High-mobility group box 1 (HMGB1) is a nuclear protein that can act as a major damage-associated molecular pattern after cerebral ischemia-reperfusion (I/R). However, the cell-type-specific contribution of microglial HMGB1 to early neuroinflammatory responses during the hyperacute phase of stroke is not fully understood. Here, we investigated the role of microglial HMGB1 in early inflammatory activation using a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and microglia-specific HMGB1 conditional knockout mice (HMGB1ΔMG). Acute neurological deficits, early ischemic lesion volume, microglial activation, inflammatory cytokine production, and neuronal integrity were evaluated at 6 h after reperfusion. In wild-type mice, hyperacute I/R induced rapid HMGB1 nuclear export, pronounced microglial activation with amoeboid-like morphology, increased TNF-α and IL-6 expression, and reduced TGF-β1 expression in vulnerable brain regions, including the medial prefrontal cortex and hippocampal CA1. Conditional deletion of microglial HMGB1 reduced early ischemic lesion volume, attenuated acute neurological deficits, dampened pro-inflammatory activation, decreased Iba1+iNOS+ cell accumulation, partially preserved or increased anti-inflammatory marker expression, and alleviated neuronal injury. These findings suggest that microglial HMGB1 acts as an important microglia-derived early trigger that contributes to hyperacute neuroinflammatory amplification and acute neuronal damage after I/R. Targeting HMGB1 mobilization in microglia may represent a promising strategy for attenuating early inflammatory amplification after ischemia-reperfusion.
Endothelial activation and stress index (EASIX) is a biomarker of endothelial dysfunction and has been validated previously as a prognostic score for mortality in various diseases, including oncologic diseases, sepsis, and cardiac disease. Since endothelial dysfunction is an established mediator of adverse outcomes in acute ischemic stroke, this study investigates the prognostic value of EASIX for risk of mortality in these patients. We analyzed data from the Heidelberg (n = 4,188) and Vienna (n = 2,273) prospective acute ischemic stroke registries. EASIX was calculated as creatinine [mg/dL] × LDH [U/L] / platelet count [109/L]. An EASIX cut-off was established using maximal Youden index. Validation was performed using Brier score and C-statistics. Higher EASIX was associated with higher risk of mortality in the training cohort in a multivariable Cox regression (HR of all-cause mortality per log2 increase: 1.20 (95% CI 1.12-1.28), p < 0.001). An optimal EASIX cut-off value of 1.211 was identified in the derivation cohort. In the independent validation cohort, this cut-off was associated with risk of 3-month mortality in a multivariable binary logistic regression model (OR 1.86 (1.28-2.70), p < 0.01). Brier score and C-statistics validated the superior predictive performance of EASIX in the multivariable model. EASIX predicts mortality in acute ischemic stroke patients and retained prognostic validity across two heterogeneous European cohorts. Incorporation of EASIX improved risk stratification beyond established clinical scores. EASIX may serve as a useful tool for risk stratification and outcome prediction in acute ischemic stroke patients.
Subsequent to an intracerebral hemorrhage (ICH), a cascade of neuroinflammatory response drives the process of secondary brain injury. At present, no anti-inflammatory nor neuroprotective pharmacological interventions have been demonstrated to improve functional outcome after ICH. This Phase 2b study was designed to establish the safety and feasibility of CN-105, a neuroprotective and anti-inflammatory pentapeptide designed from the receptor binding region of apolipoprotein E, in patients with acute primary supratentorial ICH. The Singapore CN-105 in Participants with Acute Supratentorial ICH Trial (S-CATCH, NCT03711903) was a randomized, double-blind, placebo-controlled trial involving 60 patients (30 CN-105, 30 placebo) treated within 12 h of symptom onset. Safety was assessed through adverse events (AEs) and serious AEs (SAEs), while efficacy was evaluated using functional outcome measures, including the modified Rankin Scale (mRS) at 90 days. CN-105 was safe and well tolerated in patients with acute ICH, with no significant differences in incidence of SAEs between groups (30% SAEs in placebo vs. 26.7% in CN-105). Notably, fewer patients treated with CN-105 group experienced in-hospital neurological deterioration (0 vs. 10% in placebo). While treatment was not associated with a statistically significant improvement in 90-day mRS, higher proportion of patients treated with CN-105 achieved favorable mRS scores (≤ 3) compared with those in the placebo group (77.8 vs. 66.7%; p = 0.35). This Phase 2b trial confirmed the safety and feasibility of CN-105 administration in the acute setting of ICH. Although no statistically significant improvements in neurological outcomes were found, the observed trends warrant further investigation. Future Phase 3 trials should focus on refining patient selection and assessing the therapeutic efficacy of CN-105 in more targeted subgroups such as those with medium-sized subcortical ICH. Trial registration NCT03711903, https://clinicaltrials.gov/ https://clinicaltrials.gov/study/NCT03711903?term=NCT03711903&rank=1 . Registered 16 October 2018.
Acute inflammation, when unresolved, can lead to complications that impair tissue repair and therapeutic outcomes. In this study, we employed a model of lipopolysaccharide (LPS)-induced acute subcutaneous abdominal inflammation in mice to investigate the modulatory effects of elastic compression. LPS administration elicited a robust inflammatory response, characterized by increased leukocyte infiltration, edema, and upregulation of pro-inflammatory mediators. Elastic compression significantly attenuated this response, reducing leukocyte counts in subcutaneous lavage, histological inflammatory infiltrates, and the expression of key pro-inflammatory genes and proteins, including NF-κB, IL-1β, and TNF-α, at both 24 and 72 hours post-induction. Mechanistically, these effects may result from the compressive force altering microvascular dynamics and modulating macrophage polarization and mechanotransduction pathways, including TLR4 and integrin signaling. Additionally, compression preserved redox homeostasis, as indicated by stable oxidative stress markers and antioxidant responses. To our knowledge, this is the first study to demonstrate that elastic compression modulates inflammation at molecular, cellular, and tissue levels in an acute inflammation model. These findings support the therapeutic potential of elastic compression as a non-pharmacological strategy for managing acute inflammation, with possible applications in postoperative care, traumatic edema, and other soft tissue inflammatory conditions. Further translational and clinical studies are warranted to validate these outcomes and guide evidence-based application protocols. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Acute bipolar depression poses a significant burden and socioeconomic costs. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar depression, considering dose effects across different age groups. We conducted a network meta-analysis (NMA), searching for randomized controlled trials (RCTs) comparing pharmacological interventions against each other/or placebo in patients with acute bipolar depression (Type-I/Type-II/other), indexed in PubMed/MEDLINE, Embase, Web-of-Science/and Scopus (database inception up to 2025.11.25). Co-primary outcomes were change in depressive symptoms/response/and acceptability. Tolerability/remission/change in anxious symptoms/and risk-of-manic/hypomanic switches were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. 103 RCTs, encompassing 71 distinct treatment combinations, included 20,941 participants. Sensitivity analysis including low-risk-of-bias studies only and excluding outliers for possible effect modifiers indicated that lamotrigine 50 mg/day or 200 mg/day, quetiapine extended-release 150 mg/day and 300 mg/day, and lumateperone 42 mg/day outperformed placebo for depressive symptoms, with estimates ranging from -1.53(95%C.I. = -2.13;-0.93) for lamotrigine 50 mg/day, to -0.36(95%C.I. = -0.68;-0.04) for lumateperone 42 mg/day. Several additional drugs might be efficacious, although they emerged as outliers for either mean age of participants/proportion of females/BD-II participants/psychotic features/rapid cycling/baseline severity of depression/and trial duration. No treatment outperformed placebo for response/remission/acceptability/tolerability/and manic/hypomanic switches. Our findings are consistent with previous NMAs and current guidelines, thereby expanding knowledge by concurrently appraising different drugs, doses, and age groups.
Evidence regarding the outcomes of intravenous thrombolysis (IVT) in patients taking direct oral anticoagulants (DOACs) within 1 day before acute ischemic stroke remains limited. In this study, we aimed to evaluate the bleeding risk after IVT in patients with and without recent DOAC exposure. This retrospective cohort study analyzed TriNetX global network data (January 2010-September 2024) in adults aged ≥ 20 years receiving IVT for acute ischemic stroke. Groups with DOAC and no anticoagulant (no-OAC) exposure within 1 day before stroke were compared. The primary outcome was intracranial hemorrhage (ICH) within 2 days after IVT. Secondary outcomes included major bleeding, blood transfusion within 2 days, and 30-day and 90-day mortality rates. Subgroup analyses examined individual DOACs (apixaban, rivaroxaban, edoxaban, and dabigatran). Propensity score matching controlled for confounders with risk differences (RDs) and odds ratios (ORs) to estimate outcome events. Among 64,667 patients (mean age 65.1 ± 16.1 years; 50.1% women), 1183 (1.8%) received DOACs, and 63,462 (98.1%) received no anticoagulants. After propensity score matching, the DOAC cohort had lower risks of ICH (RD, - 2.88% [95% CI, - 4.28% to - 1.48%]; OR, 0.36 [95% CI, 0.21-0.60]) and major bleeding (RD, - 2.54% [95% CI, - 4.53% to - 0.55%]; OR, 0.66 [95% CI, 0.47-0.91]) than the no-OAC cohort. Mortality rates were similar at 30 (OR, 0.87 [95% CI, 0.69-1.08]) and 90 (OR, 1.04 [95% CI, 0.85-1.26]) days. In subgroup analyses, apixaban showed lower ICH and mortality risks than no-OAC. DOAC exposure within 1 day before stroke does not result in higher bleeding or mortality risk in patients receiving IVT for acute ischemic stroke.
Acute kidney injury (AKI) is common following endovascular procedures and has been independently associated with increased hospital length of stay, mortality, and, in patients with severe chronic kidney disease (CKD), accelerated progression to end-stage renal disease (ESRD) requiring dialysis. Prior studies have often focused on peripheral angiograms and infrarenal endovascular aortic repair (EVAR), with limited contemporary multicenter studies focused on the outcomes of renal function following thoracic endovascular aortic repair (TEVAR). We analyzed the SVS-VQI TEVAR registry including patients from 2013-2025. Patients were stratified based on incidence of AKI in the post-operative period, defined as an increase in serum creatinine of either >0.3 mg/dL or 50% from pre-operative baseline. Patients who were dialysis-dependent at the time of TEVAR were excluded from this study. Patient demographics and perioperative variables were compared between the two cohorts utilizing univariate analysis. The primary outcome of this study was 30-day mortality among patients undergoing TEVAR stratified by development of AKI. Secondary outcomes included hospital and ICU length of stay, incidence of aortic-related reinterventions, and new dialysis requirement on hospital discharge. A logistic regression was subsequently performed to develop a risk prediction model utilizing AKI as a binary endpoint, with 70% of the dataset used for training and 30% for testing. A total of 26,702 patients who underwent TEVAR were included, of which 3,347 developed postoperative AKI (13%). A higher proportion of patients with AKI were male (65.8% vs 62.2%, p<0.0001), had higher preoperative creatinine (1.46 mg/dL vs 0.99 mg/dL, p<0.0001), and were more frequently diabetic (17.8% vs 15.6%, p = 0.0011). TEVAR in patients who developed AKI was more frequently performed emergently (35.2% vs 14.7%) and for the indication of acute dissection (36.4% vs 25.7%, both p<0.0001). The development of postoperative AKI was associated with significantly higher 30-day mortality (21.3% vs 4.7%) and length of stay (18.3d vs. 3.6d, both p<0.0001). For patients presenting with acute dissection, AKI development was associated with more distal extent of dissection, decreased true lumen perfusion and postoperative branch patency of all visceral vessels (all p<0.0001). AKI following TEVAR is associated with substantially increased 30-day mortality, and is strongly associated with impaired baseline renal function, existing diabetes mellitus, urgent procedures, and aortic dissection.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by neutrophil-dominant inflammation, disruption of the alveolar-capillary barrier, and severe hypoxemia, with persistently high mortality in infection-associated etiologies, including severe COVID-19 pneumonia. Neutrophil elastase (NE) is a central mediator of lung tissue destruction and inflammatory amplification in these conditions. However, currently available NE inhibitors such as Sivelestat have shown limited clinical efficacy. Here we evaluated the therapeutic potential of PD-05, a novel NE inhibitor, in murine model of ALI. ALI was induced in female C57BL/6 mice using intratracheal LPS (1 mg/kg), followed by oral administration of PD-05 (5 mg/kg). PD-05 significantly attenuated NE activity and reduced neutrophilic infiltration in lung tissue. Mechanistically, PD-05 suppressed NF-κB activation and reduced pro-inflammatory cytokines (TNF-α, IL-6, and Kc) levels, while decreasing ICAM-1 expression, consistent with reduced leukocyte recruitment and improved barrier integrity. PD-05 increased heme oxygenase-1 (HO-1) expression and restored surfactant protein C levels. These molecular changes translated into significant structural and functional improvement, evidenced by reduced septal thickening, preserved alveolar architecture, decreased HIF-1α expression, attenuation of airway hyperresponsiveness, and improved lung mechanics. Histological analysis further confirmed reduced lung injury and improved epithelial integrity in PD-05-treated mice. Collectively, PD-05 exerts coordinated anti-inflammatory and barrier-protective effects in experimental ALI, underscoring its translational potential for ALI and ARDS.
We report an urgent transfemoral transcatheter aortic valve replacement (TAVR) performed under local anesthesia in a patient with acute heparin-induced thrombocytopenia (HIT) and severe thrombocytopenia complicated by recent gastrointestinal bleeding. Argatroban was used as the periprocedural anticoagulant, and a crossover technique enabled complete hemostasis despite a critically low platelet count. This case demonstrates that a fully percutaneous TAVR strategy using argatroban can be safely performed during acute HIT and provides a practical approach for structural heart interventions in patients at high bleeding risk.
This study aimed to explore symptom clusters in children with acute lymphoblastic leukemia (ALL) during maintenance therapy, construct a symptom network, identify bridge symptoms, and lay the groundwork for precise symptom management. A cross-sectional survey was conducted among 237 children with ALL undergoing maintenance therapy using the Chinese version of the Memorial Symptom Assessment Scale 10 to 18. Exploratory factor analysis was used to identify the symptom clusters. Network analysis identified bridge symptoms between the symptom clusters. Five symptom clusters were identified: emotional, somatic, gastrointestinal, self-image disorder, and neurological. In the network, headache, feeling drowsy, and skin changes served as bridge symptoms connecting the different symptom clusters. Children with ALL experienced multiple symptom clusters during maintenance therapy. By identifying and addressing bridge symptoms, personalized management strategies can be formulated to alleviate other symptoms and interrupt the connections between symptom clusters, thereby enhancing the symptom management efficiency. This study emphasizes the need to identify the bridge symptoms in children with ALL during maintenance therapy and to develop targeted prevention and early intervention strategies for effective symptom management and alleviate the symptom burden.
Acute liver failure (ALF) is characterised by massive hepatocyte death and compromised regenerative capacity, yet the metabolic-immune crosstalk underlying these pathological processes remains poorly understood. Here, we demonstrate that lactate acts as a pivotal signal that triggers neutrophil extracellular traps (NETs) formation and release. Integrated RNA-seq and scRNA-seq analyses revealed profound glycolytic reprogramming in Kupffer cells (KCs) during ALF, leading to lactate accumulation within the hepatic microenvironment. Mechanistically, neutrophils import exogenous lactate into mitochondria via monocarboxylate transporter 1 (MCT1), which subsequently activates NETosis. Macrophage depletion or administration of an MCT1 inhibitor reduced NETs formation and ameliorated liver injury. Furthermore, we demonstrate that hepatocytes internalise NETs DNA, which is sensed by endosomal Toll-like receptor 9 (TLR9). Activation of the TLR9 signalling pathway suppresses the expression of Krüppel-like factor 15 (KLF15). This downregulation diminishes AJUBA and disrupts the KLF15-AJUBA interaction, thereby increasing the phosphorylation of YAP1 and impeding hepatocyte proliferation. Notably, KLF15 overexpression bypassed TLR9-mediated inhibitory signals and rescued the NETs-induced regenerative failure in vitro. In conclusion, our study elucidates a novel KCs-neutrophil-hepatocyte crosstalk wherein lactate-driven NETosis thwarts liver regeneration via the TLR9/KLF15/AJUBA axis, thereby identifying potential therapeutic targets for the clinical management of ALF.
Patients with multiple myeloma undergoing dorsal spinal instrumentation for malignant spinal lesions remain at high risk for postoperative complications and limited survival. Acute kidney injury (AKI) is common in myeloma and after major surgery, but its prognostic relevance in surgically treated myeloma patients and its association with subsequent CT-based body composition and bone density trajectories, remains insufficiently defined. We performed a retrospective cohort study of consecutive multiple myeloma patients undergoing dorsal spinal instrumentation between 2011 and 2024 at a tertiary referral center. Postoperative AKI was defined and staged according to KDIGO criteria based on serum creatinine changes within 7 postoperative days. Clinical outcomes included overall survival (OS), surgical site infection (SSI), and length of hospital stay (LOHS). CT-based morphometry was assessed on non-contrast whole-body CT at L3 level on a preoperative baseline scan (tCT1) and a postoperative follow-up scan. The follow-up CT scan (tCT2) was obtained approximately 9 months postoperatively as part of routine oncologic follow-up or clinical indication rather than a fixed imaging schedule, reflecting real-world clinical practice. The mean interval between tCT1 and tCT2 was 9.1 ± 1.2 months. Analysis included skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue (VAT), and vertebral trabecular bone status assessed by Hounsfield Units (HU). Multivariable Cox regression, logistic regression, and log-linear regression were used to evaluate the independent association of AKI with OS, SSI, and LOHS, adjusting for clinically relevant covariates. 59 patients were included (median age 69.0 years; 40.7% female); postoperative AKI occurred in 16 patients (27.1%). AKI was associated with significantly worse OS (median 224 vs. 396 days without AKI; log-rank p = 0.01), with progressively shorter OS across KDIGO stages. In multivariable Cox regression, AKI remained independently associated with worse OS (adjusted hazard ratio 2.35, 95% CI 1.22-4.54; p = 0.011). AKI was also associated with higher SSI rates (63% vs. 12%; p < 0.01) and longer LOHS (median 29 (IQR 8) vs. 19 (IQR 9) days; p < 0.001). After adjustment for age, sex, preoperative ECOG, and Charlson Comorbidity Index, AKI remained independently associated with higher SSI rates (adjusted odds ratio 3.20, 95% CI 1.11-9.26; p = 0.031) and prolonged hospitalization (LOS ratio 1.34, 95% CI 1.06-1.69; p = 0.014). Longitudinal CT analyses demonstrated significantly greater postoperative declines in the AKI group versus no AKI for SMI (median - 44.6% vs. -18.5%; p < 0.001), SMD (- 20.5% vs. -9.2%; p = 0.02), VAT (- 29.1% vs. -24.1%; p < 0.001), and HU (- 46.2% vs. -37.7%; p < 0.001). In multiple myeloma patients undergoing dorsal spinal instrumentation, postoperative AKI is independently associated with reduced survival, increased postoperative morbidity, and accelerated loss of muscle quantity, muscle quality, visceral fat, and vertebral bone density. These findings highlight AKI as a clinically meaningful systemic event with downstream catabolic consequences and support intensified perioperative nephroprotective and multidisciplinary supportive strategies in this high-risk population.
The interaction between injured proximal tubular epithelial cells (PTECs) and the microenvironment has been widely associated with post-AKI fibrosis; however, the underlying mechanisms remain largely unclear. In this study, we identified three distinct injury patterns of the tubular basement membrane (TBM) in kidney tissues from patients with acute kidney injury. Phosphorylated H3Ser10 and transforming growth factor-β1 (TGFB1) were co-localized in PTECs exhibiting TBM injury. To mimic this condition, we employed a low-attachment culture system (LACS). LACS induced in PTECs a morphology resembling that of maladaptive repaired PTECs, accompanied by G2/M cell-cycle arrest, as well as upregulation and secretion of TGFB1. The expression of TGFB1 was markedly suppressed when PTECs were re-attached to normal culture dishes or to medium supplemented with Matrigel. Furthermore, TGFB1 expression was not directly linked to G2/M arrest in PTECs. Mechanistically, knockdown of TGFB1 or SMAD3 attenuated the LACS-induced upregulation of SOX9, whereas SOX9 knockdown did not downregulate TGFB1 expression. We further demonstrated that TBM injury-induced upregulation of TGFB1 is mediated by ETV5. Collectively, these findings indicate that TBM damage triggered by AKI promotes renal fibrosis via activation of the ETV5/TGFB1/SMAD3/SOX9 pathway in proximal tubular epithelial cells following AKI.
Accurate pre-endoscopic risk stratification is essential in acute upper gastrointestinal bleeding (UGIB). Established scores predict mortality but have limited ability to identify patients requiring early therapeutic endoscopy. We developed and temporally validated a pre-endoscopic machine learning model to predict 30-day mortality and early (≤24 h) endoscopic hemostatic intervention and assessed model interpretability. This retrospective cohort study included consecutive adults admitted with UGIB between November 2023 and November 2025. Only pre-endoscopic variables were considered. A gradient-boosted decision tree model was developed in a derivation cohort (n=762) and temporally validated in a subsequent cohort (n=353). Discrimination, calibration, decision curve analysis, SHAP-based explainability, and complete-case sensitivity analyses were assessed and compared with Glasgow-Blatchford, AIMS65, and ABC scores. Among 1115 patients (median age: 69 y; 63.5% male; 19.0% variceal bleeding), 30-day mortality was 7.8% and early hemostatic intervention was 29.8%. In the validation cohort, the model achieved AUROCs of 0.874 for mortality and 0.848 for early intervention, with good calibration. Discrimination was significantly higher than established scores for both endpoints (all P<0.05). At a 20% intervention threshold, sensitivity was 84.9% and negative predictive value was 92.3%. Net benefit was greater across clinically relevant thresholds. SHAP analyses identified clinically plausible contributors, and complete-case analysis yielded similar performance. A pre-endoscopic machine learning model accurately predicted short-term mortality and early therapeutic endoscopy in UGIB, outperformed established risk scores, and showed interpretable feature-contribution patterns. External validation and prospective evaluation are warranted before clinical implementation.
This study investigates the use of RADA16 hydrogels for delivering carnosic acid (CA) in glaucoma treatment. Rheological tests at 0.5% (w/v), 1% (w/v), and 2% (w/v) concentrations showed significant elasticity, with Young's moduli of 30.18 Pa, 16.22 Pa, and 26.66 Pa, respectively. The 1% (w/v) concentration had the lowest stiffness, ideal for intravitreal injection. SEM revealed the hydrogel's porous microstructure. The RADA16-CA system provided sustained CA release over 72 h, peaking at 6 h. In vitro, high CA concentrations (≥ 256 μg/mL) were cytotoxic, but RADA16 and RADA16-CA enhanced cell proliferation. RADA16-CA demonstrated superior efficacy and biocompatibility. In an acute ocular hypertension model, RADA16-CA improved retinal health in rats by reducing retinal nerve fiber layer thickness, ROS-positive cells, and pro-inflammatory cytokines, while boosting cell survival and antioxidant activity.These findings highlight the potential of the RADA16-CA sustained-release system as an optimized approach for glaucoma treatment.
Acute pancreatitis (AP) is a serious inflammatory disease with significant morbidity, yet its underlying molecular mechanisms remain incompletely understood. This study reveals a novel epitranscriptomic pathway in AP pathogenesis centered on METTL1-mediated N7-methylguanosine (m7G) RNA modification. We found that METTL1 expression and global m7G levels were significantly elevated in serum from AP patients, pancreatic tissues of sodium taurocholate-induced AP mice, and in vitro models of LPS-polarized macrophages and STC-injured pancreatic acinar cells. Through integrated multi-omics analysis combining m7G methylome mapping and transcriptome profiling, we identified Musculin (MSC) as a key target whose mRNA stability is enhanced by METTL1-mediated m7G modification. Functional experiments demonstrated that MSC upregulation activates TNF signaling through phosphorylation of NF-κB, JNK, and MAPK proteins, thereby promoting macrophage M1 polarization and pancreatic acinar cell injury. The pathological significance of this pathway was confirmed in vivo, where pancreas-targeted knockdown of Mettl1 significantly attenuated AP severity. Furthermore, mechanistic studies using a catalytic-dead METTL1 mutant established that both the methyltransferase activity of METTL1 and subsequent TNF signaling activation are essential for driving inflammatory responses. Our findings delineate a previously unrecognized METTL1-m7G-MSC-TNF signaling axis that promotes AP progression, highlighting the therapeutic potential of targeting METTL1-mediated epitranscriptomic modification in inflammatory diseases.
Early risk stratification in patients after acute myocardial infarction (AMI) is critical for guiding therapy and resource allocation. While left ventricular ejection fraction (LVEF) is routinely assessed by echocardiography, novel markers offer additional prognostic utility but are not widely assessed due to time constraints or limited expertise. Artificial intelligence (AI) enables rapid, fully automated analysis of echocardiograms, producing standardized, comprehensive measurements. We evaluated the utility of AI-derived echocardiographic parameters on top of clinical variables in predicting outcomes post-AMI. Consecutive AMI patients undergoing invasive coronary angiogram were included. Echocardiograms were analyzed using Us2.ai software. Independent predictors of one-year all-cause mortality and major adverse cardiac events (MACE) were assessed using Cox regression. Clinical, echocardiographic, and combined models were compared. Among 1001 patients, aged 64 years (54, 72) and predominantly male (78.1%), 161 (16.1%) died during follow-up. AI-echocardiographic markers independently associated with one-year all-cause mortality or MACE included lower LVEF, greater LV wall thickness, lower LV mass, greater LA area, lower LA reservoir strain and lower aortic valve area. For one-year mortality, the combined model demonstrated superior discrimination compared with the clinical model alone (AUC 0.85 vs. 0.81; p = 0.018). Similarly, for one-year MACE, the combined model showed improved discrimination compared with the clinical model (AUC 0.80 vs. 0.74; p < 0.001) and yielded the lowest Akaike's and Bayesian Informations. Combining AI-derived echocardiographic parameters, together with traditional clinical risk factors, provides incremental prognostic value post-AMI. AI tools that automate complex assessments accurately and reproducibly may enhance risk stratification.
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Aortic intramural hematoma (IMH) has an unpredictable clinical course depending on the extent of disease. Management remains unclear for patients with type B IMH with concomitant type A IMH. We examine our experience with thoracic endovascular aortic repair (TEVAR) for this patient subset. The study design and research was approved by our Institutional Review Board and the need for informed consent was waived. This is a single-institution retrospective study of patients with type B IMH with an ulcer-like projection (ULP) in the descending thoracic aorta, as well as retrograde type A IMH, who underwent TEVAR between 2018-2024. IMH thickness and extent was examined on CTA imaging to assess for resolution and positive aortic remodeling after TEVAR. We identified 65 patients between 2018-2024 treated at our institution for IMH. Of those, 7 patients had a type B IMH with ulcer-like projection with concomitant retrograde arch extension of the IMH, treated with TEVAR. In our series, 5 patients had resolution of the retrograde type A IMH by 5 months, and as early as 3-5 weeks in 2 of those patients. The type B component of IMH had resolved in 5 patients by 10 months, and as early as 11-14 days in 2 patients. One of the 7 patients was lost to follow up. Early TEVAR for patients with type B IMH with ulcer-like projection with concomitant retrograde ascending aortic or arch IMH, is a management strategy that can promote favorable aortic remodeling, without the need for open ascending aortic repair.
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