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Saphenous vein graft (SVG) pseudoaneurysms are an infrequent, but life-threatening complication of coronary artery bypass grafting (CABG) surgery if left untreated. Here, we discuss the case of a 77-year-old patient, with a prior history of CABG and transcatheter aortic valve implantation (TAVI), who was incidentally found on computed tomography angiography (CTA) to have a pseudoaneurysm of his SVG with an initial chief complaint of dizziness. Despite increasing reports of SVG pseudoaneurysm, there is no consensus on definitive treatment. Due to the high mortality risk of this patient with surgical intervention, a minimally invasive percutaneous coronary intervention was performed. The patient was effectively treated with two overlapping Viabahn-covered stents, which completely excluded the pseudoaneurysm. Follow-up imaging at two months showed two well-positioned overlapping self-expanding stents with total occlusion of the pseudoaneurysm.

OBJECTIVES: The study aimed to compare the risk of gastrointestinal infections among patients with and without metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: This was a population-based, retrospective, observational study using data from the National Inpatient Sample (NIS), the largest all-payer US inpatient care database. SETTING: Hospitalisation of adults aged ≥18 years old admitted in 2020 was identified using the NIS. Patients were stratified by the presence and absence of MAFLD. PARTICIPANTS: 26.4 million adults aged ≥18 years old were included in the study. Patients younger than 18 and those with missing demographic or mortality data were excluded. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was to assess the overall risk of gastrointestinal infections in patients with and without MAFLD. Secondary outcomes were demographics and comorbidities stratified by the presence or absence of gastrointestinal infection, and the risk of specific gastrointestinal pathogens. RESULTS: Of 26.4 million patients admitted in 2020, 755 910 (2.85%) had the presence of MAFLD. There was a higher prevalence of bacterial gastrointestinal infections in patients with MAFLD than those without (1.6% vs 0.9%, p

mEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) signaling via an alternative mTOR complex, implying that mEAK-7 plays an important role in the promotion of cancer proliferation and migration. In addition, structural analyses investigating interactions between mEAK-7 and V-ATPase, a protein complex responsible for regulating pH homeostasis in cellular compartments, have suggested that mEAK-7 may contribute to V-ATPase-mediated mTORC1 activation. The C-terminal α-helix of mEAK-7 binds to the D and B subunits of the V-ATPase, creating a pincer-like grip around its B subunit. This binding undergoes partial disruption during ATP hydrolysis, potentially enabling other proteins such as mTOR to bind to the α-helix of mEAK-7. mEAK-7 also promotes chemoresistance and radiation resistance by sustaining DNA damage-mediated mTOR signaling through interactions with DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Taken together, these findings indicate that mEAK-7 may be a promising therapeutic target against tumors. However, the precise molecular mechanisms and signal transduction pathways of mEAK-7 in cancer remain largely unknown, motivating the need for further investigation. Here, we summarize the current known roles of mEAK-7 in normal physiology and cancer development by reviewing the latest studies and discuss potential future developments of mEAK-7 in targeted cancer therapy.

Introduction Gastroparesis (GP) is a chronic debilitating gastric motility disorder defined as delayed emptying of the stomach content without mechanical obstruction. It can result in nutritional deficiencies, leading to poor overall outcomes. We assessed the impact of malnutrition on in-hospital outcomes in patients with gastroparesis. Methods Patients with a primary discharge diagnosis of GP between January 2016 and December 2019 were included in the National Inpatient Sample (NIS) database. Data on patient demographics, hospital characteristics, the Charlson Comorbidity Index (CCI), and the etiology of gastroparesis were collected. The association between malnutrition and outcomes, including mortality, deep vein thrombosis (DVT), pulmonary embolism (PE), sepsis, acute kidney injury (AKI), length of stay (LOS), and total hospitalization charges (THC), were analyzed using the multivariate regression model. Results A total of 182,580 patients with gastroparesis were included in the analysis. Patients with gastroparesis and malnutrition had a higher risk of mortality (adjusted odds ratio {aOR}, 3.29; p

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.SignificanceKRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low 5-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAM), which promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In orthotopic PDAC mouse models, genetic deletion of myeloid Syk reprogrammed macrophages into immunostimulatory phenotype, increased the infiltration, proliferation, and cytotoxicity of CD8+ T cells, and repressed PDAC growth and metastasis. Furthermore, gemcitabine (Gem) treatment induced an immunosuppressive microenvironment in PDAC by promoting protumorigenic polarization of macrophages. In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, "re-educated" protumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T-cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the antitumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC.SignificanceSyk blockade induces macrophage polarization to an immunostimulatory phenotype, which enhances CD8+ T-cell responses and improves gemcitabine efficacy in pancreatic ductal adenocarcinoma, a clinically challenging malignancy.

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long-term follow-up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre-transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post-transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25-1.90]; P

ObjectivesThe concept of frailty has gained importance, especially in patients with liver disease. Our study systematically investigated the effect of frailty on post-procedural outcomes in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS).MethodsWe used National Inpatient Sample(NIS) 2016-2019 data to identify patients who underwent TIPS. Hospital frailty risk score (HFRS) was used to classify patients as frail (HFRS>=5) and non-frail (HFRS

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic was a public health crisis affecting medical, social, and psychological wellness. In a previous study, we reported a rise in alcohol-related hepatitis (ARH) cases between 2019 and 2020 in the central valley of California. Our goal in the current study was to assess the impact of COVID-19 on ARH at a national level.Materials and methodsWe used data from the 2016 to 2020 National Inpatient Sample. All adult patients diagnosed with ARH (ICD10 K70.1 and K70.4) were included. Information was collected regarding patient demographics, hospital characteristics, and severity of hospitalization. We analyzed the annual percentage changes (PC) between 2016-2019 and 2019-2020 to assess the impact of COVID-19 on hospitalizations. Multivariate logistic regression analysis was performed to identify factors associated with increased ARH admissions between 2016 and 2020.ResultsA total of 823,145 patients were admitted with ARH. The total number of cases increased from 146,370 in 2016 to 168,970 in 2019 (annual percentage change (PC) 5.1%), while the cases increased to 190,770 in 2020 (PC 12.4%). The PC in women was 6.6% between 2016 and 2019, which increased to 14.2% between 2019 and 2020. In men, PC increased by 4.4% between 2016 and 2019 to 12.2% between 2019 and 2020. On multivariate analysis, after adjusting for patient demographics and hospital characteristics, there was 46% increased odds of admission with ARH in 2020, compared to 2016. The total number of deaths increased from 8725 in 2016 to 9190 in 2019 (PC 1.7%), while the total number of deaths increased to 11,455 in 2020 (PC 24.6%).ConclusionsA sharp rise in the cases of ARH between 2019 and 2020 was noted, which aligned with the COVID-19 pandemic. Not only did total hospitalization increase, but an increase in mortality was also noted, reflecting higher severity in the patients admitted during the COVID-19 pandemic.

Background Global longitudinal strain (GLS) is a sensitive measure of left ventricular function and a risk marker in severe aortic stenosis. We sought to determine whether biomarkers of cardiac damage (cardiac troponin) and stress (NT-proBNP [N-terminal pro-B-type natriuretic peptide]) could complement GLS to identify patients with severe aortic stenosis at highest risk. Methods and Results From a multicenter prospective cohort of patients with symptomatic severe aortic stenosis who underwent transcatheter aortic valve implantation, we measured absolute GLS (aGLS), cardiac troponin, and NT-proBNP at baseline in 499 patients. Left ventricular ejection fraction 2; P≤0.002 for each) when the other biomarker was elevated, but not when the other biomarker was normal (interaction P=0.015). Conclusions Among patients with symptomatic severe aortic stenosis undergoing transcatheter aortic valve implantation, elevations in circulating cardiac troponin and NT-proBNP are more common as GLS worsens. Biomarkers of cardiac damage and stress are independently associated with mortality after transcatheter aortic valve implantation, whereas GLS is not. These findings may have implications for risk stratification of asymptomatic patients to determine optimal timing of valve replacement.