Citations

Abstract Development of a non-invasive test that can measure drug delivery and target engagement in GBM represents an opportunity to enhance knowledge during early phase clinical trials of a new compound’s pharmacological suitability and potential efficacy. We present here data supporting that the cargo within extracellular vesicles (EV) can potentially serve as a liquid biopsy that reports on the pharmacodynamics of GBM therapeutics. We treated short-term PDX cultures with vehicle, temozolomide, MLN4924, or arsenic trioxide. EVs were isolated from culture supernatants using size exclusion chromatography and then analyzed by mass spectrometry (proteomics) and RNA sequencing to characterize and compare cargo profiles for each condition. We found that at the proteome level, FDFT1 and FARSB were detected only in temozolomide EVs across all cell lines. In addition, there were drug-agnostic indications of exposure, including decreased abundance in all treated EV conditions of SLC3A2, C3, PLG, and A1BG, and increased abundance of GSTP1. These cargo changes were further validated by western blotting and ExoView immunofluorescence on isolated EVs. At the EV-transcriptome level, depending on treatment, there were shared alterations in EV cargo between models in the expression of long non-coding RNAs, genes that are overrepresented in biological processes such as cytoplasmic translation and cellular macromolecule biosynthesis, and circular RNAs. Thus, these results indicate that EV cargo post-treatment may be a novel pharmacodynamic reporter in GBM. To allow immunoprecipitation of patient GBM-derived EVs with the selective interrogation, the potential biomarkers, including PTPRZ1, B7H3, IL13RA2, and EGFR were screened across isolated EVs from both pre-clinical and clinical patient samples. Future efforts are focused on evaluating immunoprecipitated GBM-EVs from longitudinally collected patient biofluids. Overall, we anticipate that the results of this study will lead to development of a clinical test that reflects BBB penetration and tumor response, which will likely aid in novel drug development efforts.

Individuals with spinal cord injury (SCI) have significant dysfunction in cardiovascular autonomic regulation. While recent findings postulate that spinal cord stimulation improves autonomic regulation, limited scope of past methods have tested only above level sympathetic activation, leaving significant uncertainty. To identify whether transcutaneous spinal cord stimulation improves cardiovascular autonomic regulation, two pairs of well-matched individuals with and without high-thoracic, complete SCI were recruited. Baseline autonomic regulation was characterized with multiple tests of sympathoinhibition and above/below injury level sympathoexcitation. At three subsequent visits, testing was repeated with the addition sub-motor threshold transcutaneous spinal cord stimulation at three previously advocated frequencies. Uninjured controls demonstrated no autonomic deficits at baseline and had no changes with any frequency of stimulation. As expected, individuals with SCI had baseline autonomic dysfunction. In a frequency-dependent manner, spinal cord stimulation enhanced sympathoexcitatory responses, normalizing previously impaired Valsalva's maneuvers. However, stimulation exacerbated already impaired sympathoinhibitory responses, resulting in significantly greater mean arterial pressure increases with the same phenylephrine doses compared to baseline. Impaired sympathoexcitatory response below the level of injury were also further exacerbated with spinal cord stimulation. At baseline, neither individual with SCI demonstrated autonomic dysreflexia with the noxious foot cold pressor test; the addition of stimulation led to a dysreflexic response in every trial, with greater relative hypertension and bradycardia indicating no improvement in cardiovascular autonomic regulation. Collectively, transcutaneous spinal cord stimulation demonstrates no improvements in autonomic regulation after SCI, and instead likely generates tonic sympathoexcitation which may lower the threshold for dangerous autonomic dysreflexia.

Abstract Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

This Viewpoint discusses how patient blood management can help curb the demand for blood products and reduce harm by determining who would most benefit from a blood transfusion.

Background: Shoulder and elbow function is essential to basic basketball actions. Outside of anterior shoulder instability, injuries in these joints are not well characterized in National Basketball Association (NBA) players. Purpose: To describe the epidemiology and associated risk factors of shoulder and elbow injuries in NBA players and identify factors that influence player performance upon return to play. Study Design: Descriptive epidemiology study. Methods: Historical injury data from the 2015-2020 NBA seasons were retrieved from Pro Sports Transactions, a public online database. An injury was defined as a health-related concern resulting in an absence of ≥1 NBA games. Primary measures included pre- and postinjury player efficiency rating (PER) and true shooting percentage (TS%) with interquartile ranges (IQRs), stratified by extremity dominance. Multivariate logistic regression analyses with stepwise regression were performed to identify risk factors associated with return-to-play performance. Results: A total of 192 shoulder and elbow injuries were sustained among 126 NBA athletes, with incidence rates of 1.11 per 1000 game exposures (GEs) and 0.30 per 1000 GEs, respectively. Sprain/strain and general soreness were the most common injury types in both the shoulder and the elbow. In the 2 years after injury, baseline PER was achieved in all groups, except for players with dominant shoulder injuries (baseline PER, 16 [IQR, 14-18] vs 2-year PER, 13 [IQR 11-16]; P = .012). Younger age was associated with quicker return to baseline PER (odds ratio, 0.77 [95% CI, 0.67-0.88]). Shoulder and elbow injuries did not negatively influence TS% upon return to play (baseline TS%, 0.55% [IQR, 0.51%-0.58%] vs 1-year TS%, 0.55% [IQR, 0.52%-0.58%]; P = .13). Conclusion: Dominant shoulder injuries negatively influenced PER during the first 2 seasons upon return to play in NBA players. Therefore, expectations that players with this type of injury immediately achieve baseline statistical production should be tempered. Shooting accuracy appears to remain unaffected after shoulder or elbow injury.

Background and Objectives: Literature reviews are foundational to understanding medical evidence. With AI tools like ChatGPT, Bing Chat and Bard AI emerging as potential aids in this domain, this study aimed to individually assess their citation accuracy within Nephrology, comparing their performance in providing precise. Materials and Methods: We generated the prompt to solicit 20 references in Vancouver style in each 12 Nephrology topics, using ChatGPT, Bing Chat and Bard. We verified the existence and accuracy of the provided references using PubMed, Google Scholar, and Web of Science. We categorized the validity of the references from the AI chatbot into (1) incomplete, (2) fabricated, (3) inaccurate, and (4) accurate. Results: A total of 199 (83%), 158 (66%) and 112 (47%) unique references were provided from ChatGPT, Bing Chat and Bard, respectively. ChatGPT provided 76 (38%) accurate, 82 (41%) inaccurate, 32 (16%) fabricated and 9 (5%) incomplete references. Bing Chat provided 47 (30%) accurate, 77 (49%) inaccurate, 21 (13%) fabricated and 13 (8%) incomplete references. In contrast, Bard provided 3 (3%) accurate, 26 (23%) inaccurate, 71 (63%) fabricated and 12 (11%) incomplete references. The most common error type across platforms was incorrect DOIs. Conclusions: In the field of medicine, the necessity for faultless adherence to research integrity is highlighted, asserting that even small errors cannot be tolerated. The outcomes of this investigation draw attention to inconsistent citation accuracy across the different AI tools evaluated. Despite some promising results, the discrepancies identified call for a cautious and rigorous vetting of AI-sourced references in medicine. Such chatbots, before becoming standard tools, need substantial refinements to assure unwavering precision in their outputs.

OBJECTIVE The objective of this study was to analyze the hemorrhagic risk of melanoma brain metastases after Gamma Knife radiosurgery (GKRS). METHODS A prospective institutional database was retrospectively queried to identify patients who underwent GKRS for melanoma brain metastases between 1990 and 2021. Lesional hemorrhage was defined as definite or possible based on radiologists’ readings, and severity was graded according to Common Terminology Criteria for Adverse Events. RESULTS Two hundred ninety-one patients with 1083 lesions treated in 419 sessions were identified. The mean (± SD) patient age was 60 ± 15 years, and 61% were male. The median follow-up period for overall survival (OS) was 11 (range 0–214) months with 581 patient-years. Definite/possible lesional hemorrhages occurred in 13% of lesions, with grade 3 hemorrhages observed in 4% of lesions. Surgical intervention was required in 2% of cases (5% of patients), and all resected lesions were pathologically consistent with melanoma. A decreased risk of definite/possible lesional hemorrhage was associated with a later time period between 2015 and 2021 (OR 0.45, 95% CI 0.266–0.75, p = 0.0021), increased marginal dose (OR 0.91, 95% CI 0.83–0.99, p = 0.037), antiplatelet use post-GKRS (OR 0.195, 95% CI 0.083–0.46, p < 0.001), and whole-brain radiotherapy (WBRT; OR 0.53, 95% CI 0.344–0.82, p = 0.0042). After 2015, more patients received anticoagulation, B-Raf proto-oncogene inhibitors, and immune checkpoint inhibitors, and fewer received bevacizumab (p < 0.001). The cumulative risk of lesional hemorrhage was 17%–20% at 36 months from GKRS, with 95%–96% of cases occurring within 12 months. The median patient OS was 11 (95% CI 9–13) months, and multivariate Cox regression analysis revealed that antiplatelet agents (hazard ratio [HR] 0.66, 95% CI 0.45–0.96, p = 0.031) and immune checkpoint inhibitors (HR 0.35, 95% CI 0.26–0.48, p < 0.001) were associated with longer OS, while WBRT (HR 1.36, 95% CI 1.02–1.81, p = 0.037) and definite/possible hemorrhage (HR 1.39, 95% CI 1.04–1.85, p = 0.024) were associated with shorter OS. CONCLUSIONS The definite hemorrhage risk of melanoma brain metastases after GKRS was 17% in the first 3 years and 95% of the lesional hemorrhage occurred within the 1st year. Surgical intervention was needed in 5% of patients. Antiplatelet agents and immune checkpoint inhibitors were associated with improved OS, while definite/possible hemorrhage was associated with worse OS.

Patients with chronic kidney disease (CKD) necessitate specialized renal diets to prevent complications such as hyperkalemia and hyperphosphatemia. A comprehensive assessment of food components is pivotal, yet burdensome for healthcare providers. With evolving artificial intelligence (AI) technology, models such as ChatGPT, Bard AI, and Bing Chat can be instrumental in educating patients and assisting professionals. To gauge the efficacy of different AI models in discerning potassium and phosphorus content in foods, four AI models—ChatGPT 3.5, ChatGPT 4, Bard AI, and Bing Chat—were evaluated. A total of 240 food items, curated from the Mayo Clinic Renal Diet Handbook for CKD patients, were input into each model. These items were characterized by their potassium (149 items) and phosphorus (91 items) content. Each model was tasked to categorize the items into high or low potassium and high phosphorus content. The results were juxtaposed with the Mayo Clinic Renal Diet Handbook’s recommendations. The concordance between repeated sessions was also evaluated to assess model consistency. Among the models tested, ChatGPT 4 displayed superior performance in identifying potassium content, correctly classifying 81% of the foods. It accurately discerned 60% of low potassium and 99% of high potassium foods. In comparison, ChatGPT 3.5 exhibited a 66% accuracy rate. Bard AI and Bing Chat models had an accuracy rate of 79% and 81%, respectively. Regarding phosphorus content, Bard AI stood out with a flawless 100% accuracy rate. ChatGPT 3.5 and Bing Chat recognized 85% and 89% of the high phosphorus foods correctly, while ChatGPT 4 registered a 77% accuracy rate. Emerging AI models manifest a diverse range of accuracy in discerning potassium and phosphorus content in foods suitable for CKD patients. ChatGPT 4, in particular, showed a marked improvement over its predecessor, especially in detecting potassium content. The Bard AI model exhibited exceptional precision for phosphorus identification. This study underscores the potential of AI models as efficient tools in renal dietary planning, though refinements are warranted for optimal utility.