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This study investigates the prevalence and evaluates the prognostic implications of acute kidney injury (AKI) in COVID-19 patients, with a novel emphasis on the evaluation of serum uromodulin (sUmod) as a potential kidney-specific biomarker. A cohort of hospitalised COVID-19 patients (n = 378) was examined for AKI using standard criteria. In addition to traditional urinary biomarkers, sUmod levels were analysed. Univariable and multivariable regression models were employed to evaluate the association of sUmod and AKI and in-hospital mortality. Levels of sUmod were significantly lower in patients with CKD (91.8 ± 60.7 ng/ml) compared to patients with normal kidney function (204.7 ± 91.7 ng/ml; p < 0.001). 151 patients (40.0%) presented with AKI at the time of hospital admission or developed an AKI during hospitalization. 116 patients (76.8%) had an AKI already at the time of hospital admission. COVID-19 patients with AKI had significantly lower levels of sUmod compared to patients without AKI during hospitalisation (124.8 ± 79.5 ng/ml) vs 214.6 ± 92.3 ng/ml; p < 0.001). The in-hospital mortality rate in this cohort of COVID-19 patients was 15.3%. Patients with AKI had a higher probability for in-hospital death (OR 5.6, CI 1.76 to 17.881, p = 0.004). Patients who died during hospital stay, had significantly lower sUmod levels (129.14 ± 89.56 ng/ml) compared to patients surviving hospitalisation (187.71 ± 96,64 ng/ml; p < 0.001). AKI is frequently associated with COVID-19 in hospitalized patients. Serum uromodulin may emerge as a promising biomarker for AKI in COVID-19 patients. Further research is warranted to explore its clinical application and refine risk stratification in this patient population. [ABSTRACT FROM AUTHOR]

Idiopathic subglottic stenosis (ISGS) is a rare fibrotic disease of the upper trachea with an unknown pathomechanism. It typically affects adult Caucasian female patients, leading to severe airway constrictions caused by progressive scar formation and inflammation with clinical symptoms of dyspnoea, stridor and potential changes to the voice. Endoscopic treatment frequently leads to recurrence, whereas surgical resection and reconstruction provides excellent long-term functional outcome. This study aimed to identify so far unrecognized pathologic aspects of ISGS using single cell RNA sequencing. Our scRNAseq analysis uncovered the cellular composition of the subglottic scar tissue, including the presence of a pathologic, profibrotic fibroblast subtype and the presence of Schwann cells in a profibrotic state. In addition, a pathology associated increase of plasma cells was identified. Using extended bioinformatics analyses, we decoded pathology-associated changes of factors of the extracellular matrix. Our data identified ongoing fibrotic processes in ISGS and provide novel insights on the contribution of fibroblasts, Schwann cells and plasma cells to the pathogenesis of ISGS. This knowledge could impact the development of novel approaches for diagnosis and therapy of ISGS. [ABSTRACT FROM AUTHOR]

OBJECTIVES Limited data are available from randomized trials comparing outcomes between transcatheter aortic valve replacement (TAVR) and surgery in patients with different risks and with follow-up of at least 4 years or longer. In this large, population-based cohort study, long-term mortality and morbidity were investigated in patients undergoing aortic valve replacement (AVR) for severe aortic stenosis using a surgically implanted bioprosthesis (surgical/biological aortic valve replacement; sB-AVR) or TAVR. METHODS Individual data from the Austrian Insurance Funds from 2010 through 2020 were analysed. The primary outcome was all-cause mortality, assessed in the overall and propensity score-matched populations. Secondary outcomes included reoperation and cardiovascular events. RESULTS From January 2010 through December 2020, a total of 18 882 patients underwent sB-AVR (n  = 11 749; 62.2%) or TAVR (n  = 7133; 37.8%); median follow-up was 5.8 (95% CI 5.7–5.9) years (maximum 12.3 years). The risk of all-cause mortality was higher with TAVR compared with sB-AVR: hazard ratio 1.552, 95% confidence interval (CI) 1.469–1.640, P  < 0.001; propensity score-matched hazard ratio 1.510, 1.403–1.625, P  < 0.001. Estimated median survival was 8.8 years (95% CI 8.6–9.1) with sB-AVR versus 5 years (4.9–5.2) with TAVR. Estimated 5-year survival probability was 0.664 (0.664–0.686) with sB-AVR versus 0.409 (0.378–0.444) with TAVR overall, and 0.690 (0.674–0.707) and 0.560 (0.540–0.582), respectively, with propensity score matching. Separate subgroup analyses for patients aged 65–75 years and >75 years indicated a significant survival benefit in patients selected for sB-AVR in both groups. Other predictors of mortality were age, sex, previous heart failure, diabetes and chronic kidney disease. CONCLUSIONS In this retrospective national population-based study, selection for TAVR was significantly associated with higher all-cause mortality compared with sB-AVR in patients ≥65 years with severe, symptomatic aortic stenosis in the >2-year follow-up. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES This population-based cohort study investigated mid-term outcome after surgical aortic valve replacement with a bioprosthetic or mechanical valve prosthesis in patients aged <50 years in a European social welfare state. METHODS We analysed patient data from the main social insurance carriers in Austria (2010–2020). Subsequent patient-level record linkage with national health data provided patient characteristics and clinical outcome. Survival, reoperation, myocardial infarction, heart failure, embolic stroke or intracerebral haemorrhage, bleeding other than intracerebral haemorrhage and major adverse cardiac events were evaluated as outcomes. RESULTS A total of 991 patients were analysed. Regarding demographics, no major differences between groups were observed. Multivariable Cox regression revealed no significant difference in overall survival (P  = 0.352) with a median follow-up time of 6.2 years. Reoperation-free survival was decreased (hazard ratio = 1.560 [95% CI: 1.076–2.262], P  = 0.019) and the risk for reoperation was increased (hazard ratio = 2.770 [95% CI: 1.402–5.472], P  = 0.003) in patients who received bioprostheses. Estimated probability of death after reoperation was 0.23 (CL: 0.08–0.35) after 2 years and 0.34 (CL: 0.06–0.53) after 10 years over both groups. Regarding further outcomes, no significant differences between the two groups were observed. CONCLUSIONS In patients below 50 years of age receiving aortic valve replacement, implantation of bioprostheses when compared to mechanical heart valve prostheses was associated with a significantly higher rate of reoperations and reduced reoperation-free survival. Nevertheless, we could not observe a difference in overall survival. However, long-term follow-up has to evaluate that a significantly lower rate of reoperations may translate in consistently improved long-term survival. [ABSTRACT FROM AUTHOR]

Background: Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. Methods: We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. Findings: Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-γ (IFN-γ). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-γ to interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. Interpretation: Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects. [ABSTRACT FROM AUTHOR]

Background: The present population‐based cohort study investigated long‐term mortality after surgical aortic valve replacement (AVR) with bioprosthetic (B) or mechanical aortic valve prostheses (M) in a European social welfare state. Methods: We analysed patient data from health insurance records covering 98% of the Austrian population between 2010 and 2018. Subsequent patient‐level record linkage with national health data provided patient characteristics and clinical outcomes. Further reoperation, myocardial infarction, heart failure and stroke were evaluated as secondary outcomes. Results: A total of 13,993 patients were analysed and the following age groups were examined separately: <50 years (727 patients: 57.77% M, 42.23% B), 50–65 years (2612 patients: 26.88% M, 73.12% B) and >65 years (10,654 patients: 1.26% M, 98.74% B). Multivariable Cox regression revealed that the use of B‐AVR was significantly associated with higher mortality in patients aged 50–65 years compared to M‐AVR (HR = 1.676 [1.289–2.181], p < 0.001). B‐AVR also performed worse in a competing risk analysis regarding reoperation (HR = 3.483 [1.445–8.396], p = 0.005) and myocardial infarction (HR = 2.868 [1.255–6.555], p = 0.012). However, the risk of developing heart failure and stroke did not differ significantly after AVR in any age group. Conclusions: Patients aged 50–65 years who underwent M‐AVR had better long‐term survival, and a lower risk of reoperation and myocardial infarction. Even though anticoagulation is crucial in patients with M‐AVR, we did not observe significantly increased stroke rates in patients with M‐AVR. This evident survival benefit in recipients of mechanical aortic valve prostheses aged <65 years critically questions current guideline recommendations. [ABSTRACT FROM AUTHOR]

Sebaceous glands are adnexal structures, which critically contribute to skin homeostasis and the establishment of a functional epidermal barrier. Sebocytes, the main cell population found within the sebaceous glands, are highly specialized lipid-producing cells. Sebaceous gland-resembling tissue structures are also found in male rodents in the form of preputial glands. Similar to sebaceous glands, they are composed of lipid-specialized sebocytes. Due to a lack of adequate organ culture models for skin sebaceous glands and the fact that preputial glands are much larger and easier to handle, previous studies used preputial glands as a model for skin sebaceous glands. Here, we compared both types of sebocytes, using a single-cell RNA sequencing approach, to unravel potential similarities and differences between the two sebocyte populations. In spite of common gene expression patterns due to general lipid-producing properties, we found significant differences in the expression levels of genes encoding enzymes involved in the biogenesis of specialized lipid classes. Specifically, genes critically involved in the mevalonate pathway, including squalene synthase, as well as the sphingolipid salvage pathway, such as ceramide synthase, (acid) sphingomyelinase or acid and alkaline ceramidases, were significantly less expressed by preputial gland sebocytes. Together, our data revealed tissue-specific sebocyte populations, indicating major developmental, functional as well as biosynthetic differences between both glands. The use of preputial glands as a surrogate model to study skin sebaceous glands is therefore limited, and major differences between both glands need to be carefully considered before planning an experiment. [ABSTRACT FROM AUTHOR]