Low-grade myofibroblastic sarcoma (LGMS) is a rare, indolent mesenchymal neoplasm exhibiting myofibroblastic differentiation, with a propensity for local recurrence. The molecular basis of LGMS and its precise relationship with other histologic mimics have remained largely undefined. To address this gap, we conducted the first comprehensive multiomics analysis of six LGMS cases, integrating whole-exome sequencing (WES), RNA sequencing, and Illumina MethylationEPIC v2 array profiling, with comparative analysis against public sarcoma methylation cohorts and related fibroblastic tumors. Clinically, patients (median age 35.5 years) presented with small tumors (median 1.45 cm), predominantly located in the head and neck, displaying classic histologic features of diffusely infiltrative spindle cell fascicles with patchy mononuclear inflammation. Two of five patients with follow-up developed local recurrence, and none metastasized (median follow-up 92.5 months). Genomically, all LGMS exhibited low tumor mutational burden (median 2.31 mut/Mb) and minimal fraction of genome altered, with TP53 and TSC2 deletions and NTRK1 and ERBB3 amplifications found in a subset of cases. No pathogenic fusions were detected. Transcriptomic profiling revealed a distinct signature featuring prominent USP6 overexpression and upregulation of inflammatory and immune-related genes, including CD274 (PD-L1), and enrichment of inflammatory and interferon-γ response signatures. Epigenetically, LGMS formed a unique methylation cluster closest to inflammatory myofibroblastic tumor, with numerous differentially methylated regions and higher immune infiltration, particularly monocytes, compared with other fibroblastic tumors. These findings establish LGMS as a genomically stable, epigenetically distinct myofibroblastic sarcoma driven by USP6 overexpression and an inflammation-enriched transcriptome. They support its recognition as a standalone entity, facilitate integration into methylation-based sarcoma classifiers for improved diagnostic precision, and nominate USP6-associated pathways and immune checkpoint blockade as promising therapeutic strategies for recurrent or unresectable disease.

BACKGROUND Numb chin syndrome, a clinical manifestation of mental nerve neuropathy, presents with pain, numbness, or altered sensation in the mental nerve distribution. While most cases are dental or traumatic, it can signal an underlying malignancy. CASE REPORT A 57-year-old woman presented with a 2-year history of pain and hypesthesia in the left mental nerve distribution. Initial contrast-enhanced MRI showed mild bone marrow edema near the left mental foramen, which was interpreted in the radiology report as inflammatory change without a definite mass. Due to persistent symptoms, limited incisional biopsy was conducted in private practice, suggested a neuroma and likely reflecting non-representative sampling. Repeat MRI demonstrated a suspicious lesion involving the mental nerve region and the left submandibular gland with cervical lymphadenopathy. After referral to our department, ultrasound confirmed homogeneous lesions in the submandibular gland and near the mental foramen. The patient underwent surgical exploration including a targeted perilesional excision with partial osteotomy, accompanied by removal of adjacent lymph nodes and submandibular gland. Histopathology confirmed nodal marginal zone lymphoma. Staging CT showed disseminated nodal involvement and bone marrow densification without extranodal involvement. The patient developed severe mandibular pain consistent with nerve compression and received localized radiotherapy and rituximab, resulting in marked symptom relief. CONCLUSIONS This case illustrates how subtle imaging findings and non-representative biopsy can lead to diagnostic delay in malignancy-associated numb chin syndrome. Persistent unilateral mental nerve neuropathy should prompt careful reassessment and systemic evaluation, even in the absence of clear radiological or histological evidence, to enable timely diagnosis and appropriate management.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs. Its expression can vary across ethnic groups.

To compare clinical and serological manifestations of SSc between Jewish and Arab patients in Israel.

We conducted a retrospective single-center study included 100 patients with SSc selected from our rheumatology clinic at Meir Medical Center, comprising 50 Jewish and 50 Arab patients with available complete clinical and laboratory data. Demographic characteristics, disease features, autoantibody profiles, organ involvement, and treatment patterns were collected.

Most clinical, laboratory, and treatment variables did not differ significantly between Jewish and Arab patients. Significant difference was the higher prevalence of skin telangiectasia in Jewish patients (86%) compared to Arab patients (38%) (P < 0.001) as well as Raynaud phenomenon and pulmonary hypertension. Other manifestations, including organ involvement and autoantibody prevalence, were similar across the groups.

This study reveals significant similarities in the clinical and serological expression of SSc between Jewish and Arab patients in Israel. The higher prevalence of telangiectasia in Jewish patients suggests a possible ethnic or environmental influence on vascular manifestations. Further research is needed to explore the potential genetic or environmental factors contributing to this difference and to assess if this impacts disease progression or treatment outcomes.

Cardiac involvement is a leading cause of morbidity and mortality in systemic sclerosis (SSc) yet is often underdiagnosed. Early recognition is crucial but published data remains limited. This study aimed to characterize the clinical presentation, diagnostic features, and outcomes of SSc patients with acute primary heart involvement.

This multicentre retrospective case series included patients meeting the 2013 ACR/EULAR SSc classification criteria with clinically significant pericardial effusion or myocardial involvement, identified across tertiary rheumatology centres in Portugal (Coimbra, Lisbon, and Porto) and Spain (León). A complementary literature review was performed to identify additional published cases.

Of 23 screened cases, 6 met the inclusion criteria. The literature review identified 13 additional reports, totalling 19 patients. In 8 (42.1%) of patients, heart involvement was either the initial manifestation or occurred concurrently with the diagnosis of SSc. Pericardial disease (n=6) often presented as tamponade requiring emergent pericardiocentesis. Myocardial involvement (n=13) was classified as acute myocarditis (AM) in 9 (69.2%) and chronic inflammatory cardiomyopathy (CIC) in 4 (30.8%). Cardiac magnetic resonance showed late gadolinium enhancement in 9 (72.7%) and myocardial oedema in 4 (36.4%); however, both were absent in two biopsy-confirmed AM cases. Cyclophosphamide was the second most common therapy after corticosteroids. Two patients died during hospitalization, with three more deaths during long-term follow-up.

Severe cardiac manifestations in SSc frequently occur early in the disease, presenting as tamponade or myocardial involvement. Reliance solely on imaging may lead to myocarditis underdiagnosis. Distinct clinical profiles between AM and CIC point toward separate phenotypes with unique prognostic and therapeutic considerations. Large-scale, prospective studies are essential to refine early diagnostic approaches and optimize treatment.

This study aimed to compare the metabolic and inflammatory profiles of dipper and non-dipper hypertensive patients versus healthy controls, specifically evaluating the Triglyceride-glucose (TyG) index's association with nocturnal blood pressure patterns.

This retrospective, cross-sectional study included 325 participants (110 normotensive controls, 106 dipper hypertensive, and 109 non-dipper hypertensive). Circadian blood pressure phenotypes were defined using 24-hour ABPM according to the 2024 ESC Hypertension Guidelines. Inflammatory indices (NLR, LMR, and HALP score) and the TyG index were calculated from fasting blood samples.

Hypertensive groups had higher BMI and waist circumference than controls (p < 0.001). HALP, NLR, and LMR did not differ between the cohorts (p > 0.05). The TyG index showed the greatest intergroup variation and was strongly associated with the non-dipper phenotype (OR = 3.6, p = 0.004). TyG was positively correlated with nocturnal SBP/DBP and negatively correlated with nocturnal SBP decline. It showed significant diagnostic performance for hypertension and non-dipper status (AUC 0.667-0.696, p < 0.001), but limited accuracy for classifying hypertensive subgroups (AUC = 0.573, p = 0.064).

The TyG index serves as a significant independently associated with the non-dipper hypertension phenotype, reflecting predominant metabolic and cardio-renal stress rather than cellular inflammation. These findings suggest that clinical management should extend beyond blood pressure control to include early optimization of insulin resistance and atherogenic lipid imbalance. Ultimately, the TyG offers a practical and cost-effective clinical tool for multidimensional cardiometabolic and cardio-renal risk assessment.

The consumption of ultra-processed foods (UPF) has been associated with increased risks of chronic diseases, particularly cardiovascular diseases (CVD). However, specific data on the CVD burden attributable to UPF intake remains limited. This study aimed to estimate the burden of CVD attributable to ultra-processed dietary patterns among adults in Canada.

This study applied a comparative risk assessment model to estimate the burden of CVD, specifically, incident cases of heart disease and stroke, CVD-related deaths, and disability-adjusted life-years (DALYs) related to CVD, attributable to ultra-processed dietary patterns in adults aged 20 and older. Model inputs included nationally representative dietary intake data from 2015, national health statistics on CVD, and Canadian data on CVD outcomes sourced from the Global Burden of Disease Study for 2019.

In 2015, UPF constituted 43.4% of Canadian adults' total daily energy intake. Between 23% and 38% of all CVD events in 2019 were attributable to UPF intake, corresponding to 58,200 to 96,000 new cases of CVD, 10,600 to 17,400 CVD-related deaths, and 235,800 to 388,700 DALYs. Modeling counterfactual scenarios suggests that reducing UPF consumption by 20% to 50% may have prevented 16,800 to 45,900 new CVD cases, 3,100 to 8,300 CVD-related deaths, and 67,800 to 185,200 DALYs in 2019 in Canada.

UPF consumption may account for a substantial and potentially preventable burden of CVD in Canada. These findings reinforce the need for clinical and public health interventions aimed at reducing UPF intake as a key component of CVD prevention.

Atherosclerotic cardiovascular diseases (ASCVD) are the commonest cause of death. Peripheral artery disease (PAD) is an ASCVD that significantly increases risk of death and reduces quality of life; however, characterization of its consequences is limited because it requires manual adjudication of major adverse cardiovascular (MACE) and limb events (MALE). Hence, we developed and validated a system to quantify MACE and MALE using administrative data.

In a multi-hospital single healthcare system (2016-2023), we identified adult index vascular surgery clinic visits for PAD. We randomly sampled the patients for clinical adjudication of their electronic health record (EHR) data to identify long-term MACE (myocardial infarct, non-traumatic stroke, cardiac death) and MALE (major revascularization, amputation). We achieved consensus through a modified Delphi process with three rounds of EHR review by five experts, generating the gold standard diagnosis. We compared the accuracy of hospitalization diagnosis (International Clinical Diagnosis [ICD]) and/or procedure (Current Procedural Terminology [CPT]) codes to the EHR review gold standard diagnoses. Testing parameters identified the optimal administrative coding strategies when compared to the gold standard diagnoses. The predictive increment was measured by net reclassification indices (NRI).

We included 620 patients (age mean±SD, 70±12 years; 40% female; 89% White race; 16% frail). Throughout long-term follow up (median 2.7 years [IQR 1.3-4.7]), clinical adjudication identified 13% MACE and 22% MALE. Administrative strategies yielded similar rates for MACE and MALE. For MACE, diagnosis-only codes optimized identification with an F1 score of 60.3% and 0.55 Mathews Correlation Coefficient (MCC). For MALE, procedure-only codes optimized identification with an F1 score of 95.2% F1 score and 0.94 MCC. The NRI was 33% for MACE and 2% for MALE.

Administrative codes can accurately identify ASCVD outcomes among patients with PAD. MACE identification is inferior to MALE identification but optimized with ICD codes only, driven by limitations in PPV and NRI. MALE identification, which is limited to procedure-based events, is optimized with CPT codes alone, with minimal false negatives.

Microaxial flow pumps (mAFP) are increasingly used to treat cardiogenic shock (CS), but most evidence comes from acute myocardial infarction-related CS (AMI-CS). It remains unclear whether patients with non-ischemic CS (Non-AMI-CS) derive comparable benefits from mAFP support. This study aimed to compare clinical profiles, management strategies, and outcomes between AMI-CS and Non-AMI-CS patients treated with mAFP.

We retrospectively analyzed CS patients managed with mAFP (Impella CP and 5 + [5.0 and 5.5]) across 11 high-volume centers between 2010 and 2023. Propensity score matching was performed to account for baseline differences. The primary outcome was all-cause mortality at 180 days. Independent predictors of mortality were identified using multivariable logistic regression analysis.

A total of 976 patients were included (64.0% AMI-CS; 36.0% Non-AMI-CS). From 2010 to 2023, 180-day mortality significantly declined in both groups (Ptrend = 0.01 for AMI-CS and 0.03 for Non-AMI-CS). After propensity score matching (n = 444), 180-day mortality was comparable between AMI-CS and Non-AMI-CS patients (32.9% vs 33.3%; HR 0.89 [95% CI, 0.65-1.21]; p = 0.46). Rates of heart transplantation (5.0% vs 9.0%; p = 0.08) and durable LVAD implantation (10.8% vs 9.0%; p = 0.77) were also similar. These findings were consistent across all prespecified subgroups and at 10-year follow-up. Independent predictors of mortality in both groups included age (per 5-year increase), SCAI stage E, lactate ≥6 mmol/L), norepinephrine use, and renal replacement therapy. Despite similar survival, Non-AMI-CS patients demonstrated greater myocardial recovery, with larger LVEF improvement (+17.8 ± 17.0% vs +11.2 ± 14.5%; p < 0.001).

In this large, real-world cohort, ischemic and non-ischemic CS showed equivalent long-term outcomes under mAFP support. These findings suggest that patient selection should be guided by shock severity and hemodynamic phenotype rather than etiology alone, supporting broader evaluation of mAFP use.

Hepatic fibrosis, driven by oxidative stress and subsequent hepatocellular injury, represents a major worldwide health challenge. Pueraria lobata Radix, a traditional Chinese herb, contains polysaccharides with demonstrated hepatoprotective properties, though their mechanisms remain incompletely defined.

This study aims to characterize the structure of P. lobata polysaccharide (PLP2) and to decipher its protective mechanisms against hepatic fibrosis.

PLP2, a homogeneous, water-soluble polysaccharide, was purified from P. lobata and structurally characterized. Subsequently, the hepatoprotective activity of PLP2 was investigated in a CCl₄-induced murine model of hepatic fibrosis.

Structural analysis indicated that PLP2 (Mw = 142.9 kDa) was mainly composed of (1→4)-α-D-Glc and (1→4)-α-D-GalA units, with a minor presence of →4,6)-α-D-Glc-(1→ residues. In a CCl₄-induced murine model of hepatic fibrosis, PLP2 treatment effectively ameliorated liver injury, histopathological damage, and inflammatory responses. Mechanistically, PLP2 treatment restored mitochondrial ultrastructure and hepatic ATP levels, thereby suppressing hepatic ferroptosis through the activation of the Nrf2/HO-1/GPX4 axis. The indispensable role of Nrf2 was further validated using the inhibitor ML385, which abolished PLP2's protection. Notably, the hepatoprotective effects of PLP2 were predominantly dependent on gut microbiota integrity, as direct PLP2 treatment failed to protect hepatocytes in vitro. This role was further confirmed by the abolition of protection with antibiotic treatment and the transfer of benefits via fecal microbiota transplantation.

These findings provide evidence that PLP2 exerts its anti-fibrotic effects through the gut microbiota-dependent suppression of ferroptosis via the Nrf2/HO-1/GPX4 axis, providing a solid scientific foundation for the clinical application of P. lobata.

Exchange Protein Directly Activated by cAMP 1 (EPAC1) is an intracellular effector of the small GTPases Rap1 and Rap2, functioning independently of protein kinase A in the cAMP signalling pathway. The structural analysis shows that EPAC1 has an N-terminal regulatory region comprising a Dishevelled, Egl-10, and Pleckstrin (DEP) domain and a cyclic nucleotide-binding domain (cNBD) with a phosphate binding cassette (PBC) for cAMP binding, and a C-terminal catalytic region comprising Ras exchange motif, Ras association and a CDC25 homology domain (CDC25-HD). Although EPAC1 is broadly expressed, it has tissue-specific functions in endothelial barrier regulation, cardiac calcium homeostasis, vascular tone, metabolism, insulin secretion, and nociception. Dysregulation leads to cardiovascular hypertrophy, failure, diabetes-associated complications, inflammation, neuropathic pain, and cancer. Pharmacological modulation of EPAC1 with agents such as inhibitors CE3F4, AM-001, ESI-09, as well as agonist SY009, SY007 and partial agonist PWO577 holds significant therapeutic potential depending on disease context. The therapeutic effect is based on both EPAC1 activation that improves endothelial activities and glucose-stimulated insulin release, and inhibition that reduces cardiac hypertrophy and chronic pain. For example, SY009 enhances glucose-stimulated insulin secretion, and PWO577 is a Rap1 agonist that suppresses proinflammatory genes during vascular inflammatory conditions. EPAC1 is a versatile pharmaceutical target with transformative therapeutic potential in a broad range of disease pathologies.