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Cerebrospinal Creatine Kinase BB Isoenzyme: A Biomarker for Predicting Outcome After Cardiac Arrest
No full textBACKGROUND: Cerebrospinal fluid creatine kinase BB isoenzyme (CSF CK-BB) after cardiac arrest (CA) has been shown to have a high positive predictive value for poor neurological outcome, but it has not been evaluated in the setting of targeted temperature management (TTM) and modern CA care. We aimed to evaluate CSF CK-BB as a prognostic biomarker after CA. METHODS: We performed a retrospective cohort study of patients with CA admitted between 2010 and 2020 to a three-hospital health system who remained comatose and had CSF CK-BB assayed between 36 and 84 h after CA. We examined the proportion of patients at hospital discharge who achieved favorable or intermediate neurological outcome, defined as Cerebral Performance Category score of 1-3, compared with those with poor outcome (Cerebral Performance Category score 4-5) for various CSF CK-BB thresholds. We also evaluated additive value of bilateral absence of somatosensory evoked potentials (SSEPs). RESULTS: Among 214 eligible patients, the mean age was 54.7 ± 4.8 years, 72% of patients were male, 33% were nonwhite, 17% had shockable rhythm, 90% were out-of-hospital CA, and 83% received TTM. A total of 19 (9%) awakened. CSF CK-BB ≥ 230 U/L predicted a poor outcome at hospital discharge, with a specificity of 100% (95% confidence interval [CI] 82-100%) and sensitivity of 69% (95% CI 62-76%). When combined with bilaterally absent N20 response on SSEP, specificity remained 100% while sensitivity increased to 80% (95% CI 73-85%). Discordant CK-BB and SSEP findings were seen in 13 (9%) patients. CONCLUSIONS: Cerebrospinal fluid creatine kinase BB isoenzyme levels accurately predicted poor neurological outcome among CA survivors treated with TTM. The CSF CK-BB cutoff of 230 U/L optimizes sensitivity to 69% while maintaining a specificity of 100%. CSF CK-BB could be a useful addition to multimodal neurological prognostication after CA
Regional variability of the impact of cardiometabolic diseases on incident dementia in United States Medicare beneficiaries
No full textINTRODUCTION: Understanding the impact of cardiometabolic diseases (CMDs) on dementia risk can inform primary preventative measures. METHODS: We leveraged a nationwide, population-based Medicare dataset of 20,789,037 beneficiaries (756,321 with incident dementia and 20,032,716 controls) from 2017 to compute the individual and combined population attributable fractions (PAFs) of dementia attributed to eight CMDs, adjusted for age, sex, and race. We mapped PAFs at the county level to investigate the geospatial patterns of CMD burden on dementia across the United States. RESULTS: The nationwide combined weighted PAF for the eight CMDs was 37% overall, with hypertension (9.6%), ischemic heart disease (6.7%), and chronic heart failure (5.7%) associated with the greatest attributable fractions of dementia cases. The greatest fraction of county-level dementia cases attributed to CMDs were in the Southeastern United States. DISCUSSION: A substantial proportion of incident dementia cases in the United States can be attributed to CMDs, especially in the Southeastern United States. HIGHLIGHTS: Investigated the combined effect of cardiometabolic diseases (CMDs) on dementia. Used novel geospatial techniques to map the burden of dementia attributed to CMDs. If eight CMDs are mitigated, 37% of incident dementia cases could be eliminated. Identified regions of the United States with high CMD burden on dementia
Safety considerations of semaglutide in the potential treatment of Alzheimer\u27s disease: A pooled analysis of semaglutide in adults aged ≥ 65 years
No full textINTRODUCTION: The evoke/evoke+ trials are investigating semaglutide in a population with early Alzheimer\u27s disease (AD). Specific analyses of semaglutide safety data in older adults are limited; therefore, in the current analysis, we aimed to evaluate safety considerations with semaglutide in adults ≥ 65 years. METHODS: Adverse event (AE) data from three semaglutide phase 3a programs in participants ≥ 65 years with type 2 diabetes and/or overweight/obesity were pooled. Change in body weight was also assessed in a smaller subset of participants ≥ 65 years. RESULTS: The analysis included 3529 participants ≥ 65 years. Baseline mean age and body mass index in participants ≥ 65 years were 69.3 to 70.2 years and 29.7 to 35.4 kg/m, respectively, compared to 47.8 to 58.5 years and 31.3 to 36.7 kg/m in the overall population. AEs with semaglutide occurred in 73.6% to 92.4% of participants ≥ 65 years versus 73.2% to 90.8% of the overall population. AEs with semaglutide leading to permanent discontinuation appeared to be more frequent in participants ≥ 65 years (9.3%-12.4%) versus the overall population (5.7%-8.7%). Gastrointestinal disorders were the most frequently reported AEs with semaglutide in participants ≥ 65 years (44.6%-73.8%) and in the overall population (39.1%-73.4%). Participants aged ≥ 65 years receiving semaglutide had an estimated weight loss of 3.8% at week 52 compared to 0.1% with placebo. DISCUSSION: Age ≥ 65 years did not appear to affect the safety considerations of semaglutide. The ongoing evoke/evoke+ trials will elucidate the balance of efficacy and safety in the treatment of early AD with semaglutide. HIGHLIGHTS: This was a post hoc analysis evaluating adverse event (AE) data of semaglutide in people ≥ 65 years.The most common AE with semaglutide was gastrointestinal (GI).GI event rates were similar in people ≥ 65 years and the overall study populations
Prevalence and clinical considerations of Y chromosome microdeletions in azoospermic and oligozoopsermic infertile men from Al Madinah Al Munawarah, Saudi Arabia
No full textOBJECTIVES: To characterize the potential role of Y-chromosome microdeletion (YCM) as a genetic cause for infertility in the Arab population from the Al Madinah Al Munawarah. METHODS: We screened 97 infertile men from Al Madinah Al Munawarah, from February 2022 to March 2024. Genomic blood DNA was analyzed for 8 sequence tagged site (STS) markers of Y chromosome by multiplex polymerase chain reaction. RESULTS: We found microdeletions in 3 infertile men, indicating a prevalence of 3.1%. The STS markers sY254 and sY255 corresponding to AZFc regions were deleted in these men. No deletion was observed in any other STS markers investigated in this study. CONCLUSION: Our findings for prevalence in Arab population of Al Madinah Al Munawarah is comparable to other studies from Saudi Arabia. However, large variance in the prevalence of YCM in the Arab population of other Middle Eastern countries is reportedly observed. The YCM has significant prognostic value, since it indicates the spermatogenic profile, the success probability of assisted reproduction technique (ART) procedures as testicular sperm extraction and apprise of potential risk of vertical transmission of microdeletion from father to son in patients opting for ART. With these considerations, we re-emphasize the need for genetic screening of YCM in azoo- and oligozoospermic infertile men
Academic productivity and career trajectory of international medical graduates in US neurosurgery residency programs
No full textOBJECTIVE: The objective of this study was to review and compare the research experiences and career outcomes of international medical graduates (IMGs) with those of US medical graduates (USMGs). METHODS: Neurosurgery graduates from 2018 to 2020 were evaluated on the basis of medical school, degree, residency program, publications before and during residency, postresidency fellowships, and career progression. Publications were further categorized by author order and type (laboratory, comprehensive clinical, or short communication). RESULTS: Of 550 neurosurgery graduates, 39 (7%) were IMGs, with the largest percentages from India (8/39, 21%) and in a residency position in Pennsylvania (5/39, 13%). Prior to residency, IMGs had a higher median number of all publications (4 vs 1, p \u3c 0.001), first-author articles (2 vs 0, p \u3c 0.001), comprehensive clinical articles (1 vs 0, p = 0.002), and short communication articles (1 vs 0, p \u3c 0.001) than USMGs. Similarly, the median number of papers published by IMGs during residency was also higher compared with that of USMGs for all publications (20 vs 9, p = 0.004), laboratory articles (1 vs 0, p \u3c 0.001), and short communication articles (4 vs 3, p = 0.04). The percentage of early academic appointments was higher for IMGs (25/39, 64%) than for USMGs (232/511, 45%) (p = 0.03). No significant difference was observed between the percentages of postresidency clinical fellowships completed by IMGs (28/39, 72%) and USMGs (302/511, 59%) (p = 0.15). No statistical significance was found between the ranking of neurosurgery residency programs attended by IMGs and USMGs (p = 0.65). CONCLUSIONS: The results indicate that IMGs often exhibit higher academic productivity than USMGs. Although there was no discernible difference in residency program rankings or postresidency fellowships completed, early academic appointments were more prevalent among IMGs
Sexually Dimorphic Responses Reveal Multifaceted Benefits of Glibenclamide in Traumatic Brain Injury
No full textSex disparities in traumatic brain injury (TBI) remain poorly understood. Previous data suggest that males are more susceptible to acute secondary injury processes and cell death, whereas females are more vulnerable chronically. Additional sex-based differences have been reported depending on injury model/severity and post-traumatic neurodegeneration. This gap in understanding limits therapy translation. We previously demonstrated sex-based differences in genetic modulation of a key pathway of secondary injury in TBI, sulfonylurea-receptor 1 (SUR1). Glibenclamide (GLI, SUR1-inhibitor) has shown promise in pre-clinical and early clinical studies of TBI and stroke. Here, we evaluated GLI\u27s modulation of multifaceted TBI outcomes across sex for the first time. In total, 120 mice were randomized to controlled cortical impact (CCI) ± GLI or vehicle (dimethyl sulfoxide, DMSO). Either vehicle or GLI treatment was administered post-CCI using an intraperitoneal (IP) loading dose (10 µg/mouse, 10 min post-TBI), followed by a 7-day subcutaneous maintenance infusion at 0.5 µL/h using ALZET mini-osmotic pumps (1007D, Durect Corp.). Mice were tested for cognitive function (Morris water maze, MWM), motor function (rotarod), anxiety (elevated plus maze, EPM), immunofluorescence markers of neurodegeneration (TAU, TDP43), neurogenesis (SOX2, Ki67), angiogenesis (VEGFA), and cerebral blood flow (CBF) to interrogate behavioral, molecular, and physiological effects of TBI and therapy. Different measures within behavioral, immunofluorescence, and CBF outcomes varied across sex, either post-CCI and/or in response to GLI. Motor impairment had baseline differences across sex post-CCI. In both sexes, behavioral deficits were improved by GLI. The effect of GLI on behavior was moderated by sex, with greater benefit in males versus females, including improved MWM latency (p \u3c 0.0001) and rotarod latency (p = 0.016, revolutions per minute, p = 0.03). Males had increased anxiety post-CCI (EPM); GLI was beneficial across sexes. TDP43 and TAU in several brain regions were increased 72 h post-CCI (males\u3efemales, all p \u3c 0.0001). These remained markedly elevated only in females by 21 days, whereas TAU in males decreased without treatment. GLI downregulated TDP43 and TAU across sex and brain region (all p \u3c 0.01-0.0001). In females only, DMSO had similar effects as GLI on TDP43 and TAU. SOX2 was increased in the dentate gyrus (DG) only in males post-CCI (p \u3c 0.01, p \u3c 0.001). GLI increased DG SOX2 in females (p \u3c 0.05, p \u3c 0.001). GLI increased VEGFA at 72 h across sexes. CCI reduced CBF acutely in both sexes; in males, GLI improved this by 21 days (p = 0.031). In females, both GLI and DMSO-vehicle benefited CBF versus untreated-CCI. We demonstrate novel sex-based differences post-CCI and GLI-response across several metrics. TAU was chronically elevated (and responsive to treatment) in females, not males, potentially providing a sex-specific target. DMSO may have previously unrecognized benefits on certain pathways (TAU, CBF) in females. Although GLI has multifaceted benefits across sexes, effects are more pronounced in males. This may have important implications for clinical trial study design and analysis
Automated Detection of Normal Pressure Hydrocephalus Using CT Imaging for Calculating the Ventricle-to-Subarachnoid Volume Ratio
No full textBACKGROUND AND PURPOSE: Normal pressure hydrocephalus (NPH) is a diagnostic challenge because its clinical symptoms and imaging appearance resemble normal aging and other forms of dementia. Identifying NPH is essential so that patients can receive timely treatment to improve gait distortion and quality of life. An automated marker of NPH was developed and evaluated on clinical CT images, and its utility was assessed in a large patient cohort. MATERIALS AND METHODS: A retrospective review was conducted of CT images from 306 tap test-responsive patients with NPH between January 2015 and January 2022. Control CT images were obtained from patients in the emergency department who were evaluated for headache and had unremarkable CT findings between June 2021 and August 2022. The ventricle-to-subarachnoid volume ratio (VSR) was automatically calculated by the imaging software and used as a predictor of NPH in linear regression modeling with adjustment for age and sex. The correlations of VSR with age, sex, and the receiver operating characteristic were computed. RESULTS: VSR was significantly greater in patients with NPH than controls (P \u3c .001). Importantly, VSR was not significantly correlated with age (P = .56, R = 0.001). VSR identifies NPH with a sensitivity and specificity of 94.1% and 92.5%, respectively, with an area under the receiver operating characteristic curve of 0.99 (95% CI 0.975-0.995). CONCLUSIONS: Automated assessment of the VSR on head CT images identified probable NPH with 93% accuracy. The assessment of a large cohort of patients with NPH supports the generalizability of clinical screening of CT images. Moreover, the results support the utility of ventricle-to-sulcal concordance often used by radiologists but not currently a part of the accepted guidelines for imaging markers of NPH
The Complex Role of the Complement C3a Receptor (C3aR) in Cerebral Injury and Recovery Following Ischemic Stroke
No full textThe Complement C3a Receptor (C3aR) plays a multifaceted role along the varying temporal phases of brain injury following cerebral ischemia. C3aR is a G-protein-coupled receptor (GPCR) that binds to its ligand, C3a an anaphylatoxin generated during activation of the complement cascade. During ischemia, complement is activated as part of the initial inflammatory response, with C3aRs playing a time-dependent role in both brain injury and repair mechanisms. In the acute phase (minutes to hours post-ischemia), C3aR activation promotes the recruitment of immune cells and the release of chemokines and cytokines, driving blood-brain barrier (BBB) permeability and brain edema. During the subacute phase (hours to days post-ischemia), C3aR continues to modulate immune cell activity, worsening secondary brain injury, although emerging evidence suggests that C3aR activation in this phase may also aid in the clearance of cellular debris and cell survival. In the chronic phase (days to weeks post-ischemia), chronically elevated C3aR activity can prolong neuroinflammation and impair recovery, whereas controlled C3aR signaling in the subacute/chronic phase can activate reparative pathways (e.g., microglial phagocytosis, astrocyte trophic support). As a result, targeting the C3aR requires careful timing to optimize its benefits. Given the dual impact of C3aR activation, which serves to exacerbate injury in the acute phase but supports repair beginning in the subacute and chronic phases, a targeted therapeutic approach should focus on context- and time-dependent modulation of the C3a/C3aR axis. This strategy would involve blocking the C3aR during the acute phase to reduce inflammation and BBB breakdown while controlling C3a signaling in later phases to promote tissue repair
