Background: Adherence to healthy lifestyle behaviours or to prescribed medication requires perseverance with stamina, and this is captured by Grit, a non-cognitive trait defined as perseverance and passion for long-term goals. Despite predicting cognitive decline and physical, emotional, and social functioning, Grit remains poorly understood and its neural substrates are unknown in cognitive aging. Methods: Ninety-five cognitively unimpaired older adults with a family history of Alzheimer’s disease were recruited through the PREVENT-AD longitudinal cohort. Participants completed tests that assess grit and conscientiousness and underwent resting-state functional magnetic resonance imaging (fMRI). Multivariate pattern analyses (MVPA), a rigorous data-driven whole-brain approach, were used to examine if resting-state functional connectivity of connectome-wide voxels were associated with grit scores, controlling for age, sex, APOE ε4 carriership, mean displacement, and conscientiousness. Results: Our analyses identified two large (≥54 voxels) and statistically significant (p<0.01 corrected for family-wise error) clusters in the right ventrolateral prefrontal cortex and the left orbitofrontal cortex underlying grit. Conclusions: Being the first to identify functional neural correlates supporting grit in the aging population while accounting for the variance of conscientiousness, our study provides unique insights into the construct which has important applications in adherence to clinical and empirical neurological interventions as well as in successful aging.

Background: Pediatric inflammatory myopathies (PIM) are a rare, heterogenous group of disorders requiring prompt diagnosis and treatment to reduce complications and improve long-term outcome. This study reviews the clinical characteristics, management, and outcomes in PIM. Methods: A retrospective analysis of pediatric patients diagnosed with PIM at CHEO from January 2009 to December 2023 was performed. Patient data, including age at symptom onset, diagnostic testing performed, treatment, and follow-up durations, were evaluated. Results: A total of 25 patients with juvenile dermatomyositis (JDM), overlap syndromes, and necrotizing myopathy (HMG-CoA reductase and anti-SRP myositis) were identified. Symptoms began at an average age of 8.37 years (1.10-14.11), with formal diagnosis occurring at 8.57 years (2.02-16.11). Initial symptoms included skin changes, muscle weakness, joint pain, and fatigue. Diagnosis involved laboratory testing (CK, myositis antibodies), muscle MRI, electromyography, and/or muscle biopsy. Treatments included corticosteroids, IVIG, and steroid-sparing agents (methotrexate, mycophenolate mofetil, rituximab, hydroxychloroquine). Follow-up averaged 4.23 years (range: 0.5 to 13). Most patients displayed only mild residual symptoms with the exception of an anti-SRP myositis patient who became wheelchair-dependent, requiring ventilatory support. Conclusions: Inflammatory myopathies require prompt treatment to prevent complications. Most patients require multiple treatment modalities, however with early diagnosis and treatment the majority of patients’ symptoms resolve.

Background: Sex is associated with differences in early outcomes with preterm males at greater risk for mortality and morbidity. The objective of this study was to examine preterm sex differences in neurodevelopmental outcomes and brain development from early-life to 8-years. Methods: A prospective cohort of preterm infants born 24-32 weeks gestation were followed to 8-years with standardized measures. MRI scans were performed after birth, term-equivalent age and 8-years. Associations between sex, risk factors, brain volumes, white matter fractional anisotropy (FA) and outcomes were assessed using generalized estimating equations. Results: Preterm males (N=83) and females (N=72) had similar risk factors, brain injury and pain exposure. Sex was a predictor of cognitive scores (P=0.02) and motor impairment (P=0.03), with males having lower cognitive scores and higher motor impairment over time. There was a sex effect for FA (P=0.04), with males having lower FA over time. There were significant sex-brain injury and sex-pain interactions for cognitive and motor outcomes. Conclusions: In this longitudinal study, preterm males had lower cognitive scores and greater motor impairment, which may relate to differences in white matter maturation. Effects of brain injury and pain on outcomes is moderated by sex, indicating a differential response to early-life adversity in preterm males and females.

Background: Carpal tunnel syndrome (CTS) is less common in children but can be associated with significant disability. Pediatric CTS can be associated with an underlying disorder most commonly storage disorders including mucopolysaccharidoses (MPS). We report a patient with bilateral severe CTS secondary to Weill-Marchesani Syndrome (WMS). Methods: A retrospective chart review was completed. Results: A five-year-old female presented with a three-year history of bilateral thumb weakness and insensate digits two and three. Nerve conduction studies (NCS) revealed severe bilateral CTS. She underwent bilateral carpal tunnel release (CTR). Unfortunately, post-operative NCS was unchanged. Ultrasound showed significant median nerve compression with flexor tendon thickening. Metabolic investigations showed no evidence of a storage disorder. Trio whole exome sequencing showed two de novo likely pathogenic variants in ADAMTS10: c.1174delC, p.H392TfsX9 and a deletion of exons 3-8. Her exam was also noted to show bilateral camptodactyly and brachydactyly, and bilateral cataracts characteristic of WMS. Conclusions: Identifying the etiology of CTS is important for management and prognosis. WMS is a genetic connective tissue disorder that can cause brachydactyly and abnormal tendon thickening, which can have implications on surgical outcomes. Awareness of this diagnosis prior to surgery would allow for better patient counseling and management decisions.

Background: Despite the limited successes of recent amyloid-targetting biologics, the need for a new pathogenesis mechanistic model of Alzheimer’s disease (AD) is a continuing priority, to facilitate improved rational drug design. Methods: To devise a new AD model, we performed an extensive, comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic–molecular mechanisms of cytokine-mediated and amyloid-beta (Aβ)-mediated neurotoxicities in AD. Results: A new model of AD has been devised: In response to pathogen-/damage-associated molecular pattern-stimulating events (e.g., infection, trauma, ischaemia), Aβ is released as an early responder cytokine triggering an innate immunity cascade in which Aβ exhibits immunomodulatory/antimicrobial duality. However, Aβ’s antimicrobial properties result in a misdirected cytotoxic attack upon “self” neurons, arising from the electrophysiological similarities between neurons and bacteria in terms of transmembrane potential and anionic charges on outer membrane macromolecules. The subsequent breakdown products (amyloid-ganglioside complexes) released from the damaged neurons diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic, self-perpetuating disease cycle. In short, AD occurs because Aβ cannot differentiate neurons from bacteria. Conclusions: An innovative new model of AD has been devised, recognizing Aβ as a physiologically oligomerizing cytokine and conceptualizing AD as brain-centric autoimmune disorder of innate immunity.

Background: Historical studies of myelitis associated with rheumatologic disease may have featured patients with unrecognized aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) or MOG-IgG associated disease (MOGAD). Methods: Cases with rheumatologic disease and myelitis unrelated to multiple sclerosis (MS) seen at Johns Hopkins between 2018-2023 were identified by medical record query and chart review. Descriptive statistics were used to compare AQP4-IgG seropositive to seronegative subjects. Results: Of 234 patients screened, 190 were excluded (144 did not have inflammatory myelopathy, 46 had MS), resulting in a cohort of 44 patient (43 female, mean age 45 years [SD±14]). Twenty patients (45%) had AQP4-IgG seropositive NMOSD, 1 (2%) MOGAD, 20 (45%) other myelitis, and 3 (7%) AQP4-IgG seronegative NMOSD. AQP4-IgG seropositive subjects were more likely to have longitudinally extensive central cord lesions than seronegative patients. Most (n=43; 98%) were tested for serum AQP4-IgG, and 20 (46%) were positive by cell-based assay (CBA) or enzyme-linked immunosorbent assay. Of 24 AQP4-IgG seronegative patients, 8 were tested only by ELISA/unknown assay. Serum MOG-IgG was positive in 2/18 subjects. Conclusions: AQP4-IgG seropositive NMOSD was common in this cohort of patients with rheumatologic disease and myelitis, with the caveat that several seronegative cases were never tested with gold-standard CBA.

The new mineral theuerdankite, ideally Ag3AsO4, was found in the Alter Theuerdank Mine, Beerberg, St. Andreasberg, Goslar District, Lower Saxony, Germany. Theuerdankite occurs as aggregates of anhedral grains up to 3 mm in size, growing in cavities of strongly supergene-weathered material consisting of native silver and chlorargyrite (but with calcite present). It is dark violet, changing to reddish and black when exposed to the air and light. It has a grey to violet grey streak; when readily fresh, its streak is brownish-red. The Mohs hardness is ~2. It is brittle with no observable cleavage or parting and with a conchoidal fracture. The calculated density is 6.620 g⋅cm–3. In reflected light, theuerdankite is dark grey with a pinkish tint, with no observable bireflectance, pleochroism, or anisotropy. It shows dark red internal reflections. The reflectance values for wavelengths recommended by the Commission on Ore Mineralogy of the International Mineralogical Association are (R, %): 13.3 (470 nm), 12.8 (546 nm), 12.7 (589 nm) and 12.5 (650 nm). The empirical formula (based on 4 apfu) is Ag3.00As1.00O4. Theuerdankite is cubic, space group P$\bar{4}$3n, a = 6.144(2) Å, V = 231.93(13) Å3 and Z = 2. The six strongest powder X-ray diffraction lines are [dobs in Å, (I) hkl]: 3.0736, (22) 200; 2.7502, (100) 210; 2.5106, (55) 211; 1.7050, (36) 320; 1.6249, (44) 321; and 1.3412, (17) 421. The crystal structure of theuerdankite (R1 = 1.69% for 519 reflections having I > 3σ(I)), is isotypic to those of synthetic Ag3AsO4 and Ag3PO4. The Gram–Charlier development describing the higher-order tensors representing the atomic displacement parameters of the silver atom was implemented, documenting that silver tends to behave anharmonically in the theuerdankite structure at room temperature.

Background: Circadian rhythms are implicated in timing of stroke onset and infarct progression in adults, but this has not been studied in pediatric/young adult populations. Methods: We queried the RAPID Insights database from centers in USA for unique patients <25 years with a CTP (10/05/2018-09/29/2023) and a minimum ischemic core volume (defined as relative cerebral blood flow (rCBF) reduction of <30%) of >0 cc and minimum mismatch of >0 cc. Imaging time was subdivided into three epochs: Nigh (23:00 h-06:59 h), Day (07:00 h-14:59 h), and Evening (15:00 h-22:59 h). We analyzed age by pre-defined strata: <2 years, 2-5, 6-11, 12-18 and 19-25. Perfusion parameters (core, perfusion volume, mismatch ratio) were analyzed using descriptive statistics. Results: 836 patients were included; 52.3% were in the 19-25 category. Median ischemic cores were larger during the Night (23.0cc [10.0 – 58.0]) compared to Day (19.0cc [8.0-42.0]) or Evening (15.0cc [7.0-33.0]), p=0.009. There was a trend towards larger perfusion volumes in the Night epoch. In the 19-25 group, perfusion volumes were significantly larger at Night (127.5cc [51.5 – 203.5]) compared to Day (74.0cc [33.0 – 139.0]) or Evening (76.0cc [38.0 – 157.5]), with larger mismatch volumes at Night. Conclusions: This is the first study to demonstrate diurnal fluctuations in perfusion parameters in a predominantly pediatric cohort.

We prove a criterion for the constancy of the Hilbert–Samuel function for locally Noetherian schemes such that the local rings are excellent at every point. More precisely, we show that the Hilbert–Samuel function is locally constant on such a scheme if and only if the scheme is normally flat along its reduction and the reduction itself is regular. Regularity of the underlying reduced scheme is a significant new property.

Background: Infantile hydrocephalus is characterized by an atypical accumulation of cerebrospinal fluid in the brain, diagnosed and treated before the age of 2 years. Hydrocephalus development is linked to thinning of the corpus callosum (CC), mainly due to the expansion of lateral ventricles, causing upward elevation and compression of periventricular and subcortical white matter. Methods: This study investigates structural alterations in the CC in children diagnosed with infantile hydrocephalus. We examined both macrostructural and microstructural facets of the CC, providing insights into the nature and extent of alterations associated with this condition. 18 patients with infantile hydrocephalus (mean age = 9 years), and 18 age and sex matched typically-developing healthy children, participated in the study. Structural magnetic resonance imaging and diffusion tensor imaging were utilized to assess CC volume and microstructure, respectively. Results: Our findings reveal reductions in CC volume, particularly in posterior area, and distinct microstructural disparities, notably pronounced in these same segments. Conclusions: Investigating these structural alterations provides an understanding into the mechanisms underlying the effects of infantile hydrocephalus on CC integrity, given its role as a neural bridge. This knowledge offers a more nuanced perspective on neurological disorders and underscores the significance of investigating the CC’s health in such contexts.

Background: High grade gliomas (HGGs) shed extracellular vesicles (EVs) into the bloodstream. EV-derived RNA (EV-RNA) can be detected in plasma, making it a potential biomarker for HGG recurrence after treatment. We sought to establish a baseline relationship between EV-RNA in plasma and hypervascular HGG tissue on MRI. Methods: Eight patients with a new diagnosis of HGG had measurements of plasma EV-RNA and contemporaneous dynamic susceptibility contrast (DSC) MRI. Patient-specific median signal intensity of corpus callosum (mSI-CC) was determined from 10 measurements on the relative cerebral blood volume (rCBV) map. Tumour tissue with signal intensity > mSI-CC and > 2x, > 3x, > 4x and > 5x mSI-CC was segmented on the rCBV map. EV-RNA plasma concentration was correlated with tissue volumes. Results: Pearson correlation showed a significant positive relationship between EV-RNA plasma concentration and tissue volume with signal intensity > mSI-CC (r(6) = 0.899, p = 0.002). No significant relationship could be detected for progressively smaller tissue volumes with signal intensity > 2x, > 3x, > 4x and > 5x mSI-CC. Conclusions: EV-RNA plasma concentration correlates strongly with the total volume of hypervascular HGG tissue on DSC MRI at baseline and merits further evaluation as a biomarker of tumour behaviour in longitudinal imaging studies.

Background: An estimated 27-69 million individuals worldwide sustain a mild Traumatic Brain Injury (mTBI) each year, making it an important public health concern. Many victims experience post-injury neuropsychological issues such as anxiety and depression, which are associated with more post-concussive symptoms and worse functional outcomes. We sought to determine a systematic process to document the presence of anxiety and depression symptoms in mTBI patients to prevent negative impacts on their recovery. Methods: We administered the Generalized Anxiety Disorder-7 (GAD-7) and Center for Epidemiologic Studies Depression Scale Revised (CESDR-10) questionnaires, no more than three months after injury, to screen for these symptoms. A retrospective chart review was performed for 328 patients from the Montreal General Hospital mTBI Clinic who either received these questionnaires (N=143, Mage=40.36, SDage=15.557, Nfemale=90, Nmale=53) or did not (N=185, Mage=41.17, SDage=16.449, Nfemale=114, Nmale=71). The number of interventions received between groups were compared using ANOVA. Results: Patients who received the questionnaires (M=1.34, SD=0.978) were referred to significantly more interventions than those who did not (M=0.90, SD=0.876, p<0.001) and the rate of referral positively correlated with GAD-7 and CESDR-10 scores. Conclusions: Screening for symptoms of anxiety and depression post mTBI helps clinicians refer patients to the appropriate resources, which in turn should improve outcome.

Background: Despite the utility of administrative health data, there remains a lack of patient-centered outcome measures to meaningfully capture morbidity after traumatic brain injury (TBI). We sought to characterize and validate days at home (DAH) as a feasible measure to assess population-level moderate to severe TBI (msTBI) outcomes and health resource utilization. Methods: We utilized linked health administrative data sources to identify adults with msTBI patients presenting to trauma centers in Ontario injured between 2009-2021. DAH at 180 days reflects the total number of days spent alive and at home excluding the days spent institutionalized in acute care, rehabilitation, inpatient mental health settings or post-acute readmissions. Construct and predictive validity were determined; we additionally estimated minimally important difference (MID) in DAH180days. Results: There were 6340 patients that met inclusion criteria. Median DAH180days were 70 days (interquartile range 0-144). Increased health resource utilization at baseline, older age, increasing cranial injury severity and major extracranial injuries were significantly associated with fewer DAH180days. DAH180days was correlated to DAH counts at 1-3 years. The average MID estimate from anchor-based and distribution-based methods was 18 days. Conclusions: We introduce DAH180days as a feasible and sufficiently responsive patient-centered outcome measure with construct, predictive and face validity in an msTBI population.

Background: Traditional insomnia drugs enhance gamma-aminobutyric acid and are associated with abuse/dependence. Dual orexin-receptor antagonists (DORAs) represent an alternate mechanism promoting wakefulness, rather than inhibition. Nonclinical studies indicate DORAs do not demonstrate abuse potential. Nonetheless, based on human abuse potential (HAP) studies and lack of postmarketing data at approval, DORAs are Schedule 4 controlled substances. However, HAP studies may not predict real-world abuse-potential risk. Methods: Adverse events with preferred terms (PTs) of drug-withdrawal-syndrome, drug-abuse, and drug-dependence were evaluated from Eisai’s ongoing global postmarketing safety surveillance system in the US, Canada, and Japan (20/Dec/2019–30/Sep/2023) and the FDA Adverse Event Reporting System (FAERS; 01/Jan/2015–30/Jun/2023). In FAERS, reports of those PTs from DORAs (lemborexant/suvorexant/daridorexant) were compared with zolpidem and with benzodiazepines approved for patients with insomnia (estazolam/temazepam/triazolam). Results: Since lemborexant’s approval, few of the 3 PTs were reported in Eisai’s surveillance system (~0.15 cases per million patient-days of global exposure). Reports in FAERS for PTs of drug-withdrawal-syndrome, drug-abuse, and drug-dependence for DORAs (10,202 reports) were <0.1%/<0.1%/0.1%, respectively. Reports for benzodiazepines (5534 reports) were 0.8%/12.9%/3.7%, respectively, and 1.0%/9.1%/5.3% for zolpidem (18,330 reports), respectively. Conclusions: Abuse potential may be better represented by nonclinical studies and national surveillance systems, suggesting DORAs may not pose meaningful abuse potential and related risks.

Background: Sellar and suprasellar pediatric lesions are uncommon. Endoscopic transnasal transphenoidal surgery (ETTS) is the preferred treatment, but early post-op MRI is hindered by sphenoidal packing. This study aims to assess iMRI safety and efficacy in pediatric ETTS cases. Methods: We performed a retrospective review from Jan 01, 2015 to Dec 31, 2022, evaluating use of iMRI. We determined if the goals of the surgery (biopsy, cyst decompression, subtotal resection, gross total resection) were met, and iMRI’s influence on surgery outcomes. We examined patient age, surgery duration, length of stay, histopathology results, surgical complications, post-op MRIs within 1 month, and tumor progression/recurrence. Results: Over eight years, 20 pediatric ETTS procedures, 14 with iMRI, were conducted. Achieving goals in 13 cases, iMRI prompted extra surgery once. Two adenomas progressed, requiring a second surgery, and craniopharyngioma cases had complications, needing further interventions. Hospital stays varied (1-9 days), with a mean surgery duration of 6 hours and 47 minutes. The study underscores iMRI’s potential impact, stressing the necessity for more research in pediatric transsphenoidal surgeries. Conclusions: While intraoperative MRI in pediatric transsphenoidal surgeries may aid goal verification, this small study doesn’t conclusively demonstrate improved outcomes. Complication rates align with non-IMRI procedures, highlighting the need for further research.

Background: Induced pluripotent stem cells (iPSCs) have revolutionized spinal cord injury (SCI) treatment by generating neural stem/progenitor cells (NSPCs). However, understanding how iPSC-derived NSPCs compare to authentic spinal cord NSPCs remains unclear. This study thoroughly characterizes bona fide spinal cord NSPCs and their isogenic iPSC-derived counterparts, iPSC-SC and iPSC-Br. Methods: Human spinal cord and skin tissue were obtained with ethics approval to establish primary NSPC cultures. iPSCs were derived from these primary cells and differentiated into iPSC-SC and iPSC-Br NSPCs. Assessments encompassed differentiation, proliferation capabilities, immunostaining, and RNA sequencing for differential gene expression. Results: Functional and transcriptional differences were identified between bona fide NSPCs and iPSC-SC/iPSC-Br. Bona fide and iPSC-SC NSPCs exhibited spinal cord regionalization, while iPSC-Br displayed forebrain regionalization. iPSC-derived NSPCs shared features reminiscent of early developmental stages, including embryonic patterning genes and increased proliferation rates. Notably, differentiation profiles were most similar between bona fide and iPSC-Br, with substantial distinctions observed between bona fide and iPSC-SC. Conclusions: This study unveils unique regional, developmental, and functional characteristics distinguishing spinal cord NSPCs from iPSC-derived counterparts. Addressing these disparities holds promise for enhancing iPSC-derived NSPC therapies in spinal cord injuries, contributing to a deeper understanding of their potential applications in regenerative medicine.

Background: Previous research demonstrates that for acute ischemic stroke (AIS) cases, rapid endovascular therapy (EVT) performance improves outcomes. This study provides updated metrics summarizing estimates for modified Rankin Scale (mRS) gains accrued by streamlining time to EVT. Methods: A systematic review and meta-analysis (MA) was conducted using electronic databases. Eligible studies reported time-benefit slope with times from AIS onset (or time last-seen-normal) to EVT commencement; the predictor was onset-to-groin (OTG) time. Primary and secondary outcomes were 90-day functional independence (mRS 0-2) and 90-day excellent function (mRS 0-1), respectively. Results: The five included studies showed increased chance of good outcome with each hour of pre-EVT time savings for mRS 0-2 for 0-270’ (OR 1.25, 95% CI 1.16-1.35, I2 40%) and 271-360’ time frame (1.22, 95% CI 1.12-1.33, I2 58%). For studies assessing mRS 0-1, pooled effect estimates were appropriate for the 0-270’ time frame (OR 1.34, 95% CI 1.19-1.51, I2 27%) and the 271-360’ time frame (OR 1.20, 95% CI 1.03-1.38, I2 60%). Conclusions: Each hour saved from AIS onset to EVT start is associated with a 22-25% increased odds of functional independence, a useful metric to inform patient-specific and systems planning decisions.