Impact of corticosteroids use on midterm sequelae in survivors of COVID-19 admitted to hospital: A prospective cohort study.

An understanding of the midterm sequelae in COVID-19 and their association with corticosteroids use are needed. Between March and July 2020, we evaluated 1227 survivors of COVID-19, 3 months posthospitalization, of whom 213 had received corticosteroids within 7 days of admission. Main outcome was any midterm sequelae (oxygen therapy, shortness of breath, one major clinical sign, two minor clinical signs or three minor symptoms). Association between corticosteroids use and midterm sequelae was assessed using inverse propensity-score weighting models. Our sample included 753 (61%) male patients, and 512 (42%) were older than 65 years. We found a higher rate of sequelae among users than nonusers of corticosteroids (42% vs. 35%, odds ratio [OR] 1.40 [1.16-1.69]). Midterm sequelae were more frequent in users of low-dose corticosteroids than nonusers (64% vs. 51%, OR 1.60 [1.10-2.32]), whereas no association between higher doses (≥20 mg/day equivalent of dexamethasone) and sequelae was evidenced (OR 0.95 [0.56-1.61]). Higher risk of sequelae with corticosteroids use was observed among subjects with propensity score below the 90th percentile. Our study suggest that corticosteroids use during hospitalization for COVID-19 is associated with higher risk of midterm sequelae.

Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications.

A total of 2%-10% of patients with vascular liver disease (VLD) have paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab reduces complement-mediated haemolytic activity in PNH. This study was aimed at assessing the impact of eculizumab on VLD outcome. Retrospective cohort of PNH patients, in Valdig registry, who had VLD diagnosed between 1997 and 2019 is considered. Eculizumab was the exposure of interest. Studied outcomes were death, venous thrombosis, bleeding, arterial ischemic event, infection, and liver-related complications. We compared survival and new thrombotic events from PNH/VLD cohort to Envie2 non-PNH cohort. Sixty-two patients (33 women), median age 35 years (28-48) and median follow-up VLD diagnosis 4.7 years (1.2-9.5), were included. Clone size was 80% (70-90), median hemoglobin concentration was 10.0 g/dl (8-11), and lactate dehydrogenase (LDH) was 736 IU (482-1744). Forty-two patients (68%) had eculizumab; median exposure time was 40.1 [9.3-72.6] months. Mortality was significantly lower in exposed versus nonexposed period: 2.6 versus 8.7 per 100 (PY), incidence rate ratio (IRR) was 0.29, 95% CI (0.1-0.9), p = .035. Thrombosis recurrence occurred less frequently during the exposure to eculizumab: 0.5 versus 2.8 per 100 PY, IRR 0.22 (0.07-0.64). Other secondary end points (i.e., bleeding, arterial ischemic lesions, infection, and liver complications) were less common during the exposure to eculizumab, although not reaching statistical significance. Six-year thrombosis-free survival was 70%, 95% CI [0.60-0.83] for PNH cohort and 83%, 95% CI [0.70-1.00] for non-PNH Envie 2 patients, (p < .001). In conclusion, patients with PNH and VLD are at higher risk of recurrent thrombosis than non-PNH patients. Eculizumab is significantly associated with a lower mortality and less thrombotic recurrence in patients with PNH and VLD.

How is Video Efficient to Diagnose Sport-Related Concussion? A Cross-Sectional Study in the French TOP14 Rugby Championship.

OBJECTIVE: To describe the frequency of clinical signs and the accuracy of video diagnosis of sport-related concussion. DESIGN: An observational cross-sectional study. SETTING AND PARTICIPANTS: Videos from a database of all suspected sport-related concussion in TOP14 matches (French professional male rugby Championship) were used, from 2012 to 2015 seasons. The videos were analyzed by 4 observers, blinded to the concussion diagnosis, after a training phase, and an inter-rater reliability analysis. INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: Video analysis for clinical signs and presumed diagnosis of sport-related concussion. The observer's diagnosis was compared with the team physicians' diagnosis. RESULTS: Four hundred seventeen videos were analyzed with 142 concussed players. Sport-related concussions happened mostly from an impact to the head (seen by the observers in 98.4%), against an opponent (73.2%), and during a tackle (74.6%). Video signs were observable in 98.6% for suspected loss of consciousness, tonic posturing (95%), ataxia (77.2%), dazed look (35.7%), abnormal behavior (18.2%), and seizures (96.2%). Ataxia was seen in 77.7% of concussed players, suspected loss of consciousness in 61.4%, dazed look in 63.2%, abnormal behavior in 55%, and tonic posturing in 7.1%. The observers diagnosed 79.8% of concussions. CONCLUSIONS: We described the frequency of video clinical signs of sport-related concussion, with a good accuracy of the blinded observers for the diagnosis. This emphasizes the importance of pitch-side video analysis as an extra tool for sport-related concussion diagnosis.

Prion protein deficiency impairs hematopoietic stem cell determination and sensitizes myeloid progenitors to irradiation.

Highly conserved among species and expressed in various types of cells, numerous roles have been attributed to the cellular prion protein (PrPC). In hematopoiesis, PrPC regulates hematopoietic stem cell self-renewal but the mechanisms involved in this regulation are unknown. Here we show that PrPC regulates hematopoietic stem cell number during aging and their determination towards myeloid progenitors. Furthermore, PrPC protects myeloid progenitors against the cytotoxic effects of total body irradiation. This radioprotective effect was associated with increased cellular prion mRNA level and with stimulation of the DNA repair activity of the Apurinic/pyrimidinic endonuclease 1, a key enzyme of the base excision repair pathway. Altogether, these results show a previously unappreciated role of PrPC in adult hematopoiesis, and indicate that PrPC-mediated stimulation of BER activity might protect hematopoietic progenitors from the cytotoxic effects of total body irradiation.

Effects of Long-term Norfloxacin Therapy in Patients With Advanced Cirrhosis.

BACKGROUND & AIMS: There is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis. METHODS: We performed a double-blind trial of 291 patients with Child-Pugh class C cirrhosis who had not received recent fluoroquinolone therapy. The study was performed at 18 clinical sites in France from April 2010 through November 2014. Patients were randomly assigned to groups given 400 mg norfloxacin (n = 144) or placebo (n = 147) once daily for 6 months. Patients were evaluated monthly for the first 6 months and at 9 months and 12 months thereafter. The primary outcome was 6-month mortality, estimated by the Kaplan-Meier method, censoring spontaneous bacterial peritonitis, liver transplantation, or loss during follow-up. RESULTS: The Kaplan-Meier estimate for 6-month mortality was 14.8% for patients receiving norfloxacin and 19.7% for patients receiving placebo (P = .21). In competing risk analysis that took liver transplantation into account, the cumulative incidence of death at 6 months was significantly lower in the norfloxacin group than in the placebo group (subdistribution hazard ratio, 0.59; 95% confidence interval, 0.35-0.99). The subdistribution hazard ratio for death at 6 months with norfloxacin vs placebo was 0.35 (95% confidence interval, 0.13-0.93) in patients with ascites fluid protein concentrations <15 g/L and 1.39 (95% confidence interval, 0.42-4.57) in patients with ascites fluid protein concentrations ≥15 g/L. Norfloxacin significantly decreased the incidence of any and Gram-negative bacterial infections without increasing infections caused by Clostridium difficile or multiresistant bacteria. CONCLUSIONS: In a randomized controlled trial of patients with advanced cirrhosis without recent fluoroquinolone therapy, norfloxacin did not reduce 6-month mortality, estimated by the Kaplan-Meier method. Norfloxacin, however, appears to increase survival of patients with low ascites fluid protein concentrations. ClinicalTrials.gov ID: NCT01037959.

Oral Antibiotics Reduce Intestinal Necrosis in Acute Mesenteric Ischemia: A Prospective Cohort Study.

OBJECTIVES: To identify treatments likely to prevent progression towards irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI). METHODS: Prospective observational cohort study from a French intestinal stroke center. Multivariate analysis using a time-dependent Cox regression model. RESULTS: Between 2009 and 2015, 67 patients with AMI were included. ITIN occurred in 34% of patients and mortality was 13%. Oral antibiotics was independently associated with a decreased risk of ITIN (HR: 0.16 (95% CI = 0.03-0.62); p = 0.01). CONCLUSIONS: By decreasing luminal bacterial load and translocation, oral antibiotics in addition to early revascularization might reduce progression of AMI to ITIN.

Predictive Factors of Intestinal Necrosis in Acute Mesenteric Ischemia: Prospective Study from an Intestinal Stroke Center.

OBJECTIVES: To identify predictive factors for irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI) and establish a risk score for ITIN. METHODS: This single-center prospective cohort study was performed between 2009 and 2015 in patients with AMI. The primary outcome was the occurrence of ITIN, confirmed by specimen analysis in patients who underwent surgery. Patients who recovered from AMI with no need for intestinal resection were considered not to have ITIN. Clinical, biological and radiological data were compared in a Cox regression model. RESULTS: A total of 67 patients were included. The origin of AMI was arterial, venous, or non-occlusive in 61%, 37%, 2% of cases, respectively. Intestinal resection and ITIN concerned 42% and 34% of patients, respectively. Factors associated with ITIN in multivariate analysis were: organ failure (hazard ratio (HR): 3.1 (95% confidence interval (CI): 1.1-8.5); P=0.03), serum lactate levels >2 mmol/l (HR: 4.1 (95% CI: 1.4-11.5); P=0.01), and bowel loop dilation on computerized tomography scan (HR: 2.6 (95% CI: 1.2-5.7); P=0.02). ITIN rate increased from 3% to 38%, 89%, and 100% in patients with 0, 1, 2, and 3 factors, respectively. Area under the receiver operating characteristics curve for the diagnosis of ITIN was 0.936 (95% CI: 0.866-0.997) depending on the number of predictive factors. CONCLUSIONS: We identified three predictive factors for irreversible intestinal ischemic injury requiring resection in the setting of AMI. Close monitoring of these factors could help avoid unnecessary laparotomy, prevent resection, as well as complications due to unresected necrosis, and possibly lower the overall mortality.

Self-controlled designs in pharmacoepidemiology involving electronic healthcare databases: a systematic review.

BACKGROUND: Observational studies are widely used in pharmacoepidemiology. Several designs can be used, in particular self-controlled designs (case-crossover and self-controlled case series). These designs offer the advantage of controlling for time-invariant confounders, which may not be collected in electronic healthcare databases. They are particularly useful in pharmacoepidemiology involving healthcare database. To be valid, they require the presence of some characteristics (key validity assumptions), and in such situations, these designs should be preferred. We aimed at describing the appropriate use and reporting of the key validity assumptions in self-controlled design studies. METHODS: Articles published between January 2011 and December 2014, and describing a self-controlled study design involving electronic healthcare databases were retrieved. The appropriate use (fulfilment of key assumptions) was studied in terms of major (abrupt onset event, rare or recurrent event, and intermittent exposure) and minor assumptions (those for which the design can be adapted). RESULTS: Among the 107 articles describing a self-controlled design, 35/53 (66%) case-crossover studies, and 48/55 (87%) self-controlled case series fulfilled the major validity assumptions for use of the design; 4/35 and 14/48 respectively did not fulfill the minor assumptions. Overall, 31/53 (58%) case-crossover studies and 34/55 (62%) self-controlled case series fulfilled both major and minor assumptions. The reporting of the methodology or the results was appropriate, except for power calculation. CONCLUSIONS: Self-controlled designs were not appropriately used in34% and 13% of the articles we reviewed that described a case-crossover or a self-controlled case series design, respectively. We encourage better use of these designs in situations in which major validity assumptions are fulfilled (i.e., for which they are recommended), accounting for situations for which the design can be adapted.

Underuse of self-controlled designs in pharmacoepidemiology in electronic healthcare databases: a systematic review.

PURPOSE: The self-controlled (SC) designs offer the advantage of inherently controlling for time-invariant confounders, which may not be collected in electronic healthcare databases. To be valid, the design requires that some characteristics must be present. Recommendations for their use have been published in 2012, which encourage their implementation when these key characteristics are valid. We aimed at describing the potentially missed opportunities for the use of SC in pharmacoepidemiological studies on electronic healthcare databases. METHODS: We searched Medline for the articles published in two different 6-month periods before and after the 2012 recommendations. The potentially opportunity for the use of SC design is based on major required characteristics (abrupt onset event, rare or recurrent event, and acute or intermittent exposure). RESULTS: In total, 94 papers in 2011 were analysed and 106 in 2014. SC designs were rarely used (2% in 2011 and 1% in 2014). A potentially missed opportunity for SC use was found in 16% of papers in 2011 and 15% in 2014. CONCLUSIONS: We found that SC designs were underused and identified situations in which they could have been applied, but were not. Their use should be encouraged.

Long-term consequences of recurrent sports concussion.

BACKGROUND: Recurrent concussions are suspected to promote the development of long-term neurological disorders. The study was designed to assess the prevalence of major depressive disorder, mild cognitive disorders and headache in a population of retired high-level sportsmen and rugby players and to study the link between scores evaluating these disorders and the number of reported concussions (RCs). METHODS: A total of 239 retired rugby players (RRPs) and 138 other retired sportsmen (ORSs) who had reached the French national or international championship level between 1985 and 1990 filled in a self-administered questionnaire describing their sociodemographic data, comorbidities and reported history of RC. A phone interview was then conducted using validated questionnaires for the detection of major depressive disorder (PHQ-9), mild cognitive disorders (F-TICS-m) and headache (HIT-6). RESULTS: RRPs reported a higher number of RCs than ORSs (p < 0.001). A higher rate of major depressive disorder (PHQ-9 score >9) was observed among RRPs compared to ORSs (9% versus 6%) (p = 0.04), and the PHQ-9 score increased with the number of RCs regardless of the type of sport (p = 0.026). A higher rate of mild cognitive disorders (TICS-m score ≤30) was observed in RRPs compared to ORSs (57% versus 40%, p = 0.005), but no association was found with the number of RC. The HIT-6 score increased with the number of RCs (p = 0.019) CONCLUSIONS: More than 20 years after the end of their career, RRPs present higher rates of depression and lower F-TICS-m scores in favor of mild cognitive impairment compared with ORSs. PHQ-9 and HIT-6 scores were significantly associated with the number of RCs.

[Impact of Geriatric Drug Guidelines on the Quality Requirement of Elderly Patients]. / Impact d'un livret thérapeutique sur la qualité des prescriptions médicamenteuses des résidents d'EHPAD.

OBJECTIVE: Elderly with several pathologies are usually treated with many drugs, and are exposed to a majored risk of drug-induced adverse effects. A network of local nursing homes (EHPAD) in the south Seine-Saint-Denis area (France) created a geriatric drug guidelines to improve the quality of the drugs prescriptions. This study assesses the conformity of prescriptions in elderly patients prior and after the distribution of the booklet. METHODS: This before and after design study focused on the drug prescriptions for patients in eight EHPAD followed for two randomly given days in 2012 (n = 503) and 2013 (n = 334). The geriatric drug guidelines included a list of medicines suitable for the elderly (conformity list) and recommendations for prescription and monitoring. Data collection was conducted from medical records and interviews with coordinators doctors and nursing staff in nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS: Median age, weight and creatinine level were respectively 88 years, 61.0 kg, and 74.9 µmol/L (prior) and 88 years, 59.6 kg, and 77.0 µmol/L (after). Median times of latest serum creatinine dosage were 112 days (prior) and 108 days (after). The median number of prescribed drugs was 8 per resident during the two period of study. The conformity rate of prescription was better prior the distribution of the guidelines, respectively 87.5% and 80.0% (p<10⁻³). The average formal quality score was better after the distribution of the booklet increasing form 4.23 to 4.40 points (p<10⁻4). For high risk inducing drugs, monitoring was prescribed in 34.2% (prior) and 32.4% (after). CONCLUSIONS: This study shows that the drug geriatric guidelines does not improve prescription conformity and monitoring for high risk drugs, but it does significantly improve the median formal quality score.

Ventilator-associated pneumonia due to carbapenem-resistant Gram-negative bacilli in an intensive care unit without carbapenemase-producing Enterobacteriaceae or epidemic Acinetobacter baumannii.

Risk factors for ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Gram-negative bacilli (CR-GNB) have rarely been evaluated in intensive care units (ICU) without epidemic carbapenemase-producing Acinetobacter baumannii or Enterobacteriaceae. We addressed this issue in a cohort of 141 patients (previous antimicrobial exposure, n = 131) with a first episode of VAP in a medico-surgical ICU. Twenty-six VAP (18.4%) involved a CR-GNB (Pseudomonas aeruginosa, n = 14, Stenotrophomonas maltophilia, n = 11, and A. baumannii, n = 1), without previous carbapenem exposure in 12 (46.1%) cases. GNB resistant to all ß-lactams except carbapenems were equally isolated in CR-GNB VAP (co-infections, 23%) and other episodes (30%). Previous exposure to aminoglycosides (odds ratio (OR) 1.14 per day, 95% confidence interval (CI) 1.02-1.30, p = 0.02) and the number of antimicrobial classes used before VAP (OR 1.38 per class, 95% CI 1.10-1.73, p = 0.006) were the only independent predictors of CR-GNB. These results suggest that the empirical use of a carbapenem-colistin combination should be evaluated in late-onset VAP following broad-spectrum antimicrobial exposure.

[Medical treatment of the elderly in residential care: a multicenter cross-sectional study]. / Prescriptions médicamenteuses chez les personnes âgées en EHPAD: une étude transversale multicentrique.

OBJECTIVE: To retrospectively assess the quality of prescriptions in elderly patients prior the distribution of guidelines for geriatric drug prescriptions. METHODS: A cross-sectional study was conducted for one day in 2012 to investigate the quality of the prescriptions in 495 residents of 8 nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS: The median number of prescribed drugs was 8,5 per resident. Over a total of 4311 prescribed drugs, the average quality score was 4,96 ± 0,45; 4,54 ± 0,70 in computerized orders and 3,4 ± 1,02 in handwritten orders. Among 939 drugs considered as at high risk of inducing serious adverse reactions, monitoring was prescribed 154 times only (16,4%). CONCLUSIONS: A lack of drug monitoring was highlighted, especially for high risk drugs. The quality of prescription may be improved by the use of computerized orders.

Community-acquired Klebsiella pneumoniae pneumonia in ICU: a multicenter retrospective study.

BACKGROUND: Alongside the recent worldwide expansion of hypervirulent Klebsiella pneumoniae (KP) infections, the available literature regarding cases of community acquired pneumonias (KP-CAP) remains scarce but reports a strikingly high and early mortality. We performed a retrospective multicenter study (7 ICU in France) between 2015 and 2019, comparing prognosis and severity of KP-CAP versus Streptococcus pneumoniae - CAP (SP-CAP). METHODS: For each KP-CAP, three SP-CAP admitted in ICUs within the same center and within the same 6-month window were selected. When available, KP strains were studied, and bacterial virulence was genetically assessed for virulence factors. The primary outcome was in-hospital mortality. Associations between clinical outcomes and type of infection were tested using univariate and multivariate logistic regressions, adjusted for pairing variables. RESULTS: Twenty-seven KP-CAP and 81 SP-CAP were included. Respective in-hospital mortality rates were 59% (n = 16) and 17% (n = 14, p < 0.001), despite adequate antibiotic therapy. KP-CAP median time from admission to death was 26.9 h [IQR 5.75-44 h] and were significantly associated with higher rates of multiple organ failures (93% vs. 42%, p < 0.001), disseminated intravascular coagulation (12% vs. 1.3%, p = 0.046), septic shock (median lactate on ICU admission 4.60 vs. 2.90 mmol/L, p = 0.030) and kidney failure (KDIGO-3: 87% vs. 44%, p < 0.001). Interestingly, alcoholism was the only identified predisposing factor of KP-CAP. Severity on ICU admission (2-fold higher for KP-CAP) was the only factor associated with mortality in a multivariate analysis. CONCLUSION: We described a strong association between KP-CAP infection and higher and earlier mortality when compared to SP-CAP. Moreover, alcoholism was the sole predisposing factor associated with KP-CAP infection. These findings should raise awareness of clinicians involved in the management of severe CAP about this microbiological etiology. Future prospective studies are needed to confirm these results and to design strategies to improve the prognosis of such infections.

Use of the French National Health Data System (SNDS) in pharmacoepidemiology: A systematic review in its maturation phase.

AIM OF THE STUDY: The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase. METHODS: We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018. RESULTS: A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%). CONCLUSION: The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials.

Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases.

Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology. A significant number of questions were related to the pediatric population and/or rare diseases. A total of 27 regulatory-led RWD studies have been conducted. Most studies were descriptive and aimed at estimating incidence and prevalence rates of clinical outcomes including adverse events or to evaluate medicines utilization. The review highlights key learnings to guide further efforts to enable the use and establish the value of real-world evidence (RWE) for regulatory decisions. For instance, there is a need to access additional fit-for-purpose and representative data, and to explore further means to provide timely evidence that meets regulatory timelines. The need for early interactions and close collaboration with study requesters, e.g., from the Agency's scientific Committees, to better understand the research question is equally important. Finally, the review provides our perspective on the way forward to maximize the potential of regulatory-led RWE generation.

Fetal Muse-based therapy prevents lethal radio-induced gastrointestinal syndrome by intestinal regeneration.

BACKGROUND: Human multilineage-differentiating stress enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be easily obtained from various adult or fetal tissues. Regenerative effects of Muse cells have been shown in some disease models. Muse cells specifically home in damaged tissues where they exert pleiotropic effects. Exposition of the small intestine to high doses of irradiation (IR) delivered after radiotherapy or nuclear accident results in a lethal gastrointestinal syndrome (GIS) characterized by acute loss of intestinal stem cells, impaired epithelial regeneration and subsequent loss of the mucosal barrier resulting in sepsis and death. To date, there is no effective medical treatment for GIS. Here, we investigate whether Muse cells can prevent lethal GIS and study how they act on intestinal stem cell microenvironment to promote intestinal regeneration. METHODS: Human Muse cells from Wharton's jelly matrix of umbilical cord (WJ-Muse) were sorted by flow cytometry using the SSEA-3 marker, characterized and compared to bone-marrow derived Muse cells (BM-Muse). Under gas anesthesia, GIS mice were treated or not through an intravenous retro-orbital injection of 50,000 WJ-Muse, freshly isolated or cryopreserved, shortly after an 18 Gy-abdominal IR. No immunosuppressant was delivered to the mice. Mice were euthanized either 24 h post-IR to assess early small intestine tissue response, or 7 days post-IR to assess any regenerative response. Mouse survival, histological stainings, apoptosis and cell proliferation were studied and measurement of cytokines, recruitment of immune cells and barrier functional assay were performed. RESULTS: Injection of WJ-Muse shortly after abdominal IR highly improved mouse survival as a result of a rapid regeneration of intestinal epithelium with the rescue of the impaired epithelial barrier. In small intestine of Muse-treated mice, an early enhanced secretion of IL-6 and MCP-1 cytokines was observed associated with (1) recruitment of monocytes/M2-like macrophages and (2) proliferation of Paneth cells through activation of the IL-6/Stat3 pathway. CONCLUSION: Our findings indicate that a single injection of a small quantity of WJ-Muse may be a new and easy therapeutic strategy for treating lethal GIS.

High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold.

OBJECTIVE: Most people with type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH) or advanced fibrosis (AF) remain undiagnosed, resulting in missed opportunities for early intervention. This multicenter, prospective study assessed the yield of using routinely available data to identify these patients. RESEARCH DESIGN AND METHODS: A total of 713 outpatients with T2DM, screened in four diabetology clinics for nonalcoholic fatty liver disease according to American Diabetes Association criteria, were referred to hepatologists for further work-up (Fibrosis-4 and vibration-controlled transient elastography [VCTE]). A liver biopsy was proposed when ALT levels were persistently >20 IU/L in female patients or >30 IU/L in male patients, in the absence of other liver disease. RESULTS: Liver biopsies were performed in 360 patients and considered adequate for reading after central review for 330 specimens (median patient age, 59 years; male patients, 63%; median BMI and HbA1c values, 32 and 7.5%, respectively). Prevalence of NASH, AF, and cirrhosis were 58%, 38%, and 10%, respectively. Liver lesions were independently associated with the components of metabolic syndrome but not with the micro- and macrovascular complications of T2DM. Models based on routinely available data with or without VCTE had good accuracy to predict AF (respectively: area under the receiver operating characteristic curve [AUROC], 0.84 and 0.77; and correctly classified 59% and 45%) and NASH (respectively: AUROC, 0.82 and 0.81; 44% and 42%). CONCLUSIONS: Despite the use of a low ALT threshold, prevalence of NASH (58%) or AF (38%) was high. Routinely available data had a high yield in identifying patients with T2DM with AF and/or NASH requiring further liver assessment.