Molecular Dynamics for Fermions

The time-dependent variational principle for many-body trial states is used to discuss the relation between the approaches of different molecular dynamics models to describe indistinguishable fermions. Early attempts to include effects of the Pauli principle by means of nonlocal potentials as well as more recent models which work with antisymmetrized many-body states are reviewed under these premises. Keywords: Many-body theory; Fermion system; Molecular dynamics; Wave-packet dynamics; Time-dependent variational principle; Statistical properties; Canonical ensemble; Ergodicity; Time averagingComment: 97 pages, 13 postscript figures. To be published in July 2000 issue of Reviews of Modern Physics. More information at http://www-aix.gsi.de/~fmd

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Results from an Observational Trial: Digital Epiluminescence Microscopy Follow-Up of Atypical Nevi Increases the Sensitivity and the Chance of Success of Conventional Dermoscopy in Detecting Melanoma

We analyzed the value of digital epiluminescence microscopy (DELM) for the long-term follow-up of atypical nevi. Patients (n=530) were prospectively categorized into defined melanoma risk groups and followed by clinical and epiluminescence microscopy (ELM) examinations. Atypical nevi (n=7001) were additionally followed by DELM. During follow-up (median 32.2 months), we detected 53 melanomas among 637 excised lesions (8.3% overall chance of success). The chance of success for melanoma detection among lesions suspicious by ELM criteria was increased to 17% when additional DELM-documented changes were present. Moreover, 18 of the 53 melanomas were exclusively identified by DELM-documented changes, indicating that DELM increased the sensitivity of the ELM analysis by identifying additional melanomas. However, for lesions exclusively excised due to DELM changes, the chance of success was lower than for ELM (5.2 vs 11.8%). Excisions due to mere DELM changes detected 66.7% of melanomas in familial atypical mole and multiple melanoma (FAMMM) and 32.5% of melanomas in atypical mole syndrome (AMS) patients. We conclude that DELM is a valuable tool for the long-term follow-up of atypical nevi, especially in the high-risk groups of FAMMM and AMS patients. Randomized controlled trials are needed to validate the data from this clinical trial

Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma

In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value  = 0.05). Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value  = 0.003) following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis