Entwicklung einer Diagnose-Shell zur Unterstützung von Informationssystemsicherheit

Im Rahmen der Arbeit wurde ein Expertisemodell des Managements der Informationssystemsicherheit (IS-Sicherheit) entwickelt und durch eine Diagnose-Shell operationalisiert. Es stand die Wissensrepräsentation und nutzung des IS-Sicherheitswissens zur Unterstützung des IS-Sicherheitsmanagements im Mittelpunkt. Hierfür wurden Methoden des Knowledge Engineering verwendet, um die IS-Sicherheitsstrategien durch diagnostische Problemlösungsmethoden zu beschreiben. Das benötigte IS-Sicherheitswissen wird durch IS-Sicherheitskonzepte repräsentiert. Die Modelle sind auf unterschiedlichen Abstraktionsstufen entwickelt worden, die zu einem epistemologischen Expertisemodell zusammengefasst worden sind. Es werden die drei Ebenen (Aufgaben-, Inferenz- und Domänen-Ebene) des Expertisemodells beschrieben und abgegrenzt. Die Aufgaben- und Inferenzebene beschreiben die Problemlösungsmethoden. Hierfür spezifiziert die Aufgabenebene das Ziel der Diagnose und deren Teilaufgaben. Es werden auf dieser Ebene generische Kontrollstrukturen bzw. Basis-Inferenzen (z.B. eines diagnostischen Problemlösungsprozesses) beschrieben. Eine Verfeinerung der Aufgabenebene bildet die Inferenzebene, die die Abhängigkeit zwischen Inferenzen und Wissens-Rollen darstellt. In der Domänenebene wird das domänenspezifische Wissen (z.B. das Sicherheitswissen) beschrieben, das zur konkreten Problemlösung (z.B. Schwachstellenanalyse oder Risikoanalyse) benötigt wird. Für die Problemlösung werden die Konzepte der Domänenebene, wie z.B. Schwachstellen oder Gefahren, auf die Wissens-Rollen der Problemlösungsmethoden überführt. Es wurde ein Entwurfsmodell für einen wissensbasierten Fragenkatalog entwickelt, das das Expertisemodell operationalisiert und die Grundlage für die spätere Implementierung darstellt. Hierfür werden die konventionellen, computergestützten Fragenkataloge durch eine wissensbasierte Regel-Komponente erweitert, die eine explizite Repräsentation von Abhängigkeitskonzepten ermöglicht. Darauf basierend wurde ein wissensbasierter Diagnose-Prototyp implementiert, der eine direkte Wissenseingabe und nutzung durch einen IS-Sicherheitsexperten unterstützt. Das wissensbasierte System kann auf Basis der Erhebung eine spezifische Problemlösung durchführen und automatisiert ein IS-Sicherheitskonzept erstellen

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BackgroundHistologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.MethodsThis was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.FindingsOf 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.InterpretationSimple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases

Increased HEV seroprevalence in patients with autoimmune hepatitis.

BACKGROUND: Hepatitis E virus (HEV) infection takes a clinically silent, self-limited course in the far majority of cases. Chronic hepatitis E has been reported in some cohorts of immunocompromised individuals. The role of HEV infections in patients with autoimmune hepatitis (AIH) is unknown. METHODS: 969 individuals were tested for anti-HEV antibodies (MP-diagnostics) including 208 patients with AIH, 537 healthy controls, 114 patients with another autoimmune disease, rheumatoid arthritis (RA), and 109 patients with chronic HCV- or HBV-infection (HBV/HCV). Patients with AIH, RA and HBV/HCV were tested for HEV RNA. HEV-specific proliferative T cell responses were investigated using CFSE staining and in vitro stimulation of PBMC with overlapping HEV peptides. RESULTS: HEV-antibodies tested more frequently positive in patients with AIH (n = 16; 7.7%) than in healthy controls (n = 11; 2.0%; p = 0.0002), patients with RA (n = 4; 3.5%; p = 0.13) or patients with HBV/HCV infection (n = 2; 2.8%; p = 0.03). HEV-specific T cell responses could be detected in all anti-HEV-positive AIH patients. One AIH patient receiving immunosuppression with cyclosporin and prednisolone and elevated ALT levels had acute hepatitis E but HEV viremia resolved after reducing immunosuppressive medication. None of the RA or HBV/HCV patients tested HEV RNA positive. CONCLUSIONS: Patients with autoimmune hepatitis but not RA or HBV/HCV patients are more likely to test anti-HEV positive. HEV infection should been ruled out before the diagnosis of AIH is made. Testing for HEV RNA is also recommended in AIH patients not responding to immunosuppressive therapy

5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity

Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed

Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity: Validation of the Target and Identification of Novel Series

Obesity is a major risk factor for the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. Several pieces of evidence, including data in primates, have demonstrated the beneficial effects of histamine-3 receptor (H 3 R) inverse agonists in the regulation of food intake and body weight. A pharmacophore model based on selected published H 3 R ligands and validated by previ- ous investigations, was used to identify the 5-oxy-2-carboxamide-indole core as a novel series of H 3 R inverse agonists. Extensive structure-activity relationship (SAR) investigations were rewarded by the identification of several compounds reversing ( R )- α -methyl-histamine-induced water intake increase and reducing food intake/ body weight in rodent models of obesity. Among those compounds, (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5- (1-isopropyl-piperidin-4-yloxy)-1 H -indol-2-yl]-methanone, selected as a lead compound, was exhibiting a prom- ising profile, including excellent pharmacokinetic properties, good in vitro safety profile and high efficacy in a chronic rodent model of obesity

Prevalence of HEV antibodies and HEV-RNA in different patient groups.

<p>p-values for comparison with AIH patients:</p>*<p>p<0.05;</p>**<p>p-values<0.01.</p

Histology of an autoimmune hepatitis patient with acute HEV infection.

<p>(H.E. stain, original magnification 200×).</p

Machine Learning for Health: Algorithm Auditing & Quality Control.

Developers proposing new machine learning for health (ML4H) tools often pledge to match or even surpass the performance of existing tools, yet the reality is usually more complicated. Reliable deployment of ML4H to the real world is challenging as examples from diabetic retinopathy or Covid-19 screening show. We envision an integrated framework of algorithm auditing and quality control that provides a path towards the effective and reliable application of ML systems in healthcare. In this editorial, we give a summary of ongoing work towards that vision and announce a call for participation to the special issue  Machine Learning for Health: Algorithm Auditing & Quality Control in this journal to advance the practice of ML4H auditing