement of a FRED device, and one or more devices were placed in all 145 patients. 135/145 (93%) had a single device placed. Core laboratory adjudication deemed 106 (73.1%) of the aneurysms large or giant. A safety endpoint was experienced by 9/145 (6.2%) patients, successfully achieving the safety PG of <15%. The effectiveness PG of >46% aneurysm occlusion was also achieved, with the effectiveness endpoint being met in 80/139 (57.6%) CONCLUSION: As compared with historically derived performance benchmarks, the FRED flow diverter is both safe and effective for the treatment of appropriately selected intracranial aneurysms., Clinical Registration Number: NCT01801007., Competing Interests: Competing interests: CGM: consultant to Microvention and Medtronic OOD: proctor for FRED/Microvention. AB: consultant to Microvention and Vesalio. AHS:SNIS Board of Directors; current research grants: co-investigator: NIH/NINDS 1R01NS091075 Virtual intervention of intracranial aneurysms; role: co-principal investigator NIH-NINDS R21 NS109575-01 Optimizing approaches to endovascular therapy of acute ischemic stroke; financial interest: Adona Medical, Inc., Amnis Therapeutics, Bend IT Technologies, Ltd., BlinkTBI, Inc, Boston Scientific Corp (for purchase of Claret Medical), Buffalo Technology Partners, Inc., Cardinal Consultants, LLC, Cerebrotech Medical Systems, Inc, Cognition Medical, Endostream Medical, Ltd, Imperative Care, Inc., Instylla, Inc., International Medical Distribution Partners, IRRAS, LaunchNY Seed Fund Management, LLC, NeuroRadial Technologies, Inc., Neurovascular Diagnostics, Inc., Perflow Medical, Ltd., Q’Apel Medical, Inc., Radical Catheter Technologies, Inc., Rebound Therapeutics Corp. (purchased 2019 by Integra Lifesciences, Corp), Rist Neurovascular, Inc., Sense Diagnostics, Inc., Serenity Medical, Inc., Silk Road Medical, Spinnaker Medical, Inc., StimMed, Synchron, Three Rivers Medical, Inc., Truvic Medical, Inc, Vastrax, LLC, VICIS, Inc., Viseon, Inc., Viz.ai, Inc; consultant/advisory board: Amnis Therapeutics, Apellis Pharmaceuticals, Inc., Boston Scientific, Canon Medical Systems USA, Inc., Cerebrotech Medical Systems, Inc., Cerenovus, Corindus, Inc., Endostream Medical, Ltd, Imperative Care, Inc., Integra LifeSciences Corp., IRRAS, Medtronic, MicroVention, Minnetronix Neuro, Inc., Northwest University – Data Safety Monitoring Board chair for HEAT Trial, Penumbra, Perflow Medical, Ltd., Q’Apel Medical, Inc., Rapid Medical, Rebound Therapeutics Corp., Serenity Medical, Inc., Silk Road Medical, StimMed, Stryker, Three Rivers Medical, Inc., VasSol, Viz.ai, Inc., W.L. Gore & Associates; national PI/steering committees: Cerenovus NAPA Trial and ARISE II Trial; Medtronic SWIFT PRIME and SWIFT DIRECT Trials; MicroVention FRED Trial and CONFIDENCE Study; MUSC POSITIVE Trial; Penumbra 3D Separator Trial, COMPASS Trial, INVEST Trial;· No consulting salary arrangements. All consulting is per project and/or per hour. JC: No disclosures. JTF: SNIS Board of Directors; consultant to Microvention and Stryker. AST: consultant to Microvention, Medtronic, Viz AI, Siemens;.chief medical officer Imperative Care. YK: consultant to Microvention, Penumbra, Medtronic. PJ: consultant to Microvention, (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Serotonin is an important mediator modulating behavior, metabolism, sleep, control of breathing, and upper airway function, but the role of aging in serotonin-mediated effects has not been previously defined. Our study aimed to examine the effect of brain serotonin deficiency on breathing during sleep and metabolism in younger and older mice. We measured breathing during sleep, hypercapnic ventilatory response (HCVR), CO 2 production (VCO 2 ), and O 2 consumption (VO 2 ) in 16-18-week old and 40-44-week old mice with deficiency of tryptophan hydroxylase 2 (Tph2), which regulates serotonin synthesis specifically in neurons, compared to Tph2 +/+ mice. As expected, aging decreased VCO 2 and VO 2 . Tph2 knockout resulted in an increase in both metabolic indexes and no interaction between age and the genotype was observed. During wakefulness, neither age nor genotype had an effect on minute ventilation. The genotype did not affect hypercapnic sensitivity in younger mice. During sleep, Tph2 -/- mice showed significant decreases in maximal inspiratory flow in NREM sleep, respiratory rate, and oxyhemoglobin saturation in REM sleep, compared to wildtype, regardless of age. Neither serotonin deficiency nor aging affected the frequency of flow limited breaths (a marker of upper airway closure) or apneas. Serotonin deficiency increased the amount and efficiency of sleep only in older animals. In conclusion, younger Tph2 -/- mice were able to defend their ventilation and phenotypically did not differ from wildtype during wakefulness. In contrast, both young and old Tph2 -/- mice showed sleep-related hypoventilation, which was manifested by hypoxemia during REM sleep., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

In active matrix organic light emitting diode (AMOLED) displays, when a variable refresh rate is applied and the frame rate changes, the image's color and luminance quality in AMOLED displays deteriorates. The frequency-dependent cognitive differences were experimentally demonstrated by using 6.76″ AMOLED displays. This phenomenon is dependent on the emission time and the data programming time on the frame rate. This degradation of the image quality during the frequency switch could be prevented by applying a variable initial voltage (V INI ) to the OLED anode. For a frequency change between 60 and 120 Hz, the measured just noticeable color difference (JNCD) decreased from 7.50 to less than 1.00 in luminance, and from 2.34 to 0.02 in color. As our approach can prevent image quality distortion by utilizing an existing compensation pixel structure without additional compensation steps, it will be a promising technique for improving the picture quality in AMOLED displays., (© 2022. The Author(s).)