Ultrasonic chemical synthesis of zinc-manganese ferrites with improved magnetic properties.

Zinc-Manganese spinel ferrites (Zn1-xMnxFe2O4) are nowadays very attractive magnetic materials for cancer diagnostic and therapy. With the help of intense ultrasonic waves, sonochemical synthesis method was used to prepare stoichiometric and chemically homogenous nanoparticles by varying the manganese content. The crystal structure along with the size and shape of the as-prepared nanoparticles were described using XRD, TEM and FT-IR techniques, while cations distribution was carefully investigated using XPS and Mössbauer spectroscopic techniques and supported with density functional theory calculations. The crystal structure study revealed the presence of a pure single cubic spinel phase, where the unit-cell and the size were observed to decrease as the manganese incorporation was increased with clear indication of cationic redistribution and degree of inversion variations. Due to the very small variation of the total energy between different configurations, the probability of formation of a mixed phase was found to be very high in such a way that the more mixed was the phase, the more stable it was. A relevant fact was the noticed quasi-systematic ionic exchange made possible by the very short reaction times and high energy offered by the ultrasonic waves. For manganese concentrations up to 60%, the systematic ionic process started by incorporating manganese ions into octahedral sites and pushing iron ions to migrate and replace those of zinc in tetrahedral sites. Such an ionic movement was of central importance for the improvement of the magnetic properties due to the establishment of super-exchange interactions. Such an ionic engineering should definitely open the way to promising applications in biomedical imaging.

The two major splice variants of scavenger receptor BI differ by their interactions with lipoproteins and cellular localization in endothelial cells.

The scavenger receptor SR-BI facilitates the transport of both HDL and LDL through endothelial cells. Its two splice variants, SR-BIvar1 and SR-BIvar2, differ in their carboxyterminal domains. Only the one of SR-BIvar1 contains the putative binding sites for the adapter proteins PDZK1 and DOCK4, which limit the cell surface abundance and internalization of the receptor. To investigate the cellular localization of the SR-BI variants and their interaction with lipoproteins in endothelial cells, EA.hy926 cells were stably transfected with vectors encoding untagged, GFP- or mCherry-tagged constructs of the two SR-BI variants. Additionally, the cells were transfected with shRNAs against PDZK1 or DOCK4. Microscopy investigation showed that SR-BIvar1 was predominantly localized on the cell surface together with clathrin whereas SR-BIvar2 was absent from the cell surface but retrieved in endosomes and lysosomes. Accordingly, only SR-BIvar1 increased lipoprotein binding to endothelial while HDL and LDL uptake were enhanced by both variants. Silencing of PDZK1 or DOCK3 only reduced HDL association in SR-BIvar2 overexpressing cells while LDL association was reduced both in wild type and SR-BIvar2 overexpressing cells. In conclusion, either SR-BI variant facilitates the uptake of HDL and LDL into endothelial cells, however by different mechanisms and trafficking routes. This dual role may explain why the loss of DOCK4 or PDZK1 differently affects the uptake of HDL and LDL in different endothelial cells.

Modeling human atherosclerotic lesions in the test tube: Are we there yet?

Atherosclerotic cardiovascular diseases remain a leading cause of morbidity and mortality worldwide. Atherogenesis is a slow and life-long process characterized by the accumulation of lipoproteins and immune cells within the arterial wall. Atherosclerosis has been successfully modeled in animals: However, there are economic, ethical, and translational concerns when using these models. There is also growing recognition of the need for robust human-based in vitro systems that can faithfully recapitulate key aspects of human atherosclerosis. Such systems may offer advantages in terms of scalability, reproducibility, and ability to manipulate specific variables, thereby facilitating a deeper understanding of disease mechanisms and accelerating the development of targeted therapeutics. Leveraging innovative in vitro platforms holds promise in complementing traditional animal models of atherosclerosis. In the present review, we discuss the advantages and disadvantages of recently developed models of atherosclerosis and propose ideas to be considered when developing future generations of models.

Diagnosis and treatment of bacterial peritonitis in patients with gastrointestinal cancer: an observational multicenter study.

Background: Bacterial peritonitis (BP) in patients with gastrointestinal (GI) cancer has been poorly described, and its prevalence is unknown. Objectives: This study aimed to evaluate in patients with both GI cancer and ascites the prevalence of BP, associated features, mechanisms, prognosis, and the diagnostic performance of neutrophil count in ascites. Design: A retrospective, multicenter, observational study. Methods: All patients with GI cancer and ascites who underwent at least one paracentesis sample analyzed for bacteriology over a 1-year period were included. BP was defined by a positive ascites culture combined with clinical and/or biological signs compatible with infection. Secondary BP was defined as BP related to a direct intra-abdominal infectious source. Results: Five hundred fifty-seven ascites from 208 patients included were analyzed. Twenty-eight patients had at least one episode of BP and the annual prevalence rate of BP was 14%. Among the 28 patients with BP, 19 (65%) patients had proven secondary BP and 17 (59%) patients had multi-microbial BP, mainly due to Enterobacterales. A neutrophil count greater than 110/mm3 in ascites had negative and positive predictive values of 96% and 39%, respectively, for the diagnosis of BP. The median survival of patients with BP was 10 days (interquartile range 6-40) after the diagnosis. Conclusion: BP is not rare in patients with GI cancer and is associated with a poor short-term prognosis. When a patient with GI cancer is diagnosed with BP, a secondary cause should be sought. Further studies are needed to better define the best management of these patients.

[Advances in antibiotic therapy for tuberculosis]. / Avancées dans l'antibiothérapie de la tuberculose.

ADVANCES IN ANTIBIOTIC THERAPY FOR TUBERCULOSIS. Treatment of tuberculosis is experiencing significant advancements. For the first time, a therapeutic regimen based on rifapentine and moxifloxacin allows for a reduction of treatment duration of drug-susceptible tuberculosis from 6 to 4 months. Regarding multidrug-resistant tuberculosis, combinations of new antituberculosis drugs (bedaquiline, linezolid, delamanid/pretomanid, moxifloxacin) have the potential to reduce the treatment duration from 20 to 6 months. Additionally, considering the extent of anatomical involvement and bacterial burden allows for strategies that involve variable treatment durations based on the severity of the disease. The new tuberculosis treatments thus appear to be shorter and more personalized.

AVANCÉES DANS L'ANTIBIOTHÉRAPIE DE LA TUBERCULOSE. Le traitement de la tuberculose connaît de grandes avancées. Pour la première fois, un protocole thérapeutique à base de rifapentine et moxifloxacine permet de réduire de six à quatre mois la durée du traitement des tuberculoses à bacilles sensibles. S'agissant des tuberculoses à bacilles multirésistants, des combinaisons de nouveaux antituberculeux (bédaquiline, linézolide, délamanide-prétomanide, moxifloxacine) permettent de réduire de vingt à six mois la durée du traitement. Enfin, la prise en compte de l'importance de l'atteinte anatomique et de la charge bacillaire permet d'envisager des stratégies incluant des durées de traitement variables selon l'importance de l'atteinte. Les nouveaux traitements de la tuberculose apparaissent donc plus courts et plus personnalisés.

Sphingosine-1-phosphate receptor 3 regulates the transendothelial transport of high-density lipoproteins and low-density lipoproteins in opposite ways.

AIMS: The entry of lipoproteins from blood into the arterial wall is a rate-limiting step in atherosclerosis. It is controversial whether this happens by filtration or regulated transendothelial transport.Because sphingosine-1-phosphate (S1P) preserves the endothelial barrier, we investigated in vivo and in vitro, whether S1P and its cognate S1P-receptor 3 (S1P3) regulate the transendothelial transport of lipoproteins. METHODS AND RESULTS: Compared to apoE-haploinsufficient mice (CTRL), apoE-haploinsufficient mice with additional endothelium-specific knock-in of S1P3 (S1P3-iECKI) showed decreased transport of LDL and Evan's Blue but increased transport of HDL from blood into the peritoneal cave. After 30 weeks of high-fat diet feeding, S1P3-iECKI mice had lower levels of non-HDL-cholesterol and less atherosclerosis than CTRL mice. In vitro stimulation with an S1P3 agonist increased the transport of 125I-HDL but decreased the transport of 125I-LDL through human aortic endothelial cells (HAECs). Conversely, inhibition or knock-down of S1P3 decreased the transport of 125I-HDL but increased the transport of 125I-LDL. Silencing of SCARB1 encoding scavenger receptor B1 (SR-BI) abrogated the stimulation of 125I-HDL transport by the S1P3 agonist. The transendothelial transport of 125I-LDL was decreased by silencing of SCARB1 or ACVLR1 encoding activin-like kinase 1 but not by interference with LDLR. None of the three knock-downs prevented the stimulatory effect of S1P3 inhibition on transendothelial 125I-LDL transport. CONCLUSION: S1P3 regulates the transendothelial transport of HDL and LDL oppositely by SR-BI-dependent and SR-BI-independent mechanisms, respectively. This divergence supports a contention that lipoproteins pass the endothelial barrier by specifically regulated mechanisms rather than passive filtration.

Sex differences in vascular endothelial cells.

Endothelial cells are important constituents of blood vessels and play a critical role in vascular homeostasis. They do not only control the exchanges between the blood and the surrounding tissues, but are also essential in regulating blood flow, modulating immune-cell trafficking and controlling vascular growth and repair. Endothelial dysfunction leads to cardiovascular diseases and is characterized by deficiency in secretion of vasodilator molecules, elevated reactive oxygen species (ROS), expression of adhesion molecules and excretion of proinflammatory cytokines. The sex hormones, estrogens, androgens and progestogens, regulate endothelial functions. Because cardiovascular disease risk increases after menopause, it is believed that female hormones, estrogens and progestogens promote endothelial cell health and function whereas androgens, the male hormones, might be detrimental. However, as illustrated in the present review, the picture might not be that simple. In addition, sex influences endothelial cell physiology independently of sex hormones but at genetic level.

Effectiveness of third-generation cephalosporins or piperacillin compared with cefepime or carbapenems for severe infections caused by wild-type AmpC ß-lactamase-producing Enterobacterales: A multi-centre retrospective propensity-weighted study.

BACKGROUND: The optimal treatment regimen for infections caused by wild-type AmpC ß-lactamase-producing Enterobacterales remains controversial. This study compared the outcomes of bloodstream infections (BSI) and pneumonia according to the type of definitive antibiotic therapy: third-generation cephalosporin (3GC), piperacillin ± tazobactam, cefepime or carbapenem. METHODS: All cases of BSI and pneumonia caused by wild-type AmpC ß-lactamase-producing Enterobacterales over 2 years in eight university hospitals were reviewed. Patients who received definitive therapy consisting of either a 3GC (3GC group), piperacillin ± tazobactam (piperacillin group), or cefepime or a carbapenem (reference group) were included in this study. The primary endpoint was 30-day all-cause mortality. The secondary endpoint was treatment failure due to infection by emerging AmpC-overproducing strains. Propensity-score-based models were used to balance confounding factors between groups. RESULTS: In total, 575 patients were included in this study: 302 (52%) with pneumonia and 273 (48%) with BSI. Half (n=271, 47%) received cefepime or a carbapenem as definitive therapy, 120 (21%) received a 3GC, and 184 (32%) received piperacillin ± tazobactam. Compared with the reference group, 30-day mortality was similar in the 3GC [adjusted hazard ratio (aHR) 0.86, 95% confidence interval (CI) 0.57-1.31)] and piperacillin (aHR 1.20, 95% CI 0.86-1.66) groups. The likelihood of treatment failure was higher in the 3GC (aHR 6.81, 95% CI 3.76-12.4) and piperacillin (aHR 3.13, 95% CI 1.69-5.80) groups. The results were similar when stratifying the analysis on pneumonia or BSI. CONCLUSION: Treatment of included BSI or pneumonia caused by wild-type AmpC ß-lactamase-producing Enterobacterales with 3GC or piperacillin ± tazobactam was not associated with higher mortality, but was associated with increased risk of AmpC overproduction leading to treatment failure compared with cefepime or a carbapenem.

Active tuberculosis screening among the displaced population fleeing Ukraine, France, February to October 2022.

Persons fleeing Ukraine since February 2022 have potentially higher risk of tuberculosis (TB) vs all European Union countries. Interest of active TB screening among this population is debated and not widely adopted. In this screening intervention by a network of TB centres in France, the number needed to screen (NNS) was 862 to find one case. This experience shows that this strategy may be relevant for TB control in situations of massive displacement, similar to that following the Russian invasion.

Pharmacokinetics/pharmacodynamics of ceftobiprole in patients on extracorporeal membrane oxygenation.

INTRODUCTION: Due to its bacteriological spectrum and efficacy in skin and soft tissue infections, ceftobiprole may be of interest for extracorporeal membrane oxygenation (ECMO) cannula-related infection. It is unknown whether ceftobiprole pharmacokinetics (PK) are changed by ECMO. METHODS: A retrospective monocentric cohort study was performed of 35 patients with suspected ECMO-related cannula infections (28 on ECMO, seven after ECMO removal), who received ceftobiprole as empiric treatment and had ceftobiprole blood levels measured at trough, peak and CT50 (50% of the dosing interval). Ceftobiprole blood levels of the 28 patients on ECMO were compared with those of the seven patients without ECMO. Factors associated with low ceftobiprole trough levels were also explored. RESULTS: Among the 35 patients included, 29 had a confirmed cannula-related infection and 48 pathogens were isolated. Ceftobiprole MIC was determined in 29 of these 48, and 23 (79%) were susceptible to ceftobiprole. Ceftobiprole blood levels (at trough, peak and CT50) were similar in ECMO and non-ECMO patients. Moreover, in patients whose pathogens responsible for infection were susceptible to ceftobiprole, 94% had a ceftobiprole trough level above the MIC. Ceftobiprole blood levels were decreased in patients with acute renal failure requiring renal replacement therapy (RRT) and in those with increased renal clearance (defined as creatinine clearance > 130 mL/min), independent of ECMO. No other factor was associated with modification of ceftobiprole PK/pharmacodynamics (PK/PD). CONCLUSIONS: The ceftobiprole PK/PD was no different in patients during ECMO or after its withdrawal. Factors associated with decreased ceftobiprole blood levels were patients requiring RRT and those with increased renal clearance.

Decrease of hospital- and community-acquired bloodstream infections due to Streptococcus pneumoniae and Streptococcus pyogenes during the first year of the COVID-19 pandemic: A time-series analysis in Paris region.

The impact of the COVID-19 pandemic on bloodstream infections (BSIs) due to Streptococcus pneumoniae and Streptococcus pyogenes was assessed in 25 university hospitals of Paris. Monthly BSIs incidence rates that appeared stable in 2018 and 2019, decreased for the 2 pathogens during the 2 COVID-19 lockdown periods of 2020. Containment policies, including social distancing, masking and hand hygiene strengthening in both community and hospital settings are likely to reduce BSIs due to these pathogens.

Association Between Increased Linezolid Plasma Concentrations and the Development of Severe Toxicity in Multidrug-Resistant Tuberculosis Treatment.

BACKGROUND: Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity. METHODS: We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates. RESULTS: SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30-.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26-4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55-4.47; P < .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk. CONCLUSIONS: Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L.

Brain Endothelial Cells in Contrary to the Aortic Do Not Transport but Degrade Low-Density Lipoproteins via Both LDLR and ALK1.

The transport of low-density lipoprotein (LDL) through the endothelium is a key step in the development of atherosclerosis, but it is notorious that phenotypic differences exist between endothelial cells originating from different vascular beds. Endothelial cells forming the blood-brain barrier restrict paracellular and transcellular passage of plasma proteins. Here, we systematically compared brain versus aortic endothelial cells towards their interaction with LDL and the role of proteins known to regulate the uptake of LDL by endothelial cells. Both brain endothelial cells and aortic endothelial cells bind and internalize LDL. However, whereas aortic endothelial cells degrade very small amounts of LDL and transcytose the majority, brain endothelial cells degrade but do not transport LDL. Using RNA interference (siRNA), we found that the LDLR-clathrin pathway leads to LDL degradation in either endothelial cell type. Both loss- and gain-of-function experiments showed that ALK1, which promotes transcellular LDL transport in aortic endothelial cells, also limits LDL degradation in brain endothelial cells. SR-BI and caveolin-1, which promote LDL uptake and transport into aortic endothelial cells, limit neither binding nor association of LDL to brain endothelial cells. Together, these results indicate distinct LDL trafficking by brain microvascular endothelial cells and aortic endothelial cells.

Revised Definitions of Tuberculosis Resistance and Treatment Outcomes, France, 2006-2019.

Definitions of resistance in multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) have been updated. Pre-XDR TB, defined as MDR TB with additional resistance to fluoroquinolones, and XDR TB, with additional resistance to bedaquiline or linezolid, are frequently associated with treatment failure and toxicity. We retrospectively determined the effects of pre-XDR/XDR TB resistance on outcomes and safety of MDR TB treatment in France. The study included 298 patients treated for MDR TB at 3 reference centers during 2006-2019. Of those, 205 (68.8%) cases were fluoroquinolone-susceptible MDR TB and 93 (31.2%) were pre-XDR/XDR TB. Compared with fluoroquinolone-susceptible MDR TB, pre-XDR/XDR TB was associated with more cavitary lung lesions and bilateral disease and required longer treatment. Overall, 202 patients (67.8%) had favorable treatment outcomes, with no significant difference between pre-XDR/XDR TB (67.7%) and fluoroquinolone-susceptible MDR TB (67.8%; p = 0.99). Pre-XDR/XDR TB was not associated with higher risk for serious adverse events.

Investigation of healthcare-associated COVID-19 in a large French hospital group by whole-genome sequencing.

OBJECTIVES: Despite the quick implementation of infection prevention and control procedures and the use of personal protective equipment within healthcare facilities, many cases of nosocomial COVID-19 transmission have been reported. We aimed to estimate the frequency and impact of healthcare-associated COVID-19 (HA-COVID-19) and evaluate the contribution of whole-genome sequencing (WGS) in cluster investigation. METHODS: We estimated the frequency and mortality of HA-COVID-19 infections from September 1 to November 30, 2020, with a focus on the evolution of hospitalized community-associated COVID-19 (CA-COVID-19) cases and cases detected among healthcare workers (HCWs) within the Sorbonne University Hospital Group (Paris, France). We thoroughly examined 12 clusters through epidemiological investigations and WGS. RESULTS: Overall, 209 cases of HA-COVID-19 were reported. Evolution of HA-COVID-19 incidence closely correlated with the incidence of CA-COVID-19 and COVID-19 among HCWs. During the study period, 13.9 % of hospitalized patients with COVID-19 were infected in the hospital and the 30-day mortality rate of HA-COVID-19 was 31.5 %. Nosocomial transmission of SARS-CoV-2 led to clusters involving both patients and HCWs. WGS allowed the exclusion of one-third of cases initially assigned to a cluster. CONCLUSIONS: WGS analysis combined with comprehensive epidemiological investigations is essential to understand transmission routes and adapt the IPC response to protect both patients and HCWs.

Molecular detection of isoniazid monoresistance improves tuberculosis treatment: A retrospective cohort in France.

OBJECTIVES: Isoniazid-monoresistant tuberculosis (HR-TB) requires early diagnosis and adapted treatment to achieve optimal outcomes. The primary aim of the study was to assess the impact of the implementation of rapid diagnostic tests on HR-TB treatment in France. METHODS: We designed a retrospective multicentre study including consecutive HR-TB patients diagnosed in 2016 and 2017. Implementation of a molecular assay detecting isoniazid resistance directly on a clinical sample was recorded. The association between early implementation of such assays and adequate treatment was assessed by a multivariable Cox proportional hazards model. RESULTS: Overall, 99 HR-TB patients were included from 20 University Hospitals. Among all smear-positive HR-TB patients, only 26% beneficiated from early molecular HR detection. This detection was independently associated with shorter time to adequate treatment (HR = 2.0 [1.1-3.8], p = 0.03). CONCLUSION: In our study, molecular detection of HR on an initial sample was independently associated with earlier treatment adaptation.