Experiences and perspectives of implementing antimicrobial stewardship in five French hospitals: a qualitative study

Objective To describe current antimicrobial stewardship program (ASP) in France, both at policy level and at local implementation level, and to assess how ASP leaders (ASPL) worked and prioritised their activities. Methods We conducted a qualitative study based on face-to-face semi-structured interviews with healthcare professionals responsible for ASP across five French hospitals. Five infectious disease specialists and one microbiologist were interviewed between April and June 2016. Results Stewards had dedicated time to perform ASP activities in two university-affiliated hospitals while in the other hospitals (one university, one general and one semi-private), ASPLs had to balance these activities with clinical practice. Consequently, they had to adapt interventions according to their resources (IT or human). Responding to colleagues' consultation requests formed baseline work. Systematic and pro-active measures allowed for provision of unsolicited counselling, while direct counselling on wards required appropriate staffing. ASPL aimed at increasing clinicians' ability to prescribe adequately and awareness of the unintended consequences of inappropriate use of antibiotics. Thus, persuasive e.g. education measures were preferred to coercive ones. ASPL faced several challenges in implementing ASP: overcoming physicians' or units' reluctance, and balancing the influence of medical hierarchy and professional boundaries. Conclusion Beyond resources constraints, ASPLs' conceptions of their work, as well as contextual and cultural aspects, led them to adopt a persuasive and collaborative approach of counselling. This is the first qualitative study about ASP in France exploring stewards' experiences and points of view

Introduction of highly resistant bacteria into a hospital via patients repatriated or recently hospitalized in a foreign country

AbstractWe describe the prevalence of carriage and variables associated with introduction of highly drug-resistant microorganisms (HDRMO) into a French hospital via patients repatriated or recently hospitalized in a foreign country. The prevalence of HDRMO was 11% (15/132), with nine carbapenamase-producing Enterobacteriaceae, nine carbapenem-resistant Acinetobacter baumannii and six glycopeptide-resistant enterococci. Half of the admitted patients (63/132, 48%) were colonized with extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBLPE). Among the four episodes with secondary cases, three involved A. baumannii

Structure of shocks in Burgers turbulence with L\'evy noise initial data

We study the structure of the shocks for the inviscid Burgers equation in dimension 1 when the initial velocity is given by L\'evy noise, or equivalently when the initial potential is a two-sided L\'evy process $\psi_0$. When $\psi_0$ is abrupt in the sense of Vigon or has bounded variation with $\limsup_{|h| \downarrow 0} h^{-2} \psi_0(h) = \infty$, we prove that the set of points with zero velocity is regenerative, and that in the latter case this set is equal to the set of Lagrangian regular points, which is non-empty. When $\psi_0$ is abrupt we show that the shock structure is discrete. When $\psi_0$ is eroded we show that there are no rarefaction intervals.Comment: 22 page

Levonorgestrel-releasing intrauterine system versus endometrial ablation for heavy menstrual bleeding

Acknowledgments: We thank all the women who participated in this trial; the participating general practitioners, gynecologists, and hospitals; the research nurses; and the staff of the Dutch Consortium for Studies in Women’s Health and Reproduction.Peer reviewedPublisher PD

Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms

Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC50) of <1 n, and had 30–50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL–JAK2 fusion gene; IC50=11–120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors

The JAK2 V617F mutation present in over 95% of Polycythemia Vera patients and in 50% of Essential Thrombocythemia and Primary Myelofibrosis patients renders the kinase constitutively active. In the absence of a three-dimensional structure for the full-length protein, the mechanism of activation of JAK2 V617F has remained elusive. In this study, we used functional mutagenesis to investigate the involvement of the JH2 αC helix in the constitutive activation of JAK2 V617F. We show that residue F595, located in the middle of the αC helix of JH2, is indispensable for the constitutive activity of JAK2 V617F. Mutation of F595 to Ala, Lys, Val or Ile significantly decreases the constitutive activity of JAK2 V617F, but F595W and F595Y are able to restore it, implying an aromaticity requirement at position 595. Substitution of F595 to Ala was also able to decrease the constitutive activity of two other JAK2 mutants, T875N and R683G, as well as JAK2 K539L, albeit to a lower extent. In contrast, the F595 mutants are activated by erythropoietin-bound EpoR. We also explored the relationship between the dimeric conformation of EpoR and several JAK2 mutants. Since residue F595 is crucial to the constitutive activation of JAK2 V617F but not to initiation of JAK2 activation by cytokines, we suggest that small molecules that target the region around this residue might specifically block oncogenic JAK2 and spare JAK2 wild-type