Defining sepsis on the wards: results of a multi-centre point-prevalence study comparing two sepsis definitions.

Our aim was to prospectively determine the predictive capabilities of SEPSIS-1 and SEPSIS-3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24-h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS-1 definition, 212 patients had sepsis. When using the SEPSIS-3 definitions with Sequential Organ Failure Assessment (SOFA) score ≥ 2, there were 272 septic patients, whereas with quickSOFA score ≥ 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS-1 criteria had a sensitivity (95%CI) of 65% (54-75%) and specificity of 47% (41-53%); SEPSIS-3 criteria had a sensitivity of 86% (76-92%) and specificity of 32% (27-38%). SEPSIS-3 and SEPSIS-1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5-5.6) and 1.6 (1.3-2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63-0.76)), followed by NEWS (0.58 (0.51-0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49-0.61)) and quickSOFA score (0.56 (0.49-0.64)) could not predict outcome. The SEPSIS-3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis-induced organ dysfunction.

Parkin and mitophagy in cancer.

Mitophagy, the selective engulfment and clearance of mitochondria, is essential for the homeostasis of a healthy network of functioning mitochondria and prevents excessive production of cytotoxic reactive oxygen species from damaged mitochondria. The mitochondrially targeted PTEN-induced kinase-1 (PINK1) and the E3 ubiquitin ligase Parkin are well-established synergistic mediators of the mitophagy of dysfunctional mitochondria. This pathway relies on the ubiquitination of a number of mitochondrial outer membrane substrates and subsequent docking of autophagy receptor proteins to selectively clear mitochondria. There are also alternate Parkin-independent mitophagy pathways mediated by BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 and Nip-3 like protein X as well as other effectors. There is increasing evidence that ablation of mitophagy accelerates a number of pathologies. Familial Parkinsonism is associated with loss-of-function mutations in PINK1 and Parkin. A growing number of studies have observed a correlation between impaired Parkin activity and enhanced cancer development, leading to the emerging concept that Parkin activity, or mitophagy in general, is a tumour suppression mechanism. This review examines the molecular mechanisms of mitophagy and highlights the potential links between Parkin and the hallmarks of cancer that may influence tumour development and progression.

A fresh look at IBS-opportunities for systems medicine approaches.

NeuroGUT is a EU-funded initial training network (ITN) of 14 research projects in neurogastroenterology that have employed an equal number of early-stage researchers. Neurogut trainees have-among other activities-attended an international conference on irritable bowel syndrome (IBS) in Bologna in 2016 and were asked to critically review and evaluate the current knowledge on IBS for their respective research activities, and to state what they were missing. Most appreciated were the topics brain imaging of gut activity, the role of the gut microbiota, the pharmacology of gut functions, the IBS-IBD interrelation, the new Rome IV criteria, the role of gas, and the placebo response in functional disorders. Missed were more detailed coverage of high-resolution manometry, functional brain imaging, advanced "systems medicine" approaches and bioinformatics technology, better sub-classification of IBS patients, and the development of disease biomarkers, extended at the molecular (genetic/epigenetic, proteonomic) level. They summarize that despite excellent specialized research, there is a gap open that should be filled with systems medicine. For this, it would be necessary that medical research learns even more from the data sciences and other basic disciplines, for example, information technology and system biology, and also welcomes a change in paradigm that enhances open sharing of data, information, and resources.

Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease.

In humans, complex I of the respiratory chain is composed of seven mitochondrial DNA (mtDNA)-encoded and 38 nuclear-encoded subunits that assemble together in a process that is poorly defined. To date, only two complex I assembly factors have been identified and how each functions is not clear. Here, we show that the human complex I assembly factor CIA30 (complex I intermediate associated protein) associates with newly translated mtDNA-encoded complex I subunits at early stages in their assembly before dissociating at a later stage. Using antibodies we identified a CIA30-deficient patient who presented with cardioencephalomyopathy and reduced levels and activity of complex I. Genetic analysis revealed the patient had mutations in both alleles of the NDUFAF1 gene that encodes CIA30. Complex I assembly in patient cells was defective at early stages with subunits being degraded. Complementing the deficiency in patient fibroblasts with normal CIA30 using a novel lentiviral system restored steady-state complex I levels. Our results indicate that CIA30 is a crucial component in the early assembly of complex I and mutations in its gene can cause mitochondrial disease.

IgG subclass reactivity to human cardiac myosin in cardiomyopathy patients is indicative of a Th1-like autoimmune disease.

Studies performed in mice together with the demonstration of increased levels of heart-specific autoantibodies, cytokines and cytokine receptors in sera from cardiomyopathy (CMP) patients argued for a pathogenic role of autoimmune mechanisms in CMP. This study was designed to analyse the presence of IgG anti-heart antibodies in sera from patients suffering from hypertrophic and dilatative forms of CMP as well as from patients with ischaemic heart disease and healthy individuals. Patients' sera were analysed for IgG reactivity to Western-blotted extracts prepared from human epithelial and endothelial cells, heart and skeletal muscle specimens as well as from Streptococcus pyogenes. The IgG subclass (IgG1-4) reactivity to purified human cardiac myosin was analysed by ELISA. While sera from CMP patients and healthy individuals displayed comparable IgG reactivity to a variety of human proteins, cardiac myosin represented the prominent antigen detected strongly and preferentially by sera from CMP patients. Pronounced IgG anti-cardiac myosin reactivity was frequently found in sera from patients with dilatative CMP and reduced ventricular function. ELISA analyses revealed a prominent IgG2/IgG3 anti-cardiac myosin reactivity in CMP sera, indicating a preferential Th1-like immune response. Elevated anti-cytomegalovirus, anti-enterovirus IgG titres as well as IgG reactivity to nitrocellulose-blotted S. pyogenes proteins were also frequently observed in the group of CMP patients. If further work can support the hypothesis that autoreactivity to cardiac myosin represents a pathogenic factor in CMP, specific immunomodulation of this Th1- towards a Th2-like immune response may represent a promising therapeutic strategy for CMP.