Implementation of an in situ simulation-based training adapted from Morbidity and Mortality conference cases: effect on the occurrence of adverse events-study protocol of a cluster randomised controlled trial.

BACKGROUND: Morbidity and Mortality conference provides the necessary improvement measures for patient safety. However, they are an underused resource mainly because the conclusions to be drawn from the discussion and their implications for practice are not always well integrated by inpatient care teams. We therefore propose in this study two interventions to optimise their effectiveness: a passive feedback with wide dissemination by e-mail and/or on paper of the results of the Morbidity and Mortality conference to inpatient care teams and an active feedback with in situ inter-professional simulation-training programme in which scenarios will be based on cases studied in Morbidity and Mortality conference. In the present study, we hypothesise that the greatest reduction the occurrence of adverse event will be in the active feedback arm. METHODS: A cluster randomised controlled study will be performed at four study sites. The unit of randomisation is wards within the study sites. Fifteen wards will be randomly assigned to passive feedback, active feedback, or a standard MMC (control arm). Passive feedback and active feedback arms will be compared to standard arm in terms of occurrence of adverse events. The trigger tool methodology used to identify adverse events is a retrospective review of inpatient records using "triggers": an adverse event is defined as a patient's stay with at least one positive trigger. DISCUSSION: The in situ simulation training based on cases processed in Morbidity and Mortality conference is built according to the main topics identified for the successful implementation of healthcare simulation in patient safety programmes: technical skills, nontechnical skills, assessment, effectiveness, and system probing. The in situ simulation-training programme conducted as part of the study has the potential to improve patient safety during hospitalisation. We therefore expect the greatest reduction in the occurrence of adverse events in patients hospitalised in the active feedback arm. This expected result would have a direct impact on patient safety and would place in situ simulation at the highest level of the Kirkpatrick model. TRIAL REGISTRATION: Clinicaltrials.gov NCT02771613. Registered on May 12, 2016. All items from the WHO Trial Registration Data Set can be found within the protocol.

Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of young children initiated by mutations that deregulate cytokine receptor signaling. Studies of JMML are constrained by limited access to patient tissues. We generated induced pluripotent stem cells (iPSCs) from malignant cells of two JMML patients with somatic heterozygous p.E76K missense mutations in PTPN11, which encodes SHP-2, a nonreceptor tyrosine phosphatase. In vitro differentiation of JMML iPSCs produced myeloid cells with increased proliferative capacity, constitutive activation of granulocyte macrophage colony-stimulating factor (GM-CSF), and enhanced STAT5/ERK phosphorylation, similar to primary JMML cells from patients. Pharmacological inhibition of MEK kinase in iPSC-derived JMML cells reduced their GM-CSF independence, providing rationale for a potential targeted therapy. Our studies offer renewable sources of biologically relevant human cells in which to explore the pathophysiology and treatment of JMML. More generally, we illustrate the utility of iPSCs for in vitro modeling of a human malignancy.

Inhibition of SRC corrects GM-CSF hypersensitivity that underlies juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm in children characterized by the overproduction of monocytic cells that infiltrate the spleen, lung, and liver. JMML remains a disease for which few curative therapies are available other than myeloablative hematopoietic stem cell transplant (HSCT); however, relapse remains a major cause of treatment failure and the long-term morbidities of HSCT for survivors are substantial. A hallmark feature of JMML is acquired hypersensitivity by clonal myeloid progenitor cells to granulocyte macrophage-colony stimulating factor (GM-CSF) via a largely unknown mechanism. Here, we identify c-Cbl (henceforth referred to as Cbl) as a GM-CSF receptor (GMR) adaptor protein that targets Src for ubiquitin-mediated destruction upon GM-CSF stimulation and show that a loss of negative regulation of Src is pivotal in the hyperactivation of GMR signaling in Cbl-mutated JMML cells. Notably, dasatinib, an U.S. Food and Drug Administration-approved multikinase inhibitor that also targets Src family, dramatically attenuated the spontaneous and GM-CSF-induced hypersensitive growth phenotype of mononuclear cells from peripheral blood and bone marrow collected from JMML patients harboring Cbl or other known JMML-associated mutations. These findings reveal Src kinase as a critical oncogenic driver underlying JMML.

Use of a collaborative database for epidemiological analyses and professional practice evaluation.

RATIONALE: In nephrology, the NEOERICA project assessed the feasibility of the diagnosis scheme based on a general practice database. This approach opened a new area where routinely collected data could be used for purposes other than patient management, such as epidemiological analysis and professional practice evaluation. In Lyon, the TIRCEL network is made up of a coordination team and an online database. In 2008, a total of 468 professionals participated and 983 patients were in the database corresponding to 4114 consultations and 9250 biological assessments. OBJECTIVE: To investigate the impact of a quality control process on the data from operational databases. METHODS: We set up a quality control process and we described the impact of this process on data. We also specifically investigated the role of measurement scales in error frequency and we studied the impact of data quality on variables which could be used for professional practice evaluation. RESULTS: Quality control allowed us to detect as inconsistent data 7.5% of tested data. This rate is linked to the parameters and varied from less than 1% (weight, diastolic blood pressure and urinary sodium) to more than 30% (serum iron and ferritin). Quality control led mainly to the validation of the identified data for 80.4%, a direct correction was realized for 12.9%, 5.6% by the lab and only 1.2% were set to missing. Average proteinuria was modified with the quality control process (2.09 g per 24 hours vs. 0.82 g per 24 hours); however, the median remained stable (0.21 g per 24 hours). CONCLUSION: Specialty databases such as TIRCEL could not be used for epidemiological research or for the extraction of indicators for professional practice evaluation without strict quality control or the set-up of data-entering limits and alarms.

Replication and extension of association between common genetic variants in SIM1 and human adiposity.

Haplo-insufficiency of the bHLH (basic helix-loop-helix) transcription factor single-minded 1 (SIM1) causes severe obesity in mice and humans. We hypothesized that common genetic variations in/near SIM1 could exert more subtle effects on its function and associate with human adiposity. First, SIM1 coding regions were sequenced in severely obese subjects, and two common nonsynonymous single-nucleotide polymorphisms (nsSNPs) in complete linkage disequilibrium (LD) were identified: Pro352Thr (rs3734354) and Ala371Val (rs3734355). We next carried out a SNP association study of five adiposity traits (BMI, % body fat, abdominal visceral and subcutaneous fat, and leptin concentrations) in 1,699 whites and 1,173 blacks. TagSNPs covering SIM1 and nearby conserved regions, and the only common nsSNP in SIM1's binding partner aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) (Gly679Ser/rs4072568), were investigated. The effects of rs3734355/4 on SIM1 activity were tested using an in vitro reporter assay. We replicated previous observations that homozygosity for the 371Val allele was associated with higher BMI in white males (P = 0.003). Together with previous findings in white males (combined n = 3,479), BMI was increased by 1.10 kg/m(2) in 371Val homozygotes (95% confidence interval (CI): 0.25-1.95 kg/m(2), P = 0.01). In vitro, the 352Thr-371Val haplotype impaired SIM1 transcriptional activity by 22% (P < 0.0001). TagSNP analysis of SIM1 revealed two SNPs in the 3' region (rs9390322 and rs7746743) and another in intron 5 (rs3734353) to be significantly associated with various adiposity measures in ethnicity- and sex-specific manners after multiple testing correction. In white males, rs4072568 in ARNT2 was also associated with BMI (P = 9 × 10(-4)) and % body fat (P = 0.001). Our findings implicate heritable defects of the SIM1-ARNT2 axis in the predisposition to human obesity.

Identification, characterization and rescue of a novel vasopressin-2 receptor mutation causing nephrogenic diabetes insipidus.

OBJECTIVE: X-linked nephrogenic diabetes insipidus (XNDI), caused by mutations in the V2 vasopressin receptor (V2R), is clinically distinguished from central diabetes insipidus (CDI) by elevated serum vasopressin (AVP) levels and unresponsiveness to 1-desamino-8-d-arginine vasopressin (DDAVP). We report two infants with XNDI, and present the characterization and functional rescue of a novel V2R mutation. PATIENTS: Two male infants presented with poor growth and hypernatraemia. Both patients had measurable pretreatment serum AVP and polyuria that did not respond to DDAVP, suggesting NDI. However, both also had absent posterior pituitary bright spot on MRI, which is a finding more typical of CDI. METHODS: The AVPR2 gene encoding V2R was sequenced. The identified novel missense mutation was re-created by site-directed mutagenesis and expressed in HEK293 cells. V2R activity was assessed by the ability of transfected cells to produce cAMP in response to stimulation with DDAVP. Membrane localization of V2R was assessed by fluorescence microscopy. RESULTS: Patient 1 had a deletion of AVPR2; patient 2 had the novel mutation L57R. In transiently transfected HEK293 cells, DDAVP induced detectable but severely impaired L57R V2R activity compared to cells expressing wild-type V2R. Fluorescence microscopy showed that myc-tagged wild-type V2R localized to the cell membrane while L57R V2R remained intracellular. A nonpeptide V2R chaperone, SR121463, partially rescued L57R V2R function by allowing it to reach the cell membrane. CONCLUSIONS: L57R V2R has impaired in vitro activity that can be partially improved by treatment with a V2R chaperone. The posterior pituitary hyperintensity may be absent in infants with XNDI.

A conserved lysine in the estrogen receptor DNA binding domain regulates ligand activation profiles at AP-1 sites, possibly by controlling interactions with a modulating repressor.

BACKGROUND: Estrogen receptors alpha and beta (ERalpha and ERbeta) differentially activate genes with AP-1 elements. ERalpha activates AP-1 targets via activation functions with estrogens (the AF-dependent pathway), whereas ERbeta, and a short version of ERalpha (ERalpha DBD-LBD) activate only with anti-estrogens (AF-independent pathway). The DNA binding domain (DBD) plays an important role in both pathways, even though neither pathway requires ERE recognition. RESULTS: Mutations of a highly conserved DBD lysine (ERalpha.K206A/G), lead to super-activation of AP-1 through activation function dependent pathways, up to 200 fold. This super-activity can be elicited either through ER AFs 1 or 2, or that of a heterologous activation function (VP16). The homologous substitution in ERbeta, K170A, or in ERalpha DBD-LBD leads to estrogen-dependent AP-1 activation and loss of the usually potent anti-estrogen effects. Each of numerous K206 substitutions in ERalpha, except K206R, eliminates anti-estrogen activation and this loss correlates perfectly with a loss of ability to titrate a repressive function from the RU486 bound progesterone receptor. CONCLUSION: We conclude that ER DBDs contain a complex regulatory function that influences ligand activation profiles at AP-1. This function, which requires the integrity of the conserved lysine, both allows for activation at AP-1 with anti-estrogens (with ERbeta and ERalpha DBD-LBD), and prevents ERalpha from becoming superactive at AP-1 with estrogens. We discuss the possibility that a repressor interaction with the DBD both mediates the AF-independent pathway and dampens the AF dependent pathway. Mutations in the conserved lysine might, by this model, disrupt the binding or function of the repressor.