Citations

Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2high GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics.

BACKGROUND AND OBJECTIVES: The Risk Analysis Index (RAI) is a comprehensive assessment of frailty for predicting neurosurgical outcomes. The aim of this study was to assess whether frailty, measured by a modified RAI (mRAI), was an independent predictor of adverse events (AEs), nonroutine discharge (NRD), and in-hospital mortality for patients with acute cervical spinal cord injuries (SCIs). METHODS: A retrospective cohort study was performed using the American College of Surgeons Trauma Quality Programs database. Adult patients with acute cervical SCI from 2016 to 2022 were stratified by mRAI score into 3 groups: Robust (mRAI 0-10), Frail (mRAI 11-20), and Very Frail (mRAI ≥21). Patient demographics, comorbidities, injury type, diagnostic and treatment modality, AEs, and in-hospital mortality were assessed. A multivariate logistic regression analysis was used to identify independent predictors of AEs, NRD, and in-hospital mortality. RESULTS: 71 048 patients were stratified by mRAI score: 59 796 Robust (84.2%), 9558 Frail (13.5%), and 1694 Very Frail (2.4%). The proportion of SCIs secondary to a fall (Robust: 44.1% vs Frail: 70.2% vs Very Frail: 82.3%; P < .001) and AEs (Robust: 21.5% vs Frail: 24.4% vs Very Frail: 25.0%; P < .001) significantly increased with frailty. Very Frail patients experienced higher NRDs (Robust: 72.3% vs Frail: 85.2% vs Very Frail: 91.0%; P < .001) and in-hospital mortality (Robust: 10.9% vs Frail: 18.3% vs Very Frail: 29.2%; P < .001). On multivariate regression analysis, both Frail (odds ratio [OR]: 1.42; 95% CI: 1.25-1.61; P < .001) and Very Frail (OR: 2.09; 95% CI: 1.46-2.99; P < .001) mRAI scores predicted NRD, but only Frail mRAI score (OR: 1.12; 95% CI: 1.05-1.21; P = .001) was significantly associated with AEs. In addition, Frail (OR: 1.50; 95% CI: 1.36-1.65; P < .001) and Very Frail (OR: 2.79; 95% CI: 2.36-3.29; P < .001) mRAI scores were independent predictors of in-hospital mortality. CONCLUSION: Our study suggests that mRAI may be used to assess morbidity and mortality in patients presenting with spinal cord injury.

Background/Objectives: Electrode impedance is crucial for optimizing cochlear implant (CI) stimulation and hearing outcomes. While typically stable, some patients experience unexplained impedance fluctuations. This study used electrode impedance subcomponent analysis to identify the subcomponents contributing to these impedance fluctuations. Methods: This study analyzed clinical electrode impedances and transimpedance matrix (TIM) measurements in 10 CI patients with Nucleus devices (CI422, CI522, or CI622 electrode arrays) who exhibited fluctuating or rising electrode impedances. TIM measurements used a cathodic-leading biphasic pulse (110 CLs, 75 µs/phase, 7 µs interphase interval). Electrode impedances were determined at 6, 12, 18, 24, and 75 µs, and subcomponents (access resistance [near-field/far-field] and polarization impedance [Warburg capacitance/Faraday resistance]) were calculated. Results: Both access resistance and polarization impedance changes contributed to impedance fluctuations. Large changes in near-field resistance compared to far-field resistance were associated with increased resistance to current flow closer to the surface of the electrode. The decreased double-layer capacitance and slightly increased Faraday resistance further suggested increased resistance to charge transfer at the electrode–electrolyte interface. Conclusions: Electrode impedance subcomponent analysis reveals changes in the electrochemical reaction at the electrode surface that cause fluctuating or rising CI electrode impedances.

Abstract Selective activation of smaller diameter over large diameter nerve fibers represents a broad challenge in the electrical modulation of neural activity for clinical applications. For example, off-target activation of motor nerve fibers has been implicated in several failed vagus nerve stimulation (VNS) clinical trials by precluding achieving current amplitudes sufficient to activate the therapeutically targeted small diameter fibers. In this study, we evaluated the use of high-frequency (HF) stimulation to block unwanted activation of large diameter fibers evoked by traditional low-frequency (LF) VNS in a large animal (swine) model. We demonstrate that HF can eliminate specific unwanted LF-evoked components from neural recordings with high selectivity – along with their associated off-target physiological responses - while preserving the activation of smaller diameter fibers driving intended physiological responses. Conversely, block of the smaller diameter fibers was only observed at HF amplitudes much higher than amplitudes commonly used for HF block clinically. We found that in addition to blocking the LF-evoked compound action potential, lower HF amplitudes also drive asynchronous activity which can easily be overlooked. Only at high amplitudes did HF block LF-evoked activation without concomitant asynchronous activation. These data have numerous implications for existing and future LF and HF block neuromodulation therapies.

Abstract Background The Global Leadership Initiative on Malnutrition (GLIM) introduced an approach for malnutrition diagnosis in 2019 that comprised screening followed by assessment of three phenotypic criteria (weight loss, low body mass index [BMI], and low muscle mass) and two etiologic criteria (reduced food intake/assimilation and inflammation/disease burden). This planned update reconsiders the GLIM framework based on published knowledge and experience over the past 5 years. Methods A working group ( n = 43 members) conducted a literature search spanning 2019–2024 using the keywords “Global Leadership Initiative on Malnutrition or GLIM.” Prior GLIM guidance activities for using the criteria on muscle mass and inflammation were reviewed. Successive rounds of revision and review were used to achieve consensus. Results More than 400 scientific reports were published in peer‐reviewed journals, forming the basis of 10 systematic reviews, some including meta‐analyses of GLIM validity that indicate strong construct and predictive validity. Limitations and future priorities are discussed. Working group findings suggest that assessment of low muscle mass should be guided by experience and available technological resources. Clinical judgment may suffice to evaluate the inflammation/disease burden etiologic criterion. No revisions of the weight loss, low BMI, or reduced food intake/assimilation criteria are suggested. After two rounds of review and revision, the working group secured 100% agreement with the conclusions reported in the 5‐year update. Conclusion Ongoing initiatives target priorities that include malnutrition risk screening procedures, GLIM adaptation to the intensive care setting, assessment in support of the reduced food intake/assimilation criterion, and determination of malnutrition in obesity.

Background Parkinson's disease (PD) is a progressive degenerative disease affecting people at any age; however, it is generally more prevalent in older age groups. Younger individuals, especially women, are facing significant challenges that pertain to pregnancy. Unfortunately, the available information is limited and supported mostly by anecdotical experience. Objective To gain insight into the interaction between early-onset PD and pregnancy. Methods We report on a case series of women, diagnosed with PD, that underwent pregnancy to explore the disease catachrestic, natural history, and different challenges associated with these unique group of people. Results We identified a total of 9 participants who met our inclusion criteria, who had gone through a total of 12 pregnancies after onset of PD motor symptoms. In 10 out of 12 pregnancies, participants did not use any PD medication; throughout 1 pregnancy, a participant used pramipexole and throughout 1 pregnancy, a participant used levodopa/carbidopa. Conclusions Our study supports the importance of further multicentric studies on pregnant women with PD to prospectively collect data on complications, birth outcomes, lactation, and PD severity.

Abstract Precise localization of the epileptogenic zone is pivotal for planning minimally invasive surgeries in drug-resistant epilepsy. Here, we present a graph neural network (GNN) framework that integrates interictal intracranial EEG features, electrode topology, and MRI features to automate epilepsy surgery planning. We retrospectively evaluated the model using leave-one-patient-out cross-validation on a dataset of 80 drug-resistant epilepsy patients treated at St. Anne's University Hospital (Brno, Czech Republic), comprising 31 patients with good postsurgical outcomes (Engel I) and 49 with poor outcomes (Engel II–IV). The GNN predictions demonstrated a significantly better (P &lt; 0.05, Mann–Whitney-U test) area under the precision-recall curve in patients with good outcomes (area under the precision-recall curve: 0.69) compared with those with poor outcomes (area under the precision-recall curve: 0.33), indicating that the model captures clinically relevant targets in successful cases. In patients with poor outcomes, the graph neural network proposed alternative intervention sites that diverged from the original clinical plans, highlighting its potential to identify alternative therapeutic targets. We show that topology-aware GNNs significantly outperformed (P &lt; 0.05, Wilcoxon signed-rank test) traditional neural networks while using the same intracranial EEG features, emphasizing the importance of incorporating implantation topology into predictive models. These findings uncover the potential of GNNs to automatically suggest targets for epilepsy surgery, which can assist the clinical team during the planning process.

Abstract Objective The objective of this study was to examine the clinical outcomes during the implementation of a self-administered patient decision-aid (PtDA) for lupus. Methods We provided an effective computerized lupus PtDA in 15 rheumatology outpatient clinics 2019–2024 (including the COVID pandemic). We undertook Organizational Readiness to Implement Change Surveys (ORICs) and Team Learning and Psychological Safety Surveys (TLPSSs) at baseline. The primary study outcome objective measure, percent penetration/reach, was defined as the number of patients who viewed the lupus PtDA at the end of the study, divided by the total number of eligible patients (times 100). We used validated clinical personnel surveys to examine the perceived lupus PtDA appropriateness, acceptability, feasibility, success, and permanence, at 4 months, 12 months and 24 months post-PtDA implementation. Results Among the sites, the clinical personnels’ (n = 184) baseline ORIC commitment and efficacy scores (a 0–5 scale, higher = better) ranged from 3.5 to 4.2, and 3.4 to 4.4, respectively; the TLPSS scores (a 0–7 scale, higher = better) were 3.9–5.5 for internal learning, 3.7–5.6 for external learning, and 4.3–5.5 for psychological safety. The penetration (primary outcome) among 15 geographically diverse US rheumatology clinics ranged from 3% to 44%. We found that the total number of providers in the clinic was positively associated with higher penetration. Clinical personnel–perceived lupus PtDA outcomes were optimal at 4 months (all scale scores ranged from 1 to 5, higher = better): (i) appropriateness, 3.43 (s.d. 0.86); (ii) acceptability, 3.53 (s.d. 0.83); (iii) feasibility, 3.44 (s.d. 0.71); (iv) success, 3.41 (s.d. 0.73); and (v) permanence, 3.22 (s.d. 0.74). Conclusion We implemented a lupus PtDA with varied success rates during the COVID pandemic; more providers were associated with higher clinic penetration. Clinical personnel perceived high lupus PtDA appropriateness, acceptability, feasibility, success, and permanence that persisted up to 24 months. Trial Registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03735238.