Some cerebral demyelinating lesions occur after vaccination. We aimed to elucidate the precise roles of vaccine-activated immune cells and antigen-specific lymphocytes in the central nervous system of a patient who developed cerebral demyelination after vaccination.

Using comprehensive single-cell RNA sequencing and immune repertoire analysis combined with a lymphocyte stimulation assay, we characterized the immunological landscape of a patient who developed right-hand clumsiness after receiving an mRNA vaccine against SARS-CoV-2 and was subsequently diagnosed with tumefactive cerebral demyelination.

Natural killer cells and effector CD8+ T cells in the cerebrospinal fluid were more cytotoxic and activated than those in healthy controls. Effector CD8+ T cells specific to SARS-CoV-2 spike peptides were identified in the cerebrospinal fluid. The proportion of these cells in peripheral blood decreased after corticosteroid therapy, in parallel with clinical improvement and a reduction in lesion size.

Although a direct causal relationship between vaccination and demyelination remains uncertain, our findings suggest that vaccine-activated cytotoxic lymphocytes contribute to immune-mediated demyelinating events in the central nervous system.

Crisponi/Cold-Induced Sweating Syndrome Type 1 (CS/CISS1) is an ultra-rare genetic disorder caused by biallelic variants in the cytokine receptor-like factor-1 (CRLF1) gene and is associated with several comorbidities. Comprehensive data on the respiratory phenotype of this condition are lacking despite being associated with high mortality in infancy, often due to severe respiratory complications like aspiration pneumonia and sudden death related to hyperthermic crises. Our study investigates respiratory complications and lung ultrasound characteristics, enhancing the comprehension of the natural history and pathophysiology of the disease. We enrolled 13 individuals (8 children) carrying a biallelic molecular defect of the CRLF1 gene, either in a homozygous or compound heterozygous state. All were of Italian ancestry, with the majority (77%) being Sardinian. The pathogenic variant c.676dup (p.Thr226fs) in exon 4 was confirmed as the most commonly recurrent variant and was identified in 9 of the 13 patients (69%) of our cohort. Over half of the participants exhibited an ultrasound lung pattern suggestive of sonographic interstitial syndrome findings. Fifteen percent had a documented aspiration pneumonia in infancy, which required hospitalization or ventilatory support. Additionally, one adult patient showed bilateral fibrotic findings, which were validated by a CT scan.

Respiratory involvement appears to be a frequent and under-investigated feature in patients with CS/CISS1. Although lung ultrasound patterns observed in this study were largely nonspecific, LUS may represent a practical, non-invasive screening tool to identify early morphological lung changes potentially related to recurrent or chronic inflammatory processes.

• Crisponi/Cold-Induced Sweating Syndrome Type 1 (CS/CISS1) is associated with early-life respiratory complications. • Data on the long-term pulmonary involvement in CS/CISS1 patients are insufficiently documented.

• This is the first study to systematically evaluate lung ultrasound (LUS) findings in a cohort of CS/CISS1 patients, across pediatric and adult ages. • We identified recurrent nonspecific interstitial patterns that suggest chronic inflammatory or fibrotic lung involvement, supporting LUS as a feasible screening tool in disease monitoring.

Cardiac complications are common and clinically significant in COVID-19, yet their underlying molecular drivers remain poorly understood. Here, we integrate post-mortem histopathology with transcriptomic and microRNA (miRNA) analyses to delineate the regulatory architecture of SARS-CoV-2-induced myocardial injury. Histological examination of cardiac tissue from 29 deceased COVID-19 patients revealed pronounced immune infiltration, cardiomyocyte necrosis, and fibrotic remodeling. To gain new insights into these pathological processes, we first analyzed 42 transcriptomes from SARS-CoV-2-infected cardiomyocytes, including primary human, iPSC, and hESC-derived cells. We identified 871 differentially expressed genes (DEGs) in infected cardiomyocytes associated with immune activation, extracellular matrix (ECM) remodeling, and impaired contractile function. Based on these dysregulated genes, we then inferred miRNA-mRNA regulatory networks and, through miRTarBase analysis, we uncovered 331 miRNAs as putative regulators of these DEGs, including miR-29a, miR-145, and miR-199a, known to modulate fibrosis, ECM composition, and cardiomyocyte survival. Finally, selected candidates were evaluated in blood samples from COVID-19 patients. We profiled circulating miRNAs in plasma from COVID-19 patients and detected 32 dysregulated miRNAs, 11 of which overlapped with the predicted set. Notably, downregulation of miR-29a correlated with profibrotic signatures, while immune-regulatory miR-21 was upregulated in mild disease. Together, our multi-modal analysis reveals a miRNA-mRNA regulatory program orchestrating inflammation, fibrosis, and contractile dysfunction in the SARS-CoV-2-infected heart. These findings highlight molecular candidates for risk stratification and therapeutic targeting in COVID-19-associated cardiomyopathy.

Physical resilience and frailty are related but distinct constructs that may shape adaptation after stroke. Evidence concerning whether pre-stroke social participation is associated with physical resilience across different frailty levels remains limited.

This single-center cross-sectional study included 314 adults aged 45 years or older with imaging-confirmed stroke. Participants retrospectively reported seven types of social participation during the six months before stroke. Current frailty and physical resilience were assessed at enrollment using the FRAIL scale and the Physical Resilience Instrument for Older Adults. Participants were classified as non-frail, pre-frail, or frail. Multivariable linear regression with HC3 robust standard errors evaluated the association between social participation and physical resilience. Interaction terms tested whether the association differed by frailty category.

Of 314 participants, 140 (44.6%) were non-frail, 149 (47.5%) were pre-frail, and 25 (8.0%) were frail. Social participation and physical resilience showed a weak positive correlation in the full sample (r = 0.295, 95% CI 0.190 to 0.392; p < 0.001). After adjustment for age, sex, monthly income, hypertension, diabetes, and frailty category, each one-point higher social participation score was associated with a 0.725-point higher physical resilience score (95% CI 0.405 to 1.044; p < 0.001). The social participation-by-frailty interaction was not statistically significant (joint p = 0.314). Results were consistent in analyses restricted to participants aged 60 years or older and 65 years or older.

Retrospectively reported pre-stroke social participation was weakly and positively associated with current physical resilience across frailty levels. The cross-sectional design, retrospective exposure assessment, and limited size of the frail subgroup preclude causal or intervention conclusions.

The cardiovascular‑kidney‑metabolic (CKM) syndrome shows substantial heterogeneity in progression, yet existing biological age indices are not tailored to CKM pathways. We developed an aging index (CKMAI) using machine learning and evaluated its predictive performance for mortality and high‑risk CKM status.

We conducted a retrospective cohort study of 6,896 adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2018, weighted for the US adult population. A two‑stage machine learning framework evaluated over 100 candidate survival models; the optimal model was selected via Pareto front optimization. Predictive performance was assessed using time‑dependent area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration, and decision curve analysis (DCA). Nonlinear relationships and threshold effects were examined with restricted cubic splines and two‑piecewise regression. Additive interactions were quantified by relative excess risk due to interaction (RERI) and attributable proportion (AP). Unsupervised clustering identified aging‑metabolic phenotypes. Weighted bootstrap mediation analysis assessed the mediating role of depression. The Pareto‑optimal simple Cox model achieved a mean C‑index of 0.893. CKMAI consistently outperformed PhenoAge, KDM, and the cardiometabolic index (CMI) across all outcomes. For all‑cause mortality, CKMAI's time‑dependent AUCs were 0.893 (95% CI [0.851, 0.925]) at 3 years, 0.907 (95% CI [0.884, 0.927]) at 5 years, and 0.890 (95% CI [0.868, 0.910]) at 10 years; for cardiovascular mortality, 0.904 (95% CI [0.840, 0.943]), 0.937 (95% CI [0.892, 0.960]), and 0.937 (95% CI [0.900, 0.959]); for high‑risk CKM status, 0.790 (95% CI [0.765, 0.816]). NRI and IDI were significant at all time points (P < 0.05 for all), calibration was good (Greenwood‑Nam‑D'Agostino test P > 0.05), and DCA confirmed superior net benefit. Nonlinear associations were found for all three outcomes. Threshold analysis identified inflection points at CKMAI 61.587 (all‑cause mortality), 60.732 (cardiovascular mortality), and 34.092 (high‑risk CKM status), with steeper risk increases below each threshold. CKMAI exhibited super‑additive interactions with PhenoAge (RERI 15.06, 95% CI [8.14, 38.44]). Clustering revealed six distinct aging‑metabolic phenotypes; the frail elderly cluster had the highest mortality risk (hazard ratio [HR] 11.74, 95% CI [7.85, 17.57]). Depression partially mediated the CKMAI‑outcome associations (proportions mediated: 5.6% [95% CI 2.3%-9.0%] for all‑cause mortality, 8.2% [95% CI 2.8%-22.0%] for cardiovascular mortality, 11.1% [95% CI 6.7%-24.0%] for high‑risk CKM status). Findings were robust across prespecified subgroups and multiple sensitivity analyses. A key limitation is the lack of validation in geographically independent cohorts with complete mortality follow-up; however, temporal validation within NHANES and preliminary external validation in a hospital based Chinese cohort (n = 261) supported the generalizability of the CKMAI for identifying high risk CKM status.

CKMAI is a valid, CKM‑specific aging index that outperforms universal biological age measures in predicting mortality and identifying high‑risk CKM status. Its super‑additive interactions with PhenoAge and the partial mediation by depression offer new mechanistic insights into CKM heterogeneity. By integrating a diverse set of clinical laboratory measures, nutritional assessments, lifestyle factors, and social determinants of health, CKMAI provides a practical, implementable tool for risk stratification and targeted prevention in CKM syndrome.

In high cardiovascular risk populations without prior stroke, intensive blood pressure (BP) lowering confers greater reductions in cardiovascular events than standard targets. However, optimal BP targets in patients with ischaemic stroke (IS) or TIA remain uncertain. The primary objective of the OPTIMAL-STROKE trial is to assess whether an intensive systolic BP (SBP) target (SBP < 120 mmHg) reduces major cardiovascular events in patients with previous IS or TIA compared to a standard SBP target (SBP < 140 mmHg).

OPTIMAL-STROKE is a multicentre, randomised, controlled, open-label clinical trial with blinded and independent assessment of clinical outcomes and intention-to-treat primary analysis. Patients with a history of IS or TIA and high BP (SBP of 130-180 mmHg), clinically stable for at least 48 h prior to trial inclusion, are centrally randomised with concealed allocation in a 1:1 ratio to either an intensive BP control strategy targeting a SBP < 120 mmHg or a standard control strategy targeting a SBP < 140 mmHg. A total of 495 primary outcome events, 4368 patients enrolled.

The primary outcome is the first occurrence of a composite outcome of major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for unstable angina or hospitalisation for heart failure).

OPTIMAL-STROKE will be the first adequately powered trial of intensive BP control in the prevention of major cardiovascular events in patients with a history of IS or TIA.

The trial is registered at ClinicalTrials.gov (NCT04036409).

Drug-eluting stents (DES) are the current mainstay of percutaneous coronary intervention (PCI) in high bleeding risk (HBR) patients. However, drug-coated balloons may be an alternative that reduces reliance on prolonged courses of antiplatelet therapy.

The SELUTION DeNovo trial randomised 3,323 PCI candidates 1:1 to treatment with either sirolimus-eluting balloons (SEBs) and provisional stenting or systematic DES implantation. We report on a prespecified subgroup of HBR patients.

A total of 522 enrolled patients met the Academic Research Consortium-HBR criteria. At 1 year, we assessed target vessel failure (TVF; a composite of cardiac death, target vessel myocardial infarction and clinically driven target vessel revascularisation), major bleeding (Bleeding Academic Research Consortium [BARC] 3-5) and net adverse clinical events (NACE; a composite of TVF and BARC 3-5 bleeding). Antithrombotic treatment was prescribed according to current guidelines and local practice.

Altogether, 269 and 253 patients were identified as HBR in the SEB strategy and DES strategy arms, respectively. In the SEB arm, 17.1% of patients had bailout stenting. Overall, 67% of patients were discharged on oral anticoagulants. At 1 year, TVF occurred in 4.9% of the SEB arm vs 7.9% of the DES arm (absolute risk difference [RD] -3.05%, 95% confidence interval [CI]: -7.27 to 1.17). BARC 3-5 bleeding occurred in 2.3% vs 3.2% (absolute RD -0.91%, 95% CI: -3.71 to 1.89) and NACE in 6.8% vs 10.7% (absolute RD -3.94%, 95% CI: -8.80 to 0.92) in the SEB and DES arms, respectively. While the proportion of patients on dual antiplatelet therapy and single antiplatelet therapy did not differ significantly between the two groups during follow-up, all antiplatelet medication was stopped in 7.7% vs 2.5% at 30 days (p=0.005) and in 27.8% vs 14.9% of patients at 6 months (p<0.001) in the SEB and DES arms, respectively.

Although this subset analysis is not powered for definitive conclusions, our data suggest that an SEB strategy with minimal stenting appears to be a safe and effective alternative to systematic DES implantation for HBR patients.

The prognostic impact of multivessel coronary anatomy and complexity in infarct-related cardiogenic shock (CS) is insufficiently characterised.

We sought to investigate the prognostic value of baseline and residual SYNTAX scores and their influence on the effect of microaxial flow pump (mAFP) support in multivessel disease (MVD) and infarct-related CS.

In this secondary analysis of the DanGer Shock trial, MVD was defined as ≥1 non-culprit stenosis ≥70% or an isolated left main (LM) culprit lesion. Baseline SYNTAX scores were categorised as low (≤22), intermediate (23-32), or high (>32). Patients with an isolated LM culprit lesion were analysed separately. The primary outcome was 180-day all-cause mortality.

Of 355 patients included in DanGer Shock, 256 patients had MVD; 211 had an available baseline SYNTAX score, with 26% of these in the low, 47% in the intermediate, and 27% in the high baseline SYNTAX groups. In all, 35 patients had an isolated LM culprit lesion. A high baseline SYNTAX score was associated with higher odds of 180-day all-cause mortality compared with low and intermediate baseline SYNTAX scores (adjusted odds ratio [OR] 3.12, 95% confidence interval [CI]: 1.17-8.69). A higher baseline SYNTAX score was associated with a higher residual SYNTAX score (p<0.001). The residual SYNTAX score independently predicted 180-day all-cause mortality. The mAFP effect was not modified by the baseline SYNTAX group (p for interaction=0.31). In patients with an isolated LM culprit lesion, mAFP use was associated with lower odds of 180-day all-cause mortality compared with standard care alone (adjusted OR 0.17, 95% CI: 0.03-0.99).

Baseline and residual SYNTAX scores independently predicted 180-day mortality. The mAFP effect was not modified by SYNTAX measures. In the isolated left main subgroup, a hypothesis-generating signal towards a clinical benefit with mAFP use was observed.

The European Association of Percutaneous Cardiovascular Interventions (EAPCI)-endorsed algorithm for defining device success has not yet been prospectively tested against standardised quantitative coronary angiography (QCA) by a core lab.

We sought to assess whether visually evaluated device success by the operator at the end of percutaneous coronary intervention (PCI) aligns with the EAPCI-endorsed standardised definition adjudicated by the core lab and to evaluate its association with clinical outcomes.

This prespecified analysis of the Multivessel TALENT trial included 1,548 patients with three-vessel disease randomised to treatment with either Supraflex Cruz or SYNERGY stents. PCI was attempted in 4,052 lesions. The core lab assessed post-PCI residual in-stent percentage diameter stenosis (%DS) by QCA (target <20%) and exploratory delta (Δ) angiography-derived fractional flow reserve (angio-FFR) across the stent(s) (target <0.05). Device success was evaluated using the site-reported data (visual evaluation of in-stent %DS), core lab QCA, core lab angio-FFR, and combined core lab QCA+angio-FFR. The lesion-oriented composite endpoint (LOCE; comprising cardiovascular death, target vessel myocardial infarction, or target lesion revascularisation) was assessed at 1 year.

Site-reported device success was 97.4%. Core lab definitions yielded lower rates: 93.8% for Δangio-FFR <0.05, 88.0% for residual %DS <20%, and 83.2% for QCA+angio-FFR (all p<0.001 vs site report after Bonferroni correction). Lesions not meeting QCA-based device success had a higher incidence of LOCE than those meeting the definition (12.0% vs 9.1%; log-rank p=0.041). Device success and LOCE rates did not differ between the two stents for any definition.

In this prespecified lesion-level substudy, standardised assessment using the EAPCI device success algorithm with core lab QCA reclassified a substantial proportion of operator-adjudicated successes and identified lesions at higher 1-year LOCE risk. (ClinicalTrials.gov: NCT04390672).

Coil-only middle meningeal artery embolization (MMAE) remains less well characterized in the literature compared to liquid or particulate embolization for chronic subdural hematoma (cSDH). This systematic review and single-arm meta-analysis summarized clinical, radiographic, procedural, and safety outcomes after coil-only MMAE for cSDH. This systematic review followed PRISMA guidelines. PubMed, Ovid MEDLINE, Web of Science Core Collection, and Scopus were searched for English-language studies evaluating coil-only MMAE for cSDH with ≥ 5 patients and ≥ 1 predefined endpoint. Risk of bias was assessed using ROBINS-I. Single-arm random-effects meta-analyses were performed for clinical and radiographic outcomes when sufficient data were available. Anesthetic approach was summarized descriptively. Ten studies comprising 397 patients and 502 embolizations were included. Recurrence was reported in 7 studies comprising 252 patients, with a pooled rate of 4.6% (95% CI, 1.7%-12.1%). Reintervention was reported in 9 studies comprising 345 patients, with a pooled rate of 7.5% (95% CI, 4.5%-12.3%). Procedure-related complications were reported in all 10 studies, with a pooled rate of 1.3% (95% CI, 0.5%-3.0%). Radiographic reduction > 50% was reported in 6 studies comprising 220 patients, with a pooled rate of 76.7% (95% CI, 55.0%-89.8%). Heterogeneity ranged from absent to substantial across outcomes, and 9 of 10 studies were judged to have serious risk of bias. In this meta-analysis based on studies with substantial risk of bias, coil-only MMAE for cSDH was associated with low pooled rates of recurrence, reintervention, and procedure-related complications; however, these estimates should be considered hypothesis-generating rather than definitive evidence. Most included studies were retrospective and nonrandomized, treatment contexts and outcome definitions were heterogeneous, and prediction intervals were wide for several endpoints. Coil-only MMAE may represent a potential anatomy-selective embolization strategy, but current evidence does not establish equivalence, noninferiority, or superiority relative to liquid or particulate embolic agents.