Direct reprogramming of cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) holds promise as a therapeutic strategy for heart regeneration. After myocardial infarction (MI), resident quiescent CFs (QCFs) activate and differentiate into myofibroblasts (MFs) in the infarcted region that drive pathological cardiac fibrosis. Converting these injury-activated MFs into iCMs could simultaneously alleviate fibrosis and replenish lost cardiomyocytes. However, whether the marked heterogeneity of CFs in the infarcted heart, and in particular the activation of QCFs into MFs, creates an intrinsic barrier that limits the reprogramming of these injury-activated MFs remains unknown.

To define the molecular basis of this heterogeneity, we purified PDGFRα⁺ CFs and used Postn lineage tracing to distinguish injury-activated MFs from quiescent CFs, enabling matched comparison of their reprogramming competence and single-cell RNA sequencing (scRNA-seq) profiling of post-MI CF subpopulations. A targeted in vitro shRNA screen was conducted against 9 MF-enriched TFs as candidate molecular barriers for cardiac reprogramming. The lead candidate was validated in mouse MFs, human iPSC-derived MFs, primary human MFs, and in vivo using dual-recombinase-mediated lineage tracing. Mechanistic insights were gained through integrated bulk RNA-seq, scRNA-seq and Cleavage Under Targets and Tagmentation (CUT&Tag), together with functional assays including DNA-binding-deficient and domain-swap MEOX1 mutants.

We identified the upregulated transcription factor MEOX1, a known fibrosis determinant downstream of the key post-MI cytokines transforming growth factor-beta 1 and interleukin-1 beta, as the principal molecular barrier responsible for the profound reprogramming resistance of MFs. MEOX1 knockdown markedly enhanced reprogramming efficiency in both mouse and human MFs and enabled GATA4-free reprogramming combinations. This inhibition depended on the transcriptional activation activity of MEOX1, as disrupting its DNA-binding domain or fusing it to a repressor domain rescued reprogramming. Integrated scRNA-seq and CUT&Tag analyses revealed that MEOX1 binds and stabilizes a fibrotic, MF-defining transcriptional program that antagonizes the cardiogenic program while also modulating the inflammatory response; its knockdown disrupted this fibrotic network to favor iCM fate acquisition. Using stringent dual-recombinase lineage tracing, we demonstrated that MEOX1 knockdown enables highly efficient in vivo MF-to-iCM conversion, leading to significant reductions in cardiac fibrosis and substantial improvement in cardiac function after MI.

Our study identifies pathological MEOX1 upregulation as a key mechanism underlying the reprogramming resistance of post-MI mouse MFs and activated human MFs. Overcoming this barrier achieves unprecedented, lineage-confirmed in vivo reprogramming efficiency, thereby addressing a significant obstacle for the clinical translation of in situ reprogramming therapies.

Anthracyclines remain a cornerstone of anticancer therapy, but their clinical use is limited by cancer therapy-related cardiac dysfunction, a major contributor to long-term cardiovascular morbidity in cancer survivors. Although traditionally attributed to oxidative stress, DNA damage and mitochondrial toxicity, emerging evidence identifies disruption of metabolism as a central mechanism of anthracycline-induced cardiotoxicity. Anthracycline exposure promotes a distinct metabolic phenotype characterized by impaired mitochondrial oxidative phosphorylation, dysregulated metabolism of fatty acids and glucose, along with decreased metabolic flexibility, ultimately resulting in inefficient myocardial energetics. These changes are modulated by the patient's underlying cardiometabolic status, suggesting that metabolic reserve influences susceptibility to injury. In addition to direct myocardial effects, anthracyclines induce systemic metabolic changes that affect substrate availability and inter-organ communication. This review focuses on cardiotoxicity induced by anthracyclines, particularly by doxorubicin, highlighting mitochondrial dysfunction, altered substrate utilization and metabolic inflexibility in comparison with other cardiac diseases. We also discuss the newly emerging metabolic strategies aimed at improving cardioprotection.

There is a lack of comparative studies between posterior circulation saccular aneurysms (SA) and dissecting aneurysms (DA). This study aims to comprehensively compare the clinical characteristics, treatment strategies, and outcomes of SA and DA.

We included all consecutive patients with posterior circulation aneurysmal subarachnoid hemorrhage (aSAH) who underwent surgical treatment between January 2017 and December 2020 from the Chinese Multicenter Cerebral Aneurysm Database (CMAD). Baseline data were retrospectively collected, and survival status and 2-year mRS scores were prospectively assessed. Functional outcomes were categorized as favorable (mRS 0-2) and unfavorable (mRS 3-6). Logistic regression models were used to explore the association between aneurysm morphology and outcomes.

Note that 406 patients with posterior circulation aSAH who underwent surgical treatment were included, comprising 314 (77.3%) with SA and 92 (22.7%) with DA. In unadjusted analyses, DA was associated with a lower rate of unfavorable outcomes at 2 years (17.1% vs. 34.8%, p = 0.003) but a higher rate of parent vessel sacrifice (22.8% vs. 8.0%, p < 0.001), while ischemic complications were comparable between groups. After further adjustment for covariates, DA showed a trend toward a lower risk of unfavorable outcomes in Model 3 (OR = 0.490, 95% CI 0.237-1.013, p = 0.054). In addition, the association between DA and a higher risk of parent vessel sacrifice remained consistent across all models (Model 1: OR = 3.419, 95% CI 1.811-6.456, p < 0.001; Model 2: OR = 2.737, 95% CI 1.415-5.293, p = 0.003; Model 3: OR = 2.899, 95% CI 1.463-5.747, p = 0.002).

DA may be associated with a trend toward better long-term functional outcomes compared with SA. Although parent vessel sacrifice was more frequently required, it was not associated with an increased risk of ischemic complications.

ObjectiveIndobufen has been proposed as an aspirin substitute within dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), but has been compared only with aspirin plus clopidogrel. We aimed to estimate the comparative safety and efficacy of indobufen-based DAPT against contemporary antiplatelet strategies after PCI.MethodsIn a systematic review and frequentist random-effects network meta-analysis, we searched PubMed/MEDLINE, Embase, and CENTRAL from inception to May 2026 for randomised controlled trials of adults undergoing PCI with drug-eluting stents that compared antiplatelet strategies mapping onto seven pre-specified nodes, with aspirin plus clopidogrel as the reference. Crude per-arm event counts were extracted in duplicate. The connected primary safety outcome was major bleeding (Bleeding Academic Research Consortium [BARC] type 3/5); efficacy outcomes (myocardial infarction, stent thrombosis, all-cause death, stroke) were analysed per component. Odds ratios (ORs) with 95% confidence intervals (CIs) and P-scores were estimated.ResultsEleven trials enrolling more than 55, 000 patients were included. Indobufen plus clopidogrel did not differ significantly from aspirin plus clopidogrel for major bleeding (OR 1.05, 95% CI 0.62-1.78), myocardial infarction (0.91, 0.29-2.89), stent thrombosis (1.27, 0.34-4.74), or stroke (0.96, 0.27-3.44). In a disconnected direct comparison, indobufen reduced BARC 2-5 bleeding (OR 0.62, 0.45-0.84). The significant between-strategy differences concerned others: aspirin plus ticagrelor showed higher major bleeding (2.07, 1.46-2.94) and clopidogrel monotherapy lower (0.38, 0.22-0.64). Every comparison across clusters depended on a single bridging trial, and no network contained closed loops, precluding assessment of inconsistency.ConclusionsIndobufen-based DAPT was comparable, not superior, to aspirin plus clopidogrel across bleeding and ischaemic outcomes, with no signal of increased ischaemic risk. Because only one randomised trial has directly tested indobufen and all comparisons with ticagrelor-based or monotherapy strategies rest on a single bridging trial, the findings primarily support indobufen as a reasonable aspirin-sparing alternative within clopidogrel-based DAPT. Its relative position against other contemporary bleeding-reduction strategies remains unproven. These results reinforce the need for individualised antiplatelet therapy guided by patient-specific ischaemic and bleeding risk.INPLASY registration number: INPLASY202680037.

BackgroundHeart failure (HF) is closely associated with abnormalities in glucose metabolism, which substantially influence clinical outcomes. The hemoglobin glycation index (HGI), reflecting the discrepancy between observed and predicted glycated hemoglobin, has emerged as a marker of interindividual variation in glycation beyond conventional HbA1c. However, the prognostic significance of HGI in hospitalized patients with HF remains unclear.MethodsIn this retrospective cohort study, we analyzed data from the MIMIC-IV database and included 3,470 adult patients hospitalized with HF. HGI was calculated as the difference between measured HbA1c and predicted HbA1c derived from fasting plasma glucose, and participants were categorized into quartiles. The primary outcome was 365-day all-cause mortality, and the secondary outcome was 30-day all-cause mortality. Kaplan-Meier survival analysis, restricted cubic spline modeling, multivariable Cox regression, and subgroup analyses were performed to evaluate the association between HGI and mortality.ResultsAmong the 3,470 included patients, 837 (24.1%) died within 365 days after discharge. Restricted cubic spline analysis demonstrated a predominantly L-shaped association between HGI and both 30-day and 365-day all-cause mortality, with excess mortality risk mainly concentrated at low HGI values. In multivariable Cox models, compared with the lowest quartile, higher HGI quartiles were associated with significantly lower risks of both short-term and long-term mortality, supporting the particular vulnerability of patients with extremely low HGI. Subgroup analyses generally supported the robustness of these findings, although a significant interaction with diabetes status was observed for 365-day mortality.ConclusionsHGI was independently associated with short-term and long-term all-cause mortality in hospitalized patients with HF, with a predominantly L-shaped pattern observed. Excess mortality risk was mainly concentrated at low HGI values. HGI may serve as a simple and accessible marker for risk stratification in this population.

Venetoclax-based regimens have become increasingly integrated into the therapeutic landscape of acute myeloid leukemia (AML), yet primary resistance and relapses remain major barriers to durable benefits. Building on our previous discovery of CD84 as a critical survivor and redox regulator in AML, we here demonstrate that CD84 expression contributes to venetoclax sensitivity. Low CD84 expression is associated with favorable clinical response, whereas high CD84 expression correlates with primary resistance and is up-regulated at relapse in two of three paired samples. Functional perturbation of CD84 through genetic knockdown or CD84-targeted CAR-T cells sensitized AML cells to venetoclax in vitro and in vivo cell-derived xenograft models. Mechanistically, CD84 coordinates a pro-survival program with upregulating the antioxidant stress sensor SESN2, which suppresses mitochondrial reactive oxygen species and antagonizes venetoclax-induced apoptosis. SESN2 knockdown phenocopied CD84 depletion, while SESN2 overexpression partially restored venetoclax resistance in CD84-deficient cells. Our findings suggest that CD84-mediated upregulation of SESN2 contributes to venetoclax resistance and may represent a potential therapeutic target to enhance treatment efficacy in AML.

While both Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) involve vascular dysfunction, the ocular microvascular differences between them remain largely underinvestigated.

This cross-sectional study included 650 participants (149 AD, 276 CSVD, and 225 cognitively unimpaired individuals). Optical coherence tomography angiography (OCTA) metrics were analyzed to characterize ocular microvascular alterations.

CSVD patients exhibited a higher burden of retinal ischemic perivascular lesions (RIPLs) than AD patients (all p < 0.05), whereas AD patients showed reduced choriocapillaris (CC) density (p = 0.031). In the CSVD group, RIPLs were associated with total CSVD score (p = 0.049), while reduced CC density was associated with elevated phosphorylated tau 181 in the AD group (p = 0.001). Machine learning models integrating OCTA metrics effectively differentiated AD from CSVD (area under the curve = 0.86).

AD and CSVD exhibit distinct ocular microvascular alterations, supporting OCTA-derived measures as potential non-invasive biomarkers.

ChiCTR2000041386.

IntroductionImmune reconstitution inflammatory syndrome (IRIS) is a recognized complication of antiretroviral therapy (ART) in people living with HIV, typically presenting as a single opportunistic infection. Concurrent multisystem IRIS, particularly during the puerperium, is extremely rare.Case PresentationWe report a 27-year-old woman newly diagnosed with HIV during the third trimester of pregnancy who initiated dolutegravir-based ART at 35 weeks' gestation. Three months postpartum, she developed multiple concurrent IRIS manifestations, including oral candidiasis, Kaposi's sarcoma, severe thrombocytopenia, severe anemia, pulmonary embolism, viral pneumonitis, cholangitis, and peripartum cardiomyopathy. Published literature identified very few cases of three or more simultaneous IRIS events after ART initiation, with no previous reports describing such extensive multisystem involvement in the puerperium.ConclusionThis appears to be the first reported puerperal case of extensive multisystem IRIS. We propose the term "IRIS multiplex" to describe patients presenting with five or more concurrent IRIS manifestations, as a hypothesis-generating concept for future research.

Japanese encephalitis (JE) virus (JEV) is a leading cause of neurological infection in the Asia-Pacific region with devastating socioeconomic consequences. We aimed to develop a target product profile (TPP) for JE diagnostics in endemic areas in the context of other flaviviruses, to better define improvements needed for patient management and public health. Thematic experts were identified from a scoping review, World Health Organization and Encephalitis International databases, as well as author networks. Initial interviews were performed with selected experts to inform a draft TPP document and start a Delphi process, aiming for consensus of ≥75% on each characteristic. A one-day meeting facilitated in-depth discussion, with breakout groups and electronic voting to develop the final TPP document. In total, 460 participants were invited. Five interviews enabled drafting a TPP. Two iterative surveys were completed by 44 respondents, including clinicians, scientists, and public health experts from 15 countries. A hybrid meeting was attended by 42 participants. Seven priority characteristics were discussed, and consensus was achieved for six; no clear consensus was reached for the preferred test sensitivity and specificity, with 73% agreement. Discussion points and expert consensus were consolidated into a roadmap for development and implementation to guide future work. A diverse group of health professionals agreed that improved diagnostics for JE are needed, and that a priority is a test for patient management that detects JE alongside other relevant flavivirus infections. There was a mandate for a rapid diagnostic test (RDT), and it was suggested that this could be implemented in a two-tiered diagnostic algorithm. The final TPP is presented in the paper; this aims to help define the updates needed to better support patient management and public health interventions, to provide a strategic reference document to drive innovation and improve clarity for JE diagnostic test developers.

ObjectivesTo evaluate the association between early arterial hyperoxia and 28-day mortality in postcardiotomy VA-ECMO (PC-ECMO) adult patients.MethodsWe conducted a retrospective cohort study including 209 adults who received PC-ECMO across two tertiary centers between January 2019 and December 2024. The primary exposure was the 24-h mean arterial oxygen partial pressure (24h-mean PaO₂) after ECMO support. The primary outcome was 28-day all-cause mortality. Cox proportional hazards models were used to assess associations between oxygen metrics and mortality, with adjustment for confounders.ResultsThe cohort had a median age of 59 years, 130 (62.2%) were male, and 80 (38.3%) received ECMO sopport due to failure to wean from cardiopulmonary bypass. The 28-day mortality was 54.1%. Across increasing 24h-mean PaO2 categories, 28-day survival declined from 64.1% in the <150 mm Hg group to 17.9% in the ≥300 mm Hg group (P < .001). Each 10 mm Hg increase in 24h-mean PaO₂ was associated with a 2.8% increased mortality risk (adjusted HR 1.028, 95% CI: 1.011-1.046, P = .002). Severe hyperoxia (≥300 mm Hg) was independently associated with higher mortality (adjusted HR 2.392, 95% CI: 1.359-4.210). A nonlinear dose-response curve showed increased mortality beyond ∼200 mm Hg. Associations were more pronounced in elderly and male subgroups.ConclusionsEarly hyperoxia is independently associated with increased 28-day mortality in PC-ECMO patients in a dose-dependent manner, highlighting the need for conservative oxygen management.