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Serum S100B allows a one-third reduction of computed tomography (CT) scans performed for mild traumatic brain injury (mTBI) patients. In this study, we evaluated the diagnostic performance of serum NF-L in the detection of intracranial lesions induced by mTBI. One hundred seventy-nine adult mTBI patients presenting to the emergency department of Clermont-Ferrand University Hospital with a Glasgow Coma Scale (GCS) score of 14–15 were included. S100B assays were performed for clinical routine while NF-L samples were stored at −80 °C until analysis. CT scans were performed for patients with S100B levels above the decision threshold of 0.10 μg/L. Later, NF-L and S100B levels were compared to CT scan findings to evaluate the biomarkers' performances. The area under the ROC curve (AUC) evaluating the diagnostic ability in the prediction of intracranial lesions was 0.72 (95% CI; 0.58–0.87) for S100B and 0.58 (95% CI; 0.45–0.71) for NF-L, the specificities (at a threshold allowing a 100% sensitivity) were 35.7% for S100B, and 28% for NF-L (p=0.096). AUCs of NF-L and S100B for the identification of patients with neurological disorders were statistically different (p<0.001). The AUCs were 0.87 (95% CI; 0.82–0.93) for NF-L and 0.57 (95% CI; 0.48–0.66) for S100B. There was a poor correlation between NF-L and S100B, and NF-L levels were correlated to patients' age (Spearman coefficient of 0.79). NF-L showed poor performances in the early management of mTBI patients. NF-L levels are strongly correlated to neurodegeneration, whether physiological, age-related, or pathological. [ABSTRACT FROM AUTHOR]

• TIO is often caused by mesenchymal tumors and rarely reported among malignancies. • This is the first case of TIO reported for a pancreatic neuroendocrine tumor. • An elevated FGF23 level may lead to the diagnosis of a malignant disease. Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by hypophosphatemia associated with elevated fibroblast growth factor 23 (FGF23). TIO is primarily caused by benign mesenchymal tumors of the soft tissue and skeleton. Rarely, it is associated with a solid tumor or hematological malignancy. To date, no case of osteomalacia related to pancreatic cancer has been reported in the literature. Case report: A 77-year-old woman was admitted to the rheumatology department (RD) of the Clermont-Ferrand University Hospital (France) for further evaluation of her hypophosphatemia. The patient reported bone pain, myalgia, and asthenia. Further laboratory tests revealed hyperphosphaturia, normocalcemia, low serum calcitriol, elevated serum alkaline phosphatase (ALP), and elevated plasma parathyroid hormone (PTH). A renal phosphate depletion disorder was suspected as an etiology for this hypophosphatemia. Finally, FGF23 levels were found to be significantly elevated, leading to a definitive diagnosis of pancreatic neuroendocrine tumor. Conclusion: This is the first report of hypophosphatemic osteomalacia related to pancreatic cancer. Therefore, in the setting of hypophosphatemia associated with renal phosphate wasting and low calcitriol level, plasma FGF23 measurement should be considered. [ABSTRACT FROM AUTHOR]

Preclinical studies have shown that volatile anesthetics may have beneficial effects on injured lungs, and pilot clinical data support improved arterial oxygenation, attenuated inflammation, and decreased lung epithelial injury in patients with acute respiratory distress syndrome (ARDS) receiving inhaled sevoflurane compared to intravenous midazolam. Whether sevoflurane is effective in improving clinical outcomes among patients with ARDS is unknown, and the benefits and risks of inhaled sedation in ARDS require further evaluation. Here, we describe the SESAR (Sevoflurane for Sedation in ARDS) trial designed to address this question. SESAR is a two-arm, investigator-initiated, multicenter, prospective, randomized, stratified, parallel-group clinical trial with blinded outcome assessment designed to test the efficacy of sedation with sevoflurane compared to intravenous propofol in patients with moderate to severe ARDS. The primary outcome is the number of days alive and off the ventilator at 28 days, considering death as a competing event, and the key secondary outcome is 90 day survival. The planned enrollment is 700 adult participants at 37 French academic and non-academic centers. Safety and long-term outcomes will be evaluated, and biomarker measurements will help better understand mechanisms of action. The trial is funded by the French Ministry of Health, the European Society of Anaesthesiology, and Sedana Medical. [ABSTRACT FROM AUTHOR]

Phthalates are reprotoxic pollutants that are omnipresent in the environment. Detectable in amniotic fluid, these compounds (with the most concentrated being mono-2-ethylhexyl phthalate (MEHP)) are in direct contact with fetal membranes (FMs). They can lead to the premature rupture of FMs by deregulating cellular and molecular pathways, such as, for example, the nuclear transcription factor peroxysome proliferator-activated receptor gamma (PPARγ) pathway. The objective was to study the impact of MEHP on the PPARγ pathway in FMs using amnion and choriodecidua across the three trimesters of pregnancy and the amniotic epithelial AV3 cell model by analyzing (i) PPARγ expression (mRNA and proteins) using RT-qPCR and Western blot assays; (ii) cytotoxicity and cell viability following MEHP treatment by lactate dehydrogenase (LDH) measurement and using Cell-counting Kit 8; and (iii) modulation by MEHP of PPARγ transcriptional activity (using a reporter gene assay) and PPARγ anti-inflammatory properties (by measuring IL6 and IL8 levels). PPARγ is expressed in the human amnion and choriodecidua during the three trimesters of pregnancy and in amniotic cells. In the AV3 cell line, MEHP is not cytotoxic and does not reduce cell viability, but it reduces PPARγ activity, here induced by a classical agonist without influencing its expression. MEHP also reduces PPARγ's anti-inflammatory properties. In conclusion, PPARγ signaling is dysregulated by MEHP; this paves the way for future explorations to highlight the hypothesis of phthalates as an amniotic PPARγ disruptor that can explain the premature rupture of FMs. [ABSTRACT FROM AUTHOR]

The integrity of human fetal membranes is crucial for harmonious fetal development throughout pregnancy. Their premature rupture is often the consequence of a physiological phenomenon that has been exacerbated. Beyond all the implied biological processes, inflammation is of primary importance and is qualified as 'sterile' at the end of pregnancy. In this study, complementary methylomic and transcriptomic strategies on amnion and choriodecidua explants obtained from the altered (cervix zone) and intact fetal membranes at term and before labour were used. By cross-analysing genome-wide studies strengthened by in vitro experiments, we deciphered how the expression of toll-like receptor 4 (TLR4), an actor in pathological fetal membrane rupture, is controlled. Indeed, it is differentially regulated in the altered zone and between both layers by a dual mechanism: (1) the methylation of TLR4 and miRNA promoters and (2) targeting by miRNA (let-7a-2 and miR-125b-1) acting on the 3'-UTR of TLR4. Consequently, this study demonstrates that fine regulation of TLR4 is required for sterile inflammation establishment at the end of pregnancy and that it may be dysregulated in the pathological premature rupture of membranes. [ABSTRACT FROM AUTHOR]

Background. Because of the implications of Receptor for Advanced Glycation End Products (RAGE) in keratoconus (KC), we describe a differential expression of RAGE transcripts and proteins in corneal tissues and tears of KC and healthy patients. Methods. Using a case-controlled study, corneal epitheliums and tears of KC and healthy subjects were obtained during corneal collagen cross-linking and photorefractive keratectomy (PKR) and during usual consultations. Quantitative reverse transcription (RT-qPCR) and Western-Blot were performed to analyze RAGE transcripts and proteins' expression in corneal tissues and tears. Results. One hundred and six patients were included in this study. The characteristics of the patients were as follows: 56 KC (25 corneal epithelium and 31 tears) and 50 control subjects (25 corneal epithelium and 25 tears). Transcripts of RAGE, HMGB1, and S100 family ligands were quantified by RT-qPCR, identifying a significantly higher expression of RAGE and HMGB1 in the healthy group than in the KC group (p = 0.03 and 0.04, respectively). Western Blot showed a significantly higher fl-RAGE expression in KC corneal epithelium than control (p < 0.001) and lower s-RAGE expression in KC tears than control (p = 0.04). Conclusions. Linked with the inflammatory process occurring in KC pathophysiology, we propose for the first time that the RAGE expression (total and truncated forms of receptor and ligands) in KC corneal tissues and tear samples provides viable biomarkers. [ABSTRACT FROM AUTHOR]

Polyhydramnios is a common feature diagnosed by ultrasound in the second half of pregnancy. Biochemical analysis of amniotic fluid can be useful when suspecting Bartter syndrome or digestive atresia but in most of cases, no etiology of polyhydramnios is found because of the complex regulation of amniotic fluid. Aquaporins (AQP) are transmembrane channel proteins contributing to water transfers. Some of them are expressed in fetal membranes and placenta. Their expression has been shown to be disrupted in some pathological conditions such as maternal diabetes, often associated with polyhydramnios. AQP-1, 3 and 8 levels in amniotic fluid were retrospectively measured in patients suffering from polyhydramnios (n=21) from 23 weeks of gestation (WG). They were compared to the levels observed in control subjects (n=96) and their relationship with maternal factors and neonatal issues was analyzed. AQP-1, 3, 8 levels were physiologically fluctuating, AQP-1 levels always being the lowest and AQP-3 the highest, with a significant decrease at the end of pregnancy. AQPs/AFP ratios increased about 8 folds during pregnancy, their kinetic profiles reflecting physiological dynamic evolution of amniotic fluid volume. In polyhydramnios, AQP-3 level tended to be decreased whereas AQP-8 level was decreased from mid-gestation whatever the etiology of polyhydramnios. No significant relationship was found between AQPs levels and either the fetal prematurity degree or macrosomia. No specific pattern was observed in idiopathic polyhydramnios, limiting the interest of AQPs dosage in amniotic fluid in the management of those complicated pregnancies. [ABSTRACT FROM AUTHOR]

Background: We previously assessed the inclusion of S100B blood determination into clinical decision rules for mild traumatic brain injury (mTBI) management in the Emergency Department (ED) of Clermont-Ferrand Hospital. At the 0.10 µg/L threshold, S100B reduced the use of cranial computed tomography (CCT) scan in adults by at least 30% with a ~100% sensitivity. Older patients had higher serum S100B values, resulting in lower specificity (18.7%) and decreased CCT reduction. We conducted this study to confirm the age effect on S100B concentrations, and to propose new decisional thresholds for older patients.Methods: A total of 1172 mTBI patients aged 65 and over were included. They were divided into 3 age groups: 65-79, 80-89, and ≥ 90 years old. S100B's performance to identify intracranial lesions (sensitivity [SE] and specificity [SP]) was assessed using the routine 0.10 µg/L threshold and also other more efficient thresholds established for each age group.Results: S100B concentration medians were 0.18, 0.26, and 0.32 µg/L for the 65-79, 80-89, and ≥ 90 years old age groups, respectively (p < .001). The most efficient thresholds were 0.11 µg/L for the 65-79 age group and 0.15 µg/L for the other groups. At these new thresholds, SP was respectively 28.4%, 34.3%, and 20.5% for each age group versus 24.9%, 18.2%, and 10.5% at the 0.10 µg/L threshold.Conclusions: Adjustment of the S100B threshold is necessary in older patients' management. An increased threshold of 0.15 µg/L is particularly interesting for patients ≥ 80 years old, allowing a significant increase of CCT scan reduction (29.3%). [ABSTRACT FROM AUTHOR]

Global prevalence of type 2 diabetes (T2D) is rising and may affect 700 million people by 2045. Totum-63 is a polyphenol-rich natural composition developed to reduce the risk of T2D. We first investigated the effects of Totum-63 supplementation in highfat diet (HFD)-fed mice for up to 16 wk and thereafter assessed its safety and efficacy (2.5 g or 5 g per day) in 14 overweight men [mean age 51.5 yr, body mass index (BMI) 27.6 kg·m-2] for 4 wk. In HFD-fed mice, Totum-63 reduced body weight and fat mass gain, whereas lean mass was unchanged. Moreover, fecal energy excretion was higher in Totum-63-supplemented mice, suggesting a reduction of calorie absorption in the digestive tract. In the gut, metagenomic analyses of fecal microbiota revealed a partial restoration of HFD-induced microbial imbalance, as shown by principal coordinate analysis of microbiota composition. HFDinduced increase in HOMA-IR score was delayed in supplemented mice, and insulin response to an oral glucose tolerance test was significantly reduced, suggesting that Totum-63 may prevent HFD-related impairments in glucose homeostasis. Interestingly, these improvements could be linked to restored insulin signaling in subcutaneous adipose tissue and soleus muscle. In the liver, HFD-induced steatosis was reduced by 40% (as shown by triglyceride content). In the subsequent study in men, Totum-63 (5 g·day-1) improved glucose and insulin responses to a high-carbohydrate breakfast test (84% kcal carbohydrates). It was well tolerated, with no clinically significant adverse events reported. Collectively, these data suggest that Totum-63 could improve glucose homeostasis in both HFD-fed mice and overweight individuals, presumably through a multitargeted action on different metabolic organs. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a serious lung condition that often leads to hospitalization in intensive care units and a high mortality rate. Sevoflurane is a volatile anesthetic with growing interest for sedation in ventilated patients with ARDS. It has been shown to have potential lung-protective effects, such as reduced inflammation and lung edema, or improved arterial oxygenation. In this study, we investigated the effects of sevoflurane on lung injury in cultured human carcinoma-derived lung alveolar epithelial (A549) cells. We found that sevoflurane was associated with improved wound healing after exposure to inflammatory cytokines, with preserved cell proliferation but no effect on cell migration properties. Sevoflurane exposure was also associated with enhanced cell viability and active autophagy in A549 cells exposed to cytokines. These findings suggest that sevoflurane may have beneficial effects on lung epithelial injury by promoting alveolar epithelial wound healing and by influencing the survival and proliferation of A549 epithelial cells in vitro. Further research is needed to confirm these findings and to investigate the key cellular mechanisms explaining sevoflurane's potential effects on lung epithelial injury. [ABSTRACT FROM AUTHOR]

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders. Mice lacking the liver X nuclear receptors (LXRs), crucial integrators of lipid metabolism, were used to study the response of the prostate to androgen deprivation. This reveals that lack of androgens leads to chronic inflammation due to impaired clearance of castration-induced apoptotic cells, allowing production of pro-inflammatory cytokines and promoting prostate neoplasia. [ABSTRACT FROM AUTHOR]

• The S100B protein can be used in the clinical routine in the management of mTBI. • S100B levels combined with a clinical algorithm, could reduce for CT scans by 1/3. • Sampling should take place within 3 h of trauma for S100B assay. • For S100B and probably other biomarkers, specific cut-off levels and paediatric reference ranges had to be defined. • GFAP in combination with H-FABP could improve the specificity of S100B. Mild traumatic brain injury (mTBI) is one of the common causes of emergency department visits around the world. Up to 90% of injuries are classified as mTBI. Cranial computed tomography (CCT) is a standard diagnostic tool for adults with mTBI. Alternatively, children can be admitted for inpatient observation with CCT scans performed only on those with clinical deterioration. The use of blood biomarkers is a supplementary tool for identifying patients at risk of intracerebral lesions who may need imaging. This review provides a contemporary clinical and laboratory framework for blood biomarker testing in mTBI management. The S100B protein is used routinely in the management of mTBI in Europe together with clinical guidelines. Due to its excellent negative predictive value, S100B protein is an alternative choice to CCT scanning for mTBI management under considered, consensual and pragmatic use. In this review, we propose points to help clinicians and clinical pathologists use serum S100B protein in the clinical routine. A review of the literature on the different biomarkers (GFAP, UCH-L1, NF [H or L], tau, H-FABP, SNTF, NSE, miRNAs, MBP, β trace protein) is also conducted. Some of these other blood biomarkers, used alone (GFAP, UCH-L1) or in combination (GFAP + H-FABP ± S100B ± IL10) can improve the specificity of S100B. [ABSTRACT FROM AUTHOR]

Background: Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.Methods: We will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.Discussion: This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.Systematic Review Registration: PROSPERO (ID: CRD42019157236). [ABSTRACT FROM AUTHOR]

To investigate the contribution of FGF23 in explaining the cases of hypophosphatemia observed in clinical practice, we aimed to determine for the first time the prevalence of FGF23 elevation in patients with hypophosphatemia and to describe the different mechanisms of FGF23-related hypophosphatemic disorders. We performed a prospective, observational, multicenter, cohort study of 260 patients with hypophosphatemia. Blood measurements (PTH, 1,25-dihydroxyvitamin D, bone alkaline phosphatase, 25-hydroxyvitamin D, and FGF23) were performed on a Liaison XL® (DiaSorin) analyzer. Primary elevation of FGF23 (>95.4 pg/mL) was reported in 10.4% (95CI: 7.0–14.7) of patients (n = 27) with hypophosphatemia, suggesting that at least 1 in 10 cases of hypophosphatemia was erroneously attributed to an etiology other than FGF23 elevation. Patients with elevated blood FGF23 were grouped according to the etiology of the FGF23 elevation. Thus, 10 patients had a renal pathology, chronic kidney disease or post-renal transplantation condition. The remaining patients (n = 17) had the following etiologies: malignancies (n = 9), benign pancreatic tumor (n = 1), post-cardiac surgery (n = 4), cirrhosis (n = 2), and chronic obstructive pulmonary disease (n = 1). In order to improve patient management, it seems essential to better integrate plasma FGF23 measurement into the routine evaluation of hypophosphatemia. [ABSTRACT FROM AUTHOR]

Objective: The aim of this work was to assess the cost-effectiveness of the fetal fibronectin (fFN) test at 48 h after admission for threatened preterm delivery to promote early discharge.Study Design: Before-and-after study to calculate the incremental cost-effectiveness ratio (ICER). Patients were enrolled 48 h after admission in a tertiary care centre for threatened preterm delivery between 24+0 and 34+6 weeks. fFN testing was performed. During the first period, physician was blinded to fFN test and discharge occurred after apparent reduced symptomatology at physician's discretion. During the second period, fFN test was revealed to physician and discharge was immediately proposed to negative test patients. The costs considered in this analysis were the direct medical costs from the hospital perspective: costs of hospitalisation, treatment, and imaging procedures. The efficacy criterion selected was the number of deliveries at 7 and at 14 days after admission for threatened preterm delivery.Results: The study included 178 pregnant patient, 99 during the first period (July 2008-October 2009) and 79 during the second (March 2010-February 2012). The lengths of hospital stays were shorter during the second period, with more than 50% of women discharged home between 48 and 72 h (p < 0.0001) resulting in a cost-saving of 76 051 euros. The number of deliveries at 7 and at 14 days was similar between the two periods.Conclusion: The fFN test at 48 h after admission supported early discharge and was safe and cost-effective. [ABSTRACT FROM AUTHOR]

Purpose: The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury.Methods: We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume.Results: Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01-1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02-1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07-3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT.Conclusions: Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241). [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is heterogeneous by definition and patient response varies depending on underlying biology and their severity of illness. Although ARDS subtypes have been identified with different prognoses in past studies, the concept of phenotypes or endotypes does not extend to the clinical definition of ARDS. This has possibly hampered the development of therapeutic interventions that target select biological mechanisms of ARDS. Recently, a major advance may have been achieved as it may now be possible to identify ARDS subtypes that may confer different responses to therapy. The aim of personalised medicine is to identify, select, and test therapies that are most likely to be associated with a favourable outcome in a specific patient. Several promising approaches to ARDS subtypes capable of predicting therapeutic response, and not just prognosis, are highlighted in this perspective paper. An overview is also provided of current and future directions regarding the provision of personalised ARDS medicine. The importance of delivering the right care, at the right time, to the right patient, is emphasised. [ABSTRACT FROM AUTHOR]

To develop a multidisciplinary French reference that addresses initial pre- and in-hospital management of a mild traumatic brain injury patient. A panel of 22 experts was formed on request from the French Society of Emergency Medicine (SFMU) and the French Society of Anaesthesiology and Critical Care Medicine (SFAR). A policy of declaration and monitoring of links of interest was applied and respected throughout the process of producing the guidelines. Similarly, no funding was received from any company marketing a health product (drug or medical device). The expert panel had to respect and follow the Grade® (Grading of Recommendations Assessment, Development and Evaluation) methodology to evaluate the quality of the evidence on which the recommendations were based. Given the impossibility of obtaining a high level of evidence for most of the recommendations, it was decided to adopt a "Recommendations for Professional Practice" (RPP) format, rather than a Formalized Expert Recommendation (FER) format, and to formulate the recommendations using the terminology of the SFMU and SFAR Guidelines. Three fields were defined: 1) pre-hospital assessment, 2) emergency room management, and 3) emergency room discharge modalities. The group assessed 11 questions related to mild traumatic brain injury. Each question was formulated using a PICO (Patients Intervention Comparison Outcome) format. The experts' synthesis work and the application of the GRADE® method resulted in the formulation of 14 recommendations. After two rounds of rating, strong agreement was obtained for all recommendations. For one question, no recommendation could be made. There was strong agreement among the experts on important, transdisciplinary recommendations, the purpose of which is to improve management practices for patients with mild head injury. [ABSTRACT FROM AUTHOR]

Different acute respiratory distress syndrome (ARDS) phenotypes may explain controversial results in clinical trials. Lung-morphology is one of the ARDS-phenotypes and physiological studies suggest different responses in terms of positive-end-expiratory-pressure (PEEP) and recruitment-manoeuvres (RM) according to loss of aeration. To evaluate whether tailored ventilator regimens may impact ARDS outcomes, our group has designed a randomised-clinical-trial of ventilator settings according to lung morphology in moderate-to-severe ARDS (LIVE study). Method Patients will be enrolled within the first 12 hours of ARDS onset. In both groups, volume-controlled ventilation with low tidal-volumes (Vt) will be used to target a plateau pressure ≤ 30 cmH 2 O. In the control group, the PEEP level and inspired fraction of oxygen (FiO 2 ) will be set using the ARDSNet table; a Vt of 6 mL/kg of predicted body weight (PBW) will be set and prone position (PP) will be applied. In the intervention arm, the ventilator will be set according to lung morphology (focal/non-focal) that will be assessed according to CT-scan ± chest x-ray + lung echography. For focal ARDS patients, a Vt of 8 mL/kg PBW will be used along with low PEEP and PP. For non-focal ARDS patients, a Vt of 6 mL/kg PBW will be used with RM and PEEP to reach a plateau pressure ≤ 30 cmH 2 O. The primary outcome is all-cause 90-day mortality and the secondary outcomes are: in-hospital mortality, mortality at day 28, 60, 180 and 365; ventilator-free days at day 30, quality of life at one year; ventilator-associated pneumonia rate; barotrauma; ICU and hospital length of stay. This RCT is registered on Clinicaltrials.gov under identifier NCT02149589 . [ABSTRACT FROM AUTHOR]

Glaucoma is the leading cause of irreversible blindness and is usually classified as angle closure and open angle glaucoma (OAG). Primary open angle glaucoma represents the most frequent clinical presentation leading to ganglion cell death and optic nerve degeneration as a main consequence of an intraocular pressure’ (IOP) increase. The mechanisms of this IOP increase in such pathology remain unclear but one protein called Myocilin could be a part of the puzzle in the trabecular meshwork (TM). Previously described to be transcriptionally regulated by glucocorticoids, the comprehension of the trabecular regulation of Myocilin’ expression has only weakly progressed since 15 years. Due to the essential molecular and cellular implications of retinoids’ pathway in eye development and physiology, we investigate the potential role of the retinoic acid in such regulation and expression. This study demonstrates that the global retinoids signaling machinery is present in immortalized TM cells and that Myocilin ( MYOC) expression is upregulated by retinoic acid alone or combined with a glucocorticoid co-treatment. This regulation by retinoic acid acts through the MYOC promoter which contains a critical cluster of four retinoic acid responsive elements (RAREs), with the RARE-DR2 presenting the strongest effect and binding the RARα/RXRα heterodimer. All together, these results open up new perspectives for the molecular understanding glaucoma pathophysiology and provide further actionable clues on Myocilin gene regulation. [ABSTRACT FROM AUTHOR]

Background The acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that encompasses multiple phenotypes, e.g. with regards to lung morphology as assessed by computed tomography (CT). Focal or non-focal lung morphology may influence the response to positive end-expiratory pressure (PEEP), recruitment manoeuvres and prone position. Lung morphology has been hypothesized to be associated with alveolar fluid clearance (AFC), thus explaining various responses to such therapeutic interventions; however, this hypothesis has not been specifically studied in humans. Methods We measured net AFC rates in 30 patients with ARDS as a secondary data analysis of a prospective single-centre study. Net AFC rates were compared between patients with focal ARDS and those with non-focal ARDS, as assessed by lung CT-scans. Results Net AFC rates were significantly lower in patients with non-focal ARDS ( n = 23; median [interquartile range], 1.5 [0–5.5] %/h) as compared to those with focal ARDS ( n = 7; 10.3 [4.5–15] %/h) ( P = 0.01). The area under the receiver-operating characteristic curve when net AFC rates were used to differentiate the presence from absence of non-focal ARDS was 0.93 (95% confidence interval, 0.81–1). Tidal volumes and PEEP levels differed between focal and non-focal ARDS patients, but there was no difference in arterial oxygenation or in alveolar-capillary permeability. Conclusions Non-focal lung morphology may be characterized by a functional endotype consistent with marked AFC impairment. Despite study limitations and the need for validating studies in larger cohorts, such novel findings may reinforce our understanding of the association between ARDS phenotypes and therapeutic responses. [ABSTRACT FROM AUTHOR]

Adrenal insufficiency secondary to opioid use remains inadequately acknowledged in medical literature. We present the case of a 33-year-old female patient diagnosed with central adrenal insufficiency (CAI), where methadone use was identified as the underlying cause after ruling out known etiologies. This article aims to enhance awareness among prescribing clinicians and medical professionals regarding the potential occurrence of AI in patients undergoing methadone treatment. This is especially pertinent given the widespread utilization of methadone in France for managing drug withdrawal.

Traumatic brain injury (TBI) is a common reason for presenting to emergency departments (EDs). The assessment of these patients is frequently hampered by various confounders, and diagnostics is still often based on nonspecific clinical signs. Throughout Europe, there is wide variation in clinical practices, including the follow-up of those discharged from the ED. The objective is to present a practical recommendation for the assessment of adult patients with an acute TBI, focusing on milder cases not requiring in-hospital care. The aim is to advise on and harmonize practices for European settings. A multiprofessional expert panel, giving consensus recommendations based on recent scientific literature and clinical practices, is employed. The focus is on patients with a preserved consciousness (Glasgow Coma Scale 13-15) not requiring in-hospital care after ED assessment. The main results of this paper contain practical, clinically usable recommendations for acute clinical assessment, decision-making on acute head computerized tomography (CT), use of biomarkers, discharge options, and needs for follow-up, as well as a discussion of the main features and risk factors for prolonged recovery. In conclusion, this consensus paper provides a practical stepwise approach for the clinical assessment of patients with an acute TBI at the ED. Recommendations are given for the performance of acute head CT, use of brain biomarkers and disposition after ED care including careful patient information and organization of follow-up for those discharged., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite the use of validated guidelines in the management of mild traumatic brain injury (mTBI), processes to limit unnecessary brain scans are still not sufficient and need to be improved. The use of blood biomarkers represents a relevant adjunct to identify patients at risk for intracranial injury requiring computed tomography (CT) scan., Content: Biomarkers currently recommended in the management of mTBI in adults and children are discussed in this review. Protein S100 beta (S100B) is the best-documented blood biomarker due to its validation in large observational and interventional studies. Glial fibrillary acidic protein (GFAP) and ubiquitin carboxyterminal hydrolase L-1 (UCH-L1) have also recently demonstrated their usefulness in patients with mTBI. Preanalytical, analytical, and postanalytical performance are presented to aid in their interpretation in clinical practice. Finally, new perspectives on biomarkers and mTBI are discussed., Summary: In adults, the inclusion of S100B in Scandinavian and French guidelines has reduced the need for CT scans by at least 30%. S100B has significant potential as a diagnostic biomarker, but limitations include its rapid half-life, which requires blood collection within 3 h of trauma, and its lack of neurospecificity. In 2018, the FDA approved the use of combined determination of GFAP and UCH-L1 to aid in the assessment of mTBI. Since 2022, new French guidelines also recommend the determination of GFAP and UCH-L1 in order to target a larger number of patients (sampling within 12 h post-injury) and optimize the reduction of CT scans. In the future, new cut-offs related to age and promising new biomarkers are expected for both diagnostic and prognostic applications., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: In light of the burden of traumatic brain injury (TBI) in children and the excessive number of unnecessary CT scans still being performed, new strategies are needed to limit their use while minimising the risk of delayed diagnosis of intracranial lesions (ICLs). Identifying children at higher risk of poor outcomes would enable them to be better monitored. The use of the blood-based brain biomarkers glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) could help clinicians in this decision. The overall aim of this study is to provide new knowledge regarding GFAP and UCH-L1 in order to improve TBI management in the paediatric population., Methods and Analysis: We will conduct a European, prospective, multicentre study, the BRAINI-2 paediatric study, in 20 centres in France, Spain and Switzerland with an inclusion period of 30 months for a total of 2880 children and adolescents included. To assess the performance of GFAP and UCH-L1 used separately and in combination to predict ICLs on CT scans (primary objective), 630 children less than 18 years of age with mild TBI, defined by a Glasgow Coma Scale score of 13-15 and with a CT scan will be recruited. To evaluate the potential of GFAP and UCH-L1 in predicting the prognosis after TBI (secondary objective), a further 1720 children with mild TBI but no CT scan as well as 130 children with moderate or severe TBI will be recruited. Finally, to establish age-specific reference values for GFAP and UCH-L1 (secondary objective), we will include 400 children and adolescents with no history of TBI., Ethics and Dissemination: This study has received ethics approval in all participating countries. Results from our study will be disseminated in international peer-reviewed journals. All procedures were developed in order to assure data protection and confidentiality., Trial Registration Number: NCT05413499., Competing Interests: Competing interests: OM and VP are employees of bioMérieux. The other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Minor head trauma (HT) is one of the most common causes of hospitalization in children. A diagnostic test could prevent unnecessary hospitalizations and cranial computed tomographic (CCT) scans., Objective: To evaluate the effectiveness of serum S100B values in reducing exposure to CCT scans and in-hospital observation in children with minor HT., Design, Setting, and Participants: This multicenter, unblinded, prospective, interventional randomized clinical trial used a stepped-wedge cluster design to compare S100B biomonitoring and control groups at 11 centers in France. Participants included children and adolescents 16 years or younger (hereinafter referred to as children) admitted to the emergency department with minor HT. The enrollment period was November 1, 2016, to October 31, 2021, with a follow-up period of 1 month for each patient. Data were analyzed from March 7 to May 29, 2023, based on the modified intention-to-treat and per protocol populations., Interventions: Children in the control group had CCT scans or were hospitalized according to current recommendations. In the S100B biomonitoring group, blood sampling took place within 3 hours after minor HT, and management depended on serum S100B protein levels. If the S100B level was within the reference range according to age, the children were discharged from the emergency department. Otherwise, children were treated as in the control group., Main Outcomes and Measures: Proportion of CCT scans performed (absence or presence of CCT scan for each patient) in the 48 hours following minor HT., Results: A total of 2078 children were included: 926 in the control group and 1152 in the S100B biomonitoring group (1235 [59.4%] boys; median age, 3.2 [IQR, 1.0-8.5] years). Cranial CT scans were performed in 299 children (32.3%) in the control group and 112 (9.7%) in the S100B biomonitoring group. This difference of 23% (95% CI, 19%-26%) was not statistically significant (P = .44) due to an intraclass correlation coefficient of 0.32. A statistically significant 50% reduction in hospitalizations (95% CI, 47%-53%) was observed in the S100B biomonitoring group (479 [41.6%] vs 849 [91.7%]; P < .001)., Conclusions and Relevance: In this randomized clinical trial of effectiveness of the serum S100B level in the management of pediatric minor HT, S100B biomonitoring yielded a reduction in the number of CCT scans and in-hospital observation when measured in accordance with the conditions defined by a clinical decision algorithm., Trial Registration: ClinicalTrials.gov Identifier: NCT02819778.

Blood biomarkers, including neurofilament light chain (NfL), have garnered attention as potential indicators for chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting adverse effect of neurotoxic anticancer drugs. However, no blood biomarker has been established for routine application or translational research. This pilot study aimed to evaluate a limited panel of blood biomarkers in rat models of CIPN and their correlations with neuropathic pain. CIPN models were induced through repeated injections of oxaliplatin, paclitaxel, bortezomib, and vincristine. Electronic von Frey testing was used to assess tactile allodynia. Post anticancer injections, serum concentrations of 31 proteins were measured. Allodynia thresholds decreased in anticancer-treated animals compared to controls. No consistent modifications were observed in the biomarkers across CIPN models. The most noteworthy biomarkers with increased concentrations in at least two CIPN models were NfL (paclitaxel, vincristine), MCP-1, and RANTES (oxaliplatin, vincristine). Vincristine-treated animals exhibited strong correlations between LIX, MCP-1, NfL, and VEGF concentrations and tactile allodynia thresholds. No single biomarker can be recommended as a unique indicator of CIPN-related pain. Because of the study limitations (single dose of each anticancer drug, young animals, and single time measurement of biomarkers), further investigations are necessary to define the kinetics, specificities, and sensitivities of MCP-1, RANTES, and NfL.

Objectives: To compare for the first time the performance of "GFAP and UCH-L1" vs. S100B in a cohort of patients managed for mild traumatic brain injury (mTBI) according to actualized French guidelines., Methods: A prospective study was recently carried at the Emergency Department of Clermont-Ferrand University Hospital in France. Patients with mTBI presenting a medium risk of complications were enrolled. Blood S100B and "GFAP and UCHL-1" were sampled and measured according to French guidelines. S100B was measured in patients with samples within 3 h of trauma (Cobas ® , Roche Diagnostics), while GFAP and UCHL-1 were measured in all patients (samples <3 h and 3-12 h) using another automated assay (i-STAT ® Alinity, Abbott)., Results: For sampling <3 h, serum S100B correctly identifies intracranial lesions with a specificity of 25.7 % (95 % CI; 19.5-32.6 %), a sensitivity of 100 % (95 % CI; 66.4-100 %), and a negative predictive value of 100 % (95 % CI; 92.5-100 %). For sampling <12 h, plasma "GFAP and UCH-L1" levels correctly identify intracranial lesions with a specificity of 31.7 % (95 % CI; 25.7-38.2 %), a sensitivity of 100 % (95 % CI; 73.5-100 %), and a negative predictive value of 100 % (95 % CI; 95-100 %). Comparison of specificities (25.7 vs. 31.7 %) did not reveal a statistically significant difference (p=0.16)., Conclusions: We highlight the usefulness of measuring plasma "GFAP and UCH-L1" levels to target mTBI patients (sampling within 12 h post-injury) and optimize the reduction of CT scans., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

A threshold of 50 μg fecal calprotectin per g stool sample (μg/g) is commonly used to diagnose chronic inflammatory bowel disease in adult patients and children over 4 years of age. In younger children, fecal calprotectin values are physiologically increased. For the first time, the objective of our study was to establish reference ranges in newborns for the measurement of meconium calprotectin with an automated assay (Liaison® XL, DiaSorin). A prospective study was conducted in 2022 in the Maternity Unit of the Clermont-Ferrand University Hospital, with the inclusion of full-term newborns without intestinal involvement. The quantitative automated Liaison® XL calprotectin assay was assessed on a panel of meconium samples. In our cohort of 132 term neonates, calprotectin values ranged from 21 to 855 μg/g of meconium (2,5th to 97.5th percentile) and the median value was 194 μg/g. In our cohort, only sex-related differences were observed for calprotectin values. No significant differences were found for the other factors studied (maternal or neonatal). Because of inter-individual variability, a sequential measurement of newborn calprotectin from meconium should be considered.

Context: Tumor-induced osteomalacia (TIO) due to fibroblast growth factor 23 (FGF23) overexpression is becoming recognized in patients with malignancy. The condition may be underdiagnosed, with a scarce medical literature., Objective: To perform a meta-analysis of case reports to allow a better understanding of malignant TIO and its clinical implications., Methods: Full texts were selected according to strict inclusion criteria. All case reports were included where patients had hypophosphatemia, malignant TIO, and FGF23 blood levels. Thirty-two of 275 eligible studies (n = 34 patients) met inclusion criteria. A list of desired data was extracted and graded for methodological quality., Results: Prostate adenocarcinoma (n = 9) were the most tumors reported. Twenty-five of 34 patients had a metastatic disease and a poor clinical outcome was reported for 15 of 28 patients. The median levels of blood phosphate and C-terminal FGF23 (cFGF23) were 0.40 mmol/L and 788.5 RU/mL, respectively. For most of patients, blood PTH was elevated or within range, and calcitriol levels were inappropriately low or normal. Alkaline phosphatase concentrations were increased for 20 of 22 patients. The cFGF23 values were significantly higher for patients with a poor clinical outcome when compared to other patients (1685 vs 357.5 RU/mL). In case of prostate cancer, cFGF23 levels were significantly lower (429.4 RU/mL) than for other malignancies (1007.5 RU/mL)., Conclusion: We report for the first time a detailed description of the clinical and biological characteristics of malignant TIO. In this context, FGF23 blood measurement would be of value for the diagnostic workup, prognostication, and follow-up of patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: After a prolonged intensive care unit (ICU) stay patients experience increased mortality and morbidity. The primary aim of this study was to assess the prognostic value of nutritional status, body mass composition and muscle strength, as assessed by body mass index (BMI), bioelectrical impedance analysis (BIA), handgrip (HG) test, and that of the biological features to predict one-year survival at the end of a prolonged ICU stay., Methods: This was a multicenter prospective observational study. Survivor patients older than 18 years with ICU length of stay >72 h were eligible for inclusion. BIA and HG were performed at the end of the ICU stay. Malnutrition was defined by BMI and fat-free mass index (FFMI). The primary endpoint was one-year mortality. Multivariable logistic regression was performed to determine parameters associated with mortality., Results: 572 patients were included with a median age of 63 years [53.5; 71.1], BMI of 26.6 kg/m 2 [22.8; 31.3], SAPS II score of 43 [31; 58], and ICU length of stay of 9 days [6; 15]. Malnutrition was observed in 142 (24.9%) patients. During the 1-year follow-up after discharge, 96 (18.5%) patients died. After adjustment, a low HG test score (aOR = 1.44 [1.11; 1.89], p = 0.01) was associated with 1-year mortality. Patients with low HG score, malnutrition, and Albuminemia <30 g/L had a one-year death rate of 41.4%. Conversely, patients with none of these parameters had a 1-year death rate of 4.1%., Conclusion: BIA to assess FFMI, HG and albuminemia at the end of ICU stay could be used to predict 1-year mortality. Their ability to identify patients eligible for a structured recovery program could be studied., Competing Interests: Conflicts of interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

We conducted a prospective double-blind study to compare two vaginal diagnostic methods in singleton pregnancies with threatened preterm labor (TPL) at the University Hospital of Clermont-Ferrand (France) from August 2018 to December 2020. Our main objective was to compare the diagnostic capacity at admission, in terms of positive predictive value (PPV) and negative predictive value (NPV), of Premaquick ® (combined detection of IL-6/total IGFBP-1/native IGFBP-1) and QuikCheck fFN™ (fetal fibronectin) for delivery within 7 days in cases of TPL. We included 193 patients. Premaquick ® had a sensitivity close to 89%, equivalent to QuikCheck fFN™, but a higher statistical specificity of 49.5% against 38.6% for QuikCheck fFN™. We found no superiority of Premaquick ® over QuickCheck fFN™ in terms of PPV (6.6% vs. 7.9%), with NPV being equivalent in predicting childbirth within 7 days in cases of TPL (98.6% vs. 98.9%). Nevertheless, the combination of positive native and total IGFBP-1 and the combination of all three positive markers were associated with a higher PPV. Our results, though non-significant, support this combined multiple-biomarker approach to improve testing in terms of predictive values.

Objective: To develop a multidisciplinary French reference that addresses initial pre- and in-hospital management of a mild traumatic brain injury patient., Design: A panel of 22 experts was formed on request from the French Society of Emergency Medicine (SFMU) and the French Society of Anaesthesiology and Critical Care Medicine (SFAR). A policy of declaration and monitoring of links of interest was applied and respected throughout the process of producing the guidelines. Similarly, no funding was received from any company marketing a health product (drug or medical device). The expert panel had to respect and follow the Grade® (Grading of Recommendations Assessment, Development and Evaluation) methodology to evaluate the quality of the evidence on which the recommendations were based. Given the impossibility of obtaining a high level of evidence for most of the recommendations, it was decided to adopt a "Recommendations for Professional Practice" (RPP) format, rather than a Formalized Expert Recommendation (FER) format, and to formulate the recommendations using the terminology of the SFMU and SFAR Guidelines., Methods: Three fields were defined: 1) pre-hospital assessment, 2) emergency room management, and 3) emergency room discharge modalities. The group assessed 11 questions related to mild traumatic brain injury. Each question was formulated using a PICO (Patients Intervention Comparison Outcome) format., Results: The experts' synthesis work and the application of the GRADE® method resulted in the formulation of 14 recommendations. After two rounds of rating, strong agreement was obtained for all recommendations. For one question, no recommendation could be made., Conclusion: There was strong agreement among the experts on important, transdisciplinary recommendations, the purpose of which is to improve management practices for patients with mild head injury., (Copyright © 2023. Published by Elsevier Masson SAS.)

Introduction: Two blood brain-derived biomarkers, glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), can rule out intracranial lesions in patients with mild traumatic brain injury (mTBI) when assessed within the first 12 hours. Most elderly patients were excluded from previous studies due to comorbidities. Biomarker use in elderly population could be affected by increased basal levels. This study will assess the performance of an automated test for measuring serum GFAP and UCH-L1 in elderly patients to predict the absence of intracranial lesions on head CT scans after mTBI, and determine both biomarkers reference values in a non-TBI elderly population., Methods and Analysis: This is a prospective multicentre observational study on elderly patients (≥65 years) that will be performed in Spain, France and Germany. Two patient groups will be included in two independent substudies. (1) A cohort of 2370 elderly patients (1185<80 years and 1185≥80 years; BRAINI2-ELDERLY DIAGNOSTIC AND PROGNOSTIC STUDY) with mTBI and a brain CT scan that will undergo blood sampling within 12 hours after mTBI. The primary outcome measure is the diagnostic performance of GFAP and UCH-L1 measured using an automated assay for discriminating between patients with positive and negative findings on brain CT scans. Secondary outcome measures include the performance of both biomarkers in predicting early (1 week) and midterm (3 months) neurological status and quality of life after trauma. (2) A cohort of 480 elderly reference participants (BRAINI2-ELDERLY REFERENCE STUDY) in whom reference values for GFAP and UCHL1 will be determined., Ethics and Dissemination: Ethical approval was obtained from the Institutional Review Boards of Hospital 12 de Octubre in Spain (Re#22/027) and Southeast VI (Clermont Ferrand Hospital) (Re# 22.01782.000095) in France. The study's results will be presented at scientific meetings and published in peer-review publications., Trial Registration Number: NCT05425251., Competing Interests: Competing interests: OM and VP are employees of bioMérieux., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Dry eye inflammation is a key step in a vicious circle and needs to be better understood in order to break it. The goals of this work were to, first, characterize alarmins and cytokines released by ocular surface cells in the hyperosmolar context and, second, study the role of NFAT5 in this process. Finally, we studied the potential action of these alarmins in ocular surface epithelial cells and macrophages via RAGE pathways. HCE and WKD cell lines were cultured in a NaCl-hyperosmolar medium and the expression of alarmins (S100A4, S100A8, S100A9, and HMGB1), cytokines (IL6, IL8, TNFα, and MCP1), and NFAT5 were assessed using RT-qPCR, ELISA and multiplex, Western blot, immunofluorescence, and luciferase assays. In selected experiments, an inhibitor of RAGE (RAP) or NFAT5 siRNAs were added before the hyperosmolar stimulations. HCE and WKD cells or macrophages were treated with recombinant proteins of alarmins (with or without RAP) and analyzed for cytokine expression and chemotaxis, respectively. Hyperosmolarity induced epithelial cell inflammation depending on cell type. NFAT5, but not RAGE or alarmins, participated in triggering epithelial inflammation. Furthermore, the release of alarmins induced macrophage migration through RAGE. These in vitro results suggest that NFAT5 and RAGE have a role in dry eye inflammation.

Background: Preclinical studies in acute respiratory distress syndrome (ARDS) have suggested that inhaled sevoflurane may have lung-protective effects and clinical trials are ongoing to assess its impact on major clinical outcomes in patients with ARDS. However, the underlying mechanisms of these potential benefits are largely unknown. This investigation focused on the effects of sevoflurane on lung permeability changes after sterile injury and the possible associated mechanisms., Methods: To investigate whether sevoflurane could decrease lung alveolar epithelial permeability through the Ras homolog family member A (RhoA)/phospho-Myosin Light Chain 2 (Ser19) (pMLC)/filamentous (F)-actin pathway and whether the receptor for advanced glycation end-products (RAGE) may mediate these effects. Lung permeability was assessed in RAGE -/- and littermate wild-type C57BL/6JRj mice on days 0, 1, 2, and 4 after acid injury, alone or followed by exposure at 1% sevoflurane. Cell permeability of mouse lung epithelial cells was assessed after treatment with cytomix (a mixture of TNFɑ, IL-1β, and IFNγ) and/or RAGE antagonist peptide (RAP), alone or followed by exposure at 1% sevoflurane. Levels of zonula occludens-1, E-cadherin, and pMLC were quantified, along with F-actin immunostaining, in both models. RhoA activity was assessed in vitro., Results: In mice after acid injury, sevoflurane was associated with better arterial oxygenation, decreased alveolar inflammation and histological damage, and non-significantly attenuated the increase in lung permeability. Preserved protein expression of zonula occludens-1 and less increase of pMLC and actin cytoskeletal rearrangement were observed in injured mice treated with sevoflurane. In vitro, sevoflurane markedly decreased electrical resistance and cytokine release of MLE-12 cells, which was associated with higher protein expression of zonula occludens-1. Improved oxygenation levels and attenuated increase in lung permeability and inflammatory response were observed in RAGE -/- mice compared to wild-type mice, but RAGE deletion did not influence the effects of sevoflurane on permeability indices after injury. However, the beneficial effect of sevoflurane previously observed in wild-type mice on day 1 after injury in terms of higher PaO 2 /FiO 2 and decreased alveolar levels of cytokines was not found in RAGE -/- mice. In vitro, RAP alleviated some of the beneficial effects of sevoflurane on electrical resistance and cytoskeletal rearrangement, which was associated with decreased cytomix-induced RhoA activity., Conclusions: Sevoflurane decreased injury and restored epithelial barrier function in two in vivo and in vitro models of sterile lung injury, which was associated with increased expression of junction proteins and decreased actin cytoskeletal rearrangement. In vitro findings suggest that sevoflurane may decrease lung epithelial permeability through the RhoA/pMLC/F-actin pathway., (© 2023. The Author(s).)

The rat hepatic stellate cell line PAV-1 was established two decades ago and proposed as a cellular model to study aspects of hepatic retinoic acid metabolism. This cell line exhibits a myofibroblast-like phenotype but also has the ability to store retinyl esters and synthesize retinoic acid from its precursor retinol. Importantly, when cultured with palmitic acid alone or in combination with retinol, the cells switch to a deactivated phenotype in which the proliferation and expression of profibrogenic marker genes are suppressed. Despite these interesting characteristics, the cell line has somehow fallen into oblivion. However, based on the fact that working with in vivo models is becoming increasingly complicated, genetically characterized established cell lines that mimic aspects of hepatic stellate cell biology are of fundamental value for biomedical research. To genetically characterize PAV-1 cells, we performed karyotype analysis using conventional chromosome analysis and multicolor spectral karyotyping (SKY), which allowed us to identify numerical and specific chromosomal alteration in PAV-1 cells. In addition, we used a panel of 31 species-specific allelic variant sites to define a unique short tandem repeat (STR) profile for this cell line and performed bulk mRNA-sequencing, showing that PAV-1 cells express an abundance of genes specific for the proposed myofibroblastic phenotype. Finally, we used Rhodamine-Phalloidin staining and electron microscopy analysis, which showed that PAV-1 cells contain a robust intracellular network of filamentous actin and process typical ultrastructural features of hepatic stellate cells.

Background: Findings from preclinical studies and one pilot clinical trial suggest potential benefits of epidural analgesia in acute pancreatitis. We aimed to assess the efficacy of thoracic epidural analgesia, in addition to usual care, in improving clinical outcomes of intensive care unit patients with acute pancreatitis., Methods: A multicenter, open-label, randomized, controlled trial including adult patients with a clinical diagnosis of acute pancreatitis upon admission to the intensive care unit. Participants were randomly assigned (1:1) to a strategy combining thoracic epidural analgesia and usual care (intervention group) or a strategy of usual care alone (control group). The primary outcome was the number of ventilator-free days from randomization until day 30., Results: Between June 2014 and January 2019, 148 patients were enrolled, and 135 patients were included in the intention-to-treat analysis, with 65 patients randomly assigned to the intervention group and 70 to the control group. The number of ventilator-free days did not differ significantly between the intervention and control groups (median [interquartile range], 30 days [15-30] and 30 days [18-30], respectively; median absolute difference of - 0.0 days, 95% CI - 3.3 to 3.3; p = 0.59). Epidural analgesia was significantly associated with longer duration of invasive ventilation (median [interquartile range], 14 days [5-28] versus 6 days [2-13], p = 0.02)., Conclusions: In a population of intensive care unit adults with acute pancreatitis and low requirement for intubation, this first multicenter randomized trial did not show the hypothesized benefit of epidural analgesia in addition to usual care. Safety of epidural analgesia in this setting requires further investigation., Trial Registration: ClinicalTrials.gov registration number NCT02126332 , April 30, 2014., (© 2023. The Author(s).)

Objectives: The objective of our study is to evaluate the effect of storage temperature and time to analysis on arterial blood gas parameters in order to extend the CLSI recommendations., Methods: Stability of 12 parameters (pH, pCO₂, pO₂, Na + , K + , Ca 2+ , glucose, lactate, hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin) measured by GEM PREMIER™ 5000 blood gas analyzer was studied at room temperature and at +4 °C (52 patients). The storage times were 30, 45, 60, 90 and 120 min. Stability was evaluated on the difference from baseline, the difference from the analyte-specific measurement uncertainty applied to the baseline value, and the impact of the variation on the clinical interpretation., Results: At room temperature, all parameters except the lactate remained stable for at least 60 min. A statistically significant difference was observed for pH at T45 and T60 and for pCO 2 at T60 without modification of clinical interpretation. For lactate, clinical interpretation was modified from T45 and values were outside the range of acceptability defined by the measurement uncertainty. All parameters except pO 2 remained stable for at least 120 min at +4 °C., Conclusions: A one-hour transport at room temperature is compatible with the performance of all the analyses studied except lactate. If the delay exceeds 30 min, the sample should be placed at +4 °C for lactate measurement. If the samples are stored in ice, it is important to note that the pO 2 cannot be interpreted., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Mild traumatic brain injury (mTBI) accounts for approximately 80% of all TBI cases and is a growing source of morbidity and mortality worldwide. To improve the management of children and adults with mTBI, a series of candidate biomarkers have been investigated in recent years. In this context, the measurement of blood biomarkers in the acute phase after a traumatic event helps reduce unnecessary CT scans and hospitalizations. In athletes, improved management of sports-related concussions is also sought to ensure athletes' safety. S100B protein has emerged as the most widely studied and used biomarker for clinical decision making in patients with mTBI. In addition to its use as a diagnostic biomarker, S100B plays an active role in the molecular pathogenic processes accompanying acute brain injury. This review describes S100B protein as a diagnostic tool as well as a potential therapeutic target in patients with mTBI.

Background: The clinical significance of early-onset acute kidney injury (EO-AKI) and recovery in severe COVID-19 intensive care unit (ICU) patients is poorly documented., Objective: The aim of the study was to assess the epidemiology and outcome of EO-AKI and recovery in ICU patients admitted for SARS-CoV-2 pneumonia., Design: This was a retrospective single-centre study., Setting: The study was carried out at the medical ICU of the university hospital of Clermont-Ferrand, France., Patients: All consecutive adult patients aged ≥18 years admitted between 20 March 2020 and 31 August 2021 for SARS-CoV-2 pneumonia were enrolled. Patients with chronic kidney disease, referred from another ICU, and with an ICU length of stay (LOS) ≤72 h were excluded., Interventions: EO-AKI was defined on the basis of serum creatinine levels according to the Kidney Disease Improving Global Outcomes criteria, developing ≤7 days. Depending on renal recovery, defined by the normalization of serum creatinine levels, EO-AKI was transient (recovery within 48 h), persistent (recovery between 3 and 7 days) or AKD (no recovery within 7 days after EO-AKI onset)., Measurements: Uni- and multivariate analyses were performed to determine factors associated with EO-AKI and EO-AKI recovery., Main Results: EO-AKI occurred in 84/266 (31.5%) study patients, of whom 42 (50%), 17 (20.2%) and 25 (29.7%) had EO-AKI stages 1, 2 and 3, respectively. EO-AKI was classified as transient, persistent and AKD in 40 (47.6%), 15 (17.8%) and 29 (34.6%) patients, respectively. The 90-day mortality was 87/244 (35.6%) and increased with EO-AKI occurrence and severity: no EO-AKI, 38/168 (22.6%); EO-AKI stage 1, 22/39 (56.4%); stage 2, 9/15 (60%); and stage 3, 18/22 (81.8%) ( p < 0.01). The 90-day mortality in patients with transient or persistent AKI and AKD was 20/36 (55.6%), 8/14 (57.1%) and 21/26 (80.8%), respectively ( p < 0.01). MAKE-90 occurred in 42.6% of all patients., Conclusions: In ICU patients admitted for SARS-CoV-2 pneumonia, the development of EO-AKI and time to recovery beyond day 7 of onset were associated with poor outcome.

Procalcitonin (PCT) was established as a biomarker to discriminate bacterial infections from other proinflammatory conditions. Our objective was to determine whether PCT is effective in differentiating infection from antineutrophil-cytoplasmic-antibody (ANCA)-associated vasculitides (AAV) flare. In this retrospective, case-control study, PCT and other inflammatory biomarkers of patients with AAV relapse (relapsing group) were compared to infected AAV patients (infected group). In our population of 74 patients with AAV, PCT was significantly higher in the infected group than in the relapsing group (0.2 µg/L [0.08; 0.935] vs. 0.09 µg/L [0.05; 0.2], p < 0.001). Sensitivity and specificity were 53.4% and 73.6%, respectively, for an ideal threshold of 0.2 µg/L. C-reactive protein (CRP) was significantly higher in cases of infection than in relapse (64.7 mg/L [25; 131] vs. 31.5 mg/L, [10.6; 120], p = 0.001). Sensitivity and specificity for infections were 94.2% and 11.3%, respectively. Fibrinogen, white blood cell count, eosinophil count, and neutrophil count were not significantly different. In the multivariate analysis, the relative risk of infection was 2 [1.02; 4.5] ( p = 0.04) for a PCT above 0.2 µg/L. In AAV, PCT may be useful for discriminating between infections and flare in patients suffering from AAVs.

At the feto-maternal interface, fetal membranes (FM) play a crucial role throughout pregnancy. FM rupture at term implicates different sterile inflammation mechanisms including pathways activated by the transmembrane glycoprotein receptor for advanced glycation end-products (RAGE) belonging to the immunoglobulin superfamily. As the protein kinase CK2 is also implicated in the inflammation process, we aimed to characterize the expressions of RAGE and the protein kinase CK2 as a candidate regulator of RAGE expression. The amnion and choriodecidua were collected from FM explants and/or primary amniotic epithelial cells throughout pregnancy and at term in spontaneous labor (TIL) or term without labor (TNL). The mRNA and protein expressions of RAGE and the CK2α, CK2α', and CK2β subunits were investigated using reverse transcription quantitative polymerase chain reaction and Western blot assays. Their cellular localizations were determined with microscopic analyses, and the CK2 activity level was measured. RAGE and the CK2α, CK2α', and CK2β subunits were expressed in both FM layers throughout pregnancy. At term, RAGE was overexpressed in the amnion from the TNL samples, whereas the CK2 subunits were expressed at the same level in the different groups (amnion/choriodecidua/amniocytes, TIL/TNL), without modification of the CK2 activity level and immunolocalization. This work paves the way for future experiments regarding the regulation of RAGE expression by CK2 phosphorylation.

Background: Blood tryptase and fecal calprotectin levels may serve as biomarkers of necrotizing enterocolitis. However, their interpretation may be hindered by the little-known effects of perinatal factors. The aim of this study was to compare the tryptase and calprotectin levels in newborns according to their term, trophicity, and sex., Method: One hundred and fifty-seven premature newborns and 157 full-term newborns were included. Blood tryptase and fecal calprotectin were assayed., Results: Blood tryptase levels were higher in premature than in full-term newborns (6.4 vs. 5.2 µg/L; p < 0.001). In situations of antenatal use of corticosteroids ( p = 0.007) and non-exclusive use of human milk ( p = 0.02), these levels were also higher. However, in multiple linear regression analyses, only prematurity significantly influenced tryptase levels. Fecal calprotectin levels were extremely wide-ranging and were much higher in female than in male newborns (300.5 vs. 110.5 µg/g; p < 0.001)., Conclusions: The differences in tryptase levels according to term could be linked to early aggression of the still-immature digestive wall in premature newborns, in particular, by enteral feeding started early. The unexpected influence of sex on fecal calprotectin levels remains unexplained.

We prospectively evaluated a panel of seven blood biomarkers (S100 calcium-binding protein B [S100B], neuron specific enolase [NSE], spectrin breakdown products [SBDP], ubiquitin C-terminal hydrolase L1 [UCHL1], glial fibrillary acidic protein [GFAP], neurofilament light chain [NFL], and tubulin-associated unit [Tau]) for sport-related concussion (SRC) in a large multi-centric cohort of 496 professional rugby players from 14 French elite teams. Players were sampled twice during the season (beginning and end) away from any sport practice. From these two baseline samples, we evaluated the intra-individual variability to establish the effect of rugby on blood biomarkers over a season. Only S100B and GFAP remained stable over the course of a season. During the period of the study, a total of 45 SRC cases was reported for 42 players. In 45 SRCs, the head injury assessment (HIA) process was performed and blood collection was realized 36 h after the concussion (HIA-3 stage). For each biomarker, raw concentrations measured 36 h after SRC were not significantly different between players with a non-resolutive SRC ( n  = 28) and those with a resolutive SRC ( n  = 17; p between 0.06 and 0.92). In a second step, blood concentrations measured 36 h after SRC were expressed according to the basal concentrations as an individual percentage change (PCH36[%]), calculated as follows: PCH36 = 100 × (([Biomarker]36h - [Biomarker]basal)/[Biomarker]basal). S100B and NFL concentrations expressed as PCH36[%] were significantly different between non-resolutive and resolutive SRCs ( p  = 0.006 and 0.01 respectively), with a positive delta found in non-resolutive SRCs. Among the two biomarkers, it is important to note that only the S100B protein was stable during the season. In the context of our study, during HIA-3 assessment, S100B seems to perform better than NSE, SBDP, UCHL1, GFAP, NFL, and Tau as biomarker for SRC. From a clinical standpoint, the S100B modification over baseline may be valuable, at 36 h after concussion to distinguish non-resolutive SRC from resolutive SRC.

Background: Magnesium (Mg) is often used to manage de novo atrial fibrillation (AF) in the emergency department (ED) and intensive care unit (ICU). Point of care measurement of ionized magnesium (iMg) allows a rapid identification of patients with impaired magnesium status, however, unlike ionized calcium, the interpretation of iMg is not entirely understood. Thus, we evaluated iMg reference values, correlation between iMg and plasmatic magnesium (pMg), and the impact of pH and albumin variations on iMg levels. Secondary objectives were to assess the incidence of hypomagnesemia in de novo AF., Methods: A total of 236 emergency department and intensive care unit patients with de novo AF, and 198 control patients were included. Reference values were determined in the control population. Correlation and concordance between iMg and pMg were studied using calcium (ionized and plasmatic) as a control in the whole study population. The impact of albumin and pH was assessed in the discordant iMg and pMg values. Lastly, we assessed the incidence of ionized hypomagnesemia (hypoMg) among de novo AF., Results: The reference range values established in our study for iMg were: 0.48-0.65 mmol/L (the manufacturers were: 0.45-0.60 mmol/L). A strong correlation was observed between pMg and iMg (r = 0.85), but, unlike for calcium values, there was no significant impact of pH and albumin in iMg/pMg interpretation. The incidence of hypoMg among de novo AF patients was 8.5% (12.7% using our ranges). When using our ranges, we found a significant link ( p = 0.01) between hyopMg and hypokalemia., Conclusion: We highlight the need for more accurate reference range values of iMg. Furthermore, our results suggest that blood Mg content is not identical to that of calcium. The incidence of ionized hypomagnesemia among de novo AF patients in our study is 8.5%.