[Patient safety culture for health professionals in primary care : French adaptation of the MOSPSC questionnaire (Medical Office Survey on Patient Safety Culture)]. / Culture de sécurité des professionnels de santé en soins primaires : adaptation en langue française du questionnaire MOSPSC (« Medical Office Survey on Patient Safety Culture ¼).

BACKGROUND: Patient safety culture (PSC) takes into account a number of individual and organizational factors. Evaluation of PSC with the participation of primary health care professionals can be carried out through self-administered surveys such as the AHRQ's Medical Office Survey on Patient Safety Culture (MOSPSC) questionnaire. AIM: To translate the MOSPSC questionnaire into French, while analyzing its psychometric properties. METHODS: The MOSPSC questionnaire was first translated into French, with linguistic analysis included, and then back-translated into English, in accordance with the ISPOR recommendations. Lastly, the French version of the MOSPSC questionnaire was completed by health professionals from 36 outpatient structures. Study of the psychometric properties (test-retest, Cronbach's α, and factor analysis) was conducted based on the professionals' responses. RESULTS: After linguistic analysis, the notion of "team" was translated in the final questionnaire as "structure". This term was used in the pilot survey of 415 professionals. The participation rate was 64.1% (266/415); 51.9% (138/415) were paramedics (mainly nurses and physiotherapists). The Cronbach coefficient α inclusive of all dimensions was 0.94. A "reporting of safety incidents" dimension was added, and the "staff training" dimension was merged with "development and standardization of office processes", bringing to 13 the number of dimensions identified after factor analysis. CONCLUSIONS: Having been adapted and validated, the French version of the questionnaire can be used as a tool for assessment of PSC in France. It should not only facilitate the monitoring of PSC in primary care facilities, but also prove conducive to comparison of PSC evolution in different establishments. Lastly, it Could contribute to national and international research on risk management in primary care.

Management of drooling in children with cerebral palsy: A French survey.

AIM: To characterise children with cerebral palsy (CP) and pathological drooling in France, and to describe care pathways, assessment and treatment. METHOD: A transversal, observational, descriptive survey of the practices and opinions of 400 health professionals potentially involved in the care of children with CP, was carried out nationally across France in 2013. RESULTS: The response rate was 36%. Seventy-five questionnaires were returned and analysed (52%). A small proportion of children were specifically treated for drooling (<25%). Assessments were carried out in 75% of cases and 91% of professionals prescribed treatments. Use of assessment tools varied widely. The most common treatment was oro-facial rehabilitation (95% of professionals), followed by anticholinergic drugs (Scopolamine(®)) (94%) botulinum toxin injections (BT) (66%) and surgery (34%). Scopolamine was considered to be less effective than BT and to have more side effects. CONCLUSION: The rate of pathological drooling in children with CP is likely underestimated and under treated in France. There is a lack of knowledge regarding assessment tools. Aside from rehabilitation, current practice is to prescribe medication as the first-line treatment, however professionals consider that BT is more effective and has less side effects.

A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties.

The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism and cell polarity. We now report the identification of a novel isoform of LKB1 (named ΔN-LKB1) that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The ΔN-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although ΔN-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory autoinhibitory domain of AMPK. In contrast, ΔN-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showed that ΔN-LKB1 has an intrinsic oncogenic property. ΔN-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of ΔN-LKB1 decreased the survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both the LKB1 tumor suppressor gene and the oncogene ΔN-LKB1 are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.

Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1.

LKB1 is a tumor suppressor that is constitutionally mutated in a cancer-prone condition, called Peutz-Jeghers syndrome, as well as somatically inactivated in a sizeable fraction of lung and cervical neoplasms. The LKB1 gene encodes a serine/threonine kinase that associates with the pseudokinase STRAD (STE-20-related pseudokinase) and the scaffolding protein MO25, the formation of this heterotrimeric complex promotes allosteric activation of LKB1. We have previously reported that the molecular chaperone heat shock protein 90 (Hsp90) binds to and stabilizes LKB1. Combining pharmacological studies and RNA interference approaches, we now provide evidence that the co-chaperone Cdc37 participates to the regulation of LKB1 stability. It is known that the Hsp90-Cdc37 complex recognizes a surface within the N-terminal catalytic lobe of client protein kinases. In agreement with this finding, we found that the chaperones Hsp90 and Cdc37 interact with an LKB1 isoform that differs in the C-terminal region, but not with a novel LKB1 variant that lacks a portion of the kinase N-terminal lobe domain. Reconstitution of the two complexes LKB1-STRAD and LKB1-Hsp90-Cdc37 with recombinant proteins revealed that the former is catalytically active whereas the latter is inactive. Furthermore, consistent with a documented repressor function of Hsp90, LKB1 kinase activity was transiently stimulated upon dissociation of Hsp90. Finally, disruption of the LKB1-Hsp90 complex favors the recruitment of both Hsp/Hsc70 and the U-box dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein) that triggers LKB1 degradation. Taken together, our results establish that the Hsp90-Cdc37 complex controls both the stability and activity of the LKB1 kinase. This study further shows that two chaperone complexes with antagonizing activities, Hsp90-Cdc37 and Hsp/Hsc70-CHIP, finely control the cellular level of LKB1 protein.

Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2.

Pathogenic mutations in the serine/threonine kinase STK11 (alias LKB1) cause Peutz-Jeghers syndrome (PJS) in most affected individuals. However, in a considerable number of PJS-patients mutations cannot be detected in STK11 suggesting genetic heterogeneity. One PJS family without STK11 mutations (PJS07) has previously been described with significant evidence for linkage to a second potential PJS locus on 19q13.3-->q13.4. In this study we investigated candidate genes within markers D19S180 and D19S254, since multipoint linkage analysis yielded significant LOD scores for this region in this family. Four genes in the region (cytohesin 2: PSCD2, kallikrein 10: KLK10, protein kinase C gamma: PRKCG, and serine/threonine kinase 13: STK13) potentially involved in growth inhibitory pathways or in the pathophysiology of can- cer, were considered as candidates. We first determined the genomic structure of the PSCD2 and PRKCG genes, and performed mutation analysis of all exons and exon-intron junctions of the four genes, in the PJS07 family. No pathogenic mutation was identified in these four genes in affected individuals. A very rare polymorphism resulting in a conserved amino acid change Lys to Arg was found in PSCD2. These data provide considerable evidence for exclusion of these four genes as candidates for the second locus on 19q13.3-->q13.4 in PJS. Finally, we also excluded the recently identified STK11-interacting protein gene (STK11IP, alias LIP1) mapped in 2q36 as candidate for PJS in the PJS07 family, although this could be a good candidate in other non-STK11/LKB1 families.