Exploring the role of managers in the development of a safety culture in seven French healthcare facilities: a qualitative study.

BACKGROUND: Numerous studies have been conducted over the past 15 years to assess safety culture within healthcare facilities; in general, these studies have shown the pivotal role that managers play in its development. However, little is known about what healthcare managers actually do to support this development, and how caregivers and managers represent managers'role. Thus the objectives of this study were to explore: i) caregivers and managers' perceptions and representations of safety, ii) the role of managers in the development of safety culture as perceived by themselves and by caregivers, iii) managers' activities related to the development of safety culture. METHODS: An exploratory, multicentre, qualitative study was conducted from May 2014 to March 2015 in seven healthcare facilities in France. Semi-structured interviews were conducted with managers (frontline, middle and top level) and caregivers (doctors, nurses and nurse assistants) and on-site observations of two managers were carried out in all facilities. A thematic analysis of semi-structured interviews was performed. Observed activities were categorised using Luthans' typology of managerial activities. RESULTS: Participants in semi-structured interviews (44 managers and 21 caregivers) expressed positive perceptions of the level of safety in their facility. Support from frontline management was particularly appreciated, while support from top managers was identified as an area for improvement. Six main categories of safety-related activities were both observed among managers and regularly expressed by participants. However, caregivers' expectations of their managers and managerial perceptions of these expectations only partially overlapped. CONCLUSIONS: The present study highlights current categories of managerial activities that foster safety culture, and points out an important gap between caregivers' expectations of their managers, and managerial perceptions of these expectations. The findings underline the need to allow more time for managers and caregivers to talk about safety issues. The results could be used to develop training programs to help healthcare managers to understand their role in the development of safety culture.

8-BuS-ATP derivatives as specific NTPDase1 inhibitors.

BACKGROUND AND PURPOSE: Ectonucleotidases control extracellular nucleotide levels and consequently, their (patho)physiological responses. Among these enzymes, nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), -2, -3 and -8 are the major ectonucleotidases responsible for nucleotide hydrolysis at the cell surface under physiological conditions, and NTPDase1 is predominantly located at the surface of vascular endothelial cells and leukocytes. Efficacious inhibitors of NTPDase1 are required to modulate responses induced by nucleotides in a number of pathological situations such as thrombosis, inflammation and cancer. EXPERIMENTAL APPROACH: Here, we present the synthesis and enzymatic characterization of five 8-BuS-adenine nucleotide derivatives as potent and selective inhibitors of NTPDase1. KEY RESULTS: The compounds 8-BuS-AMP, 8-BuS-ADP and 8-BuS-ATP inhibit recombinant human and mouse NTPDase1 by mixed type inhibition, predominantly competitive with Ki values <1 µM. In contrast to 8-BuS-ATP which could be hydrolyzed by other NTPDases, the other BuS derivatives were resistant to hydrolysis by either NTPDase1, -2, -3 or -8. 8-BuS-AMP and 8-BuS-ADP were the most potent and selective inhibitors of NTPDase1 expressed in human umbilical vein endothelial cells as well as in situ in human and mouse tissues. As expected, as a result of their inhibition of recombinant human NTPDase1, 8-BuS-AMP and 8-BuS-ADP impaired the ability of this enzyme to block platelet aggregation. Importantly, neither of these two inhibitors triggered platelet aggregation nor prevented ADP-induced platelet aggregation, in support of their inactivity towards P2Y1 and P2Y12 receptors. CONCLUSIONS AND IMPLICATIONS: The 8-BuS-AMP and 8-BuS-ADP have therefore potential to serve as drugs for the treatment of pathologies regulated by NTPDase1.

Binary and ternary crystal structure analyses of a novel inhibitor with 17beta-HSD type 1: a lead compound for breast cancer therapy.

Oestradiol is a well-characterized sex hormone that stimulates breast cancer and other oestrogen-related diseases. 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses the last step in the synthesis of oestradiol and androstenediol in breast tumour tissue. The enzyme's high expression and activity after simultaneous blockade of oestrogen receptors and inhibition of aromatase in the tumour shows the necessity for its inhibition as a requirement for breast cancer therapy. In the present paper, we report structures of the binary and ternary complexes of 17beta-HSD1 with a new inhibitor E2B {3-[3',17'beta-dihydroxyestra-1',3',5'(10')-trien-16'beta-methyl]benzamide}, and the enzyme inhibition by the later. The IC50 value for E2B was determined to be 42 nM in T47D cells. Multiple interactions between E2B and the enzyme include hydrogen bonds and hydrophobic interactions, as well as pi-pi interactions. A kinetic study demonstrated that E2B inhibits the enzyme's reduction forming oestradiol from oestrone, with a Ki of 0.9+/-0.15 nM. Such strong inhibition is in agreement with its extensive interaction with the enzyme, suggesting its potential as a lead compound for breast cancer therapy. In fact, this possibility is enhanced by its capacity for cell penetration similar to natural steroids. Such inhibitors that block oestrogen synthesis to suppress the sulfatase pathway producing oestradiol can be used in adjuvant therapies with oestrogen receptor blockade, opening a new orientation of breast cancer treatment.

Estradiol and estrone C-16 derivatives as inhibitors of type 1 17beta-hydroxysteroid dehydrogenase: blocking of ER+ breast cancer cell proliferation induced by estrone.

Estrogens play an important role in the development of breast cancer. Inhibiting 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1)--the enzyme responsible for the last step in the biosynthesis of the most potent estrogen, estradiol (E2)--would thus allow hindering the growth of estrogen-sensitive tumors. Based on a previous study identifying 16beta-benzyl-E2 (1) as a lead compound for developing inhibitors of the transformation of estrone (E1) into E2, we modified the benzyl group of 1 to improve its inhibitory activity. Three strategies were also devised to produce compounds with less residual estrogenic activity: (1) replacing the hydroxy group by a hydrogen at position 3 (C3); (2) adding a methoxy at C2; and (3) adding an alkylamide chain known to be antiestrogenic at C7. In order to test the inhibitory potency of the new compounds, we used the human breast cancer cell line T-47D, which exerts a strong endogenous 17beta-HSD1 activity. In this intact cell model, 16beta-m-carbamoylbenzyl-E2 (4m) emerged as a potent inhibitor of 17beta-HSD1 with an IC50 value of 44 nM for the transformation of [14C]-E1 (60 nM) into [14C]-E2 (24-h incubation). In another assay aimed at assessing the unwanted estrogenic activity, a 10-day treatment with 4m at a concentration of 0.5 microM induced some proliferation (38%) of T-47D estrogen-sensitive (ER+) breast cancer cells. Interestingly, when 4m (0.5 microM) was given with E1 (0.1 nM) in a 10-day treatment, it blocked 62% of the T-47D cell proliferation induced by E1 after its reduction to E2 by 17beta-HSD1. Thus, in addition to generating useful structure-activity relationships for the development of 17beta-HSD1 inhibitors, our study demonstrates that using such inhibitors is a valuable strategy for reducing the level of E2 and consequently its proliferative effect in T-47D ER+ breast cancer cells.

C6-(N,N-butyl-methyl-heptanamide) derivatives of estrone and estradiol as inhibitors of type 1 17beta-hydroxysteroid dehydrogenase: Chemical synthesis and biological evaluation.

A series of estrone and estradiol derivatives having an N-butyl,methyl heptanamide side chain at C6-position were synthesized, tested as inhibitors of type 1 17beta-HSD and assessed for their possible estrogenic activity. A better type 1 17beta-HSD inhibition was obtained for the 6beta-side chain orientation over 6alpha; the C17-alcohols are more potent inhibitors than the corresponding ketones; introducing a 2-methoxy group decreased the inhibitory potency; and the replacement of a C-S bond by a C-C bond in the C6beta-side chain is not detrimental to inhibition. Interestingly, the new inhibitors were also found less estrogenic than the lead compound in two breast cancer cell lines, T-47D and MCF-7.

Free-radical hydroxylation reactions of alkylboronates.

The radical hydroxylation of B-alkylcatecholboranes, easily prepared by hydroboration of olefins, has been investigated. When molecular oxygen was used as oxidizing agent, the corresponding alcohols were obtained directly without alkaline treatment. The presence of Lewis base additives such as Et3N or DABCO has a benefic effect on the selectivity and yield. Alternatively, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) reacts cleanly with B-alkylcatecholboranes to afford alkyl radicals that can be trapped by a second equivalent of TEMPO to give alkoxyamines. Reduction of the alkoxyamines with zinc in acetic acid affords the desired alcohols. The whole procedure is particularly mild and does not require any basic condition. The two approaches presented in this paper are valuable and represent mild alternatives to the classical alkaline oxidation of organoboranes to alcohols.