Costs and resource utilization patterns in surgical site infections: a pre-COVID-19 perspective from France, Germany, Spain, and the UK.

BACKGROUND: Surgical site infections (SSIs), mainly caused by Staphylococcus aureus, pose a significant economic burden in Europe, leading to increased hospitalization duration, mortality, and treatment costs, particularly with drug-resistant strains such as meticillin-resistant S. aureus. AIM: To conduct a case-control study on the economic impact of S. aureus SSI in adult surgical patients across high-volume centres in France, Germany, Spain, and the UK, aiming to assess the overall and procedure-specific burden across Europe. METHODS: The SALT study is a multinational, retrospective cohort study with a nested case-control analysis focused on S. aureus SSI in Europe. The study included participants from France, Germany, Italy, Spain, and the UK who underwent invasive surgery in 2016 and employed a micro-costing approach to evaluate health economic factors, matching S. aureus SSI cases with controls. FINDINGS: In 2016, among 178,904 surgical patients in five European countries, 764 developed S. aureus SSI. Matching 744 cases to controls, the study revealed that S. aureus SSI cases incurred higher immediate hospitalization costs (€8,810), compared to controls (€6,032). Additionally, S. aureus SSI cases exhibited increased costs for readmissions within the first year post surgery (€7,961.6 versus €5,298.6), with significant differences observed. Factors associated with increased surgery-related costs included the cost of hospitalization immediately after surgery, first intensive care unit (ICU) admission within 12 months, and hospital readmission within 12 months, as identified through multivariable analysis. CONCLUSION: The higher rates of hospitalization, ICU admissions, and readmissions among S. aureus SSI cases highlight the severity of these infections and their impact on healthcare costs, emphasizing the potential benefits of evidence-based infection control measures and improved patient care to mitigate the economic burden.

Increases in Future AR Count and Size: Overview of the ARTMIP Tier 2 CMIP5/6 Experiment.

The Atmospheric River (AR) Tracking Method Intercomparison Project (ARTMIP) is a community effort to systematically assess how the uncertainties from AR detectors (ARDTs) impact our scientific understanding of ARs. This study describes the ARTMIP Tier 2 experimental design and initial results using the Coupled Model Intercomparison Project (CMIP) Phases 5 and 6 multi-model ensembles. We show that AR statistics from a given ARDT in CMIP5/6 historical simulations compare remarkably well with the MERRA-2 reanalysis. In CMIP5/6 future simulations, most ARDTs project a global increase in AR frequency, counts, and sizes, especially along the western coastlines of the Pacific and Atlantic oceans. We find that the choice of ARDT is the dominant contributor to the uncertainty in projected AR frequency when compared with model choice. These results imply that new projects investigating future changes in ARs should explicitly consider ARDT uncertainty as a core part of the experimental design.

Curcumin combined with exposure to visible light blocks bladder cancer cell adhesion and migration by an integrin dependent mechanism.

OBJECTIVE: Although the natural compound curcumin exerts antitumor properties in vitro, its clinical application is hampered due to rapid metabolism. Light exposure following curcumin application has been demonstrated to improve curcumin's bioavailability. Therefore, this investigation was directed towards evaluating whether light exposure in addition to curcumin application enhances curcumin's efficacy against bladder cancer cell adhesion and migration. MATERIALS AND METHODS: RT112, UMUC3, and TCCSUP cells were incubated with low curcumin concentrations (0.1-0.4 µg/ml) and then exposed to 1.65 J/cm2 visible light for 5 min. Controls remained untreated or were treated with curcumin or light alone. Cell adhesion to Human umbilical vein endothelial cells (HUVECs), to immobilized collagen or fibronectin and chemotactic behavior, integrin α and ß receptor expression with functional relevance, as well as focal adhesion kinase (total and phosphorylated FAK) were evaluated. RESULTS: Curcumin plus light, but neither curcumin nor light alone, significantly altered tumor cell adhesion and suppressed chemotaxis. Integrin α and ß subtypes were dissimilarly modified, depending on the cell line. Suppression of pFAK was noted in RT112 and UMUC3, but not in TCCSUP cells. The integrins α3, α5, and ß1 were involved in curcumin's regulation of adhesion and migration. Blocking studies revealed α3, α5, and ß1 to be associated with TCCSUP adhesion and migration, whereas α5 and ß1, but not α3 contributed to UMUC3 adhesion and migration. Integrin α5 and ß1 controlled RT112 chemotaxis as well, but only α5 was involved in the RT112 adhesion process. CONCLUSIONS: Combining curcumin with light exposure enhances curcumin's anti-tumor potential.

Localized increases in corticotropin-releasing factor receptors in pulp after dental injury.

Corticotropin-releasing factor (CRF) binds to membrane-bound CRF receptors (CRF-Rs). Among the actions mediated by activated CRF-Rs is beta-endorphin (END) release from immune cells, increasing peripheral antinociception. For assessment of inflammatory regulation of CRF-R expression, rats underwent pulp exposure of left, first mandibular molars and recovered for 6 days. Control pulpal tissue consisted of contralateral, uninjured molars and left, first mandibular molars of uninjured animals. Pulp tissue specimens were incubated with antibodies directed against CRF-R (both isoforms), neurofilament, CD45, and END. We observed (1) increases in pulp CRF-R immunoreactivity after injury, (2) increased CRF-R immunoreactivity expressed in 3 distinct zones in relation to the injury, and (3) increased CD45 and END immunoreactivity in regions surrounding the pulpal abscess. CRF-Rs might provide an additional target for novel analgesics to treat pulpal pain.

A site-directed spin-labeling study of ligand-induced conformational change in the ferric enterobactin receptor, FepA.

The ferric enterobactin receptor, FepA, is a TonB-dependent gated porin that transports the siderophore ferric enterobactin across the outer membrane of gram-negative bacteria. We have created two site-directed mutants of Escherichia coli FepA, in both cases introducing a cysteine residue into the putative ligand-binding domain. The introduced cysteines were then modified with nitroxide spin labels for structural and dynamic studies using electron spin resonance (ESR) spectroscopy. The mutants were fully functional, as indicated by their ability to grow under iron-limiting conditions, their uptake of [59Fe]enterobactin, and their sensitivity to colicin B. Labeling of the mutant FepA receptors proceeded easily upon incubation with sulfhydryl-specific spin labels, e.g. MTSL, (1-oxy-2,2,5,5-tetramethylpyrrolidin-3-yl)methyl methanethiosulfonate. In contrast, spin labeling of the two native cysteines (Cys486 and Cys493) within wild-type FepA occurred only after treatment with a thiol reducing agent and partial denaturation in urea, suggesting that the native cysteines are disulfide-linked. ESR spectra showed a high degree of motional restriction for all three sites. Continuous wave (CW) saturation studies indicated that one of the mutationally introduced sites (Cys280) was surface-localized as evidenced by its exposure to the aqueous paramagnetic relaxation agent chromium oxalate and its low accessibility to O2. The other (Cys310) apparently occupies a site near the membrane/aqueous interface. The native cysteines occupy a site tightly packed within the protein structure with low accessibility to both CROX and O2. A shift in both conventional and saturation-transfer ESR spectra of MTSL-labeled E280C and E310C (but not MTSL-labeled wild type) FepA was observed upon addition of ferric enterobactin. The ESR spectral shift was dependent on ferric enterobactin concentration and did not occur with siderophores not recognized by FepA. Ferric enterobactin binding did not alter the CW saturation properties of MTSL bound to these sites, but did influence their accessibility to O2. These results provide consistent evidence for a ligand-specific conformational change in the surface peptides of FepA upon the binding of ferric enterobactin.

Mechanisms of TonB-catalyzed iron transport through the enteric bacterial cell envelope.

The recent solution of enteric bacterial porin structure, and new insights into the mechanism by which outer membrane receptor proteins recognize and internalize specific ligands, advocates the re-evaluation of TonB-dependent transport physiology. In this minireview we discuss the potential structural features of siderophore receptors and TonB, and use this analysis to evaluate both existing and new models of energy and signal transduction from the inner membrane to the outer membrane of gram-negative bacteria.

Permeability properties of a large gated channel within the ferric enterobactin receptor, FepA.

FepA is an Escherichia coli outer membrane receptor protein for the siderophore ferric enterobactin. Prior studies conducted in vivo suggested that FepA and other TonB-dependent outer membrane proteins transport ligands by a gated-channel mechanism. To corroborate and extend these findings we have determined the permeability properties of the FepA channel in vitro, by measuring the diffusion rates of hydrophilic nonelectrolytes through the FepA channel in liposome swelling experiments. Like porins, the FepA deletion mutant delta RV showed a size-dependent permeability to oligosaccharides, indicating that it forms a nonspecific, hydrophilic pore. Unlike OmpF and other E. coli porins, however, delta RV proteoliposomes transported stachyose (666 Da) and ferrichrome (740 Da). These data, and other uptake results with a series of maltodextrins of increasing size, confirm the existence of a channel domain within FepA that is considerably larger than OmpF-type pores. These results represent a reconstitution of the channel function of a TonB-dependent receptor protein and establish that FepA contains the largest channel that has been characterized in the E. coli outer membrane.

Formation of a gated channel by a ligand-specific transport protein in the bacterial outer membrane.

The ferric enterobactin receptor (FepA) is a high-affinity ligand-specific transport protein in the outer membrane of Gram-negative bacteria. Deletion of the cell-surface ligand-binding peptides of FepA generated mutant proteins that were incapable of high-affinity uptake but that instead formed nonspecific, passive channels in the outer membrane. Unlike native FepA, these pores acted independently of the accessory protein TonB, which suggests that FepA is a gated porin and that TonB acts as its gatekeeper by facilitating the entry of ligands into the FepA channel. The sequence homology among TonB-dependent proteins suggests that all ligand-specific outer membrane receptors may function by this gated-porin mechanism.

Evolution of the ferric enterobactin receptor in gram-negative bacteria.

Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis of iron-deficient and replete cell envelopes, 59Fe-siderophore uptake studies, and Western immunoblots and cytofluorimetric analyses with monoclonal antibodies (MAbs), we surveyed a panel of gram-negative bacteria to identify outer membrane proteins that are structurally related to the Escherichia coli K-12 ferric enterobactin receptor, FepA. Antibodies within the panel identified FepA epitopes that are conserved among the majority of the bacteria tested, as well as epitopes present in only a few of the strains. In general, epitopes of FepA that are buried in the outer membrane bilayer were more conserved among gram-negative bacteria than epitopes that are exposed on the bacterial cell surface. The surface topology and tertiary structure of FepA are quite similar in E. coli and Shigella flexneri but differ in Salmonella typhimurium. Of the 18 different genera tested, 94% of the bacteria transported ferric enterobactin, including members of the previously unrecognized genera Citrobacter, Edwardsiella, Enterobacter, Haemophilus, Hafnia, Morganella, Neisseria, Proteus, Providencia, Serratia, and Yersinia. The ferric enterobactin receptor contains at least one buried epitope, recognized by MAb 2 (C. K. Murphy, V. I. Kalve, and P. E. Klebba, J. Bacteriol. 172:2736-2746, 1990), that is conserved within the structure of an iron-regulated cell envelope protein in all the bacteria that we have surveyed. With MAb 2, we identified and determined the Mr of cell envelope antigens that are immunologically related to E. coli FepA in all the gram-negative bacteria tested. Collectively, the library of anti-FepA MAbs showed unique patterns of reactivity with the different bacteria, allowing identification and discrimination of species within the following gram-negative genera: Aeromonas, Citrobacter, Edwardsiella, Enterobacter, Escherichia, Haemophilus, Hafnia, Klebsiella, Morganella, Neisseria, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Vibrio, and Yersinia.