A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT-0701 MAPS phase 3 trial.

The Hippo pathway effector YAP is dysregulated in malignant pleural mesothelioma (MPM). YAP's target genes include the secreted growth factor amphiregulin (AREG), which is overexpressed in a wide range of epithelial cancers and plays an elusive role in MPM. We assayed the expression of YAP and AREG in MPM pathology samples and that of AREG additionally in plasma samples of patients from the randomized phase 3 IFCT-0701 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) using immunohistochemistry and ELISA assays, respectively. MPM patients frequently presented high levels of tumor AREG (64.3%), a high cytosolic AREG expression being predictive of a better prognosis with longer median overall and progression-free survival. Surprisingly, tumor AREG cytosolic expression was not correlated with secreted plasma AREG. By investigating the AREG metabolism and function in MPM cell lines H2452, H2052, MSTO-211H and H28, in comparison with the T47D ER+ breast cancer cell line used as a positive control, we confirm that AREG is important for cell invasion, growth without anchorage, proliferation and apoptosis in mesothelioma cells. Yet, most of these MPM cell lines failed to correctly execute AREG posttranslational processing by metalloprotease ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and extracell secretion. The favorable prognostic value of high cytosolic AREG expression in MPM patients could therefore be sustained by default AREG posttranslational processing and release. Thus, the determination of mesothelioma cell AREG content could be further investigated as a prognostic marker for MPM patients and used as a stratification factor in future clinical trials.

FRENCH versus ESI: comparison between two nurse triage emergency scales with referent scenarios.

OBJECTIVES: Acute triage is needed to prioritize care and achieve optimal resource allocation in busy emergency departments. The main objective is to compare the FRench Emergency Nurse Classification in Hospital scale (FRENCH) to the American scale Emergency Severity Index (ESI). Secondary objectives are to compare for each scale the over and under-triage, the triage matching to the gold standard and the inter-individual sorting reproducibility between the nurses. METHODS: This is a prospective observational study conducting among the nursing staffs and nursing students, selected from Caen University College Hospital and Lisieux Hospital Center emergency departments between two months. Each group individually rank 60 referent clinical cases composed by scales designers. An assessment of scale practicality is collected after for each tool. The collected parameters are analyzed by a Cohen kappa concordance test (κ). RESULTS: With 8151 triage results of gold standard scenarios sorting in two scales by the same nurses, the FRENCH scale seems to give better triage results than the US ESI scale (nurse: FRENCH 60% and ESI 53%, p = 0.003 ; nursing students: FRENCH 49% and ESI 42%, p < 0.001). In the two groups ESI has also a big tendency to under-sort (p = 0.01), particularly for the most severe patients (p < 0.01). The interobserver sorting concordance for any experience gives good results for the FRENCH and the ESI without any difference (nurses : FRENCH KPQ=0.72 ESI KPQ=0.78; p = 0.32 ; students KPQ=0.44 KPQ=0.55; p = 0.22). CONCLUSION: The ESI and FRENCH scales comparison on 8151 sorting results shows direct validity in favor of FRENCH one and similar interobserver agreement for both scales.

The Use of Pro-Angiogenic and/or Pro-Hypoxic miRNAs as Tools to Monitor Patients with Diffuse Gliomas.

IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O2, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma.

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial.

BACKGROUND: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation. METHODS: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines. RESULTS: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines. CONCLUSIONS: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.

Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0-1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m(2) pemetrexed plus 75 mg/m(2) cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456. FINDINGS: From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9-22·6]) than with PC (16·1 months [14·0-17·9]; hazard ratio 0·77 [0·62-0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3-4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. INTERPRETATION: Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease. FUNDING: Intergroupe Francophone de Cancérologie Thoracique (IFCT).

Prenatal diagnosis of clubfoot: Chromosomal abnormalities associated with fetal defects and outcome in a tertiary center.

PURPOSE: Our aim was to evaluate the rate of occurrence of chromosomal abnormalities, associated findings, and outcome in a series of cases of prenatally diagnosed clubfoot. METHODS: We conducted a retrospective study of all cases of clubfoot diagnosed prenatally in the ultrasound unit of a French tertiary center from January 2004 through December 2011. Clubfoot was scored as complex or isolated depending on the presence or absence of another structural abnormality observed on sonographic examination. RESULTS: Data from 90 fetuses prenatally diagnosed with clubfoot were included in this study. Thirty-four cases were considered complex (38%) and 56 were considered isolated (62%). A chromosomal abnormality was identified in 10 of 33 of the fetuses with complex clubfoot and in 1 of 45 of those with isolated clubfoot (p < 0.001). Clubfoot was associated with a poor outcome in 5 of 52 cases of isolated clubfoot and in 31 of 34 cases associated with other structural defects (p < 0.001). The deformity was bilateral in 62 cases (69%) and unilateral in 28 (31%). No statistically significantly higher rate of poor outcome was identified when the deformity occurred bilaterally nor was a significantly higher rate of chromosomal abnormality noted in this condition. CONCLUSIONS: Aneuploidy and adverse pregnancy outcomes occur more commonly in prenatally diagnosed cases of complex clubfoot than in those of isolated clubfoot. Fetal karyotyping is required in cases of complex clubfoot, but the need for that procedure in isolated clubfoot remains controversial.

Impact of prolonged dinoprostone cervical ripening on the rate of artificial induction of labor: a prospective study of 330 patients.

AIM: The aim of this study was to evaluate two regimens of administration of sustained-release dinoprostone on the need for oxytocin induction of labor. MATERIAL AND METHODS: We carried out an open prospective study comparing labor, maternal and neonatal outcomes after 12 h of prostaglandin cervical ripening insert versus 24 h of prostaglandin cervical ripening insert in 284 patients (142 ripenings at 12 h [P12 group] and 142 ripenings at 24 h [P24 group]). RESULTS: The two groups were demographically similar. There was a significant difference in the need for artificial rupture of membranes/oxytocin induction of labor between the groups (49.3% for the P12 group vs 38% for the P24 group, P = 0.03). The delay between the beginning of ripening and delivery was significantly decreased in the P12 group, but the duration of active labor (6.6 h), the dose of oxytocics used (1326 UI), the rate of cesarean section, the rate of uterine hyperstimulation, the rates of hemorrhaging from delivery, the neonatal state and the experience of induction were similar in the two groups. CONCLUSION: This study allows us to show for the first time that sustained-release of dinoprostone leads to spontaneous induction of labor without increasing the obstetrical risk in a majority of patients.

VEGFR2 and CD34 expression associated with longer survival in patients with pleural mesothelioma in the IFCT-GFPC-0701 MAPS phase 3 trial.

OBJECTIVES: VEGF/VEGFR autocrine loop is a hallmark of pleural mesothelioma (PM). We thus assayed the prognostic and predictive values of VEGFR-2 [vascular endothelial growth factor receptor 2 or Flk-1] and CD34, a marker of endothelial cells, in samples from patients accrued in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456). MATERIALS AND METHODS: VEGFR2 and CD34 expression were assayed using immunohistochemistry in 333 MAPS patients (74.3%), and their prognostic value was evaluated in terms of overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses, before validation by bootstrap methodology. RESULTS: Positive VEGFR2 or CD34 staining was observed in 234/333 (70.2%) and 322/323 (99.6%) of tested specimens, respectively. VEGFR2 and CD34 staining correlated weakly, yet significantly, with each other (r = 0.36, p < 0.001). High VEGFR2 expression or high CD34 levels were associated with longer OS in PM patients in multivariate analysis (VEGFR2: adjusted [adj.] hazard ratio [HR]: 0.91, 95% confidence interval [CI] [0.88; 0.95], p < 0.001; CD34: adj. HR: 0.86, 95 %CI [0.76; 0.96], p = 0.010), with only high VEGFR2 expression resulting in significantly longer PFS (VEGFR2: adj. HR: 0.96, 95 %CI [0.92; 0.996], p = 0.032). Stability of these results was confirmed using bootstrap procedure. Nevertheless, VEGFR2 expression failed to specifically predict longer survival in bevacizumab-chemotherapy combination trial arm, regardless of whether the VEGFR2 score was combined or not with serum VEGF concentrations. CONCLUSION: VEGFR2 overexpression independently correlated with longer OS or PFS in PM patients, such biomarker deserving prospective evaluation as stratification variable in future clinical trials.

Obstetrical situations with a high risk of anal sphincter laceration in vacuum-assisted deliveries.

OBJECTIVE: To determine risk factors for anal sphincter laceration and define situations with a high risk for such trauma in vacuum-assisted deliveries. DESIGN: Retrospective observational study of 1961 vacuum-assisted deliveries over a period of 5 years. SETTING: French university hospital. POPULATION: All women who delivered with vacuum assistance. METHODS: Third- and fourth-degree perineal tears were reviewed. The factors studied through univariate and multivariate logistic regression were the mother's age, parity, history of assisted delivery, cesarean section, gestational age, uterine fundal height, duration of the second stage of labor, head position at expulsion, epidural anesthesia, episiotomy, biparietal diameter and birthweight. MAIN OUTCOME MEASURES: Third- and fourth-degree perineal tears. RESULTS: There were 1.9% third-degree and no fourth-degree perineal tears. Risk factors identified were occipito-posterior position (odds ratio 4.7, p < 0.001), biparietal diameter (odds ratio 2.0 for each 5 mm increase, p= 0.004), duration of second stage (only significant when parity was ≥ 1; odds ratio 1.3 for each 10 min increase, p= 0.004) and nulliparity (decreasing effect according to duration of the second stage). The patterns of the association between these factors and the risk of perineal tears were different for nulli- and multiparous women. CONCLUSIONS: In a targeted population of women having vacuum-assisted deliveries, the association of specific risk factors allows clinicians to identify women who are at high risk of anal sphincter laceration.

Ferritin as a predictive biomarker of severity in Covid-19 / La ferritine comme biomarqueur prédictif des formes sévères de Covid-19

Background: To prevent the crisis-level shortage of beds in hospitals and for a more efficient support, it's necessary to early identify coronavirus disease-19 (Covid-19) patients at risk to develop a severe form of the disease. Objective: The goal of our study was to determine whether biological markers, including the serum ferritin, could predict the severity of the Covid-19. Methods: One hundred and seventy-one patients, who were admitted to Caen University Hospital, were included retrospectively with a positive diagnosis of Covid-19 by RT-PCR. A serum ferritin measurement was performed for all patients. They were further classified either into a non-severe or a severe group based on their hospitalization in intense care unit (ICU) for mechanical ventilation or death. Results: Univariate analysis revealed a significant association between increased serum ferritin and CRP levels, obesity, CT scan lesions, pathological respiratory rate, decreased PaO2/FiO2 ratio, the NEWS-2 score and the severe (n = 59) vs the non-severe (n = 112) outcome of Covid-19 patients. However, in a multivariate analysis, only CRP and obesity were associated with the severe form of Covid-19. Conclusion: While pathological level of serum ferritin at admission is associated with severe form of Covid-19, combination of increased CRP level and obesity would better predict the severity of the disease.

Pour une meilleure prise en charge, il est nécessaire de pouvoir identifier précocement les patients atteints de la Covid-19 susceptibles de développer une forme sévère. L'objectif de notre étude était de déterminer si des marqueurs biologiques, notamment la ferritinémie, peuvent prédire la sévérité de la Covid-19. Nous avons inclus de manière rétrospective 171 patients au CHU de Caen avec un diagnostic de Covid-19. Les patients devaient avoir un bilan biologique incluant la ferritinémie à l'admission et ont été classés en formes sévères (n = 59, hospitalisation et ventilation invasive en soins intensifs ou en réanimation, et/ou décès) et non-sévères (n = 112, tous les autres patients). L'analyse univariée a montré une association entre les formes sévères de Covid-19 avec les niveaux élevés de ferritine et de CRP, l'obésité, les lésions pulmonaires, la fréquence respiratoire élevée, la diminution du ratio PaO2/FiO2 et le score de NEWS-2. Cependant, en analyse multivariée seules la CRP et l'obésité montraient une association avec les formes sévères. En conclusion, alors que la ferritinémie élevée est associée à un risque accru de développer une forme sévère de la Covid-19, la CRP et la présence d'une obésité seraient de meilleurs marqueurs prédictifs.

How Satisfied Are Women 6 Months after a Pessary Fitting for Pelvic Organ Prolapse?

BACKGROUND: The non-surgical solution for Pelvic Organ Prolapse (POP) typically consists of a pessary fitting. We aimed to assess patient satisfaction and symptom improvement 6 months after a pessary fitting and to identify risk factors associated with pessary failure. METHODS: Six months after a pessary fitting, patient satisfaction was assessed by the PGII score; symptoms and quality of life were assessed using validated questionnaires (PFDI-20, ICIQ-SF, PISQ-12, USP, and PFIQ-7). RESULTS: Of the 190 patients included in the study (mean age of 66.7 years), 141 (74%) and 113 (59%) completed the follow-up questionnaires at 1 and 6 months, respectively. Nearly all the women were menopausal (94.6%) and 45.2% declared being sexually active at inclusion. The satisfaction rate was 84.3% and 87.4% at 1 and 6 months, respectively. The global symptom score PFDI-20 had significantly improved at 6 months. A high body mass index (RR = 1.06, CI95%: [1.02-1.09]), as well as high PFDI-20 (1.05 [1.01-1.09]), PFIQ7 (1.04 [1.01, 1.08]), and PISQ12 scores at inclusion (0.75 [0.60, 0.93]), as well as higher GH and GH/TVL measurements (1.49 [1.25-1.78] and 1.39 [1.23-1.57], respectively) were associated with pessary failure. CONCLUSIONS: Pessary seems to be an effective treatment for POP with high patient satisfaction. Higher BMI, higher symptom scores, and greater genital hiatus measurements before insertion are risk factors for failure at 6 months.

La warfarine est-elle plus stable que la fluindione ? Étude rétrospective en soins premiers (étude STAB-AVK).

Malgré leur prescription en seconde intention après les anticoagulants oraux directs, les antivitamines K (AVK) sont encore largement utilisés en soins premiers. En France, la fluindione représentait 82 % des AVK prescrits en 2016 contre 13 % pour la warfarine. Pourtant, la warfarine est l'AVK de référence ailleurs dans le monde et sa demi-vie plus longue devrait la rendre plus adaptée avec des International Normalized Ratio (INR) plus stables. Les objectifs de notre travail étaient de comparer ces deux molécules en termes de stabilité de leur effet anticoagulant au long cours et sur la fréquence des INR réalisés. Nous avons mené une étude rétrospective de type exposé/non-exposé sur données issues d'un laboratoire de biologie médicale ornais concernant des patients majeurs traités par fluindione ou warfarine du 1er janvier 2014 au 31 décembre 2016 inclus, quelle que soit l'indication. La stabilité du traitement était évaluée par le temps passé dans l'intervalle thérapeutique (TTR), calculé selon la méthode de Rosendaal, à partir des INR dosés en pratique courante. Les comparaisons entre les deux groupes ont été faites par régression linéaire multi-niveaux avec analyse univariée puis multivariée avec ajustement sur l'âge, le genre et la fonction rénale. Deux-cent-quatre patients ont été inclus (77,0 ± 10,0 ans, 49,5 % de femmes), 170 sous fluindione et 34 sous warfarine. Le TTR moyen sous fluindione était de 68,0 % contre 72,0 % sous warfarine (p = 0,085). Le délai moyen entre deux INR était de 22,8 jours sous fluindione contre 31,1 jours sous warfarine (p = 0,049). Par rapport à la fluindione, la warfarine semble présenter un bénéfice en termes de qualité de vie pour les patients. Malgré nos résultats, nous invitons à privilégier la warfarine à la fluindione en soins premiers.

Integrating biomarkers into clinical trials: methodological issues for a new paradigm in nonsmall cell lung cancer.

PURPOSE OF REVIEW: To summarize the major methodological issues concerning prognostic biomarkers in nonsmall cell lung cancers (NSCLCs) and to discuss integration of biomarkers into clinical trials. RECENT FINDINGS: Large phase 3 trials have recently been published in early-resected NSCLC with studies of biomarkers identifying subsets of patients that benefited most from the experimental perioperative strategy. The IALT-bio study reported that ERCC1 DNA-repair protein had prognostic and predictive implications. Other studies reported on the prognostic role of TUBB3 expression in stages I-III NSCLCs. The IPASS study reported the predictive and prognostic impact of epidermal growth factor receptor (EGFR) mutations in stage IV patients treated with EGFR tyrosine kinase inhibitor or platinum-based chemotherapy. Whereas EGFR mutations studies received prospective validation with trials in which treatment allocation was based on biomarker status, chemotherapy biomarkers still need such prospective confirmations, and many biases were still encountered in recent published studies. SUMMARY: Biomarkers of treatment efficacy will help to tailor treatment in NSCLCs. EGFR mutations have reached that point. Markers of chemotherapy efficacy still need validation studies before coming into routine practice. Stringent methodological recommendations should avoid most of the possible pitfalls of those studies and allow clinical applicability of such biomarkers.

Is plasma concentration of coenzyme Q10 a predictive marker for left ventricular remodelling after revascularization for ST-segment elevation myocardial infarction?

BACKGROUND: Left ventricular remodelling that frequently occurs after acute myocardial infarction is associated with an increased risk of heart failure and cardiovascular death. Although several risk factors have been identified, there is still no marker in clinical use to predict left ventricular remodelling. Plasma concentration of coenzyme Q10, which plays a key role in mitochondrial energy production and as an antioxidant, seems to be negatively correlated with left ventricular function after acute myocardial infarction. OBJECTIVE: The goal of our study was to determine whether the plasma coenzyme Q10 baseline concentrations at time of the ST-elevation myocardial infarction (STEMI) could predict left ventricular remodelling at six months' follow-up. METHODS: Sixty-eight patients who were admitted to hospital for STEMI and successfully revascularized with primary percutaneous coronary intervention were recruited. All patients underwent a 3D-echocardiography examination within the first four days after percutaneous coronary intervention and six months later then divided into two groups based on the presence or not of left ventricular remodelling. Plasma coenzyme Q10 concentration at the time of percutaneous coronary intervention was determined using high-performance liquid chromatography-tandem mass spectrometry. RESULTS: While we found similar plasma coenzyme Q10 concentrations compared with other studies, no association was evidenced between coenzyme Q10 concentrations and left ventricular remodelling (P = 0.89). CONCLUSION: We found no evidence for using plasma coenzyme Q10 concentration as an early prediction marker of left ventricular remodelling after STEMI.

Assessment of concordance between diffusion of carbon monoxide through the lung using the 10 s breath-hold method, and the simultaneous NO/CO technique, in healthy participants.

INTRODUCTION: There is limited, large sample size, healthy control data comparing measurement of diffusing capacity of the lungs for carbon monoxide (DLCO) via the 10 s single-breath carbon monoxide uptake method (DLCO10) and using a DLCO-DLNO double diffusion test performed with a 5 s time of apnoea (DLCO5). OBJECTIVES: The primary objective was to compare DLCO5 and DLCO10 in healthy participants. The secondary objective was to evaluate the reproducibility of DLCO5. MATERIAL AND METHODS: We included medical students at Caen University Hospital, from 2008 to 2011. We performed a standard single-breath carbon monoxide uptake and combined DLCO and DLNO measurement for each participant. The combined test was repeated one week later. RESULTS: Among the 153 study participants, there was no statistically significant difference between the mean values of DLCO10 (10.2 ±â€¯2.2 mmol.min-1 kPa-1) and DLCO5 (10.3 ±â€¯2.2 mmol.min-1 kPa-1; paired t-test p = 0.19). Corrected for the same FiO2, DLCO5 was calculated at 10.5 ±â€¯2.3 mmol.min-1 kPa-1 and was significantly different from DLCO10 (paired t-test p < 0.001). DLCO5 deviates from 1,6 mmol.min-1 kPa-1 (4,6 mL.min-1. mmHg-1) or 15 % of DLCO10 (17 % above and 13% below, for 95 % of the subjects). Forty-seven participants were included in the DLCO5 reproducibility test. The 2 test sessions were carried out at 6 ±â€¯2 day intervals. Reproducibilities for DLCO, DLNO, DmCO and Vc was respectively 1.2 (11 %), 6.8 (13%), 16.5 (32 %), 12.5 (17 %) mmol.min-1 kPa-1. CONCLUSION: In healthy participants, discrepancies between DLCO measured during the double diffusion and DLCO measured on an apnoea of 10 s are quite large. It may be an indication that the Roughton and Forster interpretation to describe this type of measurements is inadequate.

Intravenous versus subcutaneous route pharmacokinetics of paracetamol (acetaminophen) in palliative care patients: study protocol for a randomized trial (ParaSCIVPallia).

BACKGROUND: Among palliative care (PC) patients who are administered paracetamol, the subcutaneous (SC) route is often an alternative to the intravenous (IV) route. Yet pharmacological and clinical data on whether these are equivalent pharmacokinetically are lacking. Many French palliative teams are now empirically using paracetamol by the SC route, but there are no data to support this practice. This trial aims to compare the pharmacokinetic (PK) parameters of paracetomol between the IV and SC routes in PC patients. METHODS/DESIGN: This is a randomized, open, crossover study in two PC centers. The primary endpoints are AUC0-t, AUC0-∞, Cmax, Vd, and t1/2. All adverse events will be reported for a safety analysis. Twenty adult PC patients with an IV device having spontaneous pain not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol as the usual treatment will be included. All patients also have to meet all eligibility criteria. CONCLUSION: This is the first study comparing PK parameters for IV paracetamol versus SC paracetamol in PC patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03944044. Registered on 4 June 2019. Committee for the protection of persons (CPP) 18.09.05.58206 approval 4 October 2018. National Drug Safety Agency (ANSM; Agence Nationale de Sécurité Médicament) MEDAECNAT-2018-09-00009 approval 29 November 2018.

Discontinuation of oxytocin in the active phase of labor.

OBJECTIVE: To show that early discontinuation of oxytocin will not increase the mean duration of the active labor phase in a clinically significant way. DESIGN: Controlled non-inferiority study. SETTING: Department of Obstetrics and Gynecology, University of Caen, Clemenceau Hospital, France. POPULATION: A total of 138 women with singleton pregnancy and a vertex presentation of over 34 gestational weeks, presenting a medical indication of induction of labor or a dystocia at onset of labor, from May 2005 to June 2006. METHODS: Two parallel groups were compared: continuation of oxytocin until delivery versus discontinuation of oxytocin at the onset of the active phase. The clinically acceptable increase in mean duration of the active phase of labor (non-inferiority margin) was set at 60 minutes. MAIN OUTCOME MEASURES: Primary outcome measure was duration of the active labor phase. Secondary outcome measures included total duration of labor, parameters concerning oxytocin use, rates of uterine hyperstimulation and fetal heart rate (FHR) abnormalities, and mode of delivery. Some neonatal outcomes were also analyzed. RESULTS: Equivalence of the two strategies (continuation vs. discontinuation of oxytocin) was not demonstrated (p=0.97 testing for non-inferiority), the active phase even being significantly longer by a mean of 113 minutes (p=0.0001 testing for superiority). The rates of cesarean sections, alterations of FHR and delivery hemorrhage were higher when oxytocin was continued, but not significantly. There were significantly more infants hospitalized in neonatology when oxytocin was continued (p=0.028). CONCLUSIONS: Discontinuation of oxytocin at the onset of the active phase prolongs labor. We found no argument for discontinuing the infusion of oxytocin at the onset of the active phase.

Selective prophylactic transfusion in sickle cell disease.

OBJECTIVE. To record feto-maternal complications following the use of selective prophylactic transfusions in women with major sickle cell disease (SCD) and determine whether selective prophylactic transfusion reduces these complications, through a comparison with a population of women who received transfusions for complications only. DESIGN. A retrospective cohort study. SETTING. Public regional referral hospital in western French Guyana. POPULATION. Between 1992 and 2004, in all 29 women, 55 pregnancies, and 56 neonates. METHODS. Close obstetric follow-up and selective prophylactic transfusions after 26 weeks. Main outcome measures. Adverse obstetric outcome (pre-eclampsia, preterm delivery, intrauterine growth restriction (IUGR), intrauterine fetal death (IUFD), cesarean delivery, neonatal and maternal mortality) and end-points for SCD outcome (vaso-occlusive crisis (VOC), acute chest syndrome, and infections). RESULTS. Complications involved the different major SCD types to an equal extent. Comparison with the control group showed that women who had received prophylactic transfusions had lower rates of VOC (p=0.002) and preterm deliveries (p=0.036), but a significant increase in IUGR cases (p=0.048). CONCLUSION. Selective prophylactic transfusion seems to reduce certain maternal and fetal complications in women with severe forms of SCD. These results can only be confirmed through a randomized prospective study.

Neuropsychological management of multiple sclerosis: evaluation of a supervised and customized cognitive rehabilitation program for self-used at home (SEPIA): protocol for a randomized controlled trial.

BACKGROUND: Cognitive and mood disorders negatively impact daily life in patients with multiple sclerosis (MS). Pharmacological treatments did not demonstrate any effect on cognition compared with cognitive rehabilitation (CR). However, if CR programs offer promising results on cognition, they are less consistent concerning mood and quality of life (QoL). In this context, we designed a randomized controlled trial to evaluate the efficacy of an innovative computerized CR program, conducted at home, on QoL. Secondary objectives will estimate the improvement, or the stabilization over time, of patients' cognitive performances and their emotional affects. METHODS: Forty MS patients (relapsing-remitting or secondary progressive forms) who have cognitive impairment will be recruited for the trial (called SEPIA-NCT03471338) and randomly assigned to either the experimental group or the control group. Patients randomly assigned in the experimental group will perform a home-based CR program with psychological support during eight consecutive weeks. CR will be based on computerized cognitive exercises from the PRESCO® software developed by HAPPYneuron©. Training sessions (three sessions of 45 min per week) will consist of short exercises evaluating a broad range of cognitive domains and will be personalized for each patient (tracking tool and supervised guidance). The control group, designed to control for non-specific elements of the intervention, will receive only psychological support consisting of various issues related to MS, such as everyday cognitive-related difficulties or management of emotions. QoL, assessed by the MUSIQOL (Multiple Sclerosis International Quality Of Life) questionnaire, will be evaluated three times (at baseline and after 1 week and 25 weeks after home-based intervention) as well as secondary outcomes measuring self-esteem, cognition, depression, anxiety, metacognition, fatigue, and sleep quality. Given the expected MUSIQOL variation, the inclusion of 20 patients per group (alpha risk 5% and power 80%) will be required. DISCUSSION: Evidence suggests that computerized programs may be a practice option for CR for people with MS, but there is a paucity of studies evaluating QoL. We hope that this innovative program will highlight such benefits over time in patients' daily life. In the future, such programs will allow a wider range of available therapeutic options for MS patients with cognitive impairment and for practitioners in charge of their care. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03471338. Retrospectively registered on 25 April 2018. https://clinicaltrials.gov/ct2/show/NCT03471338?term=NCT03471338&cond=Multiple+Sclerosis&draw=2&rank=1 .

Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Members Reveals Specific Alteration Pattern in Diffuse Gliomas.

Ras association domain family (RASSF)/Hippo pathway alterations are poorly characterized in diffuse gliomas. We assayed promoter methylation of LATS1/2, MST1(STK4)/MST2(STK3), RASSF1, RASSF2, Nore1A/RASSF5, RASSF6, and RASSF10 genes in 133 diffuse gliomas. The RASSF/Hippo pathway was highly silenced in gliomas, particularly RASSF1A (79.4%) and LATS2 (35.9%). The most frequent combination of promoter hypermethylation of one RASSF gene and one Hippo pathway member's gene was RASSF1/LATS2-coupled hypermethylation [n = 44 (33.08%)]. Hypermethylated profiles were related to IDH mutation, yet not randomly in IDH-mutated gliomas, because LATS2 promoter hypermethylation was more frequent in oligodendroglioma than in astrocytoma. RASSF1 and LATS2 promoter hypermethylation predicted a longer overall survival (OS). Considering hypermethylation of these two promoters, Cox proportional hazard regression analysis categorized the patients into three prognostic groups: i) high risk of death (n = 24; both RASSF1 and LATS2 unmethylated promoters; median OS, 13 months); ii) intermediate risk of death (n = 65; RASSF1 or LATS2 hypermethylated promoter; median OS, 50.5 months; HR = 3.3; 95% CI, 1.6-6.4; P = 0.001); and iii) low risk of death (n = 44; both RASSF1 and LATS2 hypermethylated promoters; median OS, 119 months; HR = 75.1; 95% CI, 3.3-15.1; P = 0.001). We have thus highlighted a simple two-gene (RASSF1/LATS2) methylation signature as a tool to stratify different prognostic groups of patients with diffuse glioma, adding further prognostic information within the IDH-mutated group.