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Background: Centrifugation is a consuming time step which participates to increase the turnaround time (TAT) in laboratories, likewise hemolysis sample that needs a re-sampling could delay management of patients. Recently, it has been postulated that BD Barricor™ tube could allow to decrease the centrifugation time and prevent hemolysis, two key feature to ensure high-quality results.Aim of the study was to evaluate the impact of replacing 4 mL BD vacutainer heparin lithium tube by low vacuum 3.5 mL BD vacutainer Barricor™ tube in an emergency department (ED) on hemolysis rate and TAT. Methods: Data of hemolysis index (HI) and TAT were compared between the first period of 15 days using 4 mL BD vacutainer heparin lithium tubes with 15 min at 2000xg as centrifugation setting and a second period of 15 days using BD vacutainer Barricor™ tube centrifuged 3 min at 4000xg. Results: A significantly reduced time duration between reception of sample and available results in informatics lab system was observed with the reduction time of centrifugation allowed by use of Barricor™ tube compared to regular heparin lithium tubes (p

The recreational use of nitrous oxide (N2O) is an emerging public health issue. Chronic N2O abuse may result in various clinical symptoms, encompassing neurological, psychiatric and cardiovascular outcomes. Despite the difficulties for the laboratory investigation of N2O intoxication, there is currently no guidelines in France to help both clinicians and biologists use appropriate biomarkers for the diagnosis and monitoring of patients with clinical symptoms potentially related to N2O intoxication. A multi-disciplinary Working Group, carried out under the auspices of the French Society of Clinical Biology (SFBC) and in collaboration with the French Societies of Emergency Medicine (SFMU), Analytical Toxicology (SFTA), Hemostasis and Thrombosis (SFTH), Vitamins and Biofactors (SFVB), and the French Federation of Neurology (FFN), was recently implemented to elaborate practical guidelines. The methodology of the Working Group is based on the critical analysis of the literature, and raising concerns and objectives are grouped into five working packages. The present manuscript primarily aims to expound upon the methodology and objectives of the ongoing SFBC Working Group on N2O.

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: The authors report the relevance of using a point of care test (Helge ® ) for free hemoglobin determination and concordance of the values the with Cobas ® 8000 and spectrophotometer methods. Results: The within-run of the point of care test was <3%. Good correlations among the three methods were observed and an acceptable concordance for hemolysis index values from 50 mg/dl. An excellent agreement between the Cobas 8000 and the spectrophotometer was found. Conclusion: Automated methods represent methods of choice for free hemoglobin determination. An advantage of the Helge system is that it can be applied to samples experiencing a delay in evaluation due to the long distance between the collection site and the central laboratory. Another advantage is its use at the bedside, in the monitoring of extracorporeal membrane oxygenation patients.

Background: The prognostic value of vitamin B12 blood levels remains controversial. An association between elevated vitamin B12 and mortality has been reported, particularly among elderly patients with cancers and liver or blood diseases. The present study explored the relationship between mortality and elevated vitamin B12 levels in a population of unscheduled inpatients in an internal medicine unit., Methods: This retrospective observational analysis was conducted between August 2014 and December 2018. We compared 165 patients with elevated plasma vitamin B12 levels (>600 pmol/l) with a random sample of 165 patients with normal B12 levels who were hospitalized during the same period. Demographic, clinical, and biological characteristics were assessed during hospitalization. The primary endpoint was all-cause death at 1 year., Results: Patients with elevated B12 were younger, with a lower body mass index and lower plasma albumin than those with normal B12 (75 ± 16 years vs 79 ± 13 years, p  = 0.047; 23 ± 5 vs 26 ± 7 kg/m 2 , p   <  0.001; and 33 ± 5 vs 35 ± 5 g/l, p   <  0.001, respectively). The prevalence of auto-immune disease and referral from an intensive care unit was higher among patients with elevated B12 (11% vs 5%, p  = 0.043 and 36% vs 10%, p   <  0.001, respectively). After 1 year of follow-up, 64 (39%) patients with elevated B12 had died compared to 43 (26%) patients with normal B12 ( p  = 0.018). Multivariate analysis using the Cox proportional hazards regression model adjusted for age, gender, body mass index, intensive care unit hospitalization, albumin level, and the presence of solid cancer or autoimmune disease revealed elevated B12 to be associated with a significant risk of death in the first year of follow-up (hazard ratio: 1.71 [1.08-2.7], p  = 0.022)., Conclusion: Elevated B12 is an early warning indicator of increased short-term mortality, such as independently of age, cancer, or comorbidities, in patients hospitalized in an internal medicine department., Competing Interests: C.R. reports personal fees from Servier and Pfizer unrelated to this work. P.F. has received travel and accommodation fees from Actelion, Johnson and Johnson, BMS, Pfizer, and Servier unrelated to this work. The remaining authors declare no conflicts of interest., (Copyright © 2023 Benjamin Eduin et al.)

Objectives: Blood microsampling, particularly dried blood spots (DBSs), is an attractive minimally-invasive approach that is well suited for home sampling and predictive medicine associated with longitudinal follow-up of the elderly. However, in vitro diagnostic quantification of biomarkers from DBS poses a major challenge. Clinical mass spectrometry can reliably quantify blood proteins in various research projects. Our goal here was to use mass spectrometry of DBS in a real-world clinical setting and compared it to the standard immunoassay method. We also sought to correlate DBS mass spectrometry measurements with clinical indices., Methods: A clinical trial of diagnostic equivalence was conducted to compare conventional venous samples quantified by immunoassay and DBSs quantified by mass spectrometry in an elderly population. We assayed three protein biomarkers of nutritional and inflammatory status: prealbumin (transthyretin), C-reactive protein, and transferrin., Results: The analysis of DBSs showed satisfactory variability and low detection limits. Statistical analysis confirmed that the two methods give comparable results at clinical levels of accuracy. In conclusion, we demonstrated, in a real-life setting, that DBSs can be used to measure prealbumin, CRP and transferrin, which are commonly used markers of nutritional status and inflammation in the elderly. However, there was no correlation with patient frailty for these proteins., Conclusions: Early detection and regular monitoring of nutritional and inflammatory problems using DBS appear to be clinically feasible. This could help resolve major public health challenges in the elderly for whom frailty leads to serious risks of health complications., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Misuse of inhaled nitrous oxide is a growing concern in France. It is known to alter concentrations of vitamin B 12, which is required as a cofactor for methionine synthase and methylmalonyl-CoA mutase activity. Hence, measurement of the concentrations of cobalamin metabolism biomarkers, including vitamin B 12 , homocysteine, and methylmalonic acid, could assist in the management of patients with a complex clinical presentation or in those who deny the consumption of nitrous oxide. Methods: We retrospectively collected clinical and biological data in patients hospitalized for nitrous oxide use in a university hospital in southern France between January 2020 and October 2022. Results: Thirty-one patients were identified during 34 months; 79% were men with a median age of 23.7 years. Most (97%) presented with peripheral polyneuropathy and/or myelopathy. The median vitamin B 12 concentration was 134.6 pmol/L, with 17 of 31 patients having values less than 145 pmol/L (the lower limit of the normal range). The median plasma folate concentration was 20.1 nmol/L, which is within the normal range. The median plasma homocysteine concentration was 87.7 µmol/L (normal range <15 µmol/L), and the median plasma methylmalonic acid concentration was 3.8 µmol/L (normal range <0.5 µmol/L). Conclusion: Nitrous oxide use is an emerging public health problem in France, as shown by the number of patients admitted to our hospital. The presence of a functional vitamin B 12 deficiency was a consistent feature that could be helpful in diagnosis in complex cases.

Background and Aims: Mobility and migration flows are growing from different countries of the world to European countries, including France and in particular the Mediterranean basin. This study aimed to investigate the presence of hemoglobin (Hb) variants in outpatients/inpatients of the Montpellier Hospital (France) in whom an HbA1c assay had been performed and for which the country of birth had been informed., Methods: This is a retrospective study from January 2016 to December 2020 based on all high-performance liquid chromatography (HPLC) chromatograms (Tosoh Bioscience HLC-723G8) having an alarm of suspected Hb variant during HbA1c measurement. The corresponding samples were systematically sent to the hematology laboratory for confirmation and identification of Hb variant. Patient's medical history, clinical and demographic data were extracted from each medical chart. Statistical analyses were performed using XLSTAT® software, version 2016.06.35661., Results: Three hundred sixty-three patients were confirmed with Hb variant exhibiting 17 different Hb profiles, highlighting the pivotal role of glycated hemoglobin (HbA1c) as a detection step. The prevalence of Hb variant in this southern French population was 0.71%, with the highest frequency for the beta-globin variants ( n  = 342/363; i.e., 94.2%), including the most common: S, C, E, and D in 200/342 (58.5%), 83/342 (24.3%), 29/342 (8.5%), and 11/342 (3.2%), respectively. Among patients with Hb variants, almost half (165/363; i.e., 45.4%) were born in the African continent with a predominance for Morocco (32/165; i.e., 19.3%) and Algeria (29/165; i.e., 17.5%)., Conclusion: HbA1c assay is a useful tool to detect Hb variants. Hemoglobinopathies are a public health issue in the current French population which is a multiethnic society. Despite the monocentric nature of our study, we note a high frequency of Hb variants in the south of France, which underlines the importance of screening for Hb variants in the whole population., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Background and Objectives: Chimeric antigen receptor (CAR) T-cell therapies have dramatically improved the prognosis of patients with relapsed or refractory hematologic malignancies; however, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) occur in ∼100 and 50% of patients, respectively. This study aimed to determine whether EEG patterns may be considered as diagnostic tools for ICANS., Methods: Patients who received CAR T-cell therapy at Montpellier University Hospital between September 2020 and July 2021 were prospectively enrolled. Neurologic signs/symptoms and laboratory parameters were monitored daily for 14 days after CAR T-cell infusion. EEG and brain MRI were performed between day 6 and 8 after CAR T-cell infusion. EEG was performed again on the day of ICANS occurrence, if outside this time window. All collected data were compared between patients with and without ICANS., Results: Thirty-eight consecutive patients were enrolled (14 women; median age: 65 years, interquartile range: [55-74]). ICANS was observed in 17 of 38 patients (44%) after a median time of 6 days after CAR T-cell infusion (4-8). The median ICANS grade was 2 (1-3). Higher C-reactive protein peak (146 mg/L [86-256], p = 0.004) at day 4 (3-6), lower natremia (131 mmol/L [129-132], p = 0.005) at day 5 (3-6), and frontal intermittent rhythmic delta activity (FIRDA, p < 0.001) on EEG between days 6 and 8 after infusion were correlated with ICANS occurrence. FIRDA was only observed in patients with ICANS (N = 15/17, sensitivity of 88%) and disappeared after ICANS resolution, usually after steroid therapy. Except for hyponatremia, no other toxic/metabolic marker was associated with FIRDA ( p = 0.002). The plasma concentration of copeptin, a surrogate marker of antidiuretic hormone secretion, assessed at day 7 after infusion, was significantly higher in patients with (N = 8) than without (N = 6) ICANS ( p = 0.043)., Discussion: FIRDA is a reliable diagnostic tool for ICANS, with a sensitivity of 88% and a negative predictive value of 100%. Moreover, as this EEG pattern disappeared concomitantly with ICANS resolution, FIRDA could be used to monitor neurotoxicity. Finally, our study suggests a pathogenic pathway that starts with increased C-reactive protein, followed by hyponatremia and eventually ICANS and FIRDA. More studies are required to confirm our results., Classification of Evidence: This study provides Class III evidence that FIRDA on spot EEG accurately distinguishes patients with ICANS compared with those without after CAR T-cell therapy for hematologic malignancy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Blood microsampling combined with large panels of clinically relevant tests are of major interest for the development of home sampling and predictive medicine. The aim of the study was to demonstrate the practicality and medical utility of microsamples quantification using mass spectrometry (MS) in a clinical setting by comparing two types of microsamples for multiplex MS protein detection. In a clinical trial based on elderly population, we compared 2 µL of plasma to dried blood spot (DBS) with a clinical quantitative multiplex MS approach. The analysis of the microsamples allowed the quantification of 62 proteins with satisfactory analytical performances. A total of 48 proteins were significantly correlated between microsampling plasma and DBS ( p < 0.0001). The quantification of 62 blood proteins allowed us to stratify patients according to their pathophysiological status. Apolipoproteins D and E were the best biomarker link to IADL (instrumental activities of daily living) score in microsampling plasma as well as in DBS. It is, thus, possible to detect multiple blood proteins from micro-samples in compliance with clinical requirements and this allows, for example, to monitor the nutritional or inflammatory status of patients. The implementation of this type of analysis opens new perspectives in the field of diagnosis, monitoring and risk assessment for personalized medicine approaches.

Background and Aims: Muscle mass (MM) impairment observed in facioscapulohumeral muscular dystrophy (FSHD) may bias estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcreat). eGFR based on cystatin C (eGFRcys), produced by all nucleated cells, should be an interesting alternative. Main objectives were to compare eGFRcreat and eGRFcys for chronic kidney disease (CKD) staging and for annual eGFR evolution. Secondary objective was to analyse creatinine, cystatin C with measured MM., Material and Methods: During 4 years, 159 FSHD patients having one or more creatinine and cystatin C measurements (total samples: n = 379), with MM determination by bio-impedancemetry during their follow-up were included. eGFR were determined with CKD-Epi and EKFC equations., Results: On first examination samples, mean eGFRcys was significantly lower than mean eGFRcreat of 25.5 and 17.9 ml/min/1.73 m 2 using CKD-Epi and EKFC equations, respectively. 53.5% (CKD-Epi) and 59.1% (EKFC) of agreement were obtained when using eGFRcys instead of eGFRcreat with reclassifications occurring mainly towards more severe stages. Age was correlated with cystatin C but not with creatinine, MM was correlated with creatinine but not with cystatin C. eGFR decreases > 1 ml/min/1.73 m 2 were more important when using eGFRcys instead of eGFRcreat (CKD-Epi: 37.5 vs 15.4%, p < 0.001; EKFC: 34.6 vs 20.2%, p < 0.01)., Conclusion: Cystatin C which is independent of MM appears as a promising candidate biomarker for CKD diagnosis and follow-up in FSHD patient., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To compare the estimated glomerular filtration rate (eGFR) using the creatinine equation (eGFRcreat) or the cystatin C equation (eGFRcys) in people with HIV (PWH) under antiretroviral drugs. We specifically included patients with an eGFRcreat around 60 ml/min per 1.73 m2 to evaluate agreement on stage 2 and 3 chronic kidney disease (CKD) classification., Design: eGFRcreat, eGFRcys and resulting CKD staging were determined in 262 consecutive patients with HIV-1 (PWH) with a suppressed viral load (<200 copies/ml) under antiretroviral drugs and having impaired renal function (eGFRcreat between 45 and 80 ml/min per 1.73 m2). Antiretroviral drugs regimens were classified into eight groups: cobicistat (COBI)+elvitegravir (EVG), ritonavir (RTV)+protease inhibitor, dolutegravir (DTG), DTG+rilpivirine (RPV), RPV, raltegravir (RAL), bictegravir (BIC), and other antiretroviral drugs., Results: Mean eGFRcys was higher than mean eGFRcreat (77.7 ± 0.5 vs. 67.9  ± 7.9 ml/min per 1.73 m2, P < 0.0001). The differences were significant in five treatment groups with COBI/EVG; DTG; DTG+RPV; RPV; RAL. CKD classification was modified for 51% of patients when using eGFRcys instead of eGFRcreat, with reclassification to less severe stages in 37% and worse stages in 14%., Conclusion: This study highlighted significant differences in eGFR depending on the renal marker used in PWH, having a significant impact on CKD classification. eGFRcys should be an additive tool for patients having eGFRcreat around 60 ml/min per 1.73 m2 for better identification of renal impairment., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Many Point-of-Care devices have been released over the past decade. However, data regarding their analytical performances in real-world situations remains scarce. Herein, we aimed to assess the analytical performances of the i-STAT Alinity system. We conducted an analytical performances study with the i-STAT Alinity device using cartridges CG4+ (pH, Pco2, Po2, lactate, bicarbonate and base excess); CHEM8+ (Na, K, Cl, ionized Ca, urea, creatinine, glucose, hematocrit and hemoglobin) and PT/INR (prothrombin time and international normalized ratio). We assessed the imprecision and compared the results to those obtained on existing instruments in the central laboratory. We found that the within-lab coefficients of variation (CV) were very low (<2%) or low (2−5%), except for creatinine and PT (CV = 5.2% and CV = 6.3%, respectively). For almost all the parameters, the results were strongly (R2 = 90−95%) or very strongly (R2 > 95%) correlated with those of the existing laboratory instruments, and the biases were very low (<2%) or low (2−5%). However, correlations of the PT and INR measurements with existing instruments were lower (R2 = 86.0% and 89.7%), and biases in the Po2 (7.9%), creatinine (5.4%) and PT (−6.6%) measurements were higher. The i-STAT Alinity appeared as a convenient device for measurements of numerous parameters. However, clinicians should interpret Po2, creatinine and PT results with caution.

Tubular injury is the main cause of acute kidney injury (AKI) in critically ill COVID-19 patients. Proximal tubular dysfunction (PTD) and changes in urinary biomarkers, such as NGAL, TIMP-2, and IGFBP7 product ([TIMP-2]•[IGFBP7]), could precede AKI. We conducted a prospective cohort study from 2020/03/09 to 2020/05/03, which consecutively included all COVID-19 patients who had at least one urinalysis, to assess the incidence of PTD and AKI, and the effectiveness of PTD, NGAL, and [TIMP-2]•[IGFBP7] in AKI and persistent AKI prediction using the area under the receiver operating characteristic curves (AUCs), Kaplan-Meier methodology (log-rank tests), and Cox models. Among the 60 patients admitted to the ICU with proven COVID-19 (median age: 63-year-old (interquartile range: IQR, 55-74), 45 males (75%), median simplified acute physiology score (SAPS) II: 34 (IQR, 22-47) and median BMI: 25.7 kg/m 2 (IQR, 23.3-30.8)) analyzed, PTD was diagnosed in 29 patients (48%), AKI in 33 (55%) and persistent AKI in 20 (33%). Urinary NGAL had the highest AUC for AKI prediction: 0.635 (95%CI: 0.491-0.779) and persistent AKI prediction: 0.681 (95%CI: 0.535-0.826), as compared to PTD and [TIMP-2]•[IGFBP7] (AUCs <0.6). AKI was independently associated with higher SAPSII (HR = 1.04, 95%CI: 1.01-1.06, p  = 0.005) and BMI (HR = 1.07, 95%CI: 1.00-1.14, p  = 0.04) and persistent AKI with higher SAPSII (HR = 1.03, 95%CI: 1.00-1.06, p  = 0.048) and nephrotoxic drug use (HR = 3.88, 95%CI: 1.20-12.5, p  = 0.02). In conclusion, in critically ill COVID-19 patients, the incidence of PTD and AKI was relatively high. NGAL was the best urinary biomarker for predicting AKI, but only clinical severity was independently associated with its occurrence.

In the early phase of the pandemic, we were among the first to postulate that neutrophil extracellular traps (NETs) play a key role in COVID-19 pathogenesis. This exploratory prospective study based on 279 individuals showed that plasma levels of neutrophil elastase, myeloperoxidase and circulating DNA of nuclear and mitochondrial origins in nonsevere (NS), severe (S) and postacute phase (PAP) COVID-19 patients were statistically different as compared to the levels in healthy individuals, and revealed the high diagnostic power of these NETs markers in respect to the disease severity. The diagnostic power of NE, MPO, and cir-nDNA as determined by the Area Under Receiver Operating Curves (AUROC) was 0.95, 097, and 0.64; 0.99, 1.0, and 0.82; and 0.94, 1.0, and 0.93, in NS, S, and PAP patient subgroups, respectively. In addition, a significant fraction of NS, S as well as of PAP patients exhibited aCL IgM/IgG and anti-B2GP IgM/IgG positivity. We first demonstrate persistence of these NETs markers in PAP patients and consequently of sustained innate immune response imbalance, and a prolonged low-level pro-thrombotic potential activity highlighting the need to monitor these markers in all COVID-19 PAP individuals, to investigate postacute COVID-19 pathogenesis following intensive care, and to better identify which medical resources will ensure complete patient recovery., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: As circulating DNA (cirDNA) is mainly detected as mononucleosome-associated circulating DNA (mono-N cirDNA) in blood, apoptosis has until now been considered as the main source of cirDNA. The mechanism of cirDNA release into the circulation, however, is still not fully understood. This work addresses that knowledge gap, working from the postulate that neutrophil extracellular traps (NET) may be a source of cirDNA, and by investigating whether NET may directly produce mono-N cirDNA., Methods: We studied (1) the in vitro kinetics of cell derived genomic high molecular weight (gHMW) DNA degradation in serum; (2) the production of extracellular DNA and NET markers such as neutrophil elastase (NE) and myeloperoxidase (MPO) by ex vivo activated neutrophils; and (3) the in vitro NET degradation in serum; for this, we exploited the synergistic analytical information provided by specifically quantifying DNA by qPCR, and used shallow WGS and capillary electrophoresis to perform fragment size analysis. We also performed an in vivo study in knockout mice, and an in vitro study of gHMW DNA degradation, to elucidate the role of NE and MPO in effecting DNA degradation and fragmentation. We then compared the NET-associated markers and fragmentation size profiles of cirDNA in plasma obtained from patients with inflammatory diseases found to be associated with NET formation and high levels of cirDNA (COVID-19, N = 28; systemic lupus erythematosus, N = 10; metastatic colorectal cancer, N = 10; and from healthy individuals, N = 114)., Results: Our studies reveal that gHMW DNA degradation in serum results in the accumulation of mono-N DNA (81.3% of the remaining DNA following 24 h incubation in serum corresponded to mono-N DNA); "ex vivo" NET formation, as demonstrated by a concurrent 5-, 5-, and 35-fold increase of NE, MPO, and cell-free DNA (cfDNA) concentration in PMA-activated neutrophil culture supernatant, leads to the release of high molecular weight DNA that degrades down to mono-N in serum; NET mainly in the form of gHMW DNA generate mono-N cirDNA (2 and 41% of the remaining DNA after 2 h in serum corresponded to 1-10 kbp fragments and mono-N, respectively) independent of any cellular process when degraded in serum; NE and MPO may contribute synergistically to NET autocatabolism, resulting in a 25-fold decrease in total DNA concentration and a DNA fragment size profile similar to that observed from cirDNA following 8 h incubation with both NE and MPO; the cirDNA size profile of NE KO mice significantly differed from that of the WT, suggesting NE involvement in DNA degradation; and a significant increase in the levels of NE, MPO, and cirDNA was detected in plasma samples from lupus, COVID-19, and mCRC, showing a high correlation with these inflammatory diseases, while no correlation of NE and MPO with cirDNA was found in HI., Conclusions: Our work describes the mechanisms by which NET and cirDNA are linked. In doing so, we demonstrate that NET are a major source of mono-N cirDNA independent of apoptosis and establish a new paradigm of the mechanisms of cirDNA release in normal and pathological conditions. We also demonstrate a link between immune response and cirDNA., (© 2022. The Author(s).)

Objectives: Aldosterone and renin determinations play an important role in the etiological diagnosis of secondary hypertension. The analytical performances of new aldosterone and renin immunoassays on the Lumipulse G600II ® system (Fujierbio) were investigated and compared with those of the iSYS ® system (IDS) on patients concerned by medical investigations in a context of suspected or proven Primary aldosteronism., Methods: By using the Lumipulse ® G Aldosterone and Renin assays we performed imprecision study, linearity and method comparison (n=107). Accuracy of this new renin assay was tested using the International Standard (WHO IS 68/356). We also assessed the equivalence of the different samples types (n=29)., Results: The imprecision evaluation showed all CVs <3% and <6% for Lumipulse ® G Aldosterone and Renin assays respectively. The linearity was excellent over the clinical range and the comparison with the iSYS ® assays (n=79) showed a strong correlation (R 2 =1) despite a slight tendency to underestimation (bias of -17.53 pg/mL or 48.56 pmol/L for aldosterone and -15.395 pg/mL for renin). Moreover, the contingency studies based on diagnostic criteria showed that Lumipulse ® G results lead to the same clinical diagnosis that iSYS ® results. A clear correlation was obtained between EDTA and heparin plasma as well as with the serum for all range of measures., Conclusions: The Lumipulse ® G Aldosterone and Renin assays present performances compatible with a routine use in medical laboratories. The precise quantification in the low range can be of interest in some clinical contexts especially standing/laying tests. However, the standardisation against the WHO International Standard Renin would be advisable., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Point-of-care testing (POCT) provides shorter turn-around times and, in many cases, potentially improves medical decision making. The AQT90 FLEX® benchtop immunoanalyzer (Radiometer Medical ApS, Copenhagen, Denmark) allows for the determination of beta-human chorionic gonadotropin (βhCG) in 18 min. The main aim of this study was to evaluate the impact of measuring βhCG using the AQT90 analyzer in the gynecology emergency department (ED) compared to the standard practice of using central laboratory blood testing on the patient length of stay (LOS). Methods: The evaluation consisted of two parts. The first one, conducted in the central laboratory, focused on the analytical performances of the AQT βhCG assay. The second one, conducted in the ED, aimed at determining the impact of POCT βhCG implementation on the timeframe in which ED patients require βhCG assessment. Results: The within-lab imprecisions at the mean values of 17 and 287 IU/L were 2.7% and 3.7%, respectively. Using Deming regression (n = 60), the following equation was obtained in the central lab: AQT90 βhCG = 1.1 Roche βhCG—12.9 (r = 0.997). The implementation of POCT βhCG in the ED significantly reduced patient LOS (145 (90−212) min vs. 205 (155−265) with and without AQT90, respectively, p < 0.001). At the 2 IU/L decision level, a 99.7% agreement with the Roche assay was reported (kappa statistics, 0.99). Conclusions: We confirm that the analytical qualities of the AQT 90 were in line with those obtained in the central lab. The implementation of the POCT βhCG is associated with a shorter LOS in the ED due to the faster availability of the results and the faster decision-making possibilities.

The screening of skeletal muscle diseases constitutes an unresolved challenge. Currently, exercise tests or plasmatic tests alone have shown limited performance in the screening of subjects with an increased risk of muscle oxidative metabolism impairment. Intensity-adjusted energy substrate levels of lactate (La), pyruvate (Pyr), β-hydroxybutyrate (BOH) and acetoacetate (AA) during a cardiopulmonary exercise test (CPET) could constitute alternative valid biomarkers to select "at-risk" patients, requiring the gold-standard diagnosis procedure through muscle biopsy. Thus, we aimed to test: (1) the validity of the V'O 2 -adjusted La, Pyr, BOH and AA during a CPET for the assessment of the muscle oxidative metabolism (exercise and mitochondrial respiration parameters); and (2) the discriminative value of the V'O 2 -adjusted energy and redox markers, as well as five other V'O 2 -adjusted TCA cycle-related metabolites, between healthy subjects, subjects with muscle complaints and muscle disease patients. Two hundred and thirty subjects with muscle complaints without diagnosis, nine patients with a diagnosed muscle disease and ten healthy subjects performed a CPET with blood assessments at rest, at the estimated 1st ventilatory threshold and at the maximal intensity. Twelve subjects with muscle complaints presenting a severe alteration of their profile underwent a muscle biopsy. The V'O 2 -adjusted plasma levels of La, Pyr, BOH and AA, and their respective ratios showed significant correlations with functional and muscle fiber mitochondrial respiration parameters. Differences in exercise V'O 2 -adjusted La/Pyr, BOH, AA and BOH/AA were observed between healthy subjects, subjects with muscle complaints without diagnosis and muscle disease patients. The energy substrate and redox blood profile of complaining subjects with severe exercise intolerance matched the blood profile of muscle disease patients. Adding five tricarboxylic acid cycle intermediates did not improve the discriminative value of the intensity-adjusted energy and redox markers. The V'O 2 -adjusted La, Pyr, BOH, AA and their respective ratios constitute valid muscle biomarkers that reveal similar blunted adaptations in muscle disease patients and in subjects with muscle complaints and severe exercise intolerance. A targeted metabolomic approach to improve the screening of "at-risk" patients is discussed.

Background: Tenfold or more overdose of a drug or preparation is a dreadful adverse event in neonatology, often due to an error in programming the infusion pump flow rate. Lipid overdose is exceptional in this context and has never been reported during the administration of a composite intravenous lipid emulsion (ILE)., Case Presentation: Twenty-four hours after birth, a 30 weeks' gestation infant with a birthweight of 930 g inadvertently received 28 ml of a composite ILE over 4 h. The ILE contained 50% medium-chain triglycerides and 50% soybean oil, corresponding to 6 g/kg of lipids (25 mg/kg/min). The patient developed acute respiratory distress with echocardiographic markers of pulmonary hypertension and was treated with inhaled nitric oxide and high-frequency oscillatory ventilation. Serum triglyceride level peaked at 51.4 g/L, 17 h after the lipid overload. Triple-volume exchange transfusion was performed twice, decreasing the triglyceride concentration to < 10 g/L. The infant's condition remained critical, with persistent bleeding and shock despite supportive treatment and peritoneal dialysis. Death occurred 69 h after the overdose in a context of refractory lactic acidosis., Conclusions: Massive ILE overdose is life-threatening in the early neonatal period, particularly in premature and hypotrophic infants. This case highlights the vigilance required when ILEs are administered separately from other parenteral intakes. Exchange transfusion should be considered at the first signs of clinical or biological worsening to avoid progression to multiple organ failure., (© 2021. The Author(s).)

Background: Recently, Ortho Clinical Diagnostics have launched a high sensitivity cardiac troponin I assay adapted on Vitros3600 / 5600. We aimed at evaluating the analytical and clinical performances using the 0/3-hour algorithm, of the Ortho hs-cTnI assay on the Vitros 3600® (Ortho Clinical Diagnostics, Illkirch, France) analyzer with comparison to Roche hs-cTnT assay on the Cobas8000/e801® module (Roche diagnostics, Meylan, France) and the Abbott STAT hs-cTnI assay on the Alinity i® (Abbott, Rungis, France) analyzer., Methods: Imprecision studies, linearity, limit of detection, and the interference to hemolysis were performed for Ortho hs-cTnI assay. The concordance study was based on results of troponin obtained from 160 patients with chest pain to the emergency department. Testing was performed simultaneously measuring the Roche hs-cTnT and the Ortho hs-cTnI, then on remaining sample the concentration of Abbott hs-cTnI (n = 150). We applied the 0/3h algorithm to rule out/rule in, in acute myocardial infarction., Results: Analytical performances were acceptable and in accordance with manufacturer's data. For late presenters 100, 92.8 and 88.8% patients could be rule-out with Roche, Ortho and Abbott assay, respectively with one NSTEMI missed with both hs-TnI assays. Applying the hs-cTn cut-offs from 0/3-hour algorithm, 107 (66.8%) could be rule out with Roche hs-cTnT with no AMI missed (sensitivity 100% [95%CI: 90.5 to 100] and NPV 100%); 89 with Ortho hs-cTnI (sensitivity 97.3% [95%CI: 85.8-99.9] and NPV 98.8% [95%CI:92.7-99.8]); and 61 with Abbott hs-cTnI (sensitivity 97% [95%CI: 84.2-99.9] and NPV 98.4% [95%CI: 89.8-99.7]). For rule-in, 23.7% (n = 37) from the total population would be designated in this group, with a specificity of 86.9% (95%CI: 79.7-92.4) and PPV of 69.8% (95%CI: 59.4-78.5) vs specificity of 72.3% (95%CI:63.5-80.0) and PPV of 51.4% (95%CI: 44.1-58.2)with Roche hs-cTnT vs Ortho hs-cTnI respectively; and with Abbott, 33 patients had constitued this group with a specificity of 52.1% (95%CI:42.7-61.4) and PPV of 36.4% (95%CI: 32.0-41.0)., Conclusion: In conclusion, according to ESC guidelines, our results indicate that the Ortho hs-cTnI assay for the Vitros 3600 instrument is a method that may be used in the clinical practice using 0/3-hour algorithm., (Copyright © 2021. Published by Elsevier B.V.)

Point of care testing makes it possible to obtain results in an extremely short time. Recently, radiometer has expanded the panel of tests available on its ABL90 FLEX PLUS blood gas analyzer (ABL90) by adding urea and creatinine. The aim of this study was to verify the performance of these new parameters. This included assessment of imprecision, linearity, accuracy by comparison with central laboratory standard assays and interferences. In addition, clinical utility in a dialysis center was evaluated. Within-lab coefficients of variation were close to 2%. The mean and limits of agreement (mean ± 1.96 SD) of the difference between ABL90 and Roche enzymatic assays on cobas 8000 were 0.5 (from -1.4 to 2.3) mmol/L and -0.9 (from -19.5 to 17.8) µmol/L for urea and creatinine, respectively. The ABL90 enzymatic urea and creatinine assays met the acceptance criteria based on biological variation for imprecision and showed good agreement with central laboratory. The two assays were unaffected by hematocrit variation between 20 and 70%, hemolysis and icterus interferences. It should be noted that the relationship between lab methods and ABL90 was conserved even for high pre-dialysis values allowing easy access to dialysis adequacy parameters ( Kt / V ) and muscle mass evaluation (creatinine index). Rapid measurement of creatinine and urea using whole blood specimens on ABL90 appears as a fast and convenient method. Analytical performances were in accordance with our expectations without any significant interferences by hemolysis or icterus.

To determine the analytical performance of Novel VITROS BRAHMS Procalcitonin Immunoassay on VITROS 3600 and correlation with BRAHMS PCT sensitive KRYPTOR reference method. Analytical performances including imprecision studies, linearity, limit of detection (LoD) and determination of hemolysis index were performed for VITROS BRAHMS PCT assay. Imprecision was assessed on plasma pool and internal control with 2 levels. The method comparison was performed using 162 plasma obtained from clinical departments. The total imprecision was acceptable and all CV were <5%. The LoD was in accordance with manufacturer's claims. The equation of linearity in the lower range was found to be y  = 1.0014 x - 0.0091, with r 2 = 1. No interference to hemoglobin up to 11 g/L was observed. Correlation studies showed a good correlation between PCT measurements using VITROS BRAHMS PCT assay against KRYPTOR system including for values lower than 2 µg/L. The novel VITROS BRAHMS PCT assay from OrthoClinical Diagnostics shows analytical performances acceptable for clinical use. In addition, the concordance with KRYPTOR method was fine at all clinical cut-offs.

Menkes disease is an X-linked recessive disorder affecting copper metabolism due to an inactivating mutation of ATP7A gene. This result in loss of copper intestinal absorption, tissue deficiency and failure in multiple essential copper-enzyme systems such as the cytochrome c oxidase. Symptoms usually occur during the first months of life with neurological signs such as epilepsy associated to other signs among them typical hair appearance. We report the case of a 3 month-old infant hospitalized due to partial tonic-clonic seizures. Laboratory findings showed increased of lactates in blood and in cerebrospinal fluid. First screenings for infectious, metabolic and genetic causes were negative. After recurrence of multifocal seizures further investigations are made according to the presence of thick and tortuous hair. Low levels of ceruloplasmin and copper in plasma are in agreement with the suspected diagnosis of Menkes disease. Molecular analysis of the ATP7A gene confirmed the diagnosis with a non-sens mutation.

Nephrogenic diabetes insipidus due to the inability of the kidneys to concentrate urine is frequently observed during lithium therapy. Lithium concentrates into principal cells in collecting ducts in the kidney and downregulates aquaporin 2 expression, which reduces renal reabsorption of water. This disease is characterized by polyuria - polydipsia leading to intracellular dehydration and hypernatremia. Water deprivation test is performed to confirm insipidus diabetes. The desmopressin permits to distinguish nephrogenic from cranial insipidus diabetes. We report the case of a 64 years old women who presented with global dehydration and severe hypernatremia. Four years ago, she was hospitalized for nephrogenic diabetes insipidus related to a self-induced lithium intoxication. Persistent nephrogenic insipidus diabetes after cessation of lithium therapy are described in literature, and this hypothesis may be consistent with this case report.

Background All general biochemistry instruments allow the measure of hemolysis index (HI), and suppliers provide an acceptable HI for each assay without consideration of the analyte value or its clinical application. Our first objective was to measure the impact of hemolysis degree on plasma biochemical and immunochemical analytes to determine the maximum allowable HI for each of them using four calculation methods as significant bias in comparison to manufacturer's data. The second objective was to assess whether the maximum allowable HI varied according to the analyte values. Methods Twenty analytes were measured in hemolyzate-treated plasma to determine the HI leading to a significant change compared to baseline value. Analytes were assessed at one (3 analytes), two (5 analytes) and three (12 analytes) values according to their sensitivity to hemolysis and their clinical impact. We used four calculation methods as significant limit from baseline value: the total change limit (TCL), the 10% change (10%Δ), the analytical change limit and the reference change value. Results Allowable HI was significantly different according to the threshold chosen for most analytes and was also dependent on the analyte value for alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatine kinase, iron, haptoglobin and high sensitivity troponin T. No hemolysis interference was observed for albumin, creatinine, C-reactive protein, and procalcitonin even at an HI value of 11 g/L. Conclusions This study highlights that TCL is the most appropriate calculation method to determine allowable HI in practice for biochemical and immunochemical parameters using Cobas 8000© from Roche Diagnostics. In addition, different allowable HI were found according to analyte value leading to optimization of resampling to save time in patient care.

We report the analytical performances of two particle-enhanced (PETIA) methods for measuring procalcitonin (PCT), the Diazyme PCT and the new DiaSys PCT assay, and their concordance of values with BRAHMS PCT Kryptor©. The total imprecisions onto two control levels and one serum pool were for DiaSys 5.42%, 3.3% and 7.53% and for Diazyme 10.7%, 2.9% and 13.23%, respectively. The limit of blank, limit of detection and limit of quantification were under the 0.25 cut-off for the two methods. The linearity in the lower range was acceptable for both methods. No significant effect on PCT determination was observed for DiaSys' assay upon addition of interfering substances. With the Diazyme assay, significant effects were seen with rheumatoid factor (RF), lipid and hemoglobin. Correlation studies on 136 sera showed a good correlation between PCT measurements using DiaSys assay against the Kryptor system, while only a poor correlation was observed between the Diazyme assay, especially for low values. The novel PETIA PCT assay from DiaSys shows analytical performances acceptable for clinical use and the concordance with Kryptor method was fine at all clinical cut-offs. In contrast, despite comparable analytical performances, the Diazyme PETIA method exhibited a poor concordance with the Kryptor method.

Introduction: The ALDH18A1 gene, encoding delta-1-pyrroline-5-carboxylate synthase (P5CS), is responsible for an autosomal recessive disease with severe developmental delay; more recently, ALDH18A1 was found to be responsible for SPG9, an autosomal dominant (AD) spastic paraplegia., Case Report: We report a three-generation family with AD SPG9, initially suspected because of low citrulline on fasting plasma amino acid chromatography (AAC). Interestingly, in two patients, the spastic paraplegia appeared during pregnancy. One subject presented a severe childhood-onset form while another subject had a mild late-onset disease., Conclusion: The description of this family is of particular interest: it highlights the possibility of transient or permanent aggravation of spastic paraplegia due to SPG9 during pregnancy, suggesting a direct link between neurological symptoms and amino acid defect in a period of higher requirements and the potential benefit of amino acid supplementation; it underscores the value of plasma citrulline on fasting plasma AAC as a biomarker for this disease; it shows the variable expression of the disease.

The extraction of accurate physiological parameters from clinical samples provides a unique perspective to understand disease etiology and evolution, including under therapy. We introduce a new methodologic framework to map patient proteome dynamics in vivo, either proteome-wide or in large targeted panels. We applied it to ventricular cerebrospinal fluid (CSF) and could determine the turnover parameters of almost 200 proteins, whereas a handful were known previously. We covered a large number of neuron biology- and immune system-related proteins, including many biomarkers and drug targets. This first large data set unraveled a significant relationship between turnover and protein origin that relates to our ability to investigate organ physiology with protein-labeling strategy specifics. Our data constitute the first draft of CSF proteome dynamics as well as a repertoire of peptides for the community to design new analyses. The disclosed methods apply to other fluids or tissues provided sequential sample collection can be performed. We show that the proposed mathematical modeling applies to other analytical methods in the field.

Background: Blood gas analyzers are frequently installed as point of care devices and thus allow rapid decision making. Few data are available regarding analytical performance of large sets of BGA. We aimed at evaluating 22 ABL 90 Flex Plus analyzers intended to be deployed. The evaluation was performed at the device level and at the entire set level to characterize the quality of measurements but also to ensure consistency across the devices deployed in the hospital., Methods: Imprecision and total error were assessed for pH, pCO2, pO2, sodium, potassium, ionized calcium, glucose, lactate and oximetry parameters. Imprecision at the hospital level including between device variability was also evaluated. One of the two analyzers used in the central laboratory was correlated with a GEM Premier 4000 and a Cobas b221 analyzers. Thereafter, we tested sequentially the 20 instruments intended to be deployed in care service in comparison with the reference device., Results: Heterogeneity of analytical performance across the different analyzers was low, allowing to consider the whole set as a unique analyzer. The total error was in line with performance goals. Analytical performance of the analyzers was found suitable for use in clinical practice., Conclusions: Our study is an example of the qualification of a set of point and underscores 1)The need for a unified qualification scheme when multiple analyzers are deployed simultaneously 2) analytical performance goals compatible with clinical use and the state of the art for all parameters., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: We report the analytical performances of a new point-of-care (POC) procalcitonin (PCT) fluorescence immunoassay that uses the AFIAS-6© system from Boditech and its concordance with results of the standard method Kryptor Compact plus from the central laboratory., Design: and methods: Analytical performances including imprecision studies, limit of blank (LoB), limit of detection (LoD) and limit of quantification (LOQ) were determined. The method comparison was performed using plasma vs. whole blood for Kryptor CompactPlus© vs. AFIAS-6©, respectively., Results: The total imprecision was far from the CV of 4.5% claimed by the manufacturer and close to 10%, for levels of PCT at 0.4 and 8.3 μg/L. The LoD of this novel PCT assay was found to close to the LoD provided by the manufacturer at 0.04 μg/L. The LOQ was higher than that claimed by the manufacturer (0.1 vs 0.002, respectively). The equation of linearity in the lower range was found to be y = 1.056x - 0.039 with r 2  = 0.993 with a mean recovery percentage of 86 ± 15%. Correlation studies showed a good correlation between PCT measurements using plasma on Kryptor system and on corresponding whole blood with POC reaching a bias of -0.04 in the range from 0.02 to 2 μg/L., Conclusion: The novel PCT assay on AFIAS-6© is an acceptable POC alternative for the diagnosis and management of sepsis at EDs to improve the flow of patients, as results are consistent with those of the standard PCT Kryptor Compact Plus© assay, despite its higher imprecision., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2019 The Authors.)

Background: Centrifugation is a consuming time step which participates to increase the turnaround time (TAT) in laboratories, likewise hemolysis sample that needs a re-sampling could delay management of patients. Recently, it has been postulated that BD Barricor™ tube could allow to decrease the centrifugation time and prevent hemolysis, two key feature to ensure high-quality results.Aim of the study was to evaluate the impact of replacing 4 mL BD vacutainer heparin lithium tube by low vacuum 3.5 mL BD vacutainer Barricor™ tube in an emergency department (ED) on hemolysis rate and TAT., Methods: Data of hemolysis index (HI) and TAT were compared between the first period of 15 days using 4 mL BD vacutainer heparin lithium tubes with 15 min at 2000xg as centrifugation setting and a second period of 15 days using BD vacutainer Barricor™ tube centrifuged 3 min at 4000xg., Results: A significantly reduced time duration between reception of sample and available results in informatics lab system was observed with the reduction time of centrifugation allowed by use of Barricor™ tube compared to regular heparin lithium tubes (p < 0.001). A significative decrease in hemolysis rate also occurred in the second period as samples with HI < 10 reached from 52.5% in the first period to 68.5% (p < 0.001) in the second., Conclusion: Low vacuum Barricor TM tubes allowing a higher speed of centrifugation improve lab TAT without impairment of sample quality as a significant reduction of hemolysis was observed, a double advantage which is of particular interest for ED.

Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations., Competing Interests: The authors have declared that no competing interests exist. We confirm that commercial affiliation of BC Platforms Ltd Oy, Espoo, Finland and Intactile Design SA, Montpellier, France does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The study was designed to evaluate the analytical performances of two ERM-DA471/IFCC traceable cystatin C (CysC) reagents available on the market for urinary CysC (u-CysC) quantification. In addition, clinical relevance was assessed by measuring u-CysC in healthy controls and in patients with tubular dysfunction., Methods: CysC in urine was measured by a particle-enhanced nephelometric immunoassay using Siemens reagents and by a particle-enhanced turbidimetric immunoassay using DiaSys reagents. Imprecision, linearity, limit of detection and limit of quantification were evaluated according to CLSI recommendations. The two methods were tested on 150 urinary samples from 50 healthy subjects, 50 HIV patients with tubular dysfunction and 50 patients who developed acute kidney acute injury., Results: Within-laboratory coefficients of variations were below 4%. The lower limit of quantification of the assay was found at 0.043 and 0.046 mg/L for DiaSys and Siemens, respectively. The following Passing-Bablok regression equations were obtained: DiaSys = 0.99 Siemens + 0.00. Using Bland-Altman analysis, the mean bias was -0.004 mg/L on the analytical range between 0.02 and 1 mg/L. Median u-CysC in 50 HIV patients with tubular dysfunction and in 50 patients with AKI was higher than in control subjects., Conclusions: Both Siemens and DiaSys reagents demonstrated reliable and reproducible performances allowing easy determination of u-CysC on automated platforms in clinical practice with potential interest for the detection of tubular dysfunction.

Nonsteroidal antiinflammatory drugs and analgesic drugs, such as N-acetyl- p-aminophenol (APAP; acetaminophen, paracetamol), are widely used by pregnant women. Accumulating evidence has indicated that these molecules can favor genital malformations in newborn boys and reproductive disorders in adults. However, the consequences on postnatal testis development and adult reproductive health after exposure during early embryogenesis are still unknown. Using the mouse model, we show that in utero exposure to therapeutic doses of the widely used APAP-ibuprofen combination during the sex determination period leads to early differentiation and decreased proliferation of male embryonic germ cells, and early 5-methylcytosine and extracellular matrix protein deposition in 13.5 d postcoitum exposed testes. Consequently, in postnatal testes, Sertoli-cell maturation is delayed, the Leydig-cell compartment is hyperplasic, and the spermatogonia A pool is decreased. This results in a reduced production of testosterone and in epididymal sperm parameter defects. We observed a reduced sperm count (19%) in utero-exposed (F0) adult males and also a reduced sperm motility (40%) in their offspring (F1) when both parents were exposed, which leads to subfertility among the 6 mo old F1 animals. Our study suggests that the use of these drugs during the critical period of sex determination affects the germ-line development and leads to adverse effects that could be passed to the offspring.-Rossitto, M., Marchive, C., Pruvost, A., Sellem, E., Ghettas, A., Badiou, S., Sutra, T., Poulat, F., Philibert, P., Boizet-Bonhoure, B. Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen.

Background: Subclinical mastitis (SCM) is relatively common in lactating women and may be associated with HIV shedding in breast milk. The potential association between HIV infection and breast milk immunologic factors and immune response to SCM needs to be addressed., Methods: In this cross-sectional study, SCM (Na/K ratio > 1) was tested in 165 mature breast milk samples collected from 40 HIV-infected women who didn't transmit HIV to their child by breastfeeding and 43 HIV-uninfected women enrolled in an interventional cohort in South-Africa (Vertical Transmission Study). The level of 33 immune markers related to Th1/Th2 related response, inflammation and bacterial exposure were compared in ART-naive HIV-infected versus HIV-uninfected women. The associations between HIV infection and SCM on the concentration of immune factors were tested separately by Wilcoxon rank-sum test and corrected for false discovery rate. To control for potential confounder effects and take into account the clustering of breast milk samples from a single woman, multivariate mixed linear models adjusted on child age at the time of sampling were performed for each immune factor., Results: Subclinical mastitis was detected in 15 (37.5%) HIV-infected women and 10 (23.3%) HIV-uninfected women. In the absence of SCM, the breast milk levels of IP-10 and MIG were higher and IL1-RA lower in HIV-infected women than in HIV-uninfected women (respectively p < 0.001, p = 0.001, p = 0.045). In HIV-uninfected women, SCM was characterized by a robust immune response with higher concentrations of a broad panel of Th1 and inflammatory related immune markers than in samples without SCM. By contrast, in HIV-infected women a limited number of immune markers were increased and lower increases were observed in samples with SCM than without SCM., Conclusion: HIV infection in ART-naïve women was associated with elevated breast milk levels of IP-10 and MIG, which areTh1-related cytokines induced by IFN-γ. During SCM, a lower and narrower immune response was observed in HIV-infected than HIV-uninfected women, suggesting that HIV infection affects the capacity of the mammary gland to respond to SCM.