Does Telemedical Support of First Responders Improve Guideline Adherence in an Offshore Emergency Scenario? A Simulator-Based Prospective Study

OBJECTIVE: To investigate, in a simulator-based prospective study, whether telemedical support improves quality of emergency first response (performance) by medical non-professionals to being non-inferior to medical professionals. SETTING: In a simulated offshore wind power plant, duos (teams) of offshore engineers and teams of paramedics conducted the primary survey of a simulated patient. PARTICIPANTS: 38 offshore engineers and 34 paramedics were recruited by the general email invitation. INTERVENTION: Teams (randomised by lot) were supported by transmission technology and a remote emergency physician in Berlin. OUTCOME MEASURES: From video recordings, performance (17 item checklist) and required time (up to 15 min) were quantified by expert rating for analysis. Differences were analysed using two-sided exact Mann-Whitney U tests for independent measures, non-inferiority was analysed using Schuirmann one-sided test. The significance level of 5 % was Holm-Bonferroni adjusted in each family of pairwise comparisons. RESULTS: Nine teams of engineers with, nine without, nine teams of paramedics with and eight without support completed the task. Two experts quantified endpoints, insights into rater dependence were gained. Supported engineers outperformed unsupported engineers (p<0.01), insufficient evidence was found for paramedics (p=0.11). Without support, paramedics outperformed engineers (p<0.01). Supported engineers' performance was non-inferior (at one item margin) to that by unsupported paramedics (p=0.03). Supported groups were slower than unsupported groups (p<0.01). CONCLUSIONS: First response to medical emergencies in offshore wind farms with substantially delayed professional care may be improved by telemedical support. Future work should test our result during additional scenarios and explore interdisciplinary and ecosystem aspects of this support. TRIAL REGISTRATION NUMBER: DRKS0001437

Virus-like particles derived from major capsid protein VP1 of different polyomaviruses differ in their ability to induce maturation in human dendritic cells

AbstractAs polyomavirus major capsid protein VP1-derived virus-like particles (VLPs) have been demonstrated to be highly immunogenic, we studied their interaction with human dendritic cells (hDCs). Exposure of hDCs to VLPs originating from murine (MPyV) or hamster polyomavirus (HaPyV) induced hDC maturation. In contrast, exposure of hDCs to VLPs derived from human polyomaviruses (BK and JC) and simian virus 40 (SV40) only marginally induced DC maturation. The hDCs stimulated by HaPyV- or MPyV-derived VLPs readily produced interleukin-12 and stimulated CD8-positive T-cell responses in vitro. The highest frequencies of activated T cells were again observed after pulsing with HaPyV- and MPyV-derived VLPs. Monocyte-derived hDCs both bound and internalized the various tested polyomavirus VP1-derived VLPs with different levels of efficiency, partially explaining their individual maturation potentials. In conclusion, our data suggest a high variability in uptake of polyomavirus-derived VLPs and potency to induce hDC maturation

Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: A FIDELITY subgroup analysis

AIM Investigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis. MATERIALS AND METHODS Post hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis-4 (FIB-4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma-glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure. RESULTS ALT, aspartate aminotransferase and gamma-glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB-4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB-4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively). CONCLUSIONS Finerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB-4 scores who were at high risk of developing cardiovascular complications

Polyomavirus-derived virus-like particles as potential vaccines

Hintergrund: Krebs-spezifische Immuntherapien stellen eine vielverspechende Möglichkeit zur Ergänzung der etablierten chirurgischen, pharmakologischen und radiologischen Krebstherapien dar. Eine spezielle Immuntherapie basiert auf der Induktion von Immunantworten gegen tumorassoziierte Autoantigene, die auf Tumorzellen überexprimiert werden wie z.B. carcinoembryonales Antigen (CEA) und Mucin 1 (MUC1). Aufgrund ihrer immunologischen Eigenschaften stellen Virus-ähnliche Partikel (VLP) interessante Träger zur Entwicklung neuer Impfstoffe dar. Zielstellung: Das Ziel der Untersuchungen bestand in der Herstellung und Charakterisierung von autologen Polyomavirus-VLP und chimären Hamsterpolyomavirus (HaPyV)-abgeleiteten VLP. Methoden: Unmodifizierte Hauptkapsidproteine VP1 von Nager- und Primatenpolyomaviren sowie VP1-Fusionsproteine von HaPyV wurden in der Hefe Saccharomyces cerevisiae hergestellt. Die VLP-Reinigung erfolgte durch Ultrazentrifugation im Cäsiumchlorid-Dichtegradienten. Zum Studium der Aufnahmewege in humane dendritische Zellen (hDC) wurden die VLP mit CFDA markiert und die Aufnahme bei Verwendung von spezifischen Hemmstoffen durch FACS-Analyse charakterisiert. Die Ausreifung von humanen dendritischen Zellen nach Applikation von VLP unterschiedlicher Polyomaviren wurde durch FACS-Analyse von Oberflächenmarkern und durch funktionelle Analysen bestimmt. Die humorale Immunität von chimären VLP mit CEA-Insertionen wurde durch Immunisierung von Balb/c-Mäusen und nachfolgende Enzymimmunoassay(EIA)-Untersuchungen der Mausseren charakterisiert. Die T-Zell-Immunität von VLP mit MUC1-Inserts wurde in vitro durch Messung der Frequenz von MUC1-spezifischen CD8+ T-Zellen im Tetramer- und Interferon-gamma-assay geprüft. Ergebnisse: Mit Hilfe des Hefeexpressionssystems konnten die chimären HaPyV-VP1-abgeleiteten VLP mit einem oder zwei CEA- oder MUC1-Insertionen in hoher Ausbeute produziert werden. Durch Herstellung von VLP mit der 238 Aminosäuren langen Sequenz des grünfluoreszierenden Proteins konnte die hohe Insertionskapazität des HaPyV- VP1 bestätigt werden. Die VLP der verschiedenen Polyomaviren wurden alle durch hDC mittels Makropinozytose aufgenommen, während sich die Rezeptor- vermittelten Aufnahmewege unterschieden. Die Nager-Polyomavirus-abgeleiteten VLP induzierten eine Reifung von hDC und vermittelten in einem in vitro-Modell eine CD8+ T-Zell-Immunität. Adjuvantfreie Immunisierungen von Balb/c-Mäusen mit chimären CEA-tragenden VLP zeigten eine Abhängigkeit der Antikörperantwort vom Insertionsort im VP1. Für ausgewählte VLP konnte in der Maus eine langanhaltende Immunität für das CEA-Fremdinsert gezeigt werden. Monoklonale Antikörper gegen MUC1-Fremdinsertion von VLP erkannten das native Mucin 1 auf Tumorzellen. Schlußfolgerung: HaPyV-abgeleitete chimäre VLP stellen einen interessanten Ansatzpunkt für zukünftige Impfstoffe zur Tumortherapie beim Menschen dar.Introduction: Cancer-specific Immunotherapies play a promising role as supplements to well-established cancer therapies such as oncological, pharmacological and radiological treatment. A group of special immunotherapies is based on inducing immuno stimulation against tumor-associated auto-antigens like carcinoembrional antigen (CEA) and mucin 1 (MUC1). Due to their immunological characteristics, virus-like particles (VLP) represent promising carrier candidates for novel vaccines. Aim: The aim of this work was to build, produce and characterize VLPs derived of autologous and chimaeric polyomaviruses. Methods: Unmodified main-capsid protein VP1 of rodent- and primate-polyomaviruses and fusion-proteins of hamsterpolyomavirus (HaPyV) were expressed in Saccharomyces cerevisiae. Purification of VLPs took place via ultracentrifugation in caesiumchlorine gradients. To study uptake characteristics into human dendritic cells (hDC), VLPs were labeled with CFDA and incubated with varying uptake inhibitors. Maturation of human dendritic cells was measured by FACS via surface maturation markers after application of autologous and chimaeric VLPs and in functional assays. The humoral immunogenicity of chimaeric VLPs with CEA-inserts was tested by immunizing Balb/c-mice and measuring serum antibody-titers in enzyme-linked immuno- assays (EIA). The CD8+ T-cell immunogenicity of chimaeric VLPs with MUC1-inserts was measured via FACS analysis of MUC1-specific CD8+ T-cells frequency and Interferon-gamma-assays. Results: Chimaeric Hamsterpolyoma-VLPs (HaPyV-VLP) with one or two MUC1- or CEA-inserts were produced with high yield in the yeast expression system. The high insertion capacity of HaPyV-VP1 was affirmed by the successful expression of VLPs with an insert of the 238 aa long green fluorescent protein. Uptake of all VLPs of different polyomaviruses took place via macropinocytosis, whereas receptor-mediated uptake pathways differed. VLPs derived of rodent origin induced maturation in human dendritic cells and CD8+ T-cell immunity. Adjuvant-free Immunization of Balb/c mice showed that long-lasting antibody-titers against the CEA-insert depends on its insertion site. Monoclonal antibodies against MUC1-inserts were able to detect native mucin in various tumorcell lines. Conclusion: Chimaeric HaPyV-derived virus-like particles represent interesting candidates for future tumor vaccines in humanes

Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor

1460-P: Prevalence of Chronic Kidney Disease Associated with Type 1 Diabetes in the U.S.

Background: Chronic kidney disease (CKD) is associated with an increased risk of kidney failure, cardiovascular events, and mortality in patients with type 1 diabetes (T1D). However, the prevalence of CKD associated with T1D in the US is unclear. The aim of this study was to estimate the prevalence of CKD in people with T1D in the US using data collected in the National Health Examinations Survey (NHANES). Methods: People with T1D were identified from NHANES using an established algorithm (Mosslemi et al. Cardiovasc Endocrinol Metab. 2020). Adults aged ≥18 years with CKD in this group were identified by single measurements of estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 or urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g. The NHANES data were used to create corresponding weighted variables to represent the US Results: During 2015 to 2018, diabetes was identified in 1647 of 19,225 adults surveyed in NHANES. Among those with diabetes, CKD was present in 20 out of 47 people with T1D with evaluable eGFR and UACR, corresponding to an unweighted estimate of 43%. CKD status was uncertain in 7 patients with T1D as their eGFR and/or UACR measurements were not available (unweighted estimate). In the CKD and T1D group, 59% were male and 60% were non-Hispanic White (weighted characteristics). Mean eGFR (SD) was 57 (4) mL/min/1.73 m2 and median UACR (IQR) was 89 (8-875) mg/g (weighted characteristics). Since the weighted overall number of adult people with T1D in the US was estimated at 1,202,739 (95% CI: 681,820-1,723,657), the corresponding number with T1D and CKD with evaluable eGFR and UACR was 258,196 (95% CI: 71,189-445,203), corresponding to a weighted estimate of 21%. Conclusions: CKD was common in people with T1D and evaluable eGFR and UACR based on recent US data. Since the absolute number in NHANES was small, these prevalence estimates should be interpreted cautiously and validated in other cohorts. Disclosure P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. P.Groop: Advisory Panel; Boehringer-Ingelheim, Bayer Inc., Speaker\u27s Bureau; AstraZeneca, Boehringer-Ingelheim, Bayer Inc., Merck Sharp & Dohme Corp., Medscape, Nestlé Health Science. R.Singh: None. R.Lawatscheck: Employee; Bayer Inc. K.R.Tuttle: Consultant; Lilly, AstraZeneca, Gilead Sciences, Inc., Research Support; Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Novo Nordisk, Goldfinch Bio, Inc., Traveere Pharmaceuticals. Funding Bayer A

Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA): Rationale and design of a prospective registry study to assess rivaroxaban 2.5 mg twice daily plus aspirin for prevention of atherothrombotic events in coronary artery disease, peripheral artery disease, or both

International audienceAims: The role and selection of antithrombotic therapy to improve limb outcomes in chronic lower extremity artery disease (LEAD) is still debated. We conducted a meta-analysis to examine the efficacy and safety of antithrombotic and more intense antithrombotic therapy on limb outcomes and limb salvage in patients with chronic LEAD.Methods and results: Study inclusion criteria were: enrolment of patients with LEAD, randomized allocation to more vs. less intense antithrombotic therapy [more vs. less intense single-antiplatelet therapy (SAPT); dual-antiplatelet therapy vs. SAPT; dual antithrombotic therapy vs. SAPT or oral anticoagulant]; enrolment of ≥200 patients; reporting of at least one of following outcomes: limb amputation or revascularization. Seven randomized studies enrolling 30 447 patients were included. Over a median follow-up of 24 months, more vs. less intense antithrombotic therapy or placebo significantly reduced the risk of limb revascularization [relative risk (RR) 0.89, 95% confidence interval (CI) 0.83-0.94] and limb amputation (RR 0.63, 95% CI 0.46-0.86), as well as stroke (RR 0.82, 95% CI 0.70-0.97). There was no statistically significant effect on the risk of myocardial infarction (RR 0.98, 95% CI 0.87-1.11), all-cause (RR 0.93, 95% CI 0.86-1.01), and cardiovascular death (RR 0.97, 95% CI 0.86-1.08). Risk of major bleeding increased (RR 1.23, 95% CI 1.04-1.44).Conclusion: In patients with LEAD, more intense antithrombotic therapy reduces the risk of limb amputation and revascularization as well as stroke with an increase in the risk of bleeding events

Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes

Background: In patients with type 2 diabetes (T2D), risks of cardiovascular mortality and heart failure (HF) increase with decreasing kidney function (estimated glomerular filtration rate [eGFR]) and increasing albuminuria (urine albumin-to-creatinine ratio [UACR]). Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and T2D in FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis). Objectives: This study sought to evaluate the effects of finerenone on HF outcomes by eGFR and/or UACR categories. Methods: FIDELITY included 13,026 patients with T2D and CKD (UACR 30-5,000 mg/g and eGFR ≥25 mL/min/1.73 m2) randomized to finerenone or placebo. Time-to-event outcomes were first hospitalization for heart failure (HHF), cardiovascular death or first HHF, recurrent HHF, and cardiovascular death or recurrent HHF, analyzed in subgroups by baseline eGFR (<60 and ≥60 mL/min/1.73 m2) and/or UACR (<300 and ≥300 mg/g). Results: Compared with placebo, finerenone significantly reduced risk of first HHF (HR: 0.78 [95% CI: 0.66-0.92]; P = 0.003), cardiovascular death or first HHF (HR: 0.83 [95% CI: 0.74-0.93]; P = 0.002), recurrent HHF (HR: 0.79 [95% CI: 0.64-0.96]; P = 0.021), and cardiovascular death or recurrent HHF (HR: 0.82 [95% CI: 0.72-0.95]; P = 0.006). The risk of outcomes increased across baseline eGFR and UACR categories; lowest incidences were seen in patients with an eGFR ≥60 mL/min/1.73 m2 and a UACR 0.10). Conclusions: Compared with placebo, finerenone improved HF-related outcomes in patients with CKD and T2D, with consistent benefits across eGFR and/or UACR categories. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Chronic Kidney Disease [FIGARO-DKD], NCT02545049)

Hyperkalemia Risk with Finerenone: Results from the FIDELIO-DKD Trial

Abstract Background: Finerenone reduced risk of cardiorenal outcomes in patients with CKD and type 2 diabetes in the FIDELIO-DKD trial. We report incidences and risk factors for hyperkalemia with finerenone and placebo in FIDELIO-DKD. Methods: This post hoc safety analysis defined hyperkalemia as ≥mild or ≥moderate based on serum potassium concentrations of >5.5 or >6.0 mmol/L, respectively, assessed at all regular visits. Cumulative incidences of hyperkalemia were based on the Aalen-Johansen estimator using death as competing risk. A multivariate Cox proportional hazards model identified significant independent predictors of hyperkalemia. Restricted cubic splines assessed relationships between short-term post-baseline changes in serum potassium or eGFR and subsequent hyperkalemia risk. During the study, serum potassium levels guided drug dosing. Patients in either group who experienced ≥mild hyperkalemia had the study drug withheld until serum potassium was ≤5.0 mmol/L; then the drug was restarted at the 10 mg daily dose. Placebo-treated patients underwent sham treatment interruption and downtitration. Results: Over 2.6 years' median follow-up, 597 of 2785 (21.4%) and 256 of 2775 (9.2%) patients treated with finerenone and placebo, respectively, experienced treatment-emergent ≥mild hyperkalemia; 126 of 2802 (4.5%) and 38 of 2796 (1.4%) patients, respectively, experienced moderate hyperkalemia. Independent risk factors for ≥mild hyperkalemia were higher serum potassium, lower eGFR, increased urine albumin-creatinine ratio, younger age, female sex, β-blocker use, and finerenone assignment. Diuretic or sodium-glucose cotransporter-2 inhibitor use reduced risk. In both groups, short-term increases in serum potassium and decreases in eGFR were associated with subsequent hyperkalemia. At month 4, the magnitude of increased hyperkalemia risk for any change from baseline was smaller with finerenone than with placebo. Conclusions: Finerenone was independently associated with hyperkalemia. However, routine potassium monitoring and hyperkalemia management strategies employed in FIDELIO-DKD minimized the impact of hyperkalemia, providing a basis for clinical use of finerenone.Bayer AG10.121 JCR (2020) Q1, 6/89 Urology & Nephrology4.451 SJR (2020) Q1, 39/2446 Medicine (miscellaneous)No data IDR 2020UE