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Despite major advances in acute interventions for myocardial infarction (MI), adverse cardiac remodeling and excess fibrosis after MI causing ischemic heart failure (IHF) remain a leading cause of death worldwide. Here we identify a profibrotic coagulation signaling pathway that can be targeted for improved cardiac function following MI with persistent ischemia. Quantitative phosphoproteomics of cardiac tissue revealed an upregulated mitogen-activated protein kinase (MAPK) pathway in human IHF. Intervention in this pathway with trametinib improves myocardial function and prevents fibrotic remodeling in a murine model of non-reperfused MI. MAPK activation in MI requires myeloid cell signaling of protease-activated receptor 2 linked to the cytoplasmic domain of the coagulation initiator tissue factor (TF). They act upstream of pro-oxidant NOX2 NADPH oxidase, ERK1/2 phosphorylation, and activation of profibrotic TGF-β1. Specific targeting with the TF inhibitor nematode anticoagulant protein c2 (NAPc2) starting 1 day after established experimental MI averts IHF. Increased TF cytoplasmic domain phosphorylation in circulating monocytes from patients with subacute MI identifies a potential thromboinflammatory biomarker reflective of increased risk for IHF and suitable for patient selection to receive targeted TF inhibition therapy.

Aims: Patients suffering from viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are at risk of developing acute respiratory distress syndrome (ARDS). ARDS is a serious complication of COVID-19 that requires early recognition and comprehensive management. Little is known about the concomitant prevalence of both entities in Germany. Thus, we sought to analyze predictors and regional trends of case fatality in patients with COVID-19 and ARDS in Germany. Methods: We analyzed data on the characteristics, comorbidities and in-hospital outcomes for all hospitalized patients with COVID-19 and compared those with and without ARDS in Germany in 2020. Results: Overall, 176,137 hospitalized patients with confirmed COVID-19 were included in this analysis; among these, 11,594 (6.6%) suffered from ARDS. Most patients with ARDS were treated in hospitals in urban areas (n = 6485); proportion rate of mechanical ventilation was higher (45.9%) compared to those treated in hospitals of suburban (36.1%) or rural areas (32.0%). Proportion of ARDS grew exponentially with age until the sixth decade of life. Case-fatality rate was considerably higher in COVID-19 patients with ARDS compared to those without (48.3% vs. 15.8%; p < 0.001). Independent predictors of in-hospital case fatality with an OR > 3 were age ≥ 70 years, severe ARDS, severe liver disease, acute renal failure, stroke, dialysis treatment, shock and necessity of ECMO. Conclusions: The case fatality of COVID-19 patients with ARDS is dramatically high and shows relevant regional disparities. Our findings may help to draw more attention to predictors for in-hospital case fatality in patients hospitalized with COVID-19 and suffering from ARDS.

Hydrogen embrittlement (HE) can significantly degrade the mechanical properties of steels. This phenomenon is particularly relevant for high-strength steels where large elastic stresses lead to detrimental localized concentrations of hydrogen at defects. In this study, unnotched rotating bending specimens of the bearing steel SAE 52100 (100Cr6) quenched and tempered at 180 °C and 400 °C were electrochemically charged with hydrogen. Charged and non-charged specimens then underwent rotating bending fatigue testing, either immediately after charging or after aging at room temperature up to 72 h. The hydrogen-charged specimens annealed at 180 °C showed a sizeable drop in fatigue limit and fatigue lifetime compared to the non-charged specimens with cracks mainly originating from near-surface non-metallic inclusions. In comparison, the specimens annealed at 400 °C exhibited a moderate drop in fatigue limit and lifetime due to hydrogen charging with cracks originating mostly from the surface. Aging had only insignificant effects on the fatigue lifetime. Notably, annealing of charged samples for 2 h at 180 °C restored their lifetime to that of non-charged specimens.

Background Kidney transplantation remains the most effective treatment for end-stage kidney disease, but sociodemographic differences, including sex and gender differences, remain a significant challenge. There is evidence that women receive fewer transplants than men, but whether gender influences the timing of transplant evaluation and waitlisting has not been analyzed yet. Therefore, we aimed to investigate gender differences in the time intervals between dialysis initiation, transplant evaluation and waitlisting. Methods We retrospectively analyzed 182 patients listed for kidney transplantation in the last quarter of 2023 (Key date 1st October 2023) or positively evaluated for listing for kidney transplantation from 2017 to 2023 at the University Medical Center Marburg, Germany. Besides baseline characteristics, we collected data on dialysis initiation, start of transplant evaluation and time from evaluation to waitlisting (Ethics approval Nr. 24-97RS, Philipps University Marburg, Germany). Results In our cohort, we did not find significant overall gender differences in the time intervals from dialysis initiation to transplant evaluation or listing. However, male patients undergoing peritoneal dialysis or scheduled for living donor transplants had significantly shorter evaluation and waitlisting times compared to their female counterparts. Conclusions The findings from our single-center analysis with a limited sample size suggest that gender disparities are pronounced in specific subgroups, with men generally benefiting from faster access to the waitlist. The results highlight the importance of recognizing gender disparities in transplantation processes to ensure equitable access for all patients. Future research should focus on interventions that address these inequalities and promote gender-sensitive nephrology care.

Background/Objectives: Fluid management in shock remains a clinical challenge, with ongoing debate about optimal guidance. Despite advanced technologies, fluid balance assessment is often inadequate. The SkInShock study investigated whether transepidermal water loss (TEWL) measurements could improve fluid balance estimation and serve as a non-invasive marker of vascular tone in patients with septic or cardiogenic shock. Methods: In this prospective single-center feasibility study (DRKS00027981), TEWL was measured daily in eight mechanically ventilated patients using a Tewameter® (Courage+Khazaka, Cologne, Germany), which quantifies transcutaneous water evaporation. Total daily skin water loss was calculated either via direct TEWL measurements or an estimation formula (6 mL/kg/day + 20%/°C deviation from 37 °C). Systemic vascular resistance index (SVRI) was measured simultaneously using PiCCO® technology (Pulsion Medical Systems, Munich, Germany) to evaluate the relationship between TEWL and vascular tone. Results: TEWL values were consistent across most body sites, except the forehead. TEWL-based estimates of skin water loss were significantly lower than formula-based estimates (p < 0.01). Formula-based values overestimated water loss at low TEWL levels and underestimated it at higher levels, with deviations reaching ±100%. While absolute TEWL values did not correlate with SVRI, intra-individually normalized values showed a significant negative correlation, indicating that higher skin water loss corresponded to lower vascular tone. Conclusions: TEWL measurement is feasible in ICU patients and may enhance fluid balance assessment and vascular tone monitoring. Our preliminary findings indicate that this non-invasive method could complement current diagnostics but warrants further investigation in larger cohorts.

Introduction: The pro-inflammatory cytokine interleukin-17A (IL-17A) has a key role in the inflammatory cascade and promotes vascular inflammation and dysfunction. In addition, IL-17A is centrally involved in several autoimmune diseases. IL-17A deficiency has been linked to reduced vascular inflammation associated with attenuated arterial hypertension under long-term angiotensin II (Ang II) exposure for four weeks. This is of interest as IL-17A is one factor linking several autoimmune diseases with cardiovascular comorbidity. So far, little is known about the effects of IL-17A during the early stages of vascular dysfunction development—an interval possibly representing an optimal therapeutic window. Methods: Mice lacking the IL-17A receptor alpha (IL-17RAdel) and wild-type counterparts were treated with Ang II for one week (1 mg/kg bodyweight/week). We assessed systemic oxidative stress formation and vascular function, as well as inflammatory cells in the vessel wall. In parallel, C57BL/6J mice treated with Ang II received anti-IL-17A therapy, to evaluate the same parameters. Results: Both IL-17RA-deficient mice and anti-IL-17A-treated C57BL/6J mice exhibited an attenuated oxidative stress response and mitigated vascular inflammation following one week of Ang II treatment. These effects did not significantly prevent the onset of Ang II-induced vascular dysfunction at that timepoint. Conclusions: After one week of Ang II treatment, antagonizing IL-17RA or IL-17A only partially reduced/attenuated the Ang II-induced effects on the vasculature. In the context of IL-17A-driven autoimmune diseases with associated vascular pathology, our findings suggest that anti-inflammatory therapies alone may not be sufficient to attenuate vascular impairment. A combined approach including agents with direct protective vascular effects may be required for effective intervention for the associated vascular comorbidity.

Key Clinical Message In near‐fatal asthma, the combination of ECMO therapy and isoflurane application via an intensive care ventilator with an anesthetic conservation device represents a therapeutic combination in seemingly hopeless clinical situations. We report a case of an adult patient with near‐fatal asthma, who was implanted venovenous extracorporeal membrane oxygenation in an extern hospital before transfer to our tertiary center. After 13 days and various therapeutic approaches, including inhaled isoflurane therapy via an anesthetic‐conserving device, the patient was decannulated and extubated 3 days later.

Background: Psoriasis is hallmarked by vascular dysfunction, arterial hypertension, and an increased risk for cardiovascular diseases. We have shown recently that skin-driven interleukin (IL)-17A expression promotes psoriasis-like disease in mice, and this is associated with vascular inflammation, vascular dysfunction, and hypertension. As an intensive risk-factor reduction is recommended for psoriasis patients, we aimed to elucidate the impact of the angiotensin II receptor type 1 (AT1) antagonist telmisartan in a mouse model of severe psoriasis-like skin disease. Methods and Results: Elevated blood pressure measured by tail-cuff plethysmography in mice with keratinocyte-specific IL-17A overexpression (K14-IL-17Aind/+ mice) was significantly reduced in response to telmisartan. Importantly, vascular dysfunction, as assessed by isometric tension studies of isolated aortic rings, vascular inflammation measured by flow cytometry analysis of CD45+CD11b+ immune cells, as well as the increased peripheral oxidative stress levels assessed by L-012-enhanced chemiluminescence were not attenuated by telmisartan treatment of K14-IL-17Aind/+ mice, nor was the persisting skin inflammation. Conclusion: We provide first evidence for an effective antihypertensive treatment in experimental psoriasis by AT1 blockade, but without any impact on vascular inflammation and dysfunction in our mouse model of severe psoriasis-like skin disease. This suggests that vascular function and inflammation in psoriasis might not be attenuated as long as skin inflammation persists.

Antibiotic stewardship (ABS) programs aim to combine effective treatment with minimized antibiotic-related harms. Common ABS interventions are simple and effective, but their implementation in daily practice is often difficult. The aim of our study was to investigate if a single, short, peer-to-peer teaching intervention (junior doctor to junior doctor) during clinical routine can successfully improve antibiotic prescriptions. We performed a quasi-experimental before–after study on a regular care cardiology ward at a large academic medical center in Germany. We evaluated antibiotic use metrics retrospectively and calculated defined daily doses (DDD) with the anatomical therapeutic chemical/DDD classification system of the World Health Organization. We hypothesize that the over-representative use of intravenous administration is a potentially modifiable target, which can be proven by antibiotic use metrics analysis. After a single peer-to-peer teaching session with a focus on indications for iv to po conversion, the normalized percentage of intravenous compared to oral administration significantly decreased (from 86.5 ± 50.3% to 41.4 ± 70.3%). Moreover, after the intervention, antibiotics with high oral bioavailability were no longer administered intravenously at all during the following quarter. Our results indicate that even a single peer-to-peer training session is highly effective in improving the iv to po conversion rate in the short term.

Aims: Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a cornerstone of drug therapy after myocardial infarction (MI) and improve left ventricular function and survival. We aimed to elucidate the impact of early treatment with the ACE inhibitor ramipril on the hematopoietic response after MI, as well as on the chronic systemic and vascular inflammation. Methods and Results: In a mouse model of MI, induced by permanent ligation of the left anterior descending artery, immediate initiation of treatment with ramipril (10 mg/k/d via drinking water) reduced cardiac inflammation and the number of circulating inflammatory monocytes, whereas left ventricular function was not altered significantly, respectively. This effect was accompanied by enhanced retention of hematopoietic stem cells, Lin−Sca1−c-Kit+CD34+CD16/32+ granulocyte–macrophage progenitors (GMP) and Lin−Sca1−c-Kit+CD150−CD48− multipotent progenitors (MPP) in the bone marrow, with an upregulation of the niche factors Angiopoetin 1 and Kitl at 7 d post MI. Long-term ACE inhibition for 28 d limited vascular inflammation, particularly the infiltration of Ly6Chigh monocytes/macrophages, and reduced superoxide formation, resulting in improved endothelial function in mice with ischemic heart failure. Conclusion: ACE inhibition modulates the myeloid inflammatory response after MI due to the retention of myeloid precursor cells in their bone marrow reservoir. This results in a reduction in cardiac and vascular inflammation with improvement in survival after MI.