[Real world data in radiotherapy: A data farming project by Unitrad]. / Données de vie réelle en radiothérapie : le data farming du groupe Unitrad.

The aim of the data farming project by the Unitrad group is to produce and use large quantities of structured real-life data throughout radiotherapy treatment. Starting in 2016, target real world data were selected at expert consensus conferences and regularly updated, then captured in MOSAIQ© as the patient was treated. For each partner institution, the data was then stored in a relational database, then extracted and used by researchers to create real world knowledge. This production was carried out in a multicentre, coordinated fashion. When necessary, the raw data was shared according to the research projects, in compliance with regulations. Feedack was provided at each stage, enabling the system to evolve flexibly and rapidly, using the "agile" method. This work, which is constantly evolving, has led to the creation of health data warehouses focused on data of interest in radiotherapy, and the publication of numerous academic studies. It forms part of the wider context of the exploitation of real-life data in cancerology. Unitrad data farming is a collaborative project for creating knowledge from real-life radiotherapy data, based on an active network of clinicians and researchers.

Medical students' learning processes the first time they role-play in psychiatry: A grounded theory study.

BACKGROUND: Recent changes in psychiatric care and teaching that limit patient contact for medical students can be overcome in part by simulation-based education. Understanding the learning processes of medical students involved in psychiatric simulation-based programmes could usefully inform efforts to improve this teaching. This study explored the learning processes of medical students the first time they role-play in psychiatry. METHODS: We used constructivist grounded theory to analyse semi-structured interviews of 13 purposively sampled medical students and the six psychiatrists who trained them. To improve the triangulation process, the results of this analysis were compared with those of the analyses of the role-play video and the debriefing audio-tapes. RESULTS: Five organising themes emerged: improving the students' immediate perception of patients with mental disorders; cultivating clinical reasoning; managing affect; enhancing skills and attitudes and fostering involvement in learning psychiatry. CONCLUSION: Results suggest that psychiatric role-playing can improve students' progressive understanding of psychiatry through the development of intuition and by allaying affects. Emotional elaboration and student involvement appear to be key features.

[Acute and chronic toxicities associated with the use and misuse of nitrous oxide: An update]. / Toxicités aiguës et chroniques associées à l'usage et au mésusage du protoxyde d'azote : mise au point.

Nitrous oxide (N2O) is used since the eighteenth century as an anesthetic and analgesic but also for recreational use. If the labelled uses of N2O and their modalities are nowadays perfectly framed, the misuse of N2O takes very alarming proportions among teenagers and young adults. This misuse is the cause of acute (hypoxia, barotrauma, burns, neuropsychiatric disorders) and chronic complications if repeated (myeloneuropathy, anemia, thrombosis, inhalant use disorder). The main mechanism of the latter is mainly related to a functional deficit in vitamin B12 induced by N2O. The management of acute complications is symptomatic. The management of chronic complications is based on vitamin B12 supplementation. The best biomarker of chronic N2O exposure is the elevation of the plasmatic level of methylmalonic acid. In all cases of recreational misuses, addiction treatment is necessary to prevent complications or their worsening by providing information in order to stop consumption.

["Somatic symptom disorders" in adolescence. A systematic review of the recent literature]. / « Troubles à symptomatologie somatique ¼ chez les adolescents. Une revue systématique.

OBJECTIVES: Body expression of mental disorders is common in adolescence. Only two literature reviews over the last five years have been identified about somatoform disorders in children., The present article provides a systematic review of articles in English, which concern "Somatic Symptom and Related Disorders" according to the DSM-5 (Diagnostic and Statistical Manual - 5th Edition) among adolescents. METHODS: The article search was made on Medline, Psychinfo, Google Scholar, BiomedCentral, Central and tripdatabase (for grey literature) according to PRISMA criteria and with the items "somatoform disorders" or "somatic symptom disorders". An age filter was applied for "adolescents", and a selection was done from the last five years. All articles concerning adolescents (often associated with children) were initially included, except for articles concerning eating disorders, dysmorphic disorders or adult population. Comments, editorials, opinion or descriptive articles were also excluded. The authors then carried out an analysis of the main topics, themes and questions covered in the selected publications and presented a descriptive synthesis. RESULTS: A total of seventy-seven publications were included in the analysis, from three hundred and seventy-two publications. First, the terms used to refer to these "somatic symptom disorders" were varied, such as "somatization", "somatic complaints/symptoms", "functional disorder", "unexplained symptoms" and "somatoform disorders". Then, studies related just to adolescents were limited: most of studies included children and adolescents in their methodologies; and some of them questioned somatic symptoms from a developmental perspective. Case reports were the most represented articles among all medical specialties, with clinical descriptions about "functional neurological symptom disorder", "factitious disorder" and "somatic symptom disorder" with a medical disease, among children and adolescents. We sometimes observed a controversial borderline between psychological and somatic disorders. Various explanatory models appeared, especially the trauma path; familial and social environment was also pointed out, with a possible peer group effect; neurocognitive theories were finally described. The literature highlights the effectiveness of psychosocial therapies (especially the cognitive-behavioral therapy) and the importance of multidisciplinary management. Finally, a few studies with a qualitative methodology are represented. CONCLUSIONS: Only nine articles included "somatic symptom disorder" in their titles, despite a terminology valued by many authors (compared to "somatoform disorders" from the DSM-IV). The heterogeneity of terminologies, case reports and explanatory models witness a lack of connexions between medical specialties. This could explain in part the wandering of adolescents and their families in the health care system. It could also contribute to the delay before diagnosis, especially when neurological symptoms exist, and a late referral for psychiatric consultation. Further studies are needed to understand difficulties to use a clinical pathway among medical specialties, when the benefit of amultidisciplinary approach seems to be unanimous.

Prediction of individual factor VIII or IX level for the correction of thrombin generation in haemophilic patients.

BACKGROUND: The thrombin generation (TG) assay can assess individual clotting potential. The thrombin generation potential is correlated with the patient's bleeding phenotype and varies from one patient to the other for the same degree of factor VIII or IX deficiency. OBJECTIVE: To define in vitro for individual haemophilic patients the target factor VIII or IX level required to normalize their TG. PATIENTS/METHODS: Plasmas from 20 haemophilic patients were spiked with increasing levels of the deficient coagulation factor and TG parameters were measured. The relationships between factor levels and TG parameters were determined by linear regression. The normal range of thrombin generation was defined in 39 healthy male volunteers. RESULTS: Despite inter-individual heterogeneity in basal TG and responses to spiking, a linear relationship was found between factor VIII or IX levels and TG parameters for individual patients. Based on the individual responses of patient plasmas to spiking, it is possible to define in vitro the target factor VIII or IX levels needed to normalize the TG parameters. For both haemophilic A and haemophilic B patients, significant correlations were found between basal peak values and their correction slopes. The correction slope was steeper in haemophilic B patients, so the factor IX level needed to normalize the TG parameters was lower than for haemophilic A patients. CONCLUSIONS: The TG assay could be used to determine in vitro the patient-specific factor VIII or IX level to be reached to effectively normalize their TG. These in vitro results should be confirmed by ex-vivo studies.

Lactobacillus helveticus as a tool to change proteolysis and functionality in Swiss-type cheeses.

Lactobacillus helveticus exhibits a great biodiversity in terms of protease gene content, with 1 to 4 cell envelope proteinases. Among them, proteinases PrtH and PrtH2 were shown to have different cleavage specificity on pure α(s1)-casein. The aim of this work was to investigate the proteolytic activity of 2L. helveticus strains in cheese matrix: ITGLH77 (PrtH2 only) and ITGLH1 (at least 2 proteinases, PrtH and PrtH2). Cell viability, proteolysis, autolysis, and stretchability of experimental Emmental cheeses were measured during ripening. The peptides identified by mass spectrometry showed very different profiles in the 2 cheeses. Regardless of the casein origin, the number of different peptides containing more than 20 amino acids was greater in cheeses manufactured with strain ITGLH77. This accumulation of large peptides, including those from α(s1)- and α(s2)-caseins, was in agreement with the lower overall extent of proteolysis obtained in ITGLH77 cheeses, which can be attributed to the presence of one cell envelope proteinase of the lactobacilli strains or lesser release of intracellular peptidases into the cheese aqueous phase. In parallel, stretchability was measured throughout ripening time. Emmental strands observed by confocal laser scanning microscopy showed microstructure similar to that of mozzarella strands. Stretchability was correlated with a specific type of peptide (hydrophobic), as shown by principal component analysis, and with a lower degree of proteolysis.

Physicochemical characterization of mozzarella cheese wheys and stretchwaters in comparison with several other sweet wheys.

To better understand the origins of the problems occurring during mozzarella cheese whey concentration, lactose crystallization, and spray-drying steps, a physicochemical characterization was achieved. For this purpose, mozzarella cheese wheys were sampled and their content in different compounds such as total nitrogen, noncasein nitrogen, nonprotein nitrogen, lactate, citrate, chloride, sulfate, phosphate anions, calcium, magnesium, potassium, sodium cations, and the sugars glucose and galactose were measured. In a second step, the results were compared with the corresponding content in cheddar cheese wheys, raclette cheese wheys, soft cheese wheys, and Swiss-type cheese wheys. At the end of this survey, it was shown that mozzarella cheese wheys were more concentrated in lactate and in minerals--especially phosphate, calcium, and magnesium--than the other cheese wheys and that they contained galactose. These constituents are known to be hygroscopic. Complementary surveys are now necessary to compare the hygroscopicity of galactose and lactate and discover whether the amounts of these compounds found in mozzarella cheese wheys are a factor in the problems encountered during the concentration, lactose crystallization, and spray-drying steps.

Thrombin generation and heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy. IgG antibodies targeting the platelet factor 4-heparin complex activate platelets and generate microparticles with procoagulant activity. OBJECTIVES: To determine whether the thrombin generation assay is capable of detecting procoagulant activity induced by patient platelet-poor plasma (PPP) in donor platelet-rich plasma (PRP). PATIENTS AND METHODS: We explored two groups of patients; group 1 (n = 23): patients with a positive clinical and biological diagnosis of HIT; group 2 (n = 25): patients with a negative clinical and biological diagnosis of HIT. Mixtures of donor PRP and patient PPP (1:1) were incubated either with unfractionated heparin 0.2 U mL(-1) or with physiological saline. Thrombin generation was assessed by calibrated thrombinography. The effect of heparin on the mixtures was evaluated according to the ratio of the values with and without heparin (wH/woH) of the five thrombogram parameters. RESULTS: With low heparin concentrations, plasma of group 1 activates donor platelets and generates procoagulant activity. A set of three ratios outside the cut-off values corresponds to the 'HIT thrombogram profile', characterized by a highly specific aspect of the thrombogram wH in relation to the thrombogram woH. None of the group 2 patients presented a HIT thrombogram profile. The results of thrombinography correlate well with the results of the platelet aggregation test. CONCLUSION: Our studies illustrate the central paradox of HIT, namely enhancement of thrombin generation in the presence of heparin. The HIT thrombogram profile as it is defined in this study can detect the procoagulant activity of HIT IgG antibodies.

Isolation and characterisation of a Lactobacillus helveticus ITG LH1 peptidase-rich sub-proteome.

Lactobacillus helveticus strains, one of the most nutritionally fastidious lactic acid bacteria, have a potent proteolytic system that makes them very interesting for different uses in the dairy industry. Its applications concern from cheese ripening to the preparation of fermented milk products with biologically active peptides. The cell-free extract (CFE) of Lactobacillus helveticus strain ITG LH1 was analysed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), using IPG immobiline dry strips (pH 4-7). With the aim to study the proteolytic enzymes expressed by Lactobacillus helveticus ITG LH1 grown in milk medium, a two step-chromatography methodology, based on ion exchange and affinity chromatography, was developed for the preparation of a peptidase-rich sub-proteome from the CFE of stationary growing cells. Several affinity chromatography columns were tested and among them a HiTrap Chelating column was selected as it provided the best performance for the enrichment in peptidases. Peptidase activities were studied using different beta-Naphtylamide (beta-NA) derivatives and specific activities were increased 50- to 100-fold by this chromatographic procedure. Sub-proteome characterisation was performed by 2D-PAGE, pH 4-7, followed by protein digestion with trypsin, analysis by MALDI-TOF mass spectrometry and subsequent database searches using peptide mass fingerprints. Among the most abundant proteins seven peptidases were present, namely the two general aminopeptidases (PepN, PepC), three dipeptidases (PepDA, PepV, PepQ) and two endopeptidases (PepO, PepO3), all of them corresponding to the catalytic classes of metallo- or cysteine-peptidases. Several stress proteins (such as heat shock proteins DnaK and GroEL) and other enzymes implied in bacterial metabolism, namely in the carbohydrate pathways (such as LDH), were also identified in the peptidase-rich sub-proteome.

Poor anticoagulant response to tissue factor pathway inhibitor in patients with venous thrombosis.

Tissue factor pathway inhibitor (TFPI) is of major importance in regulating the coagulation triggering effects of tissue factor. An association between TFPI deficiency and thrombosis has still not been clearly demonstrated. We evaluated the anticoagulant activity of exogenous TFPI added either to the plasma of patients with venous thrombosis (n = 118) or to the plasma of healthy controls similar in terms of mean age and sex ratio (n = 107). A poor anticoagulant response to TFPI, defined as TFPI resistance, was observed in 4.7% of controls and in 11.0% of patients. TFPI resistance was associated with an almost threefold increase in the risk of thrombosis and could therefore represent a novel hemostatic risk factor for venous thrombosis.

Goats' milk of defective alpha(s1)-casein genotype decreases intestinal and systemic sensitization to beta-lactoglobulin in guinea pigs.

Contradictory results have been reported on the use of goats' milk in cows' milk allergy. In this study the hypothesis was tested, using a guinea pig model of cows' milk allergy, that these discrepancies could be due to the high genetic polymorphism of goats' milk proteins. Forty guinea pigs were fed over a 20 d period with pelleted diets containing one of the following: soyabean proteins (group S), cows' milk proteins (group CM), goats' milk proteins with high (group GM1) or low (group GM2) alpha(s1)-casein content. Parenteral sensitization to GM1 and GM2 proteins as also assessed. The sensitization was measured (1) by systemic IgG1 antibodies directed against bovine or caprine beta-lactoglobulin (beta-lg), alpha-lactalbumin (alpha-la) and whole caseins, and (2) by intestinal anaphylaxis measured in vitro in Ussing chambers, by the rise in short-circuit current (delta Isc) in response to milk proteins. Guinea pigs fed on CM and GM1 developed high titres (> 1500) of anti-beta-lg IgG1, with an important cross reactivity between goat and cow beta-lg. However, in guinea pigs fed on GM2, anti-goat beta-lg IgG1 antibodies were significantly decreased compared with GM1 guinea pigs (mean IgG1 titres were 546 and 2046 respectively), and the intestinal anaphylaxis was significantly decreased (3.5+/-4.5 microA/cm2) compared with that observed in GM1 guinea pigs (8.3+/-7.6 microA/cm2). Animals receiving GM1 or GM2 proteins via the parenteral route developed a marked sensitization. These results suggest that the discrepancies observed in the use of goats milk in cows' milk allergy could be due, at least in part, to the high genetic polymorphism of goats' milk proteins.

Hydrolysis of sequenced beta-casein peptides provides new insight into peptidase activity from thermophilic lactic acid bacteria and highlights intrinsic resistance of phosphopeptides.

The peptidases of thermophilic lactic acid bacteria have a key role in the proteolysis of Swiss cheeses during warm room ripening. To compare their peptidase activities toward a dairy substrate, a tryptic/chymotryptic hydrolysate of purified beta-casein was used. Thirty-four peptides from 3 to 35 amino acids, including three phosphorylated peptides, constitute the beta-casein hydrolysate, as shown by tandem mass spectrometry. Cell extracts prepared from Lactobacillus helveticus ITG LH1, ITG LH77, and CNRZ 32, Lactobacillus delbrueckii subsp. lactis ITG LL14 and ITG LL51, L. delbrueckii subsp. bulgaricus CNRZ 397 and NCDO 1489, and Streptococcus thermophilus CNRZ 385, CIP 102303, and TA 060 were standardized in protein. The peptidase activities were assessed with the beta-casein hydrolysate as the substrate at pH 5.5 and 24 degrees C (conditions of warm room ripening) by (i) free amino acid release, (ii) reverse-phase chromatography, and (iii) identification of undigested peptides by mass spectrometry. Regardless of strain, L. helveticus was the most efficient in hydrolyzing beta-casein peptides. Interestingly, cell extracts of S. thermophilus were not able to release a significant level of free proline from the beta-casein hydrolysate, which was consistent with the identification of numerous dipeptides containing proline. With the three lactic acid bacteria tested, the phosphorylated peptides remained undigested or weakly hydrolyzed indicating their high intrinsic resistance to peptidase activities. Finally, several sets of peptides differing by a single amino acid in a C-terminal position revealed the presence of at least one carboxypeptidase in the cell extracts of these species.

Prevalence of factor V Leiden (APCR) and other inherited thrombophilias in young patients with myocardial infarction and normal coronary arteries.

OBJECTIVE: To investigate the role of activated protein C resistance (APCR, factor V Leiden) in coronary artery thrombosis. METHODS: The prevalence of APCR and of congenital deficiencies of antithrombin III, protein C, protein S, plasminogen, and factor XII was investigated in adult patients under 45 years of age with acute myocardial infarction. The results were compared with those of a group of 53 age and sex matched control subjects. RESULTS: Among 75 patients under the age of 45 years who were admitted from November 1994 to April 1996 for acute myocardial infarction, 22 (29.3%) had normal coronary arteriography (group I) and 53 (70.7%) had significant coronary artery disease (group II). Inherited thrombophilia was more often found in group I (4/22, 18.2%) than in group II (4/53, 7.5%) but the difference was not significant (F test: p = 0.22). The prevalence of APCR was 9.1% (2/22) in group I, 3.8% (2/53) in group 2 (p = 0.57), and 3.8% (2/53) in the normal control group (p = 0.57). CONCLUSIONS: The prevalence of congenital thrombophilias, including APCR, does not seem to be increased in young patients with myocardial infarction and normal coronary angiograms, compared with young patients with coronary atherosclerosis and with normal control subjects. However, the statistical power of the study is too low to detect a significant difference and these results are published to allow a meta-analysis of this problem in the future.

Four adult patients with the missense mutation L206W and a mild cystic fibrosis phenotype.

We report molecular and clinical analyses in four unrelated patients with cystic fibrosis (CF) with compound heterozygosity for the L206W mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). This uncommon missense mutation (frequency less than 1% in a sample of 336 CF chromosomes from Southern France) replaces a leucine by a tryptophan residue in the middle of the third transmembrane domain of CFTR. On the basis of the clinical features presented by the four patients, we postulate that the L206W might be associated with pancreatic sufficiency and residual transmembrane transport of chloride in lung.