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Objective: Postmenopausal nocturia is poorly understood. This study aimed to identify hormonal and lifestyle factors associated with nocturia and to understand the relative contribution of altered urine production and bladder storage dysfunction in women. Design, setting, population and methods: Women ≥40 years presenting to public continence services were enrolled in a cross‐sectional study. A total of 153 participants completed a hormone status questionnaire, a validated nocturia causality screening tool and a 3‐day bladder diary. Descriptive statistics and logistic regression models for nocturia severity and bladder diary parameters were computed. Results: Overall, 91.5% reported nocturia, 55% ≥2 /night. There was a difference of 167.5 ml (P < 0.001) in nocturnal urine volume between women with nocturia ≥2 (median 736 ml) versus less often (517 ml). Significant predictors of self‐reported disruptive nocturia were age (odds ratio [OR] 1.04, 95% CI 1.002–1.073) and vitamin D supplementation (OR 2.33, 95% CI 1.11–4.91). Nocturnal polyuria was significantly more common with nocturia ≥2 compared with less frequent nocturia (P < 0.002). Exercise for 150 minutes a week was protective for nocturnal polyuria (OR 0.22, P = 0.001). Nocturia index >1.3 was significantly predicted by age (OR 1.07, P < 0.001), regular exercise (OR 0.41, P = 0.036), day flushes (OR 4.00, P = 0.013) and use of vitamin D (OR 2.34, P = 0.043). Maximum voided volumes were significantly lower with nocturia ≥2 versus less often (night: 268 ml versus 350 ml; day: 200 ml versus 290 ml). Conclusions: Bothersome nocturia in postmenopausal women is associated with changes to both nocturnal diuresis and bladder storage. Regular physical activity, prolapse reduction and oestrogen replacement may be adjunctive in managing bothersome nocturia in women. [ABSTRACT FROM AUTHOR]

Genetically modified plant tissue materials offer possible advantages as molecular recognition elements in biosensor design. A prototype transgenic biosensor, using potato tissue transformed with a gene conferring Beta-glucuronidase (GUS) biocatalytic activity coupled with fluorescence detection, is described and evaluated. Under optimal operating conditions, the transgenic sensor system gives good response to glucuronide substrate in the micromolar range and has an operating lifetime of at least 2 months at room temperature. Parallel experiments with non-transformed potato plant tissue show no glucuronidase activity. The prototype system described here illustrates that desired pathways can be created in plant tissue through genetic manipulation of higher plants normally lacking such pathways.

Introduction: First described in 1927, a Schmorl's node (SN) is the herniation of nucleus pulposus (NP) through the cartilaginous and bony end plate into the body of the adjacent vertebra. SNs are common findings on imaging, and although most SNs are asymptomatic, some have been shown to become painful lesions. In this manuscript, we review the literature regarding the epidemiology, clinical presentation, pathogenesis, imaging, and management of SNs.Materials and Methods: Using databases from the US National Library of Medicine and the National Institutes of Health, relevant articles were identified.Results: While several theories regarding the pathogenesis of SNs have been proposed, an axial load model appears to have the greatest supporting evidence. Symptomatic SNs are thought to be due to the inflammatory response solicited by the herniation of NP into the well-vascularized vertebral body. Management options for symptomatic SNs vary, ranging from medical management to surgical fusion.Conclusion: SNs are common lesions that are often asymptomatic. In certain cases, SNs can cause back pain. No consensus on pathogenesis exists. There is no established treatment modality for symptomatic SNs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to investigate vaginal rejection of polypropylene mesh after continence taping procedures. STUDY DESIGN: Of 700 women who had undergone the procedures, 17 women with sling erosion and 7 women with voiding difficulty or symptomatic vagina prolapse (control subjects) underwent histopathologic evaluation and immunohistochemistry. RESULTS: Seven women whose condition was not responding to conservative treatment and debridements had the exposed suburethral tape excised, which revealed predominant foreign body reaction and fragmented mesh that was surrounded by histiocytes and dense fibrosis. Immunohistochemical analysis revealed that the cell density percentage of CD 20+ cells was statistically significantly greater in the persistent defective healing group than in either the single-debridement or control group ( P = .014 and P = .014, respectively). We found statistically significant differences between the persistent defective healing and single-debridement groups and between the former and control groups in the ratios of T and B cells ( P = .035 and P = .022, respectively). CONCLUSION: The rate of defective vaginal healing after the procedures was 2.4%. Removal of the prosthesis and surrounding tissue at various times for the 7 women resulted in histopathologic findings that suggested a immunologic reaction. The rate of persistent defective healing of the vagina was 1%. Copyright © 2004 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]

Background: Endovascular transmural targeting of cervical and cranial perivascular structures is a novel approach for minimally invasive delivery of therapeutics. Components of the autonomic nervous system are in close anatomic proximity to major cervical vasculature and, therefore, represent potential targets for intervention. The superior cervical ganglion (SCG) is a discrete structure of interest for this approach, as sympathetic blockade may have therapeutic effects for various conditions. Variability of SCG location and its relationship to large cervical vessels, and the feasibility of endovascular transmural targeting has not been elucidated., Methods: In this retrospective study, computed tomography angiography of head and neck from patients with subarachnoid hemorrhage or cerebral aneurysms were reviewed. SCG dimensions and spatial relationship to cervical vessels were measured. Measured anatomic parameters were used to determine endovascular transmural accessibility of the SCG from various cervical vessels., Results: A total of 159 SCGs were identified and measured from 314 unilateral neck images of sufficient quality. SCGs had an average radio-opacity of 49.6 Hounsfield Units, length of 1.91 cm, and width of 0.71 cm. Internal carotid artery (ICA) has the longest contact length with the SCG (mean = 1.80 cm) compared to other major cervical vessels. A total of 95% of SCGs were accessible from ICA using an endovascular transmural approach, with the majority of SCGs located anteromedially to the ICA., Conclusions: This is the first anatomical study to provide pertinent targeting information for endovascular transmural access to the SCG using computed tomography angiography. In most cases, endovascular transmural access to the SCG is anatomically feasible from the proximal cervical ICA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Photoredox-catalyzed cross-coupling reaction is an efficient strategy for the construction of organic molecules. Herein, we developed a method to synthesize α-arylthioanisoles by constructing C-S bonds in the presence of a Ru-photoredox catalyst. Thus, a series of α-arylthioanisole compounds were efficiently obtained through decarboxylative cross-coupling under mild conditions. This protocol features high efficiency, broad substrate scope and good functional group tolerance.

Objective: The cerebral and spinal venous systems have similar functions but unique anatomical and physiological properties. CSF occupies space in the cranial and spinal vaults, is continuously produced, and has many roles, including maintaining a favorable environment for CNS structures. The influence of the cerebrospinal venous system on CSF dynamics has been theorized since the 1940s. Newer studies suggest venous outflow pattern alterations in response to changes in body position. However, the relationship of postural cerebrospinal venous outflow shifts with and their influence on CSF homeostasis is not well understood., Methods: The authors searched the published literature related to the anatomy and function of vertebral venous plexus (VVP), CSF, and positional cerebral venous flow characteristics. A comprehensive collection of literature was compiled and reviewed, and the relationship between cerebrospinal and venous system changes and alterations in body positions, with an emphasis on the craniocervical system, is discussed., Results: The VVP is a network of valveless veins extending from the sacrum to the cranium that are interconnected with the cranial dural sinuses. The internal VVP occupies space within the extradural spinal canal and functions to return spinal venous blood to the heart, but it has additional properties, including the capability of bidirectional venous flow, an intraspinal dilatory capacity, and a role in cerebral venous outflow. When one rises to the upright position, CSF shifts toward the spinal canal and force vectors change, leading to reduced intracranial CSF pressure; simultaneously, cerebral venous outflow shifts from the jugular vein to the VVP outflow pathway. The venous outflow shift mechanism and its purpose are poorly understood. The authors review the known physiology of the system, identify gaps in knowledge to direct future research, and propose an interpretation of these data, concluding that position-dependent CSF and cerebrospinal venous shifts are part of a complementary positional craniospinal pressure regulation system that must be kept in balance for optimal CNS function., Conclusions: Current knowledge of the cerebrospinal venous anatomy, dynamic flow characteristics in response to gravity, and the venous system's influence on CSF suggests that the VVP plays a role in influencing CSF pressure, and the authors hypothesize that it plays a role in supporting intracranial pressure in the upright body posture. Further research is needed to better characterize the functional relationship of the VVP to CSF dynamics as well as identify potentially related disease states.

Background: Sympathetic-mediated vasoconstriction from the superior cervical ganglion (SCG) is a significant contributor to cerebral vasospasm. Inhibition of the SCG has been shown to improve cerebral blood flow and reverse cerebral vasospasm in swine models. We evaluated the efficacy of a novel minimally invasive endovascular approach to target and pharmacologically inhibit the SCG, using a Micro-Infusion Device for transmural drug delivery., Methods: Eight SCGs in four Yorkshire swine were surgically identified. After confirming appropriate sympathetic-mediated intracranial vasoconstriction response with SCG stimulation, an endovascular Micro-Infusion Device was used for transmural targeting of the SCG and delivery of 1.5-2 mL of 1% lidocaine-contrast mixture to the perivascular space. Digital subtraction angiography was obtained at: (1) baseline; (2) with SCG stimulation; and (3) after lidocaine delivery to the SCG using the Micro-Infusion Device with concurrent SCG stimulation. Vessel diameters were measured and compared., Results: Endovascular transmural delivery of lidocaine to the SCG and carotid perivascular tissue using the Micro-Infusion Device successfully inhibited sympathetic-mediated vasoconstriction response. Measured vessel diameters after lidocaine delivery were comparable to baseline despite SCG stimulation., Conclusion: A novel endovascular technique of transmural delivery of lidocaine to the SCG and carotid artery perivascular tissues successfully inhibits the sympathetic input to the cerebral vasculature and modulates sympathetic-mediated cerebral vasospasm. These results suggest promising steps towards translation to potential clinical use for patients suffering from cerebral vasospasm., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the clinicopathological and genetic features of confined placental mosaicism (CPM) and its effect on fetal intrauterine growth. Methods: Fourteen CPM cases of Haidian Maternal and Children Health Hospital were collected from May 2018 to March 2022. Clinicopathological examination on placental specimens and molecular genetic analysis were performed. Results: The age of the parturient women ranged from 27 to 34 years, with an average age of (30.0±3.54) years. The gestational weeks ranged from 35 +1 to 41 +2 weeks. There were 4 premature births and 10 term births, among which 6 were female and 8 were male fetuses. Nine cases (9/14) had adverse pregnancy outcomes, including 7 cases of fetal growth restriction. The weight of CPM placenta decreased, with 6 cases below the 10th percentile of weight standards and 5 cases between the 10th and 25th percentile. All 14 CPM placental specimens showed morphological changes of perfusion dysfunction to varying degrees, with mainly placental-maternal vascular malperfusion followed by placental-fetal vascular malperfusion. The mosaic chromosomes in different CPM cases varied, with 16-trisomy/monosomy mosaicism being the most common followed by 7-trisomy and 21-trisomy/monosomy mosaicism. The mosaic proportion was unequal in different parts of the same CPM placenta, with the mosaic proportion of umbilical cord, fetal membranes, fetal surface, maternal surface, and edge ranging from 1% to 70%. Conclusions: The mosaic chromosomes in different CPM cases vary, and the mosaic proportion is unequal in different parts of the same CPM placenta. The pathological morphology is mainly manifested as perfusion dysfunction, which can lead to adverse pregnancy outcomes such as fetal growth restriction and preterm birth.

Purpose: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers., Methods: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institution's review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values., Results: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted., Conclusions: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort., (© 2024. The Author(s).)

Actin-interacting proteins are important molecules for filament assembly and cytoskeletal signaling within vascular endothelium. Disruption in their interactions causes endothelial pathogenesis through redox imbalance. Actin filament redox regulation remains largely unexplored, in the context of pharmacological treatment. This work focused on the peptidyl methionine (M) redox regulation of actin-interacting proteins, aiming at elucidating its role on governing antioxidative signaling and response. Endothelial EA.hy926 cells were subjected to treatment with salvianolic acid B (Sal B) and tert-butyl-hydroperoxide (tBHP) stimulation. Mass spectrometry was employed to characterize redox status of proteins, including actin, myosin-9, kelch-like erythroid-derived cap-n-collar homology-associated protein 1 (Keap1), plastin-3, prelamin-A/C and vimentin. The protein redox landscape revealed distinct stoichiometric ratios or reaction site transitions mediated by M sulfoxide reductase and reactive oxygen species. In comparison with effects of tBHP stimulation, Sal B treatment prevented oxidation at actin M325, myosin-9 M1489/1565, Keap1 M120, plastin-3 M592, prelamin-A/C M187/371/540 and vimentin M344. For Keap1, reaction site was transitioned within its scaffolding region to the actin ring. These protein M oxidation regulations contributed to the Sal B cytoprotective effects on actin filament. Additionally, regarding the Keap1 homo-dimerization region, Sal B preventive roles against M120 oxidation acted as a primary signal driver to activate nuclear factor erythroid 2-related factor 2 (Nrf2). Transcriptional splicing of non-POU domain-containing octamer-binding protein was validated during the Sal B-mediated overexpression of NAD(P)H dehydrogenase [quinone] 1. This molecular redox regulation of actin-interacting proteins provided valuable insights into the phenolic structures of Sal B analogs, showing potential antioxidative effects on vascular endothelium., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma., Methods: We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas ( n  = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings., Results: Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions., Conclusions: This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions., Competing Interests: The authors have declared that no conflict of interest exists., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: To investigate the clinical and genetic characteristics of a case of primary ciliary dyskinesia (PCD)., Methods: We collected the clinical data on a case of PCD treated in the Department of Reproductive Medicine of Linyi People's Hospital in July 2020, detected the genes of the patient by whole-exome sequencing (WES), verified the candidate mutations by Sanger sequencing, and predicted the protein structure of the mutant gene by SWISS-MODEL., Results: The proband was found with the clinical phenotypes of chronic rhinitis, bronchiectasis, visceral transposition and male infertility. WES revealed a homozygous frameshift variation of c.12890dup (p.N4297Kfs*13) in exon 74 of the DNAH5 gene, which led to the premature termination of polypeptide chain synthesis and affected the gene function. SWISS-MODEL prediction showed that some of the amino acid residues were deleted after mutation, resulting in a 3D conformational change of the protein. This variation was not recorded in the ClinVar, gnomAD and OMIM databases and, according to the relevant guidelines of the American College of Genetics and Genomics, was classified as a pathogenic variation (PVS1+PM2&#95;P+PM3&#95;P)., Conclusion: The homozygous variation of the DNAH5 gene c.12890dup (p.N4297Kfs*13) may be the cause of the clinical phenotype of this case of PCD, and the above findings have enriched the variation spectrum of the DNAH5 gene.

Objective: Complex middle cerebral artery (MCA) aneurysms incorporating parent or branching vessels are often not amenable to standard microsurgical clipping or endovascular embolization treatments. We aim to discuss the treatment of such aneurysms via a combination of surgical revascularization and aneurysm exclusion based on our institutional experience., Methods: Thirty-four patients with complex MCA aneurysms were treated with bypass and aneurysm occlusion, 5 with surgical clipping or wrapping only, and 1 with aneurysm excision and primary reanastomosis. Bypasses included superficial temporal artery (STA)-MCA, double-barrel STA-MCA, occipital artery-MCA, and external carotid artery-MCA. After bypass, aneurysms were treated by surgical clipping, Hunterian ligation, trapping, or coil embolization., Results: The average age at diagnosis was 46 years. Of the aneurysms, 67% were large and most involved the MCA bifurcation. Most bypasses performed were STA-MCA bypasses, 12 of which were double-barrel. There were 2 wound-healing complications. All but 2 of the aneurysms treated showed complete occlusion at the last follow-up. There were 3 hemorrhagic complications, 3 graft thromboses, and 4 ischemic insults. The mean follow-up was 73 months. Of patients, 83% reported stable or improved symptoms from presentation and 73% reported a functional status (Glasgow Outcome Scale score 4 or 5) at the latest available follow-up., Conclusions: Cerebral revascularization by bypass followed by aneurysm or parent artery occlusion is an effective treatment option for complex MCA aneurysms that cannot be safely treated by standard microsurgical or endovascular techniques. Double-barrel bypass consisting of 2 STA branches to 2 MCA branches yields adequate flow replacement in most cases., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy., Methods: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/)., Results: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%., Significance: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To discuss the treatment of intracranial fusiform and giant internal carotid artery (ICA) aneurysms via revascularization based on our institutional experience., Methods: An institutional review board-approved retrospective analysis was performed of patients with unruptured fusiform and giant intracranial ICA aneurysms treated from November 1991 to May 2020. All patients were evaluated for extracranial-intracranial (EC-IC) bypass and ICA occlusion., Results: Thirty-eight patients were identified. Initially, patients failing preoperative balloon test occlusion were treated with superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and concurrent proximal ICA ligation. We then treated them with STA-MCA bypass, followed by staged balloon test occlusion, and, if they passed, endovascular ICA coil occlusion. We treat all surgical medically uncomplicated patients with double-barrel STA-MCA bypass and concurrent proximal ICA ligation. The mean length of follow-up was 99 months. Symptom stability or improvement was noted in 85% of patients. Bypass graft patency was 92.1%, and all surviving patients had patent bypasses at their last angiogram. Aneurysm occlusion was complete in 90.9% of patients completing proximal ICA ligation. Three patients experienced ischemic complications and 4 patients experienced hemorrhagic complications., Conclusions: Not all fusiform intracranial ICA aneurysms require intervention, except when life-threatening rupture risk is high or symptomatic management is necessary to preserve function and quality of life. EC-IC bypass can augment the safety of proximal ICA occlusion. The rate of complete aneurysm occlusion with this treatment is 90.9%, and long-term bypass graft-related complications are rare. Perioperative stroke is a major risk, and continued evolution of treatment is required., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Recent advances in endovascular devices have allowed access and targeting of perivascular tissues of the peripheral circulation. The perivascular tissues of the cervical and cranial circulations have many important structures of clinical significance, yet the feasibility and safety of such an approach has not been demonstrated., Objective: To evaluate the safety of a novel endovascular transmural approach to target the perivascular tissues of the common carotid artery in swine., Methods: A micro-infusion device was positioned in the carotid arteries of three Yorkshire pigs (six carotid arteries in total), and each carotid artery was punctured 10 times in the same location to gain access to the perivascular tissues. Digital subtraction angiography was used to evaluate vessel injury or contrast extravasation. MRI and MR angiography were used to evaluate evidence of cerebral ischemia or vessel injury. Post-mortem tissue analysis was performed to assess the level of extravascular hematoma and intravascular dissection., Results: None of the tested carotid arteries showed evidence of vessel injury (dissection or perforation) or intravascular thrombosis. MRI performed after repeated puncture was negative for neck hematoma and brain ischemia. Post-mortem tissue analysis of the carotid arteries showed mild adventitial staining with blood, but without associated hematoma and without vessel dissection., Conclusion: Repeated puncture of the carotid artery to gain access to the perivascular tissues using a novel endovascular transmural approach is safe in a swine model. This represents a novel approach to various tissues in close proximity to the cervical and cranial vasculature., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Although prior research predicts mainly that followers expect leaders to exert less paternalistic control (such as emphasis on discipline, didactic instruction, and belittling followers), we argue that such an expectation may not be stable overtime or across settings. Based on the connectionist perspectives of implicit leadership theories, we propose a follower expectation model of paternalistic control, in which followers compare their perceived with expected levels of paternalistic control. Two inconsistent conditions-insufficient and excessive control-are identified, and the consistency between perceived and expected paternalistic control is predicted to relate to favorable follower outcomes. We examine this model by conducting two daily experience sampling studies in Taiwan. Our findings indicate that insufficient control is as unfavorable as excessive control in lowering followers' job satisfaction and citizenship behavior, and this pattern is particularly salient in terms of emphasis on discipline and the belittling of followers. A supplemental, qualitative analysis additionally demonstrated the conditions under which the expectation-perception consistency regarding belittling followers relates to favorable follower responses. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Bacterial lipopolysaccharide (LPS) is a toxic stimulant to macrophage inflammation. Inflammation intersects cell metabolism and often directs host immunopathogenesis stress. We aim here at pharmacological discovering of formononetin (FMN) action, to which anti-inflammatory signaling spans across immune membrane receptors and second messenger metabolites. In ANA-1 macrophage stimulated by LPS, and simultaneous treatment with FMN, results show the Toll-like receptor 4 (TLR4) and estrogen receptor (ER) signals, in concert with reactive oxygen species (ROS) and cyclic adenosine monophosphate (cAMP), respectively. LPS stimulates inactivation of the ROS-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) by upregulating TLR4, but it does not affect cAMP. However, FMN treatment not only activates Nrf2 signaling by TLR4 inhibition, but also it activates cAMP-dependent protein kinase activities by upregulating ER. The cAMP activity gives rise to phosphorylation (p-) of protein kinase A, liver kinase B1 and 5'-AMP activated protein kinase (AMPK). Moreover, bidirectional signal crosstalk is amplified between p-AMPK and ROS, as FMN combinational validation with AMPK activator/inhibitor/target small-interfering RNA or ROS scavenger. The signal crosstalk is well positioned serving as the 'plug-in' knot for rather long signaling axis, and the immune-to-metabolic circuit via ER/TLR4 signal transduction. Collectively, convergence of the FMN-activated signals drives significant reduction of cyclooxygenase-2, interleukin-6 and NLR family pyrin domain-containing protein 3, in LPS-stimulated cell. Although anti-inflammatory signaling is specifically related to the immune-type macrophage, the p-AMPK antagonizing effect arises from FMN combination with ROS scavenger H-bond donors. Information of our work assists in predictive traits against macrophage inflammatory challenges, using phytoestrogen discoveries., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Qing-Shan Li reports financial support was provided by the Key Research and Development Plan (Key Project) of Shanxi Province. Yuan-Biao Qiao reports financial support was provided by the Fundamental Research Program (Free Exploration) of Shanxi Province. Yuan-Biao Qiao reports financial support was provided by the Scientific Research Initiation Fund for Doctors, Shanxi University of Traditional Medicine., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Despite a renewed focus in recent years on pain management in the inpatient hospital setting, postoperative pain after elective craniotomy remains under investigated. This study aims to identify which perioperative factors associate most strongly with postoperative pain and opioid medication requirements after inpatient craniotomy., Materials and Methods: Using an existing dataset, we selected a restricted cohort of patients who underwent elective craniotomy surgery requiring an inpatient postoperative stay during a 7-year period at our institution (n=1832). We examined pain scores and opioid medication usage and analyzed the relative contribution of specific perioperative risk factors to postoperative pain and opioid medication intake (morphine milligram equivalents)., Results: Postoperative pain was found to be highest on postoperative day 1 and decreased thereafter (up to day 5). Factors associated with greater postoperative opioid medication requirement were preoperative opioid medication use, duration of anesthesia, degree of pain in the preoperative setting, and patient age. Notably, the most significant factor associated with a higher postoperative pain score and Morphine milligram equivalents requirement was the time elapsed between the end of general anesthesia and a patient's first intravenous opioid medication., Conclusion: Postcraniotomy patients are at higher risk for requiring opioid pain medications if they have a history of preoperative opioid use, are of younger age, or undergo a longer surgery. Moreover, early requirement of intravenous opioid medications in the postoperative period should alert treating physicians that a patient's pain may require additional or alternative methods of pain control than routinely administered, to avoid over-reliance on opioid medications., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Lower-grade gliomas exhibit a high prevalence of isocitrate dehydrogenase 1 (IDH1) mutations, but faithful models for studying these tumors are lacking. Here, we present a protocol to establish a genetically engineered mouse (GEM) model of grade 3 astrocytoma driven by the Idh1 R132H oncogene. We describe steps for breeding compound transgenic mice and intracranially delivering adeno-associated virus particles, followed by post-surgical surveillance via magnetic resonance imaging. This protocol enables the generation and use of a GEM to study lower-grade IDH-mutant gliomas. For complete details on the use and execution of this protocol, please refer to Shi et al. (2022). 1 ., Competing Interests: Declaration of interests W.G.K. and S.K.M. have served as paid advisors to Agios Pharmaceuticals. W.G.K. receives compensation for roles as an Eli Lilly and LifeMine Therapeutics Board Director, a founder of Tango Therapeutics and Cedilla Therapeutics, and a scientific advisor for Fibrogen, IconOVir Bio, Circle Pharma, Nextech Invest, and Casdin Capital., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many patients with advanced cancer have misperceptions of their prognosis, which may impact end-of-life decision-making. Data regarding associations between prognostic perceptions over time and end-of-life care outcomes are lacking., Aim: To describe patients' perceptions of their prognosis with advanced cancer and examine associations between these perceptions and end-of-life care outcomes., Design: Secondary analysis of longitudinal data from a randomized controlled trial of a palliative care intervention for patients with newly diagnosed incurable cancer., Setting/participants: Conducted at an outpatient cancer center in the northeastern United States and patients were within 8 weeks of a diagnosis with incurable lung or non-colorectal gastrointestinal cancer., Results: We enrolled 350 patients in the parent trial, of which 80.5% (281/350) died during the study period. Overall, 59.4% (164/276) of patients reported they were terminally ill, and 66.1% (154/233) reported that their cancer was likely curable at the assessment closest to death. Patient acknowledgment of terminal illness was only associated with lower risk of hospitalizations in the last 30 days of life (OR = 0.52, p  = 0.025). Patients who reported their cancer as likely curable were less likely to utilize hospice (OR = 0.25, p  = 0.002) or die at home (OR = 0.56, p  = 0.043), and they were more likely to be hospitalized in the last 30 days of life (OR = 2.28, p  = 0.011)., Conclusions: Patients' perceptions of their prognosis are associated with important end-of-life care outcomes. Interventions are needed to enhance patients' perceptions of their prognosis and optimize their end-of-life care.

c-Jun N-terminal kinase (JNK) phosphorylation is widely observed during virus infection, modulating various aspects of the virus-host interaction. In our previous research, we have proved that B. mori ferritin heavy-chain homolog (BmFerHCH), an inhibitor of reactive oxygen species (ROS), facilitates B. mori nucleopolyhedrovirus (BmNPV) proliferation. However, one question remains: Which downstream signaling pathways does BmFerHCH regulate by inhibiting ROS? Here, we first determined that silencing BmFerHCH inhibits BmNPV proliferation, and this inhibition depends on ROS. Then, we substantiated that BmNPV infection activates the JNK signaling pathway. Interestingly, the JNK phosphorylation during BmNPV infection is activated by ROS. Further, we found that the enhanced nuclear translocation of phospho-JNK induced by BmNPV infection was dramatically reduced by pretreatment with the antioxidant N-acetylcysteine (NAC), whereas there was more detectable phospho-JNK in the cytoplasm. Next, we investigated how changes in BmFerHCH expression affect JNK phosphorylation. BmFerHCH overexpression suppressed the phosphorylation of JNK and nuclear translocation of phospho-JNK during BmNPV infection, whereas BmFerHCH knockdown facilitated phosphorylation of JNK and nuclear translocation of phospho-JNK. By measuring the viral load, we found the inhibitory effect of BmFerHCH knockdown on BmNPV infection depends on phosphorylated JNK. In addition, the JNK signaling pathway was involved in BmNPV-triggered apoptosis. Hence, we hypothesize that ROS-mediated JNK phosphorylation is involved in the regulation of BmFerHCH on BmNPV proliferation. These results elucidate the molecular mechanisms and signaling pathways of BmFerHCH-mediated response to BmNPV infection., Competing Interests: Declaration of competing interest The authors disclose no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

In the photovoltaic community, short circuit current (I sc ) of a current mismatched multijunction photovoltaic (MJPV) cell was usually thought to be limited by the lowest subcell photocurrent (I min ). However, under certain conditions for multijunction solar cells, I sc ≠I min was observed by researchers, while this effect has not been studied in multijunction laser power converters (MJLPCs). In this work, we provide an in-depth analysis of the formation mechanisms for the I sc of the MJPV cell by measuring I-V curves of the GaAs and InGaAs LPCs with different number of subcells and simulating the I-V curves with the reverse breakdown of each subcell considered. It is found that I sc of an N-junction PV cell can be theoretically equal to any current value within a range from a current lower than I min to the maximum subcell photocurrent, which is up to the number of subcell current steps in the forward biased I-V curve. An MJPV cell with a constant I min will demonstrate a higher I sc if it has more subcells, smaller subcell reverse breakdown voltage and smaller series resistance. As a result, I sc tends to be limited by the photocurrent of a subcell closer to the middle cell and is less sensitive to the optical wavelength than I min . This should be another possible reason why the measured EQE of a multijunction LPC exhibits a wider spectrum width than the calculated I min -based EQE, whereas this was usually attributed to the luminescent coupling effect merely.

Aneurysmal subarachnoid hemorrhage is a life-threatening, neurological emergency characterized by accumulation of blood in the subarachnoid space due to a ruptured aneurysm. Over the past several decades, improvements in the clinical management of aneurysmal subarachnoid hemorrhage have led to better patient outcomes. However, aneurysmal subarachnoid hemorrhage is still associated with high morbidity and mortality. During the acute phase of aneurysmal subarachnoid hemorrhage and prior to the definitive management of the aneurysm, numerous medical emergencies, such as elevated intracranial pressure and cerebral vasospasm, must be effectively managed to ensure the best possible neurological outcome. Early and rapid open communication between the clinical specialties caring for the aneurysmal subarachnoid hemorrhage patient is vital for rapid data collection, decision-making, and definitive treatment. In this narrative review, we aim to present the current guidelines for the multidisciplinary acute management of aneurysmal subarachnoid hemorrhage.

Objective: The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children., Methods: Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed., Results: A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications., Conclusions: SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

Background: Extracranial to intracranial bypass is used to augment and/or replace the intracranial circulation for various pathologies. The superficial temporal artery is the mainstay donor for pedicled bypasses to the anterior circulation but can be limited by its variable size, low native flow rates, and potential scalp complications. Interposition grafts such as the radial artery or greater saphenous vein are alternatives but are sometimes limited by size mismatch, length needed to reach the extracranial circulation, and loss of inherent vascular elasticity. Interposition grafts between the maxillary artery (IMA) and middle cerebral artery (MCA) address these limitations., Objective: To explore the feasibility of harvesting the IMA through an endoscopic transnasal, transmaxillary approach to perform a direct IMA to MCA bypass., Methods: Combined transcranial and endoscopic endonasal dissections were performed in embalmed human cadavers to harvest the IMAs for intracranial transposition and direct anastomosis to the MCA. Donor and recipient vessel calibers were measured and recorded., Results: A total of 8 procedures were performed using the largest and distal-most branches of the IMA (the sphenopalatine branch and the descending palatine branch) as pedicled conduits to second division of middle cerebral artery (M2) recipients. The mean diameter of the IMA donors was 1.89 mm (SD ± 0.42 mm), and the mean diameter of the recipient M2 vessels was 1.90 mm (SD ± 0.46 mm)., Conclusion: Endoscopic harvest of the IMA using a transnasal, transmaxillary approach is a technically feasible option offering an excellent size match to the M2 divisions of the MCA and the advantages of a relatively short, pedicled donor vessel., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Crouzon Syndrome is a genetic craniosynostosis disorder associated with a high risk of ophthalmologic sequelae secondary to structural causes. However, ophthalmologic disorders due to intrinsic nerve aberrations in Crouzon Syndrome have not been described. Optic pathway gliomas (OPGs) are low grade gliomas that are intrinsic to the visual pathway, frequently associated with Neurofibromatosis type 1 (NF-1). OPGs involving both optic nerves without affecting the optic chiasm are rarely seen outside of NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month-old male patient with Crouzon Syndrome without any clinical or genetic findings of NF-1. This case suggests that close ophthalmologic follow up and orbital MRIs may benefit patients with Crouzon Syndrome.

Mitochondrion-related cardiotoxicity due to cardiotoxin stimuli is closely linked to abnormal activities of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), followed by co-inactivation of nuclear respiratory factor-1(NRF1). Pharmacological interventions targeting mitochondria may be effective for developing agents against cardiotoxicity. Herein, in triptolide-treated H9C2 cardiomyocytes, we observed defective mitochondrial biogenesis and respiration, characterized by depletion of mitochondrial mass and mitochondrial DNA copy number, downregulation of mitochondrial respiratory chain complexes subunits, and disorders of mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Dysregulation of mitochondria led to cardiac pathological features, such as myocardial fiber fracture, intercellular space enlargement, and elevation of serum aspartate aminotransferase, creatine kinase isoenzyme, lactate dehydrogenase, and cardiac troponin I. However, following calycosin treatment, an active compound from Astragali Radix, the mitochondrion-related disorders at both cell and tissue levels were significantly ameliorated, which was facilitated by the activation of PGC-1α via deacetylation, followed by NRF1 co-activation. Calycosin-enhanced PGC-1α deacetylation is impelled by increasing sirtuin-1 expression and NAD + /NADH ratio. PGC-1α/NRF1 signaling in calycosin-mediated mitochondrial biogenesis protection was further confirmed by NRF1 knockdown and PGC-1α inhibition with SR18292. We conclude that calycosin ameliorated triptolide-induced cardiotoxicity by protecting PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis and respiration, which is the druggable pathway for cardiotoxicity mitigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The prevalence rates of hepatitis B and C virus (HBV/HCV) infection are high in Taiwan, and both are common causes of chronic liver disease and its related complications. Therefore, the early detection of factors associated with HBV/HCV infection is important. The aim of this study was to explore these factors in a large cohort of Taiwanese participants in the Taiwan Biobank, and also to identify sex differences in these risk factors., Methods: It was an observational cohort study. The study enrolled 121,421 participants, and divided into four groups according to the presence or absence of HBV or HCV infection. Associations between risk factors with HBV or HCV infection were examined using multivariate logistic regression analysis., Results: The mean age of the 121,421 enrolled participants (43,636 men and 77,785 women) was 49.9 ± 11.0 years. The participants were stratified into four groups according to those with ( n = 13,804; 11.4%) and without HBV infection ( n = 107,617; 88.6%), and those with ( n = 2,750; 2.3%) and without HCV infection ( n = 118,671; 97.7%). Multivariable analysis revealed that male sex [vs. female sex; odds ratio [OR] = 1.346; 95% confidence interval (CI) = 1.282-1.414; p < 0.001] was significantly associated with HBV infection, whereas female sex (vs. male sex; OR = 0.642; 95% CI = 0.575-0.716; p < 0.001) was significantly associated with HCV infection. Furthermore, there were significant interactions between sex and age ( p < 0.001), body mass index ( p < 0.001), total cholesterol ( p = 0.002), aspartate aminotransferase ( p = 0.024), and estimated glomerular filtration rate ( p = 0.012) on HBV infection. There were also significant interactions between sex and age ( p < 0.001), hypertension ( p = 0.010), fasting glucose ( p = 0.031), and uric acid ( p = 0.001) on HCV infection., Conclusion: In conclusion, sex differences were found among the risk factors for HBV and HCV infections in a large cohort of Taiwanese volunteers. When dealing with hepatitis B and hepatitis C, the physicians may need to pay attention to the differences between men and women to do different treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Geng, Wang, Wu and Chen.)

Background and Objectives: While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms., Methods: We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results., Results: Somatic variants involved in supervillin ( SVIL ) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway., Discussion: We propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation., Competing Interests: Declaration of interests R.J.D., W.G.K., and S.K.M. have served as paid advisors to Agios Pharmaceuticals. W.G.K. receives compensation for roles as an Eli Lilly and LifeMine Therapeutics Board Director, a founder of Tango Therapeutics and Cedilla Therapeutics, and a scientific advisor for Fibrogen, IconOVir Bio, Circle Pharma, Nextext Invest, and Casdin Capital. K.L.L. receives research support from Eli Lilly and Company via the DFCI. S.K.M. and W.G.K. received research funding from Bayer Pharmaceuticals. Bayer had no influence over the design, execution, or interpretation of studies. N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. S.G., A.S., M.S., A.J., and L.E. are employees at Bayer. S.G., A.S., and A.J. hold stock in Bayer. D.P.C. has consulted for Lilly, GlaxoSmithKline, and Boston Pharmaceuticals and serves on the advisory board of Pyramid Biosciences, which includes an equity interest. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Cerebral vasospasm is a complex disease resulting in reversible narrowing of blood vessels, stroke, and poor patient outcomes. Sympathetic perivascular nerve fibers originate from the superior cervical ganglion (SCG) to innervate the cerebral vasculature, with activation resulting in vasoconstriction. Sympathetic pathways are thought to be a significant contributor to cerebral vasospasm., Objective: We sought to demonstrate that stimulation of SCG in swine can cause ipsilateral cerebral perfusion deficit similar to that of significant human cerebral vasospasm. Furthermore, we aimed to show that inhibition of SCG can block the effects of sympathetic-mediated cerebral hypoperfusion., Methods: SCG were surgically identified in 15 swine and were electrically stimulated to achieve sympathetic activation. CT perfusion scans were performed to assess for changes in cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time-to-maximum (TMax). Syngo.via software was used to determine regions of interest and quantify perfusion measures., Results: SCG stimulation resulted in 20-30% reduction in mean ipsilateral CBF compared to its contralateral unaffected side (p < 0.001). Similar results of hypoperfusion were seen with CBV, MTT and TMax with SCG stimulation. Prior injection of lidocaine to SCG inhibited the effects of SCG stimulation and restored perfusion comparable to baseline (p > 0.05)., Conclusion: In swine, SCG stimulation resulted in significant cerebral perfusion deficit, and this was inhibited by prior local anesthetic injection into the SCG. Inhibiting sympathetic activation by targeting the SCG may be an effective treatment for sympathetic mediated cerebral hypoperfusion., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Importance: Pediatric patients with high-grade gliomas have a poor prognosis. The association among the extent of resection, tumor location, and survival in these patients remains unclear., Objective: To ascertain whether gross total resection (GTR) in hemispheric, midline, or infratentorial pediatric high-grade gliomas (pHGGs) is independently associated with survival differences compared with subtotal resection (STR) and biopsy at 1 year and 2 years after tumor resection., Data Sources: PubMed, EBMR, Embase, and MEDLINE were systematically reviewed from inception to June 3, 2022, using the keywords high-grade glioma, pediatric, and surgery. No period or language restrictions were applied., Study Selection: Randomized clinical trials and cohort studies of pHGGs that stratified patients by extent of resection and reported postoperative survival were included for study-level and individual patient data meta-analyses., Data Extraction and Synthesis: Study characteristics and mortality rates were extracted from each article. Relative risk ratios (RRs) were pooled using random-effects models. Individual patient data were evaluated using multivariate mixed-effects Cox proportional hazards regression modeling. The PRISMA reporting guideline was followed, and the study was registered a priori., Main Outcomes and Measures: Hazard ratios (HRs) and RRs were extracted to indicate associations among extent of resection, 1-year and 2-year postoperative mortality, and overall survival., Results: A total of 37 studies with 1387 unique patients with pHGGs were included. In study-level meta-analysis, GTR had a lower mortality risk than STR at 1 year (RR, 0.69; 95% CI, 0.56-0.83; P < .001) and 2 years (RR, 0.74; 95% CI, 0.67-0.83; P < .001) after tumor resection. Subtotal resection was not associated with differential survival compared with biopsy at 1 year (RR, 0.82; 95% CI, 0.66-1.01; P = .07) but had decreased mortality risk at 2 years (RR, 0.89; 95% CI, 0.82-0.97; P = .01). The individual patient data meta-analysis of 27 articles included 427 patients (mean [SD] age at diagnosis, 9.3 [5.9] years), most of whom were boys (169 of 317 [53.3%]), had grade IV tumors (246 of 427 [57.7%]), and/or had tumors that were localized to either the cerebral hemispheres (133 of 349 [38.1%]) or midline structures (132 of 349 [37.8%]). In the multivariate Cox proportional hazards regression model, STR (HR, 1.91; 95% CI, 1.34-2.74; P < .001) and biopsy (HR, 2.10; 95% CI, 1.43-3.07; P < .001) had shortened overall survival compared with GTR but no survival differences between them (HR, 0.91; 95% CI, 0.67-1.24; P = .56). Gross total resection was associated with prolonged survival compared with STR for hemispheric (HR, 0.29; 95% CI, 0.15-0.54; P < .001) and infratentorial (HR, 0.44; 95% CI, 0.24-0.83; P = .01) tumors but not midline tumors (HR, 0.63; 95% CI, 0.34-1.19; P = .16)., Conclusions and Relevance: Results of this study show that, among patients with pHGG, GTR is independently associated with better overall survival compared with STR and biopsy, especially among patients with hemispheric and infratentorial tumors, and support the pursuit of maximal safe resection in the treatment of pHGGs.

Purpose: To improve the performance of less experienced clinicians in the diagnosis of benign and malignant spinal fracture on MRI, we applied the ResNet50 algorithm to develop a decision support system., Methods: A total of 190 patients, 50 with malignant and 140 with benign fractures, were studied. The visual diagnosis was made by one senior MSK radiologist, one fourth-year resident, and one first-year resident. The MSK radiologist also gave the binary score for 15 qualitative imaging features. Deep learning was implemented using ResNet50, using one abnormal spinal segment selected from each patient as input. The T1W and T2W images of the lesion slice and its two neighboring slices were considered. The diagnostic performance was evaluated using tenfold cross-validation., Results: The overall reading accuracy was 98, 96, and 66% for the senior MSK radiologist, fourth-year resident, and first-year resident, respectively. Of the 15 imaging features, 10 showed a significant difference between benign and malignant groups with p <  = 0.001. The accuracy achieved by using the ResNet50 deep learning model for the identified abnormal vertebral segment was 92%. Compared to the first-year resident's reading, the model improved the sensitivity from 78 to 94% (p < 0.001) and the specificity from 61 to 91% (p < 0.001)., Conclusion: Our deep learning-based model may provide information to assist less experienced clinicians in the diagnosis of spinal fractures on MRI. Other findings away from the vertebral body need to be considered to improve the model, and further investigation is required to generalize our findings to real-world settings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with high-risk acute myeloid leukemia (AML) often experience intensive medical care at the end of life (EOL), including high rates of hospitalizations and intensive care unit (ICU) admissions. Despite this, studies examining code status transitions are lacking. We conducted a mixed-methods study of 200 patients with high-risk AML enrolled in supportive care studies at Massachusetts General Hospital between 2014 and 2021. We defined high-risk AML as relapsed/refractory or diagnosis at age ≥60. We used a consensus-driven medical record review to characterize code status transitions. At diagnosis, 86.0% (172/200) of patients were "full code" (38.5% presumed, 47.5% confirmed) and 8.5% had restrictions on life-sustaining therapies. Overall, 57.0% of patients experienced a transition during the study period. The median time from the last transition to death was 2 days (range, 0-350). Most final transitions (71.1%) were to comfort measures near EOL; only 60.5% of patients participated in these last transitions. We identified 3 conversation types leading to transitions: informative conversations focusing on futility after clinical deterioration (51.0%), anticipatory conversations at the time of acute deterioration (32.2%), and preemptive conversations (15.6%) before deterioration. Younger age (B = 0.04; P = .002) and informative conversations (B = -2.79; P < .001) were associated with shorter time from last transition to death. Over two-thirds of patients were "presumed full code" at diagnosis of high-risk AML, and most experienced code status transitions focused on the futility of continuing life-sustaining therapies near EOL. These results suggest that goals-of-care discussions occur late in the illness course for patients with AML and warrant interventions to increase earlier discussions regarding EOL preferences., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Social support is essential to the recovery of patients who have undergone hematopoietic stem cell transplantation (HSCT). We undertook a qualitative study to explore the specific sources and benefits of social support as experienced by HSCT recipients, as well as their unmet social support needs. We conducted semistructured interviews with 25 HSCT recipients recruited from the Dana Farber Cancer Institute's HSCT database. The interviews explored the sources of support that patients receive, the type of assistance social support networks provide to patients, and unmet needs of social support. Interviews were audio-recorded, transcribed, and coded using Dedoose software. The median age of participants was 63 years (range, 22 to 73 years), and 13 (52%) were female, 20 (80%) were white, and 9 (36%) had been diagnosed with acute myelogenous leukemia. Participants reported receiving a majority of support from immediate family and close friends, with the primary benefits of social support including help with essential daily tasks and household chores, and receipt of emotional support. Participants reported occasional support from other patients but highlighted a desire for increased connection with patients who have undergone the same treatment. Participants also communicated a desire for more guidance on how to optimize the support they do receive and the need for more educational resources for caregivers and supporters to enhance understanding of the HSCT process and lessen patient burden. Participants reported relying on support from their family, friends, and other social connections for essential aspects of their recovery and daily living following HSCT. Although there are many benefits from these relationships, patients emphasized the need for more guidance and resources to facilitate post-transplantation aid and support., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer's disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD., Methods: Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimer's Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication., Results: Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Aβ or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers., Conclusions: The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD., (© 2022. The Author(s).)

Down syndrome (DS) is characterized by chronic neuroinflammation, peripheral inflammation, astrogliosis, imbalanced excitatory/inhibitory neuronal function, and cognitive deficits in both humans and mouse models. Suppression of inflammation has been proposed as a therapeutic approach to treating DS co-morbidities, including intellectual disability (DS/ID). Conversely, we discovered previously that treatment with the innate immune system stimulating cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which has both pro- and anti-inflammatory activities, improved cognition and reduced brain pathology in a mouse model of Alzheimer's disease (AD), another inflammatory disorder, and improved cognition and reduced biomarkers of brain pathology in a phase II trial of humans with mild-to-moderate AD. To investigate the effects of GM-CSF treatment on DS/ID in the absence of AD, we assessed behavior and brain pathology in 12-14 month-old DS mice (Dp[16]1Yey) and their wild-type (WT) littermates, neither of which develop amyloid, and found that subcutaneous GM-CSF treatment (5 μg/day, five days/week, for five weeks) improved performance in the radial arm water maze in both Dp16 and WT mice compared to placebo. Dp16 mice also showed abnormal astrocyte morphology, increased percent area of GFAP staining in the hippocampus, clustering of astrocytes in the hippocampus, and reduced numbers of calretinin-positive interneurons in the entorhinal cortex and subiculum, and all of these brain pathologies were improved by GM-CSF treatment. These findings suggest that stimulating and/or modulating inflammation and the innate immune system with GM-CSF treatment may enhance cognition in both people with DS/ID and in the typical aging population., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)