Stoßwechselwirkungen in einem kalten Gas metastabiler Neonatome

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Development and validation of risk-adjusted quality indicators for the long-term outcome of acute sepsis care in German hospitals based on health claims data

Background Methods for assessing long-term outcome quality of acute care for sepsis are lacking. We investigated a method for measuring long-term outcome quality based on health claims data in Germany. Materials and methods Analyses were based on data of the largest German health insurer, covering 32% of the population. Cases (aged 15 years and older) with ICD-10-codes for severe sepsis or septic shock according to sepsis-1-definitions hospitalized in 2014 were included. Short-term outcome was assessed by 90-day mortality; long-term outcome was assessed by a composite endpoint defined by 1-year mortality or increased dependency on chronic care. Risk factors were identified by logistic regressions with backward selection. Hierarchical generalized linear models were used to correct for clustering of cases in hospitals. Predictive validity of the models was assessed by internal validation using bootstrap-sampling. Risk-standardized mortality rates (RSMR) were calculated with and without reliability adjustment and their univariate and bivariate distributions were described. Results Among 35,552 included patients, 53.2% died within 90 days after admission; 39.8% of 90-day survivors died within the first year or had an increased dependency on chronic care. Both risk-models showed a sufficient predictive validity regarding discrimination [ AUC = 0.748 (95% CI: 0.742; 0.752) for 90-day mortality; AUC = 0.675 (95% CI: 0.665; 0.685) for the 1-year composite outcome, respectively], calibration (Brier Score of 0.203 and 0.220; calibration slope of 1.094 and 0.978), and explained variance ( R 2 = 0.242 and R 2 = 0.111). Because of a small case-volume per hospital, applying reliability adjustment to the RSMR led to a great decrease in variability across hospitals [from median (1st quartile, 3rd quartile) 54.2% (44.3%, 65.5%) to 53.2% (50.7%, 55.9%) for 90-day mortality; from 39.2% (27.8%, 51.1%) to 39.9% (39.5%, 40.4%) for the 1-year composite endpoint]. There was no substantial correlation between the two endpoints at hospital level (observed rates: ρ = 0, p = 0.99; RSMR: ρ = 0.017, p = 0.56; reliability-adjusted RSMR: ρ = 0.067; p = 0.026). Conclusion Quality assurance and epidemiological surveillance of sepsis care should include indicators of long-term mortality and morbidity. Claims-based risk-adjustment models for quality indicators of acute sepsis care showed satisfactory predictive validity. To increase reliability of measurement, data sources should cover the full population and hospitals need to improve ICD-10-coding of sepsis

Occurrence and Risk Factors for New Dependency on Chronic Care, Respiratory Support, Dialysis and Mortality in the First Year After Sepsis

Sepsis survival is associated with adverse outcomes. Knowledge about risk factors for adverse outcomes is lacking. We performed a population-based cohort study of 116,507 survivors of hospital-treated sepsis identified in health claims data of a German health insurance provider. We determined the development and risk factors for long-term adverse events: new dependency on chronic care, chronic dialysis, long-term respiratory support, and 12-month mortality. At-risk patients were defined by absence of these conditions prior to sepsis. Risk factors were identified using simple and multivariable logistic regression analyses. In the first year post-sepsis, 48.9% (56,957) of survivors had one or more adverse outcome, including new dependency on chronic care (31.9%), dialysis (2.8%) or respiratory support (1.6%), and death (30.7%). While pre-existing comorbidities adversely affected all studied outcomes (>4 comorbidities: OR 3.2 for chronic care, OR 4.9 for dialysis, OR 2.7 for respiratory support, OR 4.7 for 12-month mortality), increased age increased the odds for chronic care dependency and 12-month mortality, but not for dialysis or respiratory support. Hospital-acquired and multi-resistant infections were associated with increased risk of chronic care dependency, dialysis, and 12-month mortality. Multi-resistant infections also increased the odds of respiratory support. Urinary or respiratory infections or organ dysfunction increased the odds of new dialysis or respiratory support, respectively. Central nervous system infection and organ dysfunction had the highest OR for chronic care dependency among all infections and organ dysfunctions. Our results imply that patient- and infection-related factors have a differential impact on adverse life changing outcomes after sepsis. There is an urgent need for targeted interventions to reduce the risk

Entry of Human Papillomavirus Type 16 by Actin-Dependent, Clathrin- and Lipid Raft-Independent Endocytosis

Infectious endocytosis of incoming human papillomavirus type 16 (HPV-16), the main etiological agent of cervical cancer, is poorly characterized in terms of cellular requirements and pathways. Conflicting reports attribute HPV-16 entry to clathrin-dependent and -independent mechanisms. To comprehensively describe the cell biological features of HPV-16 entry into human epithelial cells, we compared HPV-16 pseudovirion (PsV) infection in the context of cell perturbations (drug inhibition, siRNA silencing, overexpression of dominant mutants) to five other viruses (influenza A virus, Semliki Forest virus, simian virus 40, vesicular stomatitis virus, and vaccinia virus) with defined endocytic requirements. Our analysis included infection data, i.e. GFP expression after plasmid delivery by HPV-16 PsV, and endocytosis assays in combination with electron, immunofluorescence, and video microscopy. The results indicated that HPV-16 entry into HeLa and HaCaT cells was clathrin-, caveolin-, cholesterol- and dynamin-independent. The virus made use of a potentially novel ligand-induced endocytic pathway related to macropinocytosis. This pathway was distinct from classical macropinocytosis in regards to vesicle size, cholesterol-sensitivity, and GTPase requirements, but similar in respect to the need for tyrosine kinase signaling, actin dynamics, Na+/H+ exchangers, PAK-1 and PKC. After internalization the virus was transported to late endosomes and/or endolysosomes, and activated through exposure to low pH

Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation

Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and adiposity and is a drug target for the treatment of obesity and diabetes. Here we identify pyruvate kinase M2 (PKM2) as a novel PTP1B substrate in adipocytes. PTP1B deficiency leads to increased PKM2 total tyrosine and Tyr(105) phosphorylation in cultured adipocytes and in vivo. Substrate trapping and mutagenesis studies identify PKM2 Tyr-105 and Tyr-148 as key sites that mediate PTP1B-PKM2 interaction. In addition, in vitro analyses illustrate a direct effect of Tyr-105 phosphorylation on PKM2 activity in adipocytes. Importantly, PTP1B pharmacological inhibition increased PKM2 Tyr-105 phosphorylation and decreased PKM2 activity. Moreover, PKM2 Tyr-105 phosphorylation is regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, decreased PKM2 Tyr-105 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Together, these findings identify PKM2 as a novel substrate of PTP1B and provide new insights into the regulation of adipose PKM2 activity