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Abstract Background Parkinson's disease (PD) represents a growing global health challenge, with prevalence doubling from 2.5 million cases in 1990 to 6.1 million in 2016, and projections suggesting it will exceed 12 million by 2040. This exponential growth has been termed the "Parkinson's pandemic." China and the United States, which together account for nearly half of the global PD population, have developed markedly different approaches to end-of-life (EOL) care, shaped by their distinct healthcare systems and cultural contexts. Understanding these differences is crucial for developing effective global strategies. This systematic review and meta-analysis comprehensively compares advanced-stage PD care between these two nations to quantify disparities and inform evidence-based policy interventions. Methods We conducted a rigorous systematic review following PRISMA 2020 guidelines, searching six databases (PubMed, Embase, Scopus, Web of Science, CNKI, Wanfang) from January 2015 to October 2025. The timeframe was selected to capture contemporary care patterns following major healthcare reforms in both countries (Affordable Care Act implementation in the US; Healthy China 2030 initiative). Inclusion criteria encompassed peer-reviewed studies reporting on advanced PD (Hoehn-Yahr stage ≥ 3) with outcome measures including survival, quality of life (QoL), palliative care access, caregiver burden, rehabilitation utilization, or healthcare costs. The sample size threshold (n ≥ 100) balanced statistical power with inclusivity. Two independent reviewers screened 3,847 records with excellent agreement (Cohen's κ = 0.82–0.89). Quality assessment employed the Newcastle-Ottawa Scale (NOS ≥ 8 indicating high quality) and ROBINS-I for observational studies, with GRADE criteria determining evidence certainty. Meta-analyses utilized random-effects models with comprehensive heterogeneity assessment (I² statistics, meta-regression) and publication bias evaluation (Egger's test, trim-and-fill analysis). Sensitivity analyses included high-quality studies only and examined the influence of large database studies. Results Our analysis of 42 high-quality studies encompassing over 125,000 patients revealed profound and systematic cross-national disparities across multiple domains. In terms of care access, US patients demonstrated significantly higher hospice enrollment rates (28–35% vs. <1% in China, p < 0.001; HIGH certainty evidence) and greater access to specialized neuropalliative programs (15% of US centers vs. <1% in China). These differences translated into measurable quality of life disparities, with Chinese patients scoring 17.6 points worse on the PDQ-39 scale (95% CI 14.2–21.0; MODERATE certainty, I²=68%), a difference exceeding the minimal clinically important difference nearly four-fold. The burden on families showed equally striking patterns: Chinese families provided 94% of EOL care compared to 61% in the US, resulting in significantly higher caregiver depression rates (47% vs. 32%, OR = 1.89, 95% CI 1.45–2.47) and burden scores (Zarit difference: 10.2 points, 95% CI 7.8–12.6). Access to interventions revealed additional gaps, with only 9.2% of Chinese patients receiving physical therapy versus 14.4% in the US (OR = 0.61, 95% CI 0.49–0.76), and a 5.25-fold disparity in deep brain stimulation access (4.2% vs. 0.8%). Economic analysis demonstrated substantial out-of-pocket burden differences: Chinese families paid 58% of total costs ($4,200 annually) versus 12% for US families ($2,800). Meta-regression identified healthcare system characteristics as the primary driver of these disparities (R²=0.42, p < 0.001). Conclusions This comprehensive analysis reveals that systematic differences in healthcare infrastructure, insurance coverage, and cultural care models produce markedly divergent EOL experiences for PD patients in China versus the United States. These findings have immediate policy implications. For China, we recommend: (1) establishing pilot neuropalliative programs in tertiary centers with phased national expansion; (2) developing caregiver support infrastructure including respite care and training programs; (3) leveraging telemedicine platforms to address urban-rural disparities. For the United States, priorities include: (1) addressing racial disparities in rehabilitation access through culturally competent outreach; (2) expanding Medicare coverage for maintenance therapy; (3) earlier integration of neuropalliative care. Implementation science research is urgently needed to test culturally adapted interventions. As global PD prevalence accelerates, lessons from this bilateral comparison provide a framework for other nations confronting similar challenges in neurological care delivery.

Significance: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by reactivating antitumor immunity and improving outcomes across multiple malignancies. Yet, clinical observations and preclinical studies suggest that ICIs may increase long-term cardiovascular disease risk, including hypertension, atherosclerosis, and thrombosis. The underlying mechanisms remain incompletely defined, highlighting the need for focused investigation into the vascular consequences of immune activation. Recent Advances: ICI-induced immune activation disrupts vascular and immune homeostasis through persistent production of reactive oxygen species (ROS), mitochondrial dysfunction, and accumulation of cell-free DNA (cfDNA). Sustained T-cell activation enhances ROS generation, driving DNA damage and senescence in both endothelial and immune cells. ICIs may also promote endothelial-to-mesenchymal transition (EndoMT) through chronic oxidative and inflammatory signaling, contributing to fibrosis, vascular stiffness, and chronic inflammation. Transforming growth factor-beta, although immunosuppressive in many contexts, can drive profibrotic and EndoMT programs within the vasculature. Other cytokines and regulators, including interleukin-17 and regulator of calcineurin 1, have been implicated in vascular remodeling, atherosclerosis, and hypertension. Critical Issues: The relative roles of ROS, mitochondrial dysfunction, cfDNA-driven inflammation, and EndoMT in ICI-associated vascular senescence remain unclear. While inflammation-induced vascular damage is well-recognized, direct ICI-specific mechanisms require stronger evidence. How senescent endothelial and immune cells influence therapy resistance and remodeling of the tumor microenvironment also remains to be defined. Future Directions: Mitochondrial and cytosolic ROS sources—arising from electron leakage during oxidative phosphorylation and NADPH oxidases activity—shape immune signaling and sustain T-cell activation during checkpoint blockade. The DNA damage response kinases ataxia-telangiectasia mutated and ATM- and Rad3-related, activated by oxidative and replicative stress, engage p53-dependent senescence pathways in endothelial and immune cells. Future studies should evaluate biomarkers such as cfDNA and thrombospondin-1 and explore senescence-targeting or redox-modulating interventions that may alleviate cardiovascular toxicity without diminishing antitumor efficacy. This review outlines mechanistic pathways linking ICIs to vascular dysfunction and senescence, integrating preclinical data with emerging clinical insights. It distinguishes established processes from ICI-specific hypotheses and identifies key gaps requiring clinical validation. Antioxid. Redox Signal. 00, 000–000.

Abstract Background PET visual reads for multi‐center studies are conducted centrally by one or a few experts. In CLARiTI, a broader network of raters will perform the reads, necessitating methods to ensure their accuracy and reliability. Method All ADRC sites ( N = 37) will prospectively acquire amyloid PET scans for 800 cognitively unimpaired and 1200 cognitively impaired participants. Each site can use one of four amyloid PET tracers ([ 18 F]florbetaben, [ 18 F]florbetapir, [ 11 C]PIB, [ 18 F]NAV4694). PET scans will be visually interpreted by ten PET neuroimaging experts located across eight ADRCs, using their preferred hardware, software, and file format (DICOM, NIFTI). Calibration requires readers to perform blinded, independent visual interpretation of 180 amyloid PET scans (30 unique and 15 duplicate scans per tracer), previously read and selected by an expert (Table 1). An even mix of visually non‐elevated and elevated scans were selected, with quantitation spanning ‐26‐123 Centiloids (Figure 1), and 15% were visually borderline (similar proportion to ADNI4), with quantitation spanning 4‐48 Centiloids (mean 21). Kruskal‐Wallis H test showed no significant difference in the distribution of Centiloid values for scans in each tracer group, Χ 2 (3)=2.133, p = 0.545. Result Calibration scans were read by a second expert not serving in CLARiTI. There was 97% concordance and almost perfect agreement between readers (κ=0.932, p <0.001; Figure 2). Discordantly read scans were visually borderline elevated ( N = 2), borderline non‐elevated ( N = 1), and negative ( N = 1), with quantitation of 8‐21 Centiloids (mean 14). Intra‐rater reads were 98% concordant and had almost perfect agreement (κ=0.966, p <0.001). These findings hold promise for scaling‐up visual reads in CLARiTI, and we expect ≥80% concordance and substantial to almost perfect agreement (κ≥0.7) for inter/intra‐rater reliability. Conclusion Calibration is essential for accurate/reliable amyloid PET visual reads in large multi‐center studies with multiple raters. Through the calibration process, we will develop methods to improve the adjudication of borderline/challenging scans and formalize methods for visual reads of amyloid PET tracers that are investigational (i.e., [ 11 C]PIB, [ 18 F]NAV4694). Involving multiple raters across different sites, who use diverse hardware/software/file format combinations, will mirror the natural heterogeneity present in real‐world clinical practice. This calibration set can also serve as a standardized training tool for other studies incorporating amyloid PET visual reads.

Abstract TP53 and PPM1D are key regulators of DNA damage response and repair, and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across 4 genotypes: PPM1Dmt/TP53wt (n = 170 [50%]), PPM1Dmt/TP53mt (n = 25 [7%]), TP53mt/PPM1Dwt (n = 17 [5%]), and TP53wt/PPM1Dwt (n = 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (range, 0.3%-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy-related CH/CCUS (t-CH/t-CCUS; 80%, 66.5%, 76.5%, and 19%; P ≤ .001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; P ≤ .001) compared with PPM1Dmt/TP53wt, TP53mt/PPM1Dwt, and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in the PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups compared with PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (P ≤ .001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/t-CCUS, with low median VAFs, and are associated with low rates of progression, even when comutated with TP53.

Abstract Introduction Cannabidiol has been shown to exert significant anti-inflammatory effects and has demonstrated efficacy in murine models of autoimmune myocarditis, pericarditis, and heart failure. The ARCHER Study assessed whether a pharmaceutically produced cannabidiol formulation showed beneficial effects on cardiac magnetic resonance (CMR) endpoints known to predict prognosis in this patient population. Methods In a multicentre international double-blind placebo-controlled phase 2 study, we randomly assigned 109 patients within 10 days of CMR confirmed diagnosis of acute myocarditis to 12 weeks of pharmaceutically produced oral cannabidiol (active) or placebo. Dose was titrated up to 10 mg/kg of body weight twice daily. Primary endpoints were the difference in extracellular volume (ECV) and global longitudinal strain (GLS) measured by CMR at week 12. Other CMR endpoints included left-ventricular ejection fraction (LVEF), LV mass, intracellular volume (ICV), LV end-diastolic and end-systolic volumes (LVEDV, LVESV), and left-atrial end-systolic volume (LAESV). Results All randomized patients (56 active/53 placebo) completed the study with no loss to follow-up. Study drug appeared safe and well tolerated. Baseline mean ECV 38.9 ± 10.9 ml, GLS −15.3 ± 3.6%, and LVEF 60.6 ± 9.9% were consistent with mild to moderate myocarditis and predominantly intact LV function. Week 12 mean ECV was 33.6 ml in the active group and 37.3 ml in the placebo group, a difference of −3.7 ml, confidence interval (CI): −7.4 to 0.1; P = .0538; GLS was −16.0% in the active group and −15.9% in the placebo group, difference of −0.1, CI: −1.2 to 1.1; P = .90. Left ventricular mass was significantly reduced in the active group at 121.1 g compared to placebo 130.3 g, a difference of −9.2, CI: −16.4 to −2.1; P = .0117. In terms of remodelling, LAESV was significantly reduced in the active group (−8.1 ml; P = .0376) while the reduction in LVEDV failed to reach significance (−7.4 ml; P = .098). Conclusion In mild-to-moderate acute myocarditis, treatment with pharmaceutically manufactured cannabidiol was not associated with a statistically significant change in myocardial ECV or GLS, although a trend towards reduction in ECV was observed. In addition, improvement in other potential markers of myocardial recovery, including a significant reduction in LV mass, was seen in the active treatment group. Further investigation of the therapeutic potential of this therapy in inflammatory cardiac conditions is warranted.

Objectives: To evaluate evolving management, ICU admission, and outcomes for critically ill chimeric antigen receptor (CAR) T-cell patients over a 6-year period. Design: Multicenter retrospective cohort study from January 2018 to September 2023. Setting: Eight U.S. centers. Patients: Adult CAR T-cell patients requiring ICU admission. Interventions: None. Methods: Summary statistics included mean, sd , median, and interquartile range (IQR). Fisher exact test or chi-square test were used to evaluate association between year treated and other categorical variables. Cochran-Armitage test was performed to assess significance of trends across years. Multivariable logistic regression was performed to assess covariates associated with mortality. Measurements and Main Results: Demographics, toxicity management, ICU admission, support modalities, toxicity severity, and survival (ICU, hospital, and 3-mo) were compared year-to-year. From 2018 to 2023, 2238 patients received CAR T cells, with increasing number of patients treated yearly; 398 (17.8%) required ICU care. Of those admitted to the ICU, 66.1% were male, 89.2% had lymphoma, and median age was 64 years (53–71 yr). ICU admission rates declined from 38.5% (95% CI, 31.6–45.8%) in 2018 to 16.4% in 2023 (95% CI, 13.5–19.7%; p < 0.0001). Cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was the reason for ICU admission in 87.9%. In 2023 vs. 2018, ICU patients were older (median, 65 yr [IQR, 55–73 yr] vs. 58 yr [48–67 yr]; p = 0.003) with higher comorbidity indices (4 [4–6] vs. 3 [2–4]; p = 0.005) and more severe toxicities (≥ grade 3: 90.1% vs. 69.9%; p = 0.004). Corticosteroid use for less severe toxicities (≤ grade 2 toxicity: 73.8% vs. 40.6%; p = 0.0001) and anakinra use (56% vs. 5.5%; p < 0.0001) increased throughout the years. Mortality from cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome remained low (5.5%). Age, Sequential Organ Failure Assessment greater than or equal to 10 at ICU admission, and ICU admission for noncytokine release/neurotoxicity syndrome reasons were associated with hospital mortality (odds ratios, 1.02 [95% CI, 1–1.04; p = 0.046], 4.69 [2.44–9.01; p < 0.0001], and 3.74 [1.91–7.3; p = 0.0001], respectively). Conclusions: ICU admission rates after CAR T-cell treatment are declining. Although ICU patients are older with higher severity of illness and toxicity grades, ICU mortality after CAR T-cell therapy remains low.

Uncontrolled systemic inflammatory responses are a critical pathological feature of fatal Ebola virus (EBOV) infection. While some inflammatory responses may originate from mononuclear phagocytes (MNPs), nonimmune cells vastly outnumber MNPs and may be an important source of inflammation. Here, we demonstrated that highly virulent EBOV induced a high and sustained pro-inflammatory response compared to less virulent ebolaviruses in non-MNPs through TLR4-independent NF-κB activation. We identified the EBOV matrix protein VP40 as a potent activator of NF-κB in non-MNPs, whose intrinsic inflammatory activation ability is higher than VP40 proteins from less virulent ebolaviruses. This suggests that VP40 is a virulence determinant inducing distinct degrees of pro-inflammatory responses among ebolaviruses. Mechanistically, VP40 activated the NF-κB signaling pathway, primarily via TNFR1 using a ligand-independent mechanism. These findings reveal mechanisms that may drive systemic inflammation and promote EBOV pathogenesis, suggesting potential therapeutic strategies to mitigate immune dysregulation in severe EBOV infections.

Parkinson’s Disease (PD) is a neurodegenerative disorder in which gait abnormalities serve as key indicators of motor impairment and disease progression. Although wearable sensor-based gait analysis has advanced, existing methods still face challenges in modeling multi-sensor spatial relationships, extracting adaptive multi-scale temporal features, and effectively integrating time–frequency information. To address these issues, this paper proposes a multi-sensor gait neural network that integrates biomechanical priors with time–frequency collaborative learning for the automatic assessment of PD gait severity. The framework consists of three core modules: (1) BGS-GAT (Biomechanics-Guided Graph Attention Network), which constructs a sensor graph based on plantar anatomy and explicitly models inter-regional force dependencies via graph attention; (2) AMS-Inception1D (Adaptive Multi-Scale Inception-1D), which employs dilated convolutions and channel attention to extract multi-scale temporal features adaptively; and (3) TF-Branch (Time–Frequency Branch), which applies Real-valued Fast Fourier Transform (RFFT) and frequency-domain convolution to capture rhythmic and high-frequency components, enabling complementary time–frequency representation. Experiments on the PhysioNet multi-channel foot pressure dataset demonstrate that the proposed model achieves 0.930 in accuracy and 0.925 in F1-score for four-class severity classification, outperforming state-of-the-art deep learning models.