Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease.

Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD.

Serum levels of the incretin-like peptide 26RFa are diminished in women living with obesity and diabetes and restored after sleeve gastrectomy: Results from the prospective pilot RFa-Ba-S study.

AIM: To investigate the evolution of the incretin-like peptide 26RFa in a prospective cohort of women living with obesity with or without type 2 diabetes (T2D) before and after sleeve gastrectomy (SG). METHODS: In this study, a total of 61 women were divided into three groups: women living with severe obesity without T2D (WlwOB group), women living with severe obesity and T2D (WlwOB-T2D group) and lean healthy volunteers (control group). Serum 26RFa concentrations were measured using a 26RFa enzyme-linked immunosorbent assay developed specifically for this study during meal tests before SG, and 30 and 180 days after SG. RESULTS: At baseline, serum 26RFa levels were reduced in the WlwOB (P < .05) and WlwOB-T2D (P < .01) groups compared with controls. In the WlwOB-T2D group, fasting 26RFa levels were found to increase throughout the entire follow-up period up to 6 months after the SG (P < .001). During the meal tests, serum 26RFa levels increased, especially in the WlwOB-T2D group at baseline. At the end of the follow-up, the profile of 26RFa concentrations obtained during the meal test in patients with severe obesity and T2D was similar to that of the controls. CONCLUSIONS: This prospective clinical study provides the first evidence that circulating 26RFa is altered mainly in WlwOB-T2D, and that these defects are partially reversed after SG.

Lipid and hemolysis parameters predicting acute chest syndrome in adulthood with sickle cell disease.

Sickle cell disease (SCD) is a lifelong blood disorder affecting approximately 100,000 people in the United States and is one of the most common monogenic diseases. A serious complication of SCD is acute chest syndrome (ACS). ACS is a condition with a high rate of morbidity and mortality. The aim of the study was to assess hemolysis and lipid parameters in a cohort of confirmed SCD patients to predict ACS development in the following year.Standard lipid were performed (triglycerides, total cholesterol, high-density cholesterol, low-density cholesterol) panel to calculate of non-HDL-C, large buoyant LDL cholesterol (lbLDL-C) and small dense LDL cholesterol (sdLDL-C) with Sampson equation. Hemolysis and hematologic parameters were also evaluated.Among 91 patients included between September 2018 and June 2021, thirty-seven patients had history of ACS and 6 patients developed ACS during following year. In unadjusted logistic regression, total bilirubin was associated with ACS occurrence (RR: 1.2 [1.05-1.51] p = 0.013). Concerning lipid profile, non-HDL-C (RR: 0.87 [0.0.67-0.99] p = 0.04) and sdLDL-C (RR: 0.78 [0.49-0.96] p = 0.03) were associated with ACS occurrence decrease. C-reactive protein was associated with ACS occurrence (RR: 1.27 [1.065-1.85] p = 0.011).Based on these findings, this study demonstrated that several biomarker easily available can be used at steady state to predict ACS in the following year. The validation of these results are required to ensure the reproducibility of the findings.

Analytical Evaluation of Lumipulse Anti-Mullerian Hormone Assay.

BACKGROUND: The measurement of serum Anti-Mullerian hormone (AMH) is used in daily practice to estimate the ovarian reserve in women. METHODS: The aim of this study was to evaluate the new Lumipulse AMH® immunoassay (Fujirebio) with regard to the reliability with two preexisting assays: Elecsys AMH Plus® (cobas®, Roche) and Vidas AMH® (bioMérieux). Precision of Lumipulse AMH was evaluated on the Lumipulse G600 II using the manufacturer's quality controls. Thirty-three samples were used for method comparison. RESULTS: Lumipulse AMH repeatability and intermediate precision did not exceed 4.1 %. There was a proportional bias between Lumipulse and Cobas method and between Lumipulse and Vidas whereas a good agreement was found between Cobas and Vidas. CONCLUSIONS: Lumipulse AMH assay demonstrated good precision and good agreement with the two other methods up to 6 ng/mL. Nevertheless, this study shows the need to standardize AMH assays to improve the comparability of the methods.

Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.

An Additional Case of Hb Saint Nazaire [ß103(G5)Phe→Ile; HBB: c.310T>A] Leading to Moderate Erythrocytosis in a French Family.

We report two members of a French family who are carriers of a rare hemoglobin (Hb) variant leading to erythrocytosis: Hb Saint Nazaire [ß103(G5)Phe→Ile; HBB: c.310T>A]. The proband is a 38-year-old woman referred to our institution for a moderate but persistent polycythemia without any clinical consequence. As her mother had a similar blood count, a diagnosis of a Hb variant with high oxygen affinity was proposed. The variant was difficult to detect by capillary electrophoresis (CE) and not distinguishable by high performance liquid chromatography (HPLC) and isoelectric focusing. Finally, a heterozygous mutation on the HBB gene corresponding to Hb Saint Nazaire was identified. This case report illustrates that this rare cause of erythrocytosis can be easily under or misdiagnosed unless several Hb separation techniques are used.

Preliminary evaluation of the diagnostic performance of Roche Elecsys® active vitamin B12 versus total vitamin B12 for vitamin B12 deficiency screening.

INTRODUCTION: The prevalence of vitamin B12 deficiency is high in at-risk populations with sometimes irreversible consequences. Beside total B12 (TVB12), active B12 (AVB12) is a promising first-line marker. Only Abbott AVB12 assays were largely evaluated and generally demonstrated benefit in clinical practice. More recently developed Roche AVB12 still requires some investigations. OBJECTIVES: Our study aimed to evaluate the Roche Elecsys® AVB12 immunoassay performance versus Roche Elecsys® TVB12 competition assay. DESIGN: and Methods: We included 175 patients at Rouen University Hospital who had a TVB12 value <300 pmol/L. We evaluated performance of AVB12 by comparing the results with TVB12 and MMA values in case of disagreement. RESULTS: Positive correlation was found between the AVB12 and TVB12. We found a disagreement between TVB12 and AVB12 in 18.8% of cases. Among 33 cases of disagreement, 76% had normal AVB12 but low TVB12, whereas 24% had low AVB12 and normal TVB12. Thirty-one MMA determinations were performed: 71% showed agreement between MMA and AVB12, versus 29% between MMA and TVB12. TVB12 reported a sensitivity (Se) at 66.7%, specificity (Sp) at 20%, positive predictive value (PPV) at 16.7% and negative predictive value (NPV) at 71.4% for the prediction of MMA elevation. We determined an optimized cut-off value of 45.5 pmol/L for AVB12, which reported a Se 66.7%, Sp 60%, PPV 30.7%, and NPV 88.9%. CONCLUSIONS: Our results provide preliminary evidence that Roche AVB12 may offer better discrimination than Roche TVB12 in the diagnosis of vitamin B12 deficiency. Further more detailed evaluation is warranted.

Stability of adrenocorticotropic hormone in whole blood samples: effects of storage conditions.

Introduction: Adrenocorticotropic hormone (ACTH) is a peptide secreted by pituitary gland that plays an important role in regulating cortisol secretion. Its determination is difficult because of instability in whole blood. Several factors that influence ACTH stability in blood before analysis have been identified: temperature, hemolysis, time to centrifugation and presence of protease inhibitors. Published results on ACTH whole blood stability seem contradictory. Materials and methods: We performed a stability study in 10 healthy volunteers. Three different conditions were tested: ethylenediaminetetraacetic acid (EDTA) at 4 °C, EDTA + aprotinin at 4 °C, EDTA + aprotinin at room temperature. Stability was evaluated for 8 hours. Adrenocorticotropic hormone measurements and hemolysis index were performed respectively on Cobas e602 and c701 (Roche Diagnostics, Mannheim, Germany). We compared percentage deviations with total change limit using a threshold of 7.5%. Results: We showed that ACTH is stable 8 hours with EDTA at 4 °C, 4 hours with EDTA + aprotinin at 4 °C and 2 hours with EDTA + aprotinin at 22 °C. Conclusions: Aprotinin does not appear to give ACTH greater stability but can be used without exceeding 4 hours at 4 °C. Refrigerated pouch transport also seems to be more appropriate for ACTH in whole blood.

Association between volume of lung damage and endoplasmic reticulum stress expression among severe COVID-19 ICU patients.

Introduction: Links have been established between SARS-CoV-2 and endoplasmic reticulum stress (ERS). However, the relationships between inflammation, ERS, and the volume of organ damage are not well known in humans. The aim of this study was to explore whether ERS explains lung damage volume (LDV) among COVID-19 patients admitted to the intensive care unit (ICU). Materials and methods: We conducted a single-center retrospective study (ancillary analysis of a prospective cohort) including severe COVID-19 ICU patients who had a chest computed tomography (CT) scan 24 h before/after admission to assess LDV. We performed two multivariate linear regression models to identify factors associated with plasma levels of 78 kDa-Glucose-Regulated Protein (GRP78; ERS marker) and Interleukin-6 (IL-6; inflammation marker) at admission. Results: Among 63 patients analyzed, GRP78 plasma level was associated with LDV in both multivariate models (ß = 22.23 [4.08;40.38]; p = 0.0179, ß = 20.47 [0.74;40.20]; p = 0.0423) but not with organ failure (Sequential Organ Failure Assessment (SOFA) score) at admission (r = 0.03 [-0.22;0.28]; p = 0.2559). GRP78 plasma level was lower among ICU survivors (1539.4 [1139.2;1941.1] vs. 1714.2 [1555.2;2579.1] pg./mL. respectively; p = 0.0297). IL-6 plasma level was associated with SOFA score at admission in both multivariate models (ß = 136.60 [65.50;207.70]; p = 0.0003, ß = 193.70 [116.60;270.90]; p < 0.0001) but not with LDV (r = 0.13 [-0.14;0.39]; p = 0.3219). IL-6 plasma level was not different between ICU survivors and non-survivors (12.2 [6.0;43.7] vs. 30.4 [12.9;69.7] pg./mL. respectively; p = 0.1857). There was no correlation between GRP78 and IL-6 plasma levels (r = 0.13 [-0.13;0.37]; p = 0.3106). Conclusion: Among severe COVID-19 patients, ERS was associated with LDV but not with systemic inflammation, while systemic inflammation was associated with organ failure but not with LDV.

[SFBC Working Group on sources of errors in laboratory medicine: objectives and key areas of work]. / Groupe de travail SFBC Sur les sources d'erreurs en biologie clinique: Objectifs et axes de travail.

Laboratory medicine plays a crucial role in patient care, contributing to approximately 70 % of clinical decisions. In collaboration with clinicians, laboratory medicine specialists perform analyses that are useful for diagnosis, screening and prevention. Laboratories are known for their efficiency, which is reached through a rigorous quality system. However, errors can occur, especially given the complexity of the total testing process. These errors may lead to severe consequences, such as incorrect diagnoses or delays in treatment. Errors can occur at every stage of the total testing process, those related to the pre-analytical phase being the most prevalent. To reduce medical errors related to laboratory processes, it is essential to provide training for medical and paramedical staff, optimize production automation, and leverage technological advancements. These considerations have led to the creation of a French Working Group on Sources of Errors in Laboratory Medicine, under the aegis of the French lean society of clinical chemistry and laboratory medicine (Société Française de Biologie Clinique - SFBC). The objectives of this working group are to produce an educational handbook on sources of errors in laboratory medicine, provide training for clinical chemists, and conducting applied research projects to better understand the mechanisms behind specific errors. Ultimately, the aim is to minimize errors and enhance the quality of laboratory tests.

A novel fully-automated method to measure steroids in serum by liquid chromatography-tandem mass spectrometry.

Background: Steroids play a key role in numerous physiological processes. Steroid determination is a useful tool to explore various endocrine diseases. Because of its specificity, mass spectrometry is considered to be a reference method for the determination of steroids in serum compared to radioimmunoassay. This technology could progress towards more automation for the optimal organization of clinical laboratories and ultimately for the benefit of patients. Methods: A fully automated ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed and fully validated to determine five steroids in serum. Sample preparation was based on protein precipitation with filtration followed by online solid phase extraction. Chromatographic separation was performed using a biphenyl stationary phase. Results: The method was successfully validated according to European Medicine Agency guidelines. Coefficients of variation did not exceed, respectively, 8.4% and 8.1% for intra- and inter-assay precision. Method comparison with radioimmunoassay showed a proportional bias for all compounds, except for testosterone in men. Comparison with another LC-MS/MS method demonstrated acceptable concordance for all steroids, although a small bias was observed for androstenedione. Conclusion: The novelty of this method is that it has been fully automated. Automation provides benefits in traceability and allows significant savings in cost and time.

Lactate dehydrogenase and hemolysis index to predict vaso-occlusive crisis in sickle cell disease.

Sickle cell disease (SCD) is an inherited hemoglobinopathy disorder associated with chronic hemolysis. A major complication is vaso-occlusive crisis (VOC), associating frequent hospitalization, morbidity and mortality. The aim of this study was to investigate whether hemolysis biomarkers were able to predict VOC risk in adult patients with SCD requiring hospitalization within 1 year. This single-center prospective study included adult patients with SCD at steady state or during VOC. A total of 182 patients with SCD were included, 151 at steady state and 31 during VOC. Among the 151 patients at steady state 41 experienced VOC within 1 year (median: 3.0 months [2.0-6.5]). We observed an increase of lactate dehydrogenase (LDH) (p = 0.01) and hemolysis index (HI) (p = 0.0043) during VOC compared to steady state. Regarding patients with VOC requiring hospitalization, LDH (p = 0.0073) and HI (p = 0.04) were increased. In unadjusted logistic regression, LDH > median (> 260 U/L) (RR = 3.6 [1.29-10.88], p = 0.0098) and HI > median (> 8 UA/L) (RR = 3.13 [1.91-5.33]; p < 0.001) were associated with VOC. The association of LDH > 260 U/L and HI > 12 UA/L presented a sensitivity of 90%, and a specificity of 72.9% to predict VOC. The association of LDH and HI cut-off was able to predict VOC risk in SCD.

[Real-life evaluation of hypersensitive I-troponin on a point-of care analyser in an emergency unit]. / Évaluation en vie réelle de la mesure de troponine I hypersensible sur un système de biologie délocalisée pour un service d'urgences.

European Society of Cardiology (ESC) guidelines allow to perform rapid rule-in and rule-out algorithm with rapid troponin kinetics for the management of suspected Non ST-elevation acute coronary syndrome. These recommendations allow the use of point-of-care testing (POCT) systems provided that they have sufficient analytical performance. The aim of our study was to evaluate in real life the feasibility and performance of using a high sensitivity cardiac troponin I POCT system assay (hs-cTnI, Atellica® VTLi, Siemens) compared to high sensitivity cardiac troponin T values (hs-cTnT, e602®, Roche) obtained for patients admitted to emergency department. Analytical verification showed a coefficient of variation below 10% for hs-cTnI. Comparison of both troponins was moderate (r = 0.7). The study included 117 patients with a median age of 65 years, 30% had renal failure and 36% presented with chest pain. In this study, the hs-cTnT value was, more often, higher than the 99th percentile than the hs-cTnl value, even for an age-adjusted 99th percentile hs-cTnT value. The concordance of the results was moderate (Cohen's Kappa: 0.54), age remaining the most important explanatory value of discordance. Only hs-cTnT had a predictive value for hospitalization. We did not observe any interpretation discrepancies for patients who had troponin kinetics. This study confirms the feasibility of using a POCT analyzer in the emergency department, provided that it performs high sensitivity troponin. However, some data are missing to be able to use it in the framework of rapid algorithm. Finally, the implementation of POCT requires collaboration between biologists and emergency physicians in terms of organization and interpretation of values, for the overall benefit of the patient.

Subtotal Nephrectomy Associated with a High-Phosphate Diet in Rats Mimics the Development of Calcified Aortic Valve Disease Associated with Chronic Renal Failure.

Introduction. This study addressed the hypothesis that subtotal nephrectomy associated with a high-phosphorus diet (5/6Nx + P) in rats represents a suitable animal model to mimic the cardiovascular consequences of chronic kidney disease (CKD) including calcified aortic valve disease (CAVD). Indeed, the latter contributes to the high morbidity and mortality of CKD patients and sorely lacks preclinical models for pathophysiological and pharmacological studies. Methods. Renal and cardiovascular function and structure were compared between sham-operated and 5/6 Nx rats + P 10 to 12 weeks after surgery. Results. As expected, 11 weeks after surgery, 5/6Nx + P rats developed CKD as demonstrated by their increase in plasma creatinine and urea nitrogen and decrease in glomerular filtration rate, estimated by using fluorescein-isothiocyanate-labelled sinistrin, anemia, polyuria, and polydipsia compared to sham-operated animals on a normal-phosphorus diet. At the vascular level, 5/6Nx + P rats had an increase in the calcium content of the aorta; a decrease in mesenteric artery dilatation in response to a stepwise increase in flow, illustrating the vascular dysfunction; and an increase in blood pressure. Moreover, immunohistology showed a marked deposition of hydroxyapatite crystals in the aortic valve of 5/6Nx + P rats. Echocardiography demonstrated that this was associated with a decrease in aortic valve cusp separation and an increase in aortic valve mean pressure gradient and in peak aortic valve velocity. Left-ventricular diastolic and systolic dysfunction as well as fibrosis were also present in 5/6Nx + P rats. Conclusion. This study demonstrates that 5/6Nx + P recapitulates the cardiovascular consequences observed in humans with CKD. In particular, the initiation of CAVD was shown, highlighting the interest of this animal model to study the mechanisms involved in the development of aortic stenosis and test new therapeutic strategies at an early stage of the disease.

Inhibition of Soluble Epoxide Hydrolase Does Not Promote or Aggravate Pulmonary Hypertension in Rats.

Inhibitors of soluble epoxide hydrolase (sEH), which catalyzes the hydrolysis of various natural epoxides to their corresponding diols, present an opportunity for developing oral drugs for a range of human cardiovascular and inflammatory diseases, including, among others, diabetes and neuropathic pain. However, some evidence suggests that their administration may precipitate the development of pulmonary hypertension (PH). We thus evaluated the impact of chronic oral administration of the sEH inhibitor TPPU (N-[1-(1-Oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]-urea) on hemodynamics, pulmonary vascular reactivity, and remodeling, as well as on right ventricular (RV) dimension and function at baseline and in the Sugen (SU5416) + hypoxia (SuHx) rat model of severe PH. Treatment with TPPU started 5 weeks after SU5416 injection for 3 weeks. No differences regarding the increase in pulmonary vascular resistance, remodeling, and inflammation, nor the abolishment of phenylephrine-induced pulmonary artery constriction, were noted in SuHx rats. In addition, TPPU did not modify the development of RV dysfunction, hypertrophy, and fibrosis in SuHx rats. Similarly, none of these parameters were affected by TPPU in normoxic rats. Complementary in vitro data demonstrated that TPPU reduced the proliferation of cultured human pulmonary artery-smooth muscle cells (PA-SMCs). This study demonstrates that inhibition of sEH does not induce nor aggravate the development of PH and RV dysfunction in SuHx rats. In contrast, a potential beneficial effect against pulmonary artery remodeling in humans is suggested.

CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury.

INTRODUCTION: Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown. OBJECTIVES: This study aimed to assess in vivo the physiological role of sEH-P. METHODS: CRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity. RESULTS: The sEH-P KI rats has a decreased metabolism of lysophosphatidic acids to monoacyglycerols. KI rats grew almost normally but with less weight and fat mass gain while insulin sensitivity was increased compared to wild-type rats. This lean phenotype was more marked in males than in female KI rats and mainly due to decreased food consumption and enhanced energy expenditure. In fact, sEH-P KI rats had an increased lipolysis allowing to supply fatty acids as fuel to potentiate brown adipose thermogenesis under resting condition and upon cold exposure. The potentiation of thermogenesis was abolished when blocking PPARγ, a nuclear receptor activated by intracellular lysophosphatidic acids, but also when inhibiting simultaneously sEH-H, showing a functional interaction between the two domains. Furthermore, sEH-P KI rats fed a high-fat diet did not gain as much weight as the wild-type rats, did not have increased fat mass and did not develop insulin resistance or hepatic steatosis. In addition, sEH-P KI rats exhibited enhanced basal cardiac mitochondrial activity associated with an enhanced left ventricular contractility and were protected against cardiac ischemia-reperfusion injury. CONCLUSION: Our study reveals that sEH-P is a key player in energy and fat metabolism and contributes together with sEH-H to the regulation of cardiometabolic homeostasis. The development of pharmacological inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeutic strategy in the management of obesity and cardiac ischemic complications.

Novel threshold value of midnight serum cortisol for diagnosis of hypercortisolism using the Roche Cortisol II assay.

BACKGROUND: The diagnosis of hypercortisolism requires multiple biochemical investigations, due to variations in cortisol production during the 24-hour circadian cycle. Midnight serum cortisol is difficult to interpret since the threshold value is dependent on the analytical method used and is often not provided by the manufacturer. Second-generation assays are more specific than first-generation assays and may have lower threshold values. OBJECTIVES: The aim of this study was to determine a novel threshold value of midnight serum cortisol for the biochemical diagnosis of hypercortisolism, using the Roche Cobas Cortisol® second-generation assay. METHODS: This study was performed in adult patients hospitalized in the endocrinology unit of a university hospital. Patients had a complete assessment of their 24-hour cortisol cycle, i.e., a serum cortisol test every four hours and at least two first-line tests: late night salivary cortisol, dexamethasone suppression test and/or 24-hour urinary free cortisol. First-line tests were used to identify patients with hypercortisolism. Serum samples were analyzed by second-generation electrochemiluminescence immunoassays (ECLIA) from Roche Cobas Cortisol®. RESULTS: Midnight serum cortisol samples were obtained from 175 hospitalized patients. The novel threshold value obtained was 157 nmol/L with a sensitivity of 82.9% (68.6 to 94.3%) and a specificity of 90.0% (85.0 to 95.0%). CONCLUSION: Our study confirms that the threshold value of midnight serum cortisol is not comparable between first- and second-generation Roche Cobas Cortisol® assays and that the threshold value is lower with the second-generation assay.

Soluble RAGE as a Prognostic Marker of Worsening in Patients Admitted to the ICU for COVID-19 Pneumonia: A Prospective Cohort Study.

Background: The different waves of SARS-CoV-2 infection have strained hospital resources and, notably, intensive care units (ICUs). Identifying patients at risk of developing a critical condition is essential to correctly refer patients to the appropriate structure and to spare limited resources. The soluble form of RAGE (sRAGE), the endoplasmic stress response and its surrogates, GRP78 and VEGF-A, may be interesting markers. Methods: This was a prospective monocenter cohort study of adult patients admitted to the ICU for severe COVID-19 pneumonia. The plasma levels of sRAGE, GRP78 and VEGF-A were measured within the first 24 h. Patients were classified as critical if they further needed vasopressor therapy, renal replacement therapy, or invasive mechanical ventilation, or died during their ICU stay, and were otherwise classified as not critical. Results: A total of 98 patients were included and 39 developed a critical condition. Critical patients presented higher sRAGE (626 [450−1043] vs. 227 [137−404] pg/mL, p < 0.0001), interleukin-6 (43 [15−112] vs. 11 [5−20] pg/mL, p < 0.0001), troponin T (17 [9−39] vs. 10 [6−18] pg/mL, p = 0.003) and NT-pro-BNP (321 [118−446] vs. 169 [63−366] pg/mL, p = 0.009) plasma levels. No difference was observed for VEGF-A and GRP78. The variables independently associated with worsening in the ICU were sRAGE (1.03 [1.01−1.05] per 10 pg/mL) and age (1.7 [1.2−2.4] per 5 years). An sRAGE value of 449.5 pg/mL predicted worsening with a sensitivity of 77% and a specificity of 80%. Conclusion: sRAGE may allow the identification of patients at risk of developing a critical form of COVID-19 pneumonia, and thus may be useful to correctly refer patients to the appropriate structure of care.