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Intracranial epidermoid cysts (ECs) are rare, benign lesions typically found in the cerebellopontine angle, suprasellar spaces, and middle cranial fossa. While these cysts are congenital, originating from ectodermal cell remnants during embryogenesis, it is not until middle age that patients present with symptoms secondary to local mass effect. Here, we present an interesting case of an EC arising from the midline anterior skull base in a 69-year-old male, presenting with symptoms ensuing from the spontaneous rupture of cyst contents into the brain parenchyma. As this is a highly unusual location and presentation for intracranial ECs, this report provides valuable information to the literature on ECs., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Leavitt et al.)

Background and Objectives: Stereotactic radiosurgery (SRS) with neoadjuvant embolization is a treatment strategy for brain arteriovenous malformations (AVMs), especially for those with large nidal volume or concomitant aneurysms. The aim of this study was to assess the effects of pre-SRS embolization in AVMs with an associated intracranial aneurysm (IA)., Methods: The International Radiosurgery Research Foundation AVM database from 1987 to 2018 was retrospectively reviewed. SRS-treated AVMs with IAs were included. Patients were categorized into those treated with upfront embolization (E + SRS) vs stand-alone SRS (SRS). Primary end point was a favorable outcome (AVM obliteration + no permanent radiation-induced changes or post-SRS hemorrhage). Secondary outcomes included AVM obliteration, mortality, follow-up modified Rankin Scale, post-SRS hemorrhage, and radiation-induced changes., Results: Forty four AVM patients with associated IAs were included, of which 23 (52.3%) underwent pre-SRS embolization and 21 (47.7%) SRS only. Significant differences between the E + SRS vs SRS groups were found for AVM maximum diameter (1.5 ± 0.5 vs 1.1 ± 0.4 cm3, P = .019) and SRS treatment volume (9.3 ± 8.3 vs 4.3 ± 3.3 cm3, P = .025). A favorable outcome was achieved in 45.4% of patients in the E + SRS group and 38.1% in the SRS group (P = .625). Obliteration rates were comparable (56.5% for E + SRS vs 47.6% for SRS, P = .555), whereas a higher mortality rate was found in the SRS group (19.1% vs 0%, P = .048). After adjusting for AVM maximum diameter, SRS treatment volume, and maximum radiation dose, the likelihood of achieving favorable outcome and AVM obliteration did not differ between groups (P = .475 and P = .820, respectively)., Conclusion: The likelihood of a favorable outcome and AVM obliteration after SRS with neoadjuvant embolization in AVMs with concomitant IA seems to be comparable with stand-alone SRS, even after adjusting for AVM volume and SRS maximum dose. However, the increased mortality among the stand-alone SRS group and relatively low risk of embolization-related complications suggest that these patients may benefit from a combined treatment approach., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Federally qualified health centers (FQHC) aim to improve cancer prevention by providing screening options and efforts to prevent harmful behavior. Patient portals are increasingly being used to deliver health promotion initiatives. However, little is known about patient portal activation rates in FQHC settings and the factors associated with activation. This study examined patient portal activation among FQHC patients and assessed correlations with demographic, clinical, and health service use variables. We analyzed electronic health record data from adults >18 years old with at least one appointment. Data were accessed from the electronic health records for patients seen between 1 September 2018 and 31 August 2022 (n = 40,852 patients). We used multivariate logistic regression models to examine the correlates of having an activated EPIC-supported MyChart patient portal account. One-third of patients had an activated MyChart portal account. Overall, 35% of patients with an activated account had read at least one portal message, 69% used the portal to schedule an appointment, and 90% viewed lab results. Demographic and clinical factors associated with activation included younger age, female sex, white race, English language, being partnered, privately insured, non-smoking, and diagnosed with a chronic disease. More frequent healthcare visits were also associated with an activated account. Whether or not a patient had an email address in the EHR yielded the strongest association with patient portal activation. Overall, 39% of patients did not have an email address; only 2% of those patients had activated their accounts, compared to 54% of those with an email address. Patient portal activation rates were modest and associated with demographic, clinical, and healthcare utilization factors. Patient portal usage to manage one's healthcare needs is increasing nationally. As such, FQHC clinics should enhance efforts to improve the uptake and usage of patient portals, including educational campaigns and eliminating email requirements for portal activation, to reinforce cancer prevention efforts.

Objective: Assess the feasibility and concurrent validity of a modified Uniform Data Set version 3 (UDSv3) for remote administration for individuals with normal cognition (NC), mild cognitive impairment (MCI), and early dementia., Method: Participants (N = 93) (age: 72.8 [8.9] years; education: 15.6 [2.5] years; 72% female; 84% White) were enrolled from the Wake Forest ADRC. Portions of the UDSv3 cognitive battery, plus the Rey Auditory Verbal Learning Test, were completed by telephone or video within ~6 months of participant's in-person visit. Adaptations for phone administration (e.g., Oral Trails for Trail Making Test [TMT] and Blind Montreal Cognitive Assessment [MoCA] for MoCA) were made. Participants reported on the pleasantness, difficulty, and preference for each modality. Staff provided validity ratings for assessments. Participants' remote data were adjudicated by cognitive experts blinded to the in person-diagnosis (NC [N = 44], MCI [N = 35], Dementia [N = 11], or other [N = 3])., Results: Remote assessments were rated as pleasant as in-person assessments by 74% of participants and equally difficult by 75%. Staff validity rating (video = 92%; phone = 87.5%) was good. Concordance between remote/in-person scores was generally moderate to good (r = .3 -.8; p < .05) except for TMT-A/OTMT-A (r = .3; p > .05). Agreement between remote/in-person adjudicated cognitive status was good (k = .61-.64)., Conclusions: We found preliminary evidence that older adults, including those with cognitive impairment, can be assessed remotely using a modified UDSv3 research battery. Adjudication of cognitive status that relies on remotely collected data is comparable to classifications using in-person assessments., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Intraoperative rupture (IOR) is the most common adverse event encountered during surgical clip obliteration of ruptured intracranial aneurysms. Besides increasing surgeon experience and early proximal control, no methods exist to decrease IOR risk. Thus, our objective was to assess if partial endovascular coil embolization to protect the aneurysm before clipping decreases IOR., Methods: We conducted a retrospective analysis of patients with ruptured intracranial aneurysms that were treated with surgical clipping at two tertiary academic centers. We compared patient characteristics and outcomes of those who underwent partial endovascular coil embolization to protect the aneurysm before clipping to those who did not. The primary outcome was IOR. Secondary outcomes were inpatient mortality and discharge destination., Results: We analyzed 100 patients. Partial endovascular aneurysm protection was performed in 27 patients. Age, sex, subarachnoid hemorrhage severity, and aneurysm location were similar between the partially-embolized and non-embolized groups. The median size of the partially-embolized aneurysms was larger (7.0 mm [interquartile range 5.95-8.7] vs. 4.6 mm [3.3-6.0]; P < 0.001). During surgical clipping, IOR occurred less frequently in the partially-embolized aneurysms than non-embolized aneurysms (2/27, 7.4%, vs. 30/73, 41%; P = 0.001). Inpatient mortality was 14.8% (4/27) in patients with partially-embolized aneurysms and 28.8% (21/73) in patients without embolization (P = 0.20). Discharge to home or inpatient rehabilitation was 74.0% in patients with partially-embolized aneurysms and 56.2% in patients without embolization (P = 0.11). A complication from partial embolization occurred in 2/27 (7.4%) patients., Conclusions: Preoperative partial endovascular coil embolization of ruptured aneurysms is associated with a reduced frequency of IOR during definitive treatment with surgical clip obliteration. These results and the impact of preoperative partial endovascular coil embolization on functional outcomes should be confirmed with a randomized trial., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: A growing body of literature examines the utility of emotion-focused parenting programs, as behaviorally based programs currently dominate the parenting literature. Few of those studies examine differences in how Black parents may benefit. This mixed-methods pilot study examined preliminary fidelity, efficacy, and acceptability of Tuning in to Kids (TIK), an emotion-focused parenting program targeting parenting practices and children's emotion regulation through a strengths-based approach., Methods: Pre, post, and one-month follow-up measurements were collected from 21 parents in the United States who were randomly assigned to a treatment (i.e., TIK) or waitlist control group. They were assessed across several self-report parent measures (parental emotion regulation, emotion socialization parenting practices and beliefs) and parent-report of children's social-emotional competence. Parents in the TIK group completed interviews to further understand their experience participating in the intervention., Results: Descriptive analyses showed general improvements and positive change in parenting practices, beliefs, parental emotion regulation, and children's self-regulation. Large effect sizes indicate reductions of parents emotion dismissing and distressed reactions to children's negative emotions. TIK was overall rated as a highly acceptable intervention. Parent interviews offer essential information to provide context to Black parents' experiences utilizing TIK as well as themes related to challenges in raising Black children with self-regulation difficulties., Conclusions: Overall, these preliminary mixed-methods outcomes suggest that TIK is a promising parenting program to improve Black parents' emotion regulation, emotion coaching beliefs and positive parenting practices. Further research is needed to investigate the effectiveness of TIK and other emotion-focused parenting programs with Black parents and assess the necessity of future cultural adaptations.

Glioblastoma (GBM) is a highly invasive, aggressive brain cancer that carries a median survival of 15 months and is resistant to standard therapeutics. Recent studies have demonstrated that intratumoral heterogeneity plays a critical role in promoting resistance by mediating tumor adaptation through microenvironmental cues. GBM can be separated into two distinct regions-a core and a rim, which are thought to drive specific aspects of tumor evolution. These differences in tumor progression are regulated by the diverse biomolecular and biophysical signals in these regions, but the acellular biophysical characteristics remain poorly described. This study investigates the mechanical and ultrastructural characteristics of the tumor extracellular matrix (ECM) in patient-matched GBM core and rim tissues. Seven patient-matched tumor core and rim samples and one non-neoplastic control were analyzed using atomic force microscopy, scanning electron microscopy, and immunofluorescence imaging to quantify mechanical, ultrastructural, and ECM composition changes. The results reveal significant differences in biophysical parameters between GBM core, rim, and non-neoplastic tissues. The GBM core is stiffer, denser, and is rich in ECM proteins hyaluronic acid and tenascin-C when compared to tumor rim and non-neoplastic tissues. These alterations are intimately related and have prognostic effect with stiff, dense tissue correlating with longer progression-free survival. These findings reveal new insights into the spatial heterogeneity of biophysical parameters in the GBM tumor microenvironment and identify a set of characteristics that may correlate with patient prognosis. In the long term, these characteristics may aid in the development of strategies to combat therapeutic resistance., Competing Interests: The authors have no conflicts to disclose., (© 2024 Author(s).)

Digital pathology (the technology whereby glass histology slides are scanned at high resolution, digitised, stored and shared with pathologists, who can view them using microscopy software on a screen) is transforming the delivery of clinical diagnostic pathology services around the world. In addition to adding value to clinical histopathology practice, digital histology slides provide a versatile medium to achieve the educational needs of a variety of learners including undergraduate students, postgraduate doctors in training and those pursuing continuing professional development portfolios. In this guide, we will review the principal use cases for digital slides in training and education and I will share tips for successful use of digital pathology to support a range of learners based on experience gathered at Leeds Teaching Hospitals National Health Service Trust and the National Pathology Imaging Co-Operative during the last 5 years of digital slide usage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Glioblastoma (GBM) tumors are rich in tumor-associated microglia/macrophages. Changes associated with treatment in this specific cell population are poorly understood. Therefore, we studied changes in gene expression of tumor-associated microglia/macrophages (Iba1+) cells in de novo versus recurrent GBMs., Methods: NanoString GeoMx ® Digital Spatial Transcriptomic Profiling of microglia/macrophages (Iba1+) and glial cells (Gfap+) cells identified on tumor sections was performed on paired de novo and recurrent samples obtained from three IDH-wildtype GBM patients. The impact of differentially expressed genes on patient survival was evaluated using publicly available data., Results: Unsupervised analyses of the NanoString GeoMx ® Digital Spatial Profiling data revealed clustering based on the transcriptomic data from Iba1+ and Gfap+ cells. As expected, conventional differential gene expression and enrichment analyses revealed upregulation of immune-function-related genes in Iba1+ cells compared to Gfap+ cells. A focused differential gene expression analysis revealed upregulation of phagocytosis and fatty acid/lipid metabolism genes in Iba1+ cells in recurrent GBM samples compared to de novo GBM samples. Importantly, of these genes, the lipid metabolism gene PLD3 consistently correlated with survival in multiple different publicly available datasets., Conclusion: Tumor-associated microglia/macrophages in recurrent GBM overexpress genes involved in fatty acid/lipid metabolism. Further investigation is needed to fully delineate the role of PLD phospholipases in GBM progression.

The Alaskan Layered Pollution And Chemical Analysis (ALPACA) field experiment was a collaborative study designed to improve understanding of pollution sources and chemical processes during winter (cold climate and low-photochemical activity), to investigate indoor pollution, and to study dispersion of pollution as affected by frequent temperature inversions. A number of the research goals were motivated by questions raised by residents of Fairbanks, Alaska, where the study was held. This paper describes the measurement strategies and the conditions encountered during the January and February 2022 field experiment, and reports early examples of how the measurements addressed research goals, particularly those of interest to the residents. Outdoor air measurements showed high concentrations of particulate matter and pollutant gases including volatile organic carbon species. During pollution events, low winds and extremely stable atmospheric conditions trapped pollution below 73 m, an extremely shallow vertical scale. Tethered-balloon-based measurements intercepted plumes aloft, which were associated with power plant point sources through transport modeling. Because cold climate residents spend much of their time indoors, the study included an indoor air quality component, where measurements were made inside and outside a house to study infiltration and indoor sources. In the absence of indoor activities such as cooking and/or heating with a pellet stove, indoor particulate matter concentrations were lower than outdoors; however, cooking and pellet stove burns often caused higher indoor particulate matter concentrations than outdoors. The mass-normalized particulate matter oxidative potential, a health-relevant property measured here by the reactivity with dithiothreiol, of indoor particles varied by source, with cooking particles having less oxidative potential per mass than pellet stove particles., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans., Methods: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER., Results: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing., Discussion: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The preclinical Alzheimer's cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers., Objective: We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-β., Methods: We examined 648 participants' neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer's Disease Research Center's Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants., Results: There was a significant positive relationship between tPACCin - person and PACC5-RAVLT (Overall group: r2 = 0.94, N = 648), and tPACCin - person and tPACCremote (validation subgroup: ICC = 0.82, n = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-β deposition., Conclusions: There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer's disease.

Introduction: We assessed the effects of multivitamin-mineral and cocoa extract supplementation on incident mild cognitive impairment (MCI) and all-cause probable dementia., Methods: COSMOS-Mind (N = 2262), a 2 × 2 factorial, randomized-controlled clinical trial administered a telephone-based cognitive battery at baseline and annually for 3 years. Incidence rates of MCI, and separately dementia, were compared among treatment arms with proportional hazards regression., Results: Over 3 years, 110 incident MCI and 14 incident dementia cases were adjudicated. Incidence rates did not vary by assignment to multivitamin-mineral or cocoa extract (all p's ≥ 0.05); however, statistical power was low. When participants assigned to multivitamin-mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p < 0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function)., Discussion: Multivitamin-mineral therapy may provide cognitive resilience, countering conversion to MCI, but not significantly reduce its incidence over 3 years., Highlights: Multivitamin-mineral supplementation did not reduce risks for cognitive impairment. Cocoa extract supplementation did not reduce risks for cognitive impairment. Multivitamin-mineral supplementation slowed cognitive declines for incident mild cognitive impairment., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Glioblastoma (GBM), the most common human brain tumor, has been notoriously resistant to treatment. As a result, the dismal overall survival of GBM patients has not changed over the past three decades. GBM has been stubbornly resistant to checkpoint inhibitor immunotherapies, which have been remarkably effective in the treatment of other tumors. It is clear that GBM resistance to therapy is multifactorial. Although therapeutic transport into brain tumors is inhibited by the blood brain barrier, there is evolving evidence that overcoming this barrier is not the predominant factor. GBMs generally have a low mutation burden, exist in an immunosuppressed environment and they are inherently resistant to immune stimulation, all of which contribute to treatment resistance. In this review, we evaluate the contribution of multi-omic approaches (genomic and metabolomic) along with analyzing immune cell populations and tumor biophysical characteristics to better understand and overcome GBM multifactorial resistance to treatment., (Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: It has been argued that ethics review committees-e.g., Research Ethics Committees, Institutional Review Boards, etc.- have weaknesses in reviewing big data and artificial intelligence research. For instance, they may, due to the novelty of the area, lack the relevant expertise for judging collective risks and benefits of such research, or they may exempt it from review in instances involving de-identified data., Main Body: Focusing on the example of medical research databases we highlight here ethical issues around de-identified data sharing which motivate the need for review where oversight by ethics committees is weak. Though some argue for ethics committee reform to overcome these weaknesses, it is unclear whether or when that will happen. Hence, we argue that ethical review can be done by data access committees, since they have de facto purview of big data and artificial intelligence projects, relevant technical expertise and governance knowledge, and already take on some functions of ethical review. That said, like ethics committees, they may have functional weaknesses in their review capabilities. To strengthen that function, data access committees must think clearly about the kinds of ethical expertise, both professional and lay, that they draw upon to support their work., Conclusion: Data access committees can undertake ethical review of medical research databases provided they enhance that review function through professional and lay ethical expertise., (© 2023. The Author(s).)

Objectives: The trend of practice pattern and impact on health care utilization for surgery and radiation therapy (RT) in patients with glomus jugulare tumors (GJTs) is not well defined., Methods: The IBM (Armonk, NY) MarketScan database was queried using the ICD-9/10 and CPT 4th edition, 2000-2020. We included patients ≥18 years of age who underwent either surgery or RT with at-least 1-year follow-up. We compared the health care utilization at 3-month, 6-month, and 1-year follow up using the inverse probability of treatment weight technique., Results: A cohort of 333 patients was identified. Of these, 72.7% (n = 242) underwent RT and 27.3% (n = 91) underwent surgery. RT use increased from 2002-2004 (50%) to 2017-2019 (91%). Patients in the surgery cohort were younger (median age 49 vs. 56 years, P < 0.0001) and had a higher 3+ comorbidity index (34% vs. 30%, P = 0.43) compared with patients in the RT cohort. Patients who underwent surgery had higher complications at index hospitalization (22% vs. 6%, P < 0.0001) and at 30 days (14% vs. 5%, P = 0.0042). No difference in combined index and 6- or 12-month payments were noted (6-months: surgery, $66m108, RT: $43m509, P = 0.1034; 12-months: surgery, $73,259, RT: $51,576, P = 0.1817). Only 4% of patients who had initial RT underwent RT and none underwent surgery at 12 months, whereas 6% of patients who had initial surgery underwent RT and 2% underwent surgery at 12 months., Conclusions: RT plays an increasingly important role in the treatment for patients with GJTs, with fewer complications and a comparable health care utilization at 1 year., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Regional heterothermy is a pattern whereby different body regions are maintained at different temperatures, often to prioritize the function of certain body parts over others, or to maximize the function of organs and tissues that vary in thermal sensitivity. Regional heterothermy is relatively well understood in endotherms, where physiological mechanisms maintain heterogeneity. However, less is known about regional heterothermy in ectotherms, where behavioral mechanisms are more important for generating thermal variation. In particular, whether small and elongate ectotherms with high surface area to volume ratios such as diminutive snakes can maintain regional heterothermy, despite rapid thermal equilibration, is not yet known. We measured regional variation in body temperature and tested whether environmental heterogeneity is used to generate regional heterothermy in the ring-necked snake (Diadophis punctatus) using both field and laboratory studies. We found that ring-necked snakes have robust regional heterothermy in a variety of contexts, despite their small body size and elongate body shape. Temperature variation along the length of their bodies was not detectable when measured externally. However, snakes had higher mouth than cloacal temperatures both in the field and in laboratory thermal gradients. Further, this regional heterothermy was maintained even in ambient laboratory conditions, where the thermal environment was relatively homogeneous. Our results indicate that regional heterothermy in ring-necked snakes is not solely driven by environmental variation but is instead linked to physiological or morphological mechanisms that maintain regional variation in body temperature irrespective of environmental context., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Objective: Gliomas exhibit high intratumor and interpatient heterogeneity. Recently, it has been shown that the microenvironment and phenotype differ significantly between the glioma core (inner) and edge (infiltrating) regions. This proof-of-concept study differentiates metabolic signatures associated with these regions, with the potential for prognosis and targeted therapy that could improve surgical outcomes., Methods: Paired glioma core and infiltrating edge samples were obtained from 27 patients after craniotomy. Liquid-liquid metabolite extraction was performed on the samples and metabolomic data were obtained via 2D liquid chromatography-mass spectrometry/mass spectrometry. To gauge the potential of metabolomics to identify clinically relevant predictors of survival from tumor core versus edge tissues, a boosted generalized linear machine learning model was used to predict metabolomic profiles associated with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation., Results: A panel of 66 (of 168) metabolites was found to significantly differ between glioma core and edge regions (p ≤ 0.05). Top metabolites with significantly different relative abundances included DL-alanine, creatine, cystathionine, nicotinamide, and D-pantothenic acid. Significant metabolic pathways identified by quantitative enrichment analysis included glycerophospholipid metabolism; butanoate metabolism; cysteine and methionine metabolism; glycine, serine, alanine, and threonine metabolism; purine metabolism; nicotinate and nicotinamide metabolism; and pantothenate and coenzyme A biosynthesis. The machine learning model using 4 key metabolites each within core and edge tissue specimens predicted MGMT promoter methylation status, with AUROCEdge = 0.960 and AUROCCore = 0.941. Top metabolites associated with MGMT status in the core samples included hydroxyhexanoycarnitine, spermine, succinic anhydride, and pantothenic acid, and in the edge samples metabolites included 5-cytidine monophosphate, pantothenic acid, itaconic acid, and uridine., Conclusions: Key metabolic differences are identified between core and edge tissue in glioma and, furthermore, demonstrate the potential for machine learning to provide insight into potential prognostic and therapeutic targets.

Background: Intraoperative magnetic resonance imaging (iMRI) use in transsphenoidal approach (TSA) for pituitary tumors (PTs) has been reported to improve the extent of resection (EOR). The aim of this study is to report the trends and the impact of iMRI on healthcare utilization in patients who underwent TSA for PTs., Materials and Methods: MarketScan database were queried using the ICD-9/10 and CPT-4, from 2004 to 2020. We included patients ≥ 18 years of age PTs with > 1 year follow-up. Outcomes were length of stay (LOS), discharge disposition, hospital/emergency room (ER) re-admissions, outpatient services, medication refills and corresponding payments., Results: A cohort of 10,192 patients were identified from the database, of these 141 patients (1.4%) had iMRI used during the procedure. Use of iMRI for PTs remained stable (2004-2007: 0.85%; 2008-2011: 1.6%; 2012-2015:1.4% and 2016-2019: 1.46%). No differences in LOS (median 3 days each), discharge to home (93% vs. 94%), complication rates (7% vs. 13%) and payments ($34604 vs. $33050) at index hospitalization were noted. Post-discharge payments were not significantly different without and with iMRI use at 6-months ($8315 vs. $ 7577, p = 0.7) and 1-year ($13,654 vs. $ 14,054, p = 0.70), following the index procedure., Conclusion: iMRI use during TSA for PTs remained stable with no impact on LOS, complications, discharge disposition and index payments. Also, there was no difference in combined index payments at 6-months, and 1-year after the index procedure in patients with and without iMRI use for PTs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To compare the impact of different management strategies on diagnosis of new-onset mental health disorders (MHDs) in patients with vestibular schwannoma (VS) and health care utilization at 1-year follow-up., Methods: MarketScan databases were queried using the International Classification of Diseases, Ninth Revision and Tenth Revision and Current Procedural Terminology, Fourth Edition, 2000-2020. We included patients ≥18 years old with a diagnosis of VS who underwent clinical observation, surgery, or stereotactic radiosurgery (SRS) with at least 1 year of follow-up. We looked at health care outcomes and MHDs at 3-month, 6-month, and 1-year follow-up., Results: The database search identified 23,376 patients. Of these, 94.2% (n = 22,041) were managed conservatively with clinical observation at the initial diagnosis, and 2% (n = 466) underwent surgery. The surgery cohort had the highest incidence of new-onset MHDs followed by SRS and clinical observation cohorts at 3 months (surgery: 17%; SRS: 12%; clinical observation: 7%), 6 months (surgery: 20%; SRS: 16%; clinical observation: 10%), and 12 months (surgery: 27%; SRS: 23%; clinical observation: 16%) (P < 0.0001). The median difference in combined payments between patients with and without MHDs was highest in the surgery cohort followed by SRS and clinical observation cohorts at all time points (12 months: surgery: $14,469; SRS: $10,557; clinical observation: $6439; P = 0.0002)., Conclusions: Compared with clinical observation only, patients who underwent surgery for VS were 2 times more likely and patients who underwent SRS were 1.5 times more likely to develop MHDs with corresponding increase in health care utilization at 1-year follow-up., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: The aim of this study was to analyze the trends, demographic differences in the type and time to initiation (TTI) of adjunct treatment AT following surgery for anaplastic astrocytoma (AA)., Material and Methods: The National Cancer Database (NCDB) was queried for patients diagnosed with AA from 2004 to 2016. Cox proportional hazards and modeling was used to determine factors influencing survival, including the impact of time to initiation (TTI) of adjuvant therapy., Results: Overall, 5890 patients were identified from the database. The use of combined RT + CT temporally increased from 66.3% (2004-2007) to 79% (2014-2016), p < 0001. Patients more likely to receive no treatment following surgical resection included elderly (> 60 years old), hispanic patients, those with either no or government insurance, those living > 20 miles from the cancer facility, those treated at low volume centers (< 2 cases/year). AT was received following surgical resection within 0-4 weeks, 4.1-8 weeks, and > 8 weeks in 41%, 48%, and 3%, respectively. Compared to patients who received RT + CT, patients were likely to receive RT only as AT either at 4-8 weeks or > 8 weeks after the surgical procedure. Patients who received AT within 0-4 weeks had the 3-year OS of 46% compared to 56.7% for patients who received treatment at 4.1-8 weeks., Conclusion: We found significant variation in the type and timing of adjunct treatment following surgical resection of AA in the United States. A considerable number of patients (15%) received no AT following surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Intraoperative neuromonitoring (IONM) is routinely used during neurosurgical procedures. Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (LITT) is increasingly being used in patients with various brain lesions. Use of IONM (transcranial motor evoked potential [TcMEP] and electromyography [EMG]) during LITT of a brain lesion has not been described previously., Methods: In this report, we describe a 70-year-old man who presented with motor weakness in whom imaging revealed a left thalamic lesion. Due to the difficulty in accessing the lesion and proximity to the motor tracts, patient was offered MRI-guided LITT using TcMEP and EMG., Results: The patient underwent satisfactory ablation of the lesion with successful recording of the TcMEP and EMG. Technical nuances related to the set-up and procedure is discussed in this report. No procedure-related complications were encountered., Conclusions: We describe the first report of safety and feasibility of TcMEP and EMG during MRI-guided LITT for left thalamic glioblasatoma. This report paves the way for further prospective investigations regarding the utility of this technique for eloquent brain tumors., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Glioblastoma (GBM) has a very poor prognosis despite current treatment. We previously found cytotoxic synergy between the AURKA inhibitor alisertib and the CNS-penetrating taxane TPI 287 against GBM tumor cells in vitro., Methods: We used an orthotopic human GBM xenograft mouse model to test if TPI 287 potentiates alisertib in vivo. Western blotting, immunohistochemistry, siRNA knockdown, annexin V binding, and 3-dimensional Matrigel invasion assays were used to investigate potential mechanisms of alisertib and TPI 287 treatment interactions., Results: Alisertib + TPI 287 combination therapy significantly prolonged animal survival compared to vehicle (p = 0.011), but only marginally compared to alisertib alone. Alisertib, TPI 287, and combined alisertib + TPI 287 reduced animal tumor volume compared to vehicle-treated controls. This was statistically significant for the combination therapy at 4 weeks (p < 0.0001). Alisertib + TPI 287 treatment decreased anti-apoptotic Bcl-2 protein levels in vivo and in vitro. Expression of the pro-apoptotic protein Bak was significantly increased by combination treatment (p < 0.0001). Pro-apoptotic Bim and Bak knockdown by siRNA decreased apoptosis by alisertib + TPI 287 in GB9, GB30, and U87 cells (p = 0.0005 to 0.0381). Although alisertib and TPI 287 significantly reduced GBM cell invasion (p < 0.0001), their combination was no more effective than TPI 287 alone., Conclusions: Results suggest that apoptosis is the dominant mechanism of potentiation of GBM growth inhibition by alisertib + TPI 287, in part through effects on Bcl-2 family proteins, providing a rationale for further laboratory testing of an AURKA inhibitor plus TPI 287 as a potential therapy against GBM., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Disulfide bonds in proteins have a substantial impact on protein structure, stability, and biological activity. Localizing disulfide bonds is critical for understanding protein folding and higher-order structure. Conventional top-down mass spectrometry (TD-MS), where only terminal fragments are assigned for disulfide-intact proteins, can access disulfide information, but suffers from low fragmentation efficiency, thereby limiting sequence coverage. Here, we show that assigning internal fragments generated from TD-MS enhances the sequence coverage of disulfide-intact proteins by 20-60% by returning information from the interior of the protein sequence, which cannot be obtained by terminal fragments alone. The inclusion of internal fragments can extend the sequence information of disulfide-intact proteins to near complete sequence coverage. Importantly, the enhanced sequence information that arise from the assignment of internal fragments can be used to determine the relative position of disulfide bonds and the exact disulfide connectivity between cysteines. The data presented here demonstrates the benefits of incorporating internal fragment analysis into the TD-MS workflow for analyzing disulfide-intact proteins, which would be valuable for characterizing biotherapeutic proteins such as monoclonal antibodies and antibody-drug conjugates.

Background: Intraoperative magnetic resonance imaging (iMRI) is a useful adjunct for resection of primary malignant brain tumors (MBTs). The aim of our study is to investigate the impact of iMRI on health care utilization in patients who underwent craniotomy for resection of MBTs., Materials and Methods: MarketScan database were queried using the ICD-9/10 and CPT 4th edition, from 2008 to 2020. We included patients ≥ 18 years of age who underwent a craniotomy with at-least one year follow-up. Outcomes were length of stay (LOS), discharge disposition, hospital/emergency room (ER) re-admissions, outpatient services, medication refills and corresponding payments., Results: Of 6,640 patients who underwent craniotomy for MBTs, 465 patients (7%) had iMRI used during the procedure with 0.7% per year increase in iMRI use during the study period. Patients without iMRI use had higher complications at index hospitalization compared to those with iMRI use (19% vs. 14%, p = 0.04). There was no difference in the ER admission rates among the patients who underwent surgery with and without iMRI use at 6-months and 1-year after the index procedure. In terms of post-discharge payments, no significant differences were noted among the patients without and with iMRI use at 6-months ($81,107 vs. $ 81,458, p = 0.26) and 1-year ($132,657 vs. $ 118,113, p = 0.12)., Conclusion: iMRI use during craniotomy for MBT gradually increased during the study period. iMRI did not result in higher payments at index hospitalization, 6-months, and 1-year after the index procedure., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endometriosis patients experience debilitating chronic pain, and the first-line treatment is ineffective at managing symptoms. Although surgical removal of the lesions provides temporary relief, more than 50% of the patients experience disease recurrence. Despite being a leading cause of hysterectomy, endometriosis lacks satisfactory treatments and a cure. Another challenge is the poor understanding of disease pathophysiology which adds to the delays in diagnosis and overall compromised quality of life. Endometriosis patients are in dire need of an effective therapeutic strategy that is both economical and effective in managing symptoms, while fertility is unaffected. Endocannabinoids and phytocannabinoids possess anti-inflammatory, anti-nociceptive, and anti-proliferative properties that may prove beneficial for endometriosis management, given that inflammation, vascularization, and pain are hallmark features of endometriosis. Endocannabinoids are a complex network of molecules that play a central role in physiological processes including homeostasis and tissue repair, but endocannabinoids have also been associated in the pathophysiology of several chronic inflammatory diseases including endometriosis and cancers. The lack of satisfactory treatment options combined with the recent legalization of recreational cannabinoids in some parts of the world has led to a rise in self-management strategies including the use of cannabinoids for endometriosis-related pain and other symptoms. In this review, we provide a comprehensive overview of endocannabinoids with a focus on their potential roles in the pathophysiology of endometriosis. We further provide evidence-driven perspectives on the current state of knowledge on endometriosis-associated pain, inflammation, and therapeutic avenues exploiting the endocannabinoid system for its management., (© 2022. The Author(s).)

Amines are frequently included in formulations of the herbicides glyphosate, 2,4-D, and dicamba to increase herbicide solubility and reduce herbicide volatilization by producing herbicide-amine salts. Amines, which typically have higher vapor pressures than the corresponding herbicides, could potentially volatilize from these salts and enter the atmosphere, where they may impact atmospheric chemistry, human health, and climate. Amine volatilization from herbicide-amine salts may additionally contribute to volatilization of dicamba and 2,4-D. In this study, we established that amines applied in herbicide-amine salt formulations undergo extensive volatilization. Both dimethylamine and isopropylamine volatilized when aqueous salt solutions were dried to a residue at ∼20 °C, while lower-vapor pressure amines like diglycolamine and n , n - bis -(3-aminopropyl)methylamine did not. However, all four amines volatilized from salt residues at 40-80 °C. Because amine loss typically exceeded herbicide loss, we proposed that neutral amines dominated volatilization and that higher temperatures altered their protonation state and vapor pressure. Due to an estimated 4.0 Gg N/yr applied as amines to major U.S. crops, amine emissions from herbicide-amine salts may be important on regional scales. Further characterization of worldwide herbicide-amine use would enable this contribution to be compared to the 285 Gg N/yr of methylamines emitted globally.

Malignant melanotic nerve sheath tumor (MMNST) is a rare and potentially aggressive lesion defined in the 2021 WHO Classification of Tumors of the Central Nervous System. MMNST demonstrate overlapping histologic and clinical features of schwannoma and melanoma. MMNST often harbor PRKAR1A mutations, especially within the Carney Complex. We present a case of aggressive MMNST of the sacral region in a 48-year-old woman. The tumor contained PRKAR1A frameshift pR352Hfs*89, KMT2C splice site c .7443-1G>T and GNAQ p. R183L missense mutations, as well as BRAF and MYC gains. Genomic DNA methylation analysis using the Illumina 850K EpicBead chip revealed that the lesion did not match an established methylation class; however, uniform manifold approximation and projection (UMAP) placed the tumor very near schwannomas. The tumor expressed PD-L1, and the patient was treated with radiation and immune checkpoint inhibitors following en bloc resection. Although she had symptomatic improvement, she suffered early disease progression with local recurrence, and distant metastases, and died 18 months after resection. It has been suggested that the presence of GNAQ mutations can differentiate leptomeningeal melanocytic neoplasms and uveal melanoma from MMNST. This case and others demonstrate that GNAQ mutations may exist in malignant nerve sheath tumors; that GNAQ and PRKAR1A mutations are not always mutually exclusive and that neither can be used to differentiate MMNST or MPNST from all melanocytic lesions.

Background: Although complete nidal obliteration of brain arteriovenous malformations (AVM) is generally presumed to represent durable cure, postobliteration hemorrhage, and AVM recurrence have become increasingly recognized phenomena. The goal of the study was to define hemorrhage and nidal recurrence risks of obliterated AVMs treated with stereotactic radiosurgery (SRS)., Methods: This is a retrospective cohort study from the International Radiosurgery Research Foundation comprising AVM patients treated between 1987 and 2020. Patients with AVM obliteration on digital subtraction angiography (DSA) were included. Outcomes were (1) hemorrhage and (2) AVM recurrence. Follow-up duration began at the time of AVM obliteration and was censored at subsequent hemorrhage, AVM recurrence, additional AVM treatment, or loss to follow-up. Annualized risk and survival analyses were performed. A sensitivity analysis comprising patients with AVM obliteration on magnetic resonance imaging or DSA was also performed for postobliteration hemorrhage., Results: The study cohort comprised 1632 SRS-treated patients with AVM obliteration on DSA. Pediatric patients comprised 15% of the cohort, and 42% of AVMs were previously ruptured. The mean imaging follow-up after AVM obliteration was 22 months. Among 1607 patients with DSA-confirmed AVM obliteration, 16 hemorrhages (1.0%) occurred over 2223 patient-years of follow-up (0.72%/y). Of the 1543 patients with DSA-confirmed AVM obliteration, 5 AVM recurrences (0.32%) occurred over 2071 patient-years of follow-up (0.24%/y). Of the 16 patients with postobliteration hemorrhage, AVM recurrence was identified in 2 (12.5%). In the sensitivity analysis comprising 1939 patients with post-SRS AVM obliteration on magnetic resonance imaging or DSA, 16 hemorrhages (0.83%) occurred over 2560 patient-years of follow-up (0.63%/y)., Conclusions: Intracranial hemorrhage and recurrent arteriovenous shunting after complete nidal obliteration are rare in AVM patients treated with SRS, and each phenomenon harbors an annual risk of <1%. Although routine postobliteration DSA cannot be recommended to SRS-treated AVM patients, long-term neuroimaging may be advisable in these patients.

Introduction: Arterial stiffness may play a role in the development of dementia through poorly understood effects on brain microstructural integrity and perfusion., Methods: We examined markers of arterial stiffness (carotid-femoral pulse wave velocity [cfPWV]) and elevated systolic blood pressure (SBP) in relation to cognitive function and brain magnetic resonance imaging macrostructure (gray matter [GM] and white matter [WM] volumes), microstructure (diffusion based free water [FW] and fractional anisotropy [FA]), and cerebral blood flow (CBF) in WM and GM in models adjusted for age, race, sex, education, and apolipoprotein E ε4 status., Results: Among 460 participants (70 ± 8 years; 44 dementia, 158 mild cognitive impairment, 258 normal cognition), higher cfPWV and SBP were independently associated with higher FW, higher WM hyperintensity volume, and worse cognition (global and executive function). Higher SBP alone was significantly associated with lower WM and GM CBF., Discussion: Arterial stiffness is associated with impaired WM microstructure and global and executive cognitive function., Competing Interests: Hughes reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution, including R01AG054069 and R01AG058969. Lockhart reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Williams reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Espeland reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution; payments to him from Boehringer‐Ingelheim; and support from the DSMB for Jackson Heart, Ironwood Pharmaceuticals, Kaiser Permanente, Washington Health Research Institute. Williamson reports funding for this work from NIH P30 AG072947, additional funding from other NIH grants, Biogen, the Centers for Disease Control, and PCORI all to the institution. Bateman reports funding for this work from NIH P30 AG072947, other NIH grants, and funding for the ASPECT 20‐AVP‐786‐306 to the institution. Whitlow reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Cleveland reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Rogers reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Baker reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Sachs reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Hayden reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution; payments to her from Fred Hutchinson Cancer Research Center, University of North Carolina at Chapel Hill, the Alzheimer's Association, and NIH CSR. Yang reports funding for this work from NIH P30 AG072947 and additional funding for other NIH grants to the institution. Craft reports funding for this work from NIH P30 AG072947, additional funding from other NIH grants, and reports disclosures for: vTv Therapeutics, T3D Therapeutics, Cyclerion Inc, and Cognito Inc., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Aims: This study describes patients with complex Special Health Care Needs (SHCN) transitioning from a pediatric hospital clinic dental home to adult care and evaluates effectiveness of transition practices., Methods and Results: Demographics, medical/behavioral complexity, and documentation of transition processes were collected for patients graduated from the service in 2018/2019. An invitation to complete a survey assessing transition was sent to patients/guardians ≥ 14 months after the final visit. Seventy-nine patients graduated and 94% required accommodation for SHCN: 47% medical, 42% medical + behavioral, and 5% behavioral only. Of 63 eligible patients/guardians, 29 completed surveys. While 90% of surveyed patients had established some/all adult medical care, only 41% completed a dental visit, and less than 28% established a dental home. Medical/behavioral complexity, payer, and time since graduation did not impact having a visit., Conclusions: This study found ineffectiveness of departmental protocol for transition to adult dental homes for patients with SHCN. Developing an optimal transition process is complex and will require collaboration of all stakeholders. Introducing transition in early teen years, tracking progress at subsequent visits, assessing patient readiness, summarizing history for receiving providers, and verifying transition are elements of medical transition programs that should be included in dental transitions., (© 2022 Special Care Dentistry Association and Wiley Periodicals LLC.)

There is a growing consensus among scholars, national governments, and intergovernmental organisations of the need to involve the public in decision-making around the use of artificial intelligence (AI) in society. Focusing on the UK, this paper asks how that can be achieved for medical AI research, that is, for research involving the training of AI on data from medical research databases. Public governance of medical AI research in the UK is generally achieved in three ways, namely, via lay representation on data access committees, through patient and public involvement groups, and by means of various deliberative democratic projects such as citizens' juries, citizen panels, citizen assemblies, etc.-what we collectively call "citizen forums". As we will show, each of these public involvement initiatives have complementary strengths and weaknesses for providing oversight of medical AI research. As they are currently utilized, however, they are unable to realize the full potential of their complementarity due to insufficient information transfer across them. In order to synergistically build on their contributions, we offer here a multi-scale model integrating all three. In doing so we provide a unified public governance model for medical AI research, one that, we argue, could improve the trustworthiness of big data and AI related medical research in the future., (© 2022. The Author(s).)

Digital pathology - the digitalisation of clinical histopathology services through the scanning and storage of pathology slides - has opened up new possibilities for health care in recent years, particularly in the opportunities it brings for artificial intelligence (AI)-driven research. Recognising, however, that there is little scholarly debate on the ethics of digital pathology when used for AI research, this paper summarises what it sees as four key ethical issues to consider when deploying AI infrastructures in pathology, namely, privacy, choice, equity, and trust. The themes are inspired from the authors' experience grappling with the challenge of deploying an ethical digital pathology infrastructure to support AI research as part of the National Pathology Imaging Cooperative (NPIC), a collaborative of universities, hospital trusts, and industry partners largely located across the North of England. Though focusing on the UK case, internationally, few pathology departments have gone fully digital, and so the themes developed here offer a heuristic for ethical reflection for other departments currently making a similar transition or planning to do so in the future. We conclude by promoting the need for robust public governance mechanisms in AI-driven digital pathology., (© 2022 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes., (© 2022. The Author(s).)

Introduction: Little is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health., Methods: We examined baseline VRFs, and cognitive testing and neuroimaging measures (β-amyloid [Aβ] PET, MRI) in a diverse longitudinal cohort (N = 159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core., Results: African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline., Discussion: Results suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline., (© 2021 the Alzheimer's Association.)

Background: Cardiometabolic disorders (hypertension, diabetes) are key modifiable risk factors for Alzheimer's disease and related disorders. They often co-occur; yet, the extent to which they independently affect brain structure and function is unclear., Objective: We hypothesized their combined effect is greater in associations with cognitive function and neuroimaging biomarkers of white matter (WM) health and cerebral perfusion in a diverse older adult cohort., Methods: Participants aged 50-85 years received: clinical evaluation, oral glucose tolerance testing, neuroimaging, cognitive testing, and adjudication. Neuroimaging included: T1 (gray [GM]/WM segmentation, regional volumes/thicknesses); FLAIR (WM hyperintensity volume [WMHv]; arterial spin labeling (cerebral blood flow); diffusion tensor imaging (fractional anisotropy [FA]); and neurite orientation dispersion and density imaging (Free Water). Hypertension (HTN) and impaired glucose tolerance (IGT) were staged and cardiometabolic status was categorized (HTN only, IGT only, IGT+HTN, neither). Multivariable linear regression modeled associations with cognitive and neuroimaging measures (covariates: age, gender, race)., Results: MRI was available for 478 participants (35% mild cognitive impairment, 10% dementia) with mean age 70±8 years, 74% with HTN, 61% with IGT, and 15% self-identified as Black/African-American. IGT+HTN was significantly associated with cognitive impairment, higher WM Free Water and WMHv, lower FA, and lower GM perfusion compared to neither factor. HTN alone was associated with poorer cognition and lower GM perfusion. Cardiometabolic factors were not associated with GM macrostructure (volumes, temporal lobe cortical thickness) or cognitive status., Conclusion: HTN and its co-occurrence with IGT (HTN+IGT) were associated with lower global cognitive performance and reduced GM perfusion and impaired WM microstructure.

Background: Multiple neuroimaging and clinical biomarkers have been identified to predict cognitive decline and clinical progression to mild cognitive impairment (MCI) or dementia. However, early biomarkers associated with transition to and reversion from cognitive impairment (cognitive migration) require further understanding. We investigated the impacts of baseline neuroimaging and clinical biomarkers on cognitive migration in a community-dwelling older cohort., Methods: We studied 391 participants from the Wake Forest Alzheimer's Disease Research Center Clinical Core cohort who underwent neuropsychological assessment and magnetic resonance imaging (MRI). At baseline, each participant was categorized to a functional/cognitive state using global Clinical Dementia Rating (CDR) score: CDR = 0 indicates normal cognitive function; CDR = 0.5 is minimal cognitive impairment. The primary outcome was cognitive migration status determined by CDR change between baseline and follow-up (mean difference = 13.9 months): CDR-0 Stables (no migration; maintained CDR = 0), CDR-0.5 Stables (no migration; maintained CDR = 0.5), Migrants - (negative migration; CDR 0 to CDR 0.5), and Reverters + (positive migration; CDR 0.5 to CDR 0). Baseline T1-weighted MRI was analyzed for gray matter (GM) volume using voxel-based morphometry (VBM). For VBM, we used a two-sample t-test controlling for age, sex, education years and intracranial volume for group comparisons: CDR-0 Stables vs CDR-0.5 Stables, CDR-0 Stables vs Migrants - , CDR-0.5 Stables vs Reverters + and Migrants - vs Reverters + (thresholded at k = 30 voxels, p <.01 uncorrected). Oral Glucose Tolerance Testing (OGTT-2h) assessed blood glucose 120-minute post challenge. Multinomial logistic regression estimated average predicted probabilities of cognitive migration status using OGTT-2h and age range (55-65, 65-75 and 75+) as predictors., Results: VBM analyses revealed lower GM volume in inferior and middle temporal gyri, hippocampus, parahippocampal gyrus, and superior and inferior frontal regions in Migrants - and CDR-0.5 Stables. Predicted probabilities indicated that individuals aged 55-65 with normal OGTT-2h levels were more likely to have better cognitive migration status (e.g., CDR-0 Stables or Reverters + ) than those aged 75+ with high OGTT-2h., Conclusions: Lower GM volumes and high OGTT-2h glucose levels may predict worse cognitive migration status in early stages of disease. The opposite is true for better cognitive migration. Validating these biomarkers may guide clinical diagnosis and treatments., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ms. Tugce Duran, Drs. James Bateman, Benjamin Williams and Melissa Rundle, and Ms. Stephanie Okonmah-Obazee have no declarations of interest. Drs. Mark Espeland, Timothy Hughes, Suzanne Craft and Samuel Lockhart receive NIH grant support. Dr. Espeland also receives funding from the Alzheimer’s Association. Dr. Craft also reports financial interest from vTv Therapeutics, T3D Therapeutics, Cyclerion Inc., and Cognito Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Context  Bundled payment and health care utilization models inform cost optimization and surgical outcomes. Economic analysis of payment plans for craniopharyngioma resection is unknown. Objective  This study aimed to identify impact of endocrine and nonendocrine complications (EC and NEC, respectively) on health care utilization and bundled payments following craniopharyngioma resection. Design  This study is presented as a retrospective cohort analysis (2000-2016) with 2 years of follow-up. Setting  The study included national inpatient hospitalization and outpatient visits. Patients  Patients undergoing craniopharyngioma resection were divided into the following four groups: group 1, no complications (NC); group 2, only EC; group 3, NEC; and group 4, both endocrine and nonendocrine complications (ENEC). Interventions  This study investigated transphenoidal or subfrontal approach for tumor resection. Main Outcome  Hospital readmission, health care utilization up to 24 months following discharge, and 90-day bundled payment performances are primary outcomes of this study. Results  Median index hospitalization payments were significantly lower for patients in NC cohort ($28,672) compared with those in EC ($32,847), NEC ($36,259), and ENEC ($32,596; p  < 0.0001). Patients in ENEC incurred higher outpatient services and overall median payments at 6 months (NC: 38,268; EC: 49,844; NEC: 68,237; and ENEC: 81,053), 1 year (NC: 46,878; EC: 58,210; NEC: 81,043; and ENEC: 94,768), and 2 years (NC: 58,391; EC: 70,418; NEC: 98,838; and ENEC: 1,11,841; p  < 0.0001). The 90-day median bundled payment was significantly different among the cohorts with the highest in ENEC ($60,728) and lowest in the NC ($33,089; p  < 0.0001). Conclusion  ENEC following surgery incurred almost two times the overall median payments at 90 days, 6 months, 1 year. and 2 years compared with those without complications. Bundled payment model may not be a feasible option in this patient population. Type of complications and readmission rates should be considered to optimize payment model prediction following craniopharyngioma resection., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

In recent years, off-target herbicide drift has been increasingly reported to lead to damage to nontarget vegetation in the U.S. These reports have coincided with the widespread adoption of genetically modified crops with new herbicide-tolerance traits. Planting crops with these traits may indirectly lead to increased drift both by increasing the use of the corresponding herbicides and by facilitating their use as postemergence herbicides later in the season. While extensive efforts have aimed to reduce herbicide drift, critical uncertainties remain regarding the physiochemical phenomena that drive the entry of herbicides into the atmosphere as well as the atmospheric processes that may influence short- and long-range transport. Resolving these uncertainties will support the development of effective approaches to reduce herbicide drift.

Despite extensive research and aggressive therapies, glioblastoma (GBM) remains a central nervous system malignancy with poor prognosis. The varied histopathology of GBM suggests a landscape of differing microenvironments and clonal expansions, which may influence metabolism, driving tumor progression. Indeed, GBM metabolic plasticity in response to differing nutrient supply within these microenvironments has emerged as a key driver of aggressiveness. Additionally, emergent biophysical and biochemical interactions in the tumor microenvironment (TME) are offering new perspectives on GBM metabolism. Perivascular and hypoxic niches exert crucial roles in tumor maintenance and progression, facilitating metabolic relationships between stromal and tumor cells. Alterations in extracellular matrix and its biophysical characteristics, such as rigidity and topography, regulate GBM metabolism through mechanotransductive mechanisms. This review highlights insights gained from deployment of bioengineering models, including engineered cell culture and mathematical models, to study the microenvironmental regulation of GBM metabolism. Bioengineered approaches building upon histopathology measurements may uncover potential therapeutic strategies that target both TME-dependent mechanotransductive and biomolecular drivers of metabolism to tackle this challenging disease. Longer term, a concerted effort integrating in vitro and in silico models predictive of patient therapy response may offer a powerful advance toward tailoring of treatment to patient-specific GBM characteristics., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Background: Posterior reversible encephalopathy syndrome (PRES) represents a transient change in mental status with associated vasogenic edema of cortical and subcortical brain structures. It is often attributed to multifactorial etiology including hypertension and altered hemodynamics and disruption of vessel integrity. Patients with autoimmune disease and certain immune modulator therapies are at greater risk., Case Presentation: A 54-year-old female with past medical history of well-controlled multiple sclerosis on interferon-beta since 2013, presented with witnessed tonic colonic seizure. She also was noted to demonstrate left gaze deviation and left-sided hemiparesis. MRI fluid-attenuated inversion recovery sequence showed hyperintensity of the subcortical U fibers, concentrated in the occipital, parietal lobes and frontal lobes. Systolic blood pressure was 160 mmHg on arrival. The patient was started on seizure prophylxis and Interferon beta was discontinued. The patient's mentation, seizures and hemiapresis significantly improved in next 72 h with tight blood pressure control, and had notble improvement on MRI imaging and inflammatory markers. Lumbar puncture CSF results were devoid of infectious and autoimmune pathology., Conclusions: A middle-aged female with multiple sclerosis who was on chronic IFN-beta presented to the emergency room with a witnessed tonic-clonic seizure, with MRI T2 FLAIR imaging consistent with PRES. She had notable clinical improvement with decreased edema on imaging and improved inflammatory markers 72 h after cessation of IFN-beta therapy., (© 2021. The Author(s).)

Objective: The COVID-19 pandemic has precipitated widespread shortages of filtering facepiece respirators (FFRs) and the creation and sharing of proposed substitutes (novel designs, repurposed materials) with limited testing against regulatory standards. We aimed to categorically test the efficacy and fit of potential N95 respirator substitutes using protocols that can be replicated in university laboratories., Setting: Academic medical centre with occupational health-supervised fit testing along with laboratory studies., Participants: Seven adult volunteers who passed quantitative fit testing for small-sized (n=2) and regular-sized (n=5) commercial N95 respirators., Methods: Five open-source potential N95 respirator substitutes were evaluated and compared with commercial National Institute for Occupational Safety and Health (NIOSH)-approved N95 respirators as controls. Fit testing using the 7-minute standardised Occupational Safety and Health Administration fit test was performed. In addition, protocols that can be performed in university laboratories for materials testing (filtration efficiency, air resistance and fluid resistance) were developed to evaluate alternate filtration materials., Results: Among five open-source, improvised substitutes evaluated in this study, only one (which included a commercial elastomeric mask and commercial HEPA filter) passed a standard quantitative fit test. The four alternative materials evaluated for filtration efficiency (67%-89%) failed to meet the 95% threshold at a face velocity (7.6 cm/s) equivalent to that of a NIOSH particle filtration test for the control N95 FFR. In addition, for all but one material, the small surface area of two 3D-printed substitutes resulted in air resistance that was above the maximum in the NIOSH standard., Conclusions: Testing protocols such as those described here are essential to evaluate proposed improvised respiratory protection substitutes, and our testing platform could be replicated by teams with similar cross-disciplinary research capacity. Healthcare professionals should be cautious of claims associated with improvised respirators when suggested as FFR substitutes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Detailed offline speciation of gas- and particle-phase organic compounds was conducted using gas/liquid chromatography with traditional and high-resolution mass spectrometers in a hybrid targeted/nontargeted analysis. Observations were focused on an unoccupied home and were compared to two other indoor sites. Observed gas-phase organic compounds span the volatile to semivolatile range, while functionalized organic aerosols extend from intermediate volatility to ultra-low volatility, including a mix of oxygen, nitrogen, and sulfur-containing species. Total gas-phase abundances of hydrocarbon and oxygenated gas-phase complex mixtures were elevated indoors and strongly correlated in the unoccupied home. While gas-phase concentrations of individual compounds generally decreased slightly with greater ventilation, their elevated ratios relative to controlled emissions of tracer species suggest that the dilution of gas-phase concentrations increases off-gassing from surfaces and other indoor reservoirs, with volatility-dependent responses to dynamically changing environmental factors. Indoor-outdoor emissions of gas-phase intermediate-volatility/semivolatile organic hydrocarbons from the unoccupied home averaged 6-11 mg h -1 , doubling with ventilation. While the largest single-compound emissions observed were furfural (61-275 mg h -1 ) and acetic acid, observations spanned a wide range of individual volatile chemical products (e.g., terpenoids, glycol ethers, phthalates, other oxygenates), highlighting the abundance of long-lived reservoirs resulting from prior indoor use or materials, and their gradual transport outdoors.

Reactive oxygen species (ROS) are an important contributor to adverse health effects associated with ambient air pollution. Despite infiltration of ROS from outdoors, and possible indoor sources (eg, combustion), there are limited data available on indoor ROS. In this study, part of the second phase of Air Composition and Reactivity from Outdoor aNd Indoor Mixing campaign (ACRONIM-2), we constructed and deployed an online, continuous, system to measure extracellular gas- and particle-phase ROS during summer in an unoccupied residence in St. Louis, MO, USA. Over a period of one week, we observed that the non-denuded outdoor ROS (representing particle-phase ROS and some gas-phase ROS) concentration ranged from 1 to 4 nmol/m 3 (as H 2 O 2 ). Outdoor concentrations were highest in the afternoon, coincident with peak photochemistry periods. The indoor concentrations of particle-phase ROS were nearly equal to outdoor concentrations, regardless of window-opening status or air exchange rates. The indoor/outdoor ratio of non-denuded ROS (I/O ROS ) was significantly less than 1 with windows open and even lower with windows closed. Combined, these observations suggest that gas-phase ROS are efficiently removed by interior building surfaces and that there may be an indoor source of particle-phase ROS., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To train and individually validate the neuropathologists in digital primary diagnosis and frozen section reporting using a novel protocol endorsed by the Royal College of Pathologists. The protocol allows early exposure to live digital reporting in a risk mitigated environment., Methods: Two specialist neuropathologists completed training in the use of a digital microscopy system for primary neuropathological diagnosis and frozen section assessment. Participants were exposed to training sets of 20 histology cases and 10 frozen sections designed to help them identify their personal digital diagnostic pitfalls. Following this, the pathologists viewed 340 live, complete neuropathology cases. All primary diagnoses were made on digital slides with immediate glass slide reconciliation before final case sign-out., Results: There was 100% clinical concordance between the digital slide and glass slide assessment of frozen section cases for each pathologist, and these assessments corresponded with the ground truth diagnoses obtained from examination of definitive histology. For primary diagnosis, there was complete clinical concordance between digital slide and glass slide diagnosis in 98.1% of cases. The majority of discordances were related to grading differences attributable to mitotic count differences., Conclusion: Neuropathologists can develop the ability to make primary digital diagnosis competently and confidently following a course of individual training and validation., Competing Interests: Competing interests: DT and BJW are part of the Northern Pathology Imaging Co-Operative, which is supported by Leica Biosystems and Roche Ventana. Leeds Teaching Hospitals NHS Trust has a collaborative research partnership with Leica Biosystems for digital pathology deployment., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of facemasks is proven to mitigate the spread of the coronavirus and other biological agents that cause disease. Various forms of facemasks, made using different materials, are being used extensively, and it is important to determine their performance characteristics. The size-dependent filtration efficiency and breathing resistance of household sterilization wrap fabrics, and isolation media (American Society for Testing and Materials (ASTM)- and non-ASTM-rated), were measured in filter-holder- and mannequin-in-chamber-based systems, focusing on particles sizes between 20 nm and 2 μm. Double-layer MERV-14 (Minimum Efficiency Reporting Values with rating 14) showed the highest filtration efficiency (94.9-73.3%) amongst household filter media, whereas ASTM-rated isolation masks showed the highest filtration efficiencies (95.6-88.7) amongst all the masks considered. Filtration efficiency of 3D-printed masks with replaceable filter media was found to depend on the degree of sealing around the media holder, which depended on the material's compressibility. Filtration efficiencies of triple-layer combinations (95.8-85.3%) follow a profile similar to single layers but with improved filtration efficiencies.

Recent multi-dimensional simulations suggest that high-entropy buoyant plumes help massive stars to explode 1,2 . Outwardly protruding iron (Fe)-rich fingers of gas in the galactic supernova remnant 3,4 Cassiopeia A seem to match this picture. Detecting the signatures of specific elements synthesized in the high-entropy nuclear burning regime (that is, α-rich freeze out) would constitute strong substantiating evidence. Here we report observations of such elements-stable titanium (Ti) and chromium (Cr)-at a confidence level greater than 5 standard deviations in the shocked high-velocity Fe-rich ejecta of Cassiopeia A. We found that the observed Ti/Fe and Cr/Fe mass ratios require α-rich freeze out, providing evidence of the existence of the high-entropy ejecta plumes that boosted the shock wave at explosion. The metal composition of the plumes agrees well with predictions for strongly neutrino-processed proton-rich ejecta 2,5,6 . These results support the operation of the convective supernova engine via neutrino heating in the supernova that produced Cassiopeia A.