A novel fatty acid analogue triggers CD36-GPR120 interaction and exerts anti-inflammatory action in endotoxemia.

Inflammation is a mediator of a number of chronic pathologies. We synthesized the diethyl (9Z,12Z)-octadeca-9,12-dien-1-ylphosphonate, called NKS3, which decreased lipopolysaccharide (LPS)-induced mRNA upregulation of proinflammatory cytokines (IL-1ß, IL-6 and TNF-α) not only in primary intraperitoneal and lung alveolar macrophages, but also in freshly isolated mice lung slices. The in-silico studies suggested that NKS3, being CD36 agonist, will bind to GPR120. Co-immunoprecipitation and proximity ligation assays demonstrated that NKS3 induced protein-protein interaction of CD36 with GPR120in RAW 264.7 macrophage cell line. Furthermore, NKS3, via GPR120, decreased LPS-induced activation of TAB1/TAK1/JNK pathway and the LPS-induced mRNA expression of inflammatory markers in RAW 264.7 cells. In the acute lung injury model, NKS3 decreased lung fibrosis and inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and nitric oxide (NO) production in broncho-alveolar lavage fluid. NKS3 exerted a protective effect on LPS-induced remodeling of kidney and liver, and reduced circulating IL-1ß, IL-6 and TNF-α concentrations. In a septic shock model, NKS3 gavage decreased significantly the LPS-induced mortality in mice. In the last, NKS3 decreased neuroinflammation in diet-induced obese mice. Altogether, these results suggest that NKS3 is a novel anti-inflammatory agent that could be used, in the future, for the treatment of inflammation-associated pathologies.

Efficacy of Nissen Sleeve Gastrectomy on Mid-term Barrett's Esophagus Regression.

INTRODUCTION: Sleeve gastrectomy is the most commonly performed bariatric operation globally. The main complication is GERD. In the medium term, it can increase the incidence of Barrett's esophagus (BE), which is a risk factor for esophageal adenocarcinoma. Following conventional sleeve gastrectomy, BE is noted in up to 16% of patients postoperatively. Recently, Nissen sleeve gastrectomy (NSG) has been shown to reduce the frequency of postoperative GERD compared to conventional sleeve gastrectomy. This study aims to evaluate the impact of NSG on the incidence and remission of BE in the long term. MATERIAL AND METHOD: This bicentric retrospective study included 692 patients who received NSG from September 2013 to July 2021. All patients underwent preoperative upper GI endoscopy and were then scheduled to receive upper GI endoscopy between 1 and 2 years and then between 3 and 5 years postoperatively. BE was systematically confirmed by biopsies. RESULTS: Seventy-four patients had endoscopic suspicion of BE, which was confirmed on 54/692 patients by histology. The BE lesions consisted of 18.5% intestinal metaplasia and 75.9% fundal metaplasia. Among these 54 patients, 38 underwent endoscopic investigation within 2 years postoperatively. The biopsies showed healed BE in 25/38 patients (64.1%). At 5 years, two patients had proven BE. Concerning the incidence of BE post NSG: 234 performed the follow-up endoscopy within 2 years. The incidence of de novo BE is nil. CONCLUSION: The NSG is associated with healing of known BE in approximately two-thirds of patients at 2-year follow-up. This is consistent with the GERD improvement that has been shown with NSG.

Effect of Nutritional Deprivation after Sleeve Gastrectomy on Bone Mass, Periostin, Sclerostin and Semaphorin 4D: A Two-Year Longitudinal Study.

Bariatric surgery induces bone loss, but the exact mechanisms by which this process occurs are not fully known. The aims of this 2-year longitudinal study were to (i) investigate the changes in areal bone mineral density (aBMD) and bone turnover markers following sleeve gastrectomy (SG) and (ii) determine the parameters associated with the aBMD variations. Bone turnover markers, sclerostin, periostin and semaphorin 4D were assessed before and 1, 12 and 24 months after SG, and aBMD was determined by DXA at baseline and after 12 and 24 months in 83 patients with obesity. Bone turnover increased from 1 month, peaked at 12 months and remained elevated at 24 months. Periostin and sclerostin presented only modest increases at 1 month, whereas semaphorin 4D showed increases only at 12 and 24 months. A significant aBMD decrease was observed only at total hip regions at 12 and 24 months. This demineralisation was mainly related to body weight loss. In summary, reduced aBMD was observed after SG in the hip region (mechanical-loading bone sites) due to an increase in bone turnover in favour of bone resorption. Periostin, sclerostin and semaphorin 4D levels varied after SG, showing different time lags, but contrary to weight loss, these biological parameters did not seem to be directly implicated in the skeletal deterioration.

Inflammation and oxidative stress markers in type 2 diabetes patients with Advanced Carotid atherosclerosis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease. METHODS: The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes. RESULTS: In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1ß, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes. CONCLUSION: Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets. TRIAL REGISTRATION: The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

Humid Evolution of Haze in the Atmosphere of Super-Earths in the Habitable Zone.

Abstract Photochemical hazes are expected to form and significantly contribute to the chemical and radiative balance of exoplanets with relatively moderate temperatures, possibly in the habitable zone of their host star. In the presence of humidity, haze particles might thus serve as cloud condensation nuclei and trigger the formation of water droplets. In the present work, we are interested in the chemical impact of such a close interaction between photochemical hazes and humidity on the organic content composing the hazes and on the capacity to generate organic molecules with high prebiotic potential. For this purpose, we explore experimentally the sweet spot by combining N-dominated super-Earth exoplanets in agreement with Titan's rich organic photochemistry and humid conditions expected for exoplanets in habitable zones. A logarithmic increase with time is observed for the relative abundance of oxygenated species, with O-containing molecules dominating after 1 month only. The rapidity of the process suggests that the humid evolution of N-rich organic haze provides an efficient source of molecules with high prebiotic potential.

Endotoxemia in Acute Heart Failure and Cardiogenic Shock: Evidence, Mechanisms and Therapeutic Options.

Acute heart failure and cardiogenic shock are frequently occurring and deadly conditions. In patients with those conditions, endotoxemia related to gut injury and gut barrier dysfunction is usually described as a driver of organ dysfunction. Because endotoxemia might reciprocally alter cardiac function, this phenomenon has been suggested as a potent vicious cycle that worsens organ perfusion and leading to adverse outcomes. Yet, evidence beyond this phenomenon might be overlooked, and mechanisms are not fully understood. Subsequently, even though therapeutics available to reduce endotoxin load, there are no indications to treat endotoxemia during acute heart failure and cardiogenic shock. In this review, we first explore the evidence regarding endotoxemia in acute heart failure and cardiogenic shock. Then, we describe the main treatments for endotoxemia in the acute setting, and we present the challenges that remain before personalized treatments against endotoxemia can be used in patients with acute heart failure and cardiogenic shock.

Relationship Between Oral Temperature and Bacteremia in Hospitalized Patients.

BACKGROUND: Early recognition and treatment of bacteremia can be lifesaving. Fever is a well-known marker of bacteremia, but the predictive value of temperature has not been fully explored. OBJECTIVE: To describe temperature as a predictor of bacteremia and other infections. DESIGN: Retrospective review of electronic health record data. SETTING: A single healthcare system comprising 13 hospitals in the United States. PATIENTS: Adult medical patients admitted in 2017 or 2018 without malignancy or immunosuppression. MAIN MEASURES: Maximum temperature, bacteremia, influenza and skin and soft tissue (SSTI) infections based on blood cultures and ICD-10 coding. KEY RESULTS: Of 97,174 patients, 1,518 (1.6%) had bacteremia, 1,392 (1.4%) had influenza, and 3,280 (3.3%) had an SSTI. There was no identifiable temperature threshold that provided adequate sensitivity and specificity for bacteremia. Only 45% of patients with bacteremia had a maximum temperature ≥ 100.4˚F (38˚C). Temperature showed a U-shaped relationship with bacteremia with highest risk above 103˚F (39.4˚C). Positive likelihood ratios for influenza and SSTI also increased with temperature but showed a threshold effect at ≥ 101.0 ˚F (38.3˚C). The effect of temperature was similar but blunted for patients aged ≥ 65 years, who frequently lacked fever despite bacteremia. CONCLUSIONS: The majority of bacteremic patients had maximum temperatures below 100.4 ˚F (38.0˚C) and positive likelihood ratios for bacteremia increased with high temperatures above the traditional definition of fever. Efforts to predict bacteremia should incorporate temperature as a continuous variable.

A Video-Based Review of Important Technical Concepts in the Nissen-Sleeve Gastrectomy.

PURPOSE: The development of gastroesophageal reflux disease (GERD) is a commonly encountered scenario after sleeve gastrectomy. A recently reported technical amendment to incorporate a Nissen fundoplication is discussed in this multimedia article focussing on optimising outcomes and reducing complications. MATERIALS AND METHODS: An intraoperative video has been edited to demonstrate the Nissen-Sleeve Gastrectomy and important technical considerations in its technical performance. RESULTS: Gastrolysis is performed proximally from 6 cm proximal to the pylorus. Routine full mediastinal mobilisation of the oesophagus (5 cm) is completed. Cruroplasty is routinely performed. A short Nissen fundoplication is completed calibrated on a 37 French bougie and then sleeve gastrectomy is performed. Our team's experience suggests that careful manipulation of the fundus and using reproducible measurements of the fundus are key to completing the fundoplication whilst minimising complications. A control test with mobilisation of the bougie through the wrap is recommended at the end of the procedure. CONCLUSION: The Nissen-Sleeve Gastrectomy, as presented in this video, is safe and has good short-term efficacy outcomes. Longer term and randomised studies are ongoing.

Bacteroides fragilis derived metabolites, identified by molecular networking, decrease Salmonella virulence in mice model.

In the gut microbiota, resident bacteria prevent pathogens infection by producing specific metabolites. Among bacteria belonging to phylum Bacteroidota, we have previously shown that Bacteroides fragilis or its cell-free supernatant inhibited in vitro Salmonella Heidelberg translocation. In the present study, we have analyzed this supernatant to identify bioactive molecules after extraction and subsequent fractionation using a semi-preparative reversed-phase Liquid Chromatography High-Resolution Tandem Mass Spectrometry (LC-HRMS/MS). The results indicated that only two fractions (F3 and F4) strongly inhibited S. Heidelberg translocation in a model mimicking the intestinal epithelium. The efficiency of the bioactive fractions was evaluated in BALB/c mice, and the results showed a decrease of S. Heidelberg in Peyer's patches and spleen, associated with a decrease in inflammatory cytokines and neutrophils infiltration. The reduction of the genus Alistipes in mice receiving the fractions could be related to the anti-inflammatory effects of bioactive fractions. Furthermore, these bioactive fractions did not alter the gut microbiota diversity in mice. To further characterize the compounds present in these bioactive fractions, Liquid Chromatography High-Resolution Tandem Mass Spectrometry (LC-HRMS/MS) data were analyzed through molecular networking, highlighting cholic acid (CA) and deoxycholic acid. In vitro, CA had inhibitory activity against the translocation of S. Heidelberg by significantly decreasing the expression of Salmonella virulence genes such as sipA. The bioactive fractions also significantly downregulated the flagellar gene fliC, suggesting the involvement of other active molecules. This study showed the interest to characterize better the metabolites produced by B. fragilis to make them means of fighting pathogenic bacteria by targeting their virulence factor without modifying the gut microbiota.

Role of apolipoprotein C1 in lipoprotein metabolism, atherosclerosis and diabetes: a systematic review.

Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.

Increased Weight Gain and Insulin Resistance in HF-Fed PLTP Deficient Mice Is Related to Altered Inflammatory Response and Plasma Transport of Gut-Derived LPS.

Bacterial lipopolysaccharides (LPS, endotoxins) are found in high amounts in the gut lumen. LPS can cross the gut barrier and pass into the blood (endotoxemia), leading to low-grade inflammation, a common scheme in metabolic diseases. Phospholipid transfer protein (PLTP) can transfer circulating LPS to plasma lipoproteins, thereby promoting its detoxification. However, the impact of PLTP on the metabolic fate and biological effects of gut-derived LPS is unknown. This study aimed to investigate the influence of PLTP on low-grade inflammation, obesity and insulin resistance in relationship with LPS intestinal translocation and metabolic endotoxemia. Wild-type (WT) mice were compared with Pltp-deficient mice (Pltp-KO) after a 4-month high-fat (HF) diet or oral administration of labeled LPS. On a HF diet, Pltp-KO mice showed increased weight gain, adiposity, insulin resistance, lipid abnormalities and inflammation, together with a higher exposure to endotoxemia compared to WT mice. After oral administration of LPS, PLTP deficiency led to increased intestinal translocation and decreased association of LPS to lipoproteins, together with an altered catabolism of triglyceride-rich lipoproteins (TRL). Our results show that PLTP, by modulating the intestinal translocation of LPS and plasma processing of TRL-bound LPS, has a major impact on low-grade inflammation and the onset of diet-induced metabolic disorders.

Roseburia intestinalis Modulates PYY Expression in a New a Multicellular Model including Enteroendocrine Cells.

The gut microbiota contributes to human health and disease; however, the mechanisms by which commensal bacteria interact with the host are still unclear. To date, a number of in vitro systems have been designed to investigate the host-microbe interactions. In most of the intestinal models, the enteroendocrine cells, considered as a potential link between gut bacteria and several human diseases, were missing. In the present study, we have generated a new model by adding enteroendocrine cells (ECC) of L-type (NCI-H716) to the one that we have previously described including enterocytes, mucus, and M cells. After 21 days of culture with the other cells, enteroendocrine-differentiated NCI-H716 cells showed neuropods at their basolateral side and expressed their specific genes encoding proglucagon (GCG) and chromogranin A (CHGA). We showed that this model could be stimulated by commensal bacteria playing a key role in health, Roseburia intestinalis and Bacteroides fragilis, but also by a pathogenic strain such as Salmonella Heidelberg. Moreover, using cell-free supernatants of B. fragilis and R. intestinalis, we have shown that R. intestinalis supernatant induced a significant increase in IL-8 and PYY but not in GCG gene expression, while B. fragilis had no impact. Our data indicated that R. intestinalis produced short chain fatty acids (SCFAs) such as butyrate whereas B. fragilis produced more propionate. However, these SCFAs were probably not the only metabolites implicated in PYY expression since butyrate alone had no effect. In conclusion, our new quadricellular model of gut epithelium could be an effective tool to highlight potential beneficial effects of bacteria or their metabolites, in order to develop new classes of probiotics.

Lipoprotein interactions with water-soluble NIR-II emitting aza-BODIPYs boost the fluorescence signal and favor selective tumor targeting.

Following intravenous administration, the interaction of fluorescent exogenous molecules with circulating endogenous transporters can influence their photophysical properties as well as their fate and distribution, and possibly their recognition by different cell types. This type of interaction can be used to optimize the drug delivery but also the imaging properties of a compound of interest. In this study, we investigated the behavior of SWIR-WAZABY-01 fluorophore, a water-soluble aza-BODIPY dye emitting in the NIR-II region, both in vitro and in vivo. While the fluorescence emission of SWIR-WAZABY-01 was weak in aqueous solutions, it was intensely magnified in plasma (∼ ×30). Further analyses using lipoprotein gel electrophoresis and ultracentrifugation revealed interactions between SWIR-WAZABY-01 and plasma lipoproteins in vitro and ex vivo, in particular with LDL. The tumor uptake mechanism of SWIR-WAZABY-01 was investigated based on the presence of low-density lipoprotein (LDL) receptors and passive tumor uptake. Overall, we found that SWIR-WAZABY-01 interacts with lipoproteins enhancing their NIR-II fluorescence emission, and driving the tumor accumulation with regards to the expression of lipoprotein receptors (LDLR, SR-BI). Moreover, SWIR-WAZABY-01, by exploiting endogenous lipoproteins, arises as a new, potent and relevant tool to efficiently label LDL involved in pathologies.

Peri-operative Morbidity of Nissen Sleeve Gastrectomy: Prospective Evaluation of a Cohort of 365 Patients, Beyond the Learning Curve.

PURPOSE: Over the last decade, an important interest was taken to prevent the reflux following sleeve. A new variant, Nissen-sleeve, was described with the purpose to prevent GERD and to decrease the occurrence of leak. The current study reports the preliminary results of a prospective trial. MATERIALS AND METHODS: All consecutive patients who underwent a Nissen-Sleeve between January 2018 and September 2020 were included. Baseline characteristics including age, gender, weight, body mass index (BMI), GERD symptoms, and treatment were evaluated after 1 year. Operative time, length of stay, complication, and reoperation data were also collected. RESULTS: Three hundred sixty-five consecutive patients decided to undergo Nissen-sleeve: 75% females with median age of 41.2 years (+ / - 14.1) and an average BMI of 41.6 kg/m2 (+ / - 5.4). There were 16 cases (4.4%) of early postoperative complications (< 30 days): six cases of acute wrap perforation (1.6%), intraabdominal bleeding for 5 patients (1.4%), one case of wrap dilatation (0.3%), one case of acute complete aphagia, one case of incarcerated umbilical hernia, and 2 cases (0.5%) of pulmonary atelectasis/pneumonia and one venous pulmonary embolism. We recorded the following complications: 16 patients (4.4%) mild dysphagia; 3 patients (0.8%) chronic dysphagia; and 2 cases of wrap perforation that have been diagnosed 8 and 9 months respectively, after the procedure due to the use of steroids not associated with PPI intake. The mean operative time was 83 min (46-125 min). The conversion and mortality rates were nil. CONCLUSION: Following the initial learning curve and additional technical modifications, the Nissen-Sleeve appears to be a safe surgical technique with an acceptable early postoperative complication rate. CLINICAL TRIAL REGISTRATION: NCT02310178.

COSAC's Only Gas Chromatogram Taken on Comet 67P/Churyumov-Gerasimenko.

The Philae lander of the Rosetta space mission made a non-nominal landing on comet 67P/Churyumov-Gerasimenko on November 12, 2014. Shortly after, using the limited power available from Philae's batteries, the COSAC instrument performed a single 18-minutes gas chromatogram, which has remained unpublished until now due to the lack of identifiable elution. This work shows that, despite the unsuccessful drilling of the comet and deposition of surface material in the SD2 ovens, the measurements from the COSAC instrument were executed nominally. We describe an automated search for extremely small deviations from noise and discuss the possibility of a signal from ethylene glycol at m/z 31. Arguments for and against this detection are listed, but the results remain inconclusive. Still, the successful operations of an analytical chemistry laboratory on a cometary nucleus gives great hope for the future of space exploration.

ESA's Cometary Mission Rosetta-Re-Characterization of the COSAC Mass Spectrometry Results.

The most pristine material of the Solar System is assumed to be preserved in comets in the form of dust and ice as refractory matter. ESA's mission Rosetta and its lander Philae had been developed to investigate the nucleus of comet 67P/Churyumov-Gerasimenko in situ. Twenty-five minutes after the initial touchdown of Philae on the surface of comet 67P in November 2014, a mass spectrum was recorded by the time-of-flight mass spectrometer COSAC onboard Philae. The new characterization of this mass spectrum through non-negative least squares fitting and Monte Carlo simulations reveals the chemical composition of comet 67P. A suite of 12 organic molecules, 9 of which also found in the original analysis of this data, exhibit high statistical probability to be present in the grains sampled from the cometary nucleus. These volatile molecules are among the most abundant in the comet's chemical composition and represent an inventory of the first raw materials present in the early Solar System.

New therapeutic horizons for plasma phospholipid transfer protein (PLTP): Targeting endotoxemia, infection and sepsis.

Phospholipid Transfer Protein (PLTP) transfers amphiphilic lipids between circulating lipoproteins and between lipoproteins, cells and tissues. Indeed, PLTP is a major determinant of the plasma levels, turnover and functionality of the main lipoprotein classes: very low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). To date, most attention has been focused on the role of PLTP in the context of cardiometabolic diseases, with additional insights in neurodegenerative diseases and immunity. Importantly, beyond its influence on plasma triglyceride and cholesterol transport, PLTP plays a key role in the modulation of the immune response, with immediate relevance to a wide range of inflammatory diseases including bacterial infection and sepsis. Indeed, emerging evidence supports the role of PLTP, in the context of its association with lipoproteins, in the neutralization and clearance of bacterial lipopolysaccharides (LPS) or endotoxins. LPS are amphipathic molecules originating from Gram-negative bacteria which harbor major pathogen-associated patterns, triggering an innate immune response in the host. Although the early inflammatory reaction constitutes a key step in the anti-microbial defense of the organism, it can lead to a dysregulated inflammatory response and to hemodynamic disorders, organ failure and eventually death. Moreover, and in addition to endotoxemia and acute inflammation, small amounts of LPS in the circulation can induce chronic, low-grade inflammation with long-term consequences in several metabolic disorders such as atherosclerosis, obesity and diabetes. After an updated overview of the role of PLTP in lipid transfer, lipoprotein metabolism and related diseases, current knowledge of its impact on inflammation, infection and sepsis is critically appraised. Finally, the relevance of PLTP as a new player and novel therapeutic target in the fight against inflammatory diseases is considered.

High-density lipoprotein infusion protects from acute graft-versus-host disease in experimental allogeneic hematopoietic cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram-negative bacteria are well-known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in aGVHD mouse models using an innovative quantification method. We demonstrated that systemic LPS accumulation after transplantation was due, at least partly, to a defect in its clearance through lipoprotein-mediated transport to the liver (i.e., the so-called reverse LPS transport). After transplantation, reduced circulating HDL concentration impaired LPS neutralization and elimination through biliary flux. Accordingly, HDL-deficient (Apoa1tm1Unc ) recipient mice developed exacerbated aGVHD. Repeated administration of HDL isolated from human plasma significantly decreased the mortality and the severity of aGVHD. While the potential role of HDL in scavenging circulating LPS was examined in this study, it appears that HDL plays a more direct immunomodulatory role by limiting or controlling aGVHD. Notably, HDL infusion mitigated liver aGVHD by diminishing immune infiltration (e.g., interferon-γ-secreting CD8+ T cells and non-resident macrophages), systemic and local inflammation (notably cholangitis). Hence, our results revealed the interest of HDL-based therapies in the prevention of aGVHD.

Derivation and Validation of a Risk Factor Model to Identify Medical Inpatients at Risk for Venous Thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) prophylaxis is recommended for hospitalized medical patients at high risk for VTE. Multiple risk assessment models exist, but few have been compared in large datasets. METHODS: We constructed a derivation cohort using 6 years of data from 12 hospitals to identify risk factors associated with developing VTE within 14 days of admission. VTE was identified using a complex algorithm combining administrative codes and clinical data. We developed a multivariable prediction model and applied it to three validation cohorts: a temporal cohort, including two additional years, a cross-validation, in which we refit the model excluding one hospital each time, applying the refitted model to the holdout hospital, and an external cohort. Performance was evaluated using the C-statistic. RESULTS: The derivation cohort included 155,026 patients with a 14-day VTE rate of 0.68%. The final multivariable model contained 13 patient risk factors. The model had an optimism corrected C-statistic of 0.79 and good calibration. The temporal validation cohort included 53,210 patients, with a VTE rate of 0.64%; the external cohort had 23,413 patients and a rate of 0.49%. Based on the C-statistic, the Cleveland Clinic Model (CCM) outperformed both the Padua (0.76 vs. 0.72, p = 0.002) and IMPROVE (0.68, p < 0.001) models in the temporal cohort. C-statistics for the CCM at individual hospitals ranged from 0.68 to 0.78. In the external cohort, the CCM C-statistic was similar to Padua (0.70 vs. 0.66, p = 0.17) and outperformed IMPROVE (0.59, p < 0.001). CONCLUSION: A new VTE risk assessment model outperformed recommended models.