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Purpose Sepsis is recognized as a global public health problem, but the proportion due to hospital-acquired infections remains unclear. We aimed to summarize the epidemiological evidence related to the burden of hospital-acquired (HA) and ICU-acquired (ICU-A) sepsis. Methods We searched MEDLINE, Embase and the Global Index Medicus from 01/2000 to 03/2018. We included studies conducted hospital-wide or in intensive care units (ICUs), including neonatal units (NICUs), with data on the incidence/prevalence of HA and ICU-A sepsis and the proportion of community and hospital/ICU origin. We did random-effects meta-analyses to obtain pooled estimates; inter-study heterogeneity and risk of bias were assessed. Results Of the 13,239 studies identified, 51 met the inclusion criteria; 22 were from low- and middle-income countries. Twenty-eight studies were conducted in ICUs, 13 in NICUs, and ten hospital-wide. The proportion of HA sepsis among all hospital-treated sepsis cases was 23.6% (95% CI 17-31.8%, range 16-36.4%). In the ICU, 24.4% (95% CI 16.7-34.2%, range 10.3-42.5%) of cases of sepsis with organ dysfunction were acquired during ICU stay and 48.7% (95% CI 38.3-59.3%, range 18.7-69.4%) had a hospital origin. The pooled hospital incidence of HA sepsis with organ dysfunction per 1000 patients was 9.3 (95% CI 7.3-11.9, range 2-20.6)). In the ICU, the pooled incidence of HA sepsis with organ dysfunction per 1000 patients was 56.5 (95% CI 35-90.2, range 9.2-254.4) and it was particularly high in NICUs. Mortality of ICU patients with HA sepsis with organ dysfunction was 52.3% (95% CI 43.4-61.1%, range 30.1-64.6%). There was a significant inter-study heterogeneity. Risk of bias was low to moderate in ICU-based studies and moderate to high in hospital-wide and NICU studies. Conclusion HA sepsis is of major public health importance, and the burden is particularly high in ICUs. There is an urgent need to improve the implementation of global and local infection prevention and management strategies to reduce its high burden among hospitalized patients., Author(s): Robby Markwart [sup.1], Hiroki Saito [sup.2] [sup.3], Thomas Harder [sup.1], Sara Tomczyk [sup.1], Alessandro Cassini [sup.2], Carolin Fleischmann-Struzek [sup.4], Felix Reichert [sup.1] [sup.5] [sup.6], Tim Eckmanns [sup.1], Benedetta Allegranzi [...]

RasGTPases undergo post-translationalmodifications that govern their subcellular trafficking and localization. In particular, palmitoylation of the Golgi tags N-Ras and H-Ras for exocytotic transport and residency at the PM (plasma membrane). Following depalmitoylation, PM-Ras redistributes to all subcellular membranes causing an accumulation of palmitate-free Ras at endomembranes, including the Golgi and endoplasmic reticulum. Palmitoylation is unanimously regarded as a critical modification at the crossroads of Ras activity and trafficking control, but its precise relevance to native wild-type Ras function in growth factor signalling is unknown. We show in the present study by use of palmitoylation-deficient N-Ras mutants and via the analysis of palmitate content of agonist-activated GTP-loaded N-Ras that only palmitoylated N-Ras becomes activated by agonists. In line with an essential role of palmitoylation in Ras activation, dominant-negative RasS17N loses its blocking potency if rendered devoid of palmitoylation. Live-cell Ras- GTP imaging shows that N-Ras activation proceeds only at the PM, consistent with activated N-Ras-GTP being palmitoylated. Finally, palmitoylation-deficient N-Ras does not sustain EGF (epidermal growth factor) or serum-elicited mitogenic signalling, confirming that palmitoylation is essential for signal transduction by N-Ras. These findings document that N-Ras activation proceeds at the PM and suggest that depalmitoylation, by removing Ras from the PM, may contribute to the shutdown of Ras signalling. [ABSTRACT FROM AUTHOR]

Background: Point-of-care tests (POCTs) for C-reactive protein can support clinical decision-making of general practitioners (GPs) but are not widely used in German general practices., Aim: To investigate the utilization of semi-quantitative CRP-POCTs in routine primary care., Design & Setting: Prospective observational study in 49 general practices in Germany (Nov/2022 to Apr/2023)., Method: GPs were provided with CRP-POCTs and collected data for each CRP-POCT use using standardized data collection sheets., Results: Data from 1,740 CRP-POCT uses were recorded. GPs employed CRP-POCTs mainly for patients with respiratory tract infections (RTIs, 70.9% of all cases) and to a lesser extent for gastrointestinal infections (GIs, 10.3%). In RTIs, CRP-POCTs were frequently used to distinguish between bacterial and viral aetiology (60.8%) and to guide decisions on antibiotic prescribing (62.8%). In GIs, CRP-POCTs were mainly used to rule out severe disease progressions (53.2%) and for decisions on further diagnostic procedures (45.6%). In RTIs, CRP-POCTs influenced antibiotic prescribing in 77.5 % of the cases (32.3% in favour vs . 45.2% waiver). In GIs, CRP levels mainly affected decisions on further diagnostic procedures. GPs reported that CRP-POCTs were helpful in 88.6% of all cases., Conclusions: When available, German GPs predominantly use semi-quantitative CRP-POCTs to guide decisions on antibiotic prescribing in patients with RTI. CRP-POCT use improves clinical decision-making and increases the GPs' clinical confidence., (Copyright © 2024, The Authors.)

Receptor tyrosine kinases participate in several signaling pathways through small G proteins such as Ras (rat sarcoma). An important component in the activation of these G proteins is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras. For optimal activity, a second Ras molecule acts as an allosteric activator by binding to a second Ras-binding site within SOS. This allosteric Ras-binding site is blocked by autoinhibitory domains of SOS. We have reported recently that Ras activation also requires the actin-binding proteins ezrin, radixin, and moesin. Here we report the mechanism by which ezrin modulates SOS activity and thereby Ras activation. Active ezrin enhances Ras/MAPK signaling and interacts with both SOS and Ras in vivo and in vitro. Moreover, in vitro kinetic assays with recombinant proteins show that ezrin also is important for the activity of SOS itself. Ezrin interacts with GDP-Ras and with the Dbl homology (DH)/pleckstrin homology (PH) domains of SOS, bringing GDP-Ras to the proximity of the allosteric site of SOS. These actions of ezrin are antagonized by the neurofibromatosis type 2 tumor-suppressor protein merlin. We propose an additional essential step in SOS/Ras control that is relevant for human cancer as well as all physiological processes involving Ras.