[Engagement of students enrolled in fifth year of pharmacy studies in their academic or salaried pharmaceutical activities during the first period of lockout due to the COVID-19 pandemic (16th March-11th May 2020)]. / Engagement d'étudiants de cinquième année de pharmacie dans leurs activités pharmaceutiques, académiques et salariées, au cours de la première période de confinement liée à la pandémie de COVID-19 (16 mars­11 mai 2020).

OBJECTIVES: To characterize the engagement of students enrolled in the fifth year of pharmaceutical studies in the management of the health crisis due to the COVID-19 pandemic, and to identify some determinants of this engagement during this period. METHODS: With the health crisis, new missions have been entrusted during hospital internships, whereas certain internship sites were removed in hospitals and as part of the health service organization. In addition, some students who were no longer in internship returned to the hospital setting for helping in critical activities. Student engagement was studied with a questionnaire and focus groups including six or seven students in each group. RESULTS: Forty-three students participated to the study. The answers to the questionnaire highlighted that they were engaged, that they usually did not wait for compensation, and that most of them were satisfied by their activity during the crisis. The thematic analysis demonstrated that despite a feeling of frustration, which was often associated with the interruption of rewarded activities, and despite a stress due to the particular context, student engagement was supported by a better consideration of the pharmacist's role as a professional in public health and by a better acknowledgement of this role by other health professionals. CONCLUSION: This level of engagement is particularly encouraging because it is the witness of the ability of pharmacists to mobilize for general interest, even in adverse context.

Long-term contamination of sink drains by carbapenemase-producing Enterobacterales in three intensive care units: characteristics and transmission to patients.

This study aimed to describe the contamination of sink drains (SDs) with carbapenemase-producing Enterobacterales (CPE) in three intensive care units (ICUs), and to assess the risk of transmission to hospitalized patients. All SDs were sampled monthly for CPE screening by culture. Rectal screening for CPE carriage was conducted weekly for hospitalized patients. CPE were isolated from 22% of SD samples. Some SDs remained colonized with the same strain for several months. No CPE acquisition occurred among hospitalized patients during the study. Certain strategies, such as systematic sampling of SDs in ICUs for screening for contamination by CPE, should be discouraged apart from during outbreaks.

Linezolid versus vancomycin cost in the treatment of staphylococcal pneumonia.

OBJECTIVE: Staphylococcusaureus is involved in around 20% of nosocomial pneumonia cases. Vancomycin used to be the reference antibiotic in this indication, but new molecules have been commercialized, such as linezolid. Previous studies comparing vancomycin and linezolid were based on models. Comparing their real costs from a hospital perspective was needed. METHODS: We performed a bicentric retrospective analysis with a cost-minimization analysis. The hospital antibiotic acquisition costs were used, as well as the laboratory test and administration costs from the health insurance cost scale. The cost of each hospital stay was evaluated using the national cost scale per diagnosis related group (DRG), and was then weighted by the stay duration. RESULTS: Fifty-eight patients were included. All bacteria identified in pulmonary samples were S. aureus. The cost of nursing care per stay with linezolid was €234.10 (SD=91.50) vs. €381.70 (SD=184.70) with vancomycin (P=0.0029). The cost of laboratory tests for linezolid was €172.30 (SD=128.90) per stay vs. €330.70 (SD=198.40) for vancomycin (P=0.0005). The acquisition cost of linezolid per stay was not different from vancomycin based on the price of the generic drug (€54.92 [SD=20.54] vs. €40.30 [SD=22.70]). After weighting by the duration of stay observed, the mean cost per hospital stay was €47,411.50 for linezolid and €57,694.0 for vancomycin (NSD). CONCLUSION: These results, in favor of linezolid, support other former pharmacoeconomic study based on models. The mean cost per hospitalization stay was not statistically different between the two study groups, but a trend in favor of linezolid is emerging.

Miconazole mucoadhesive buccal tablet in high-dose therapy with autologous stem cell transplantation (HDT/ASCT)-induced mucositis.

Oral mucositis is a major cause of morbidity in high-dose therapy/autologous stem cell transplantation (HDT/ASCT), where microbial colonization has an important pathological implication. In this study, we evaluated the impact of miconazole mucoadhesive buccal tablet (MBT) on mucositis-related complications. During two consecutive 34-month periods, patients treated with HDT/ASCT in our hematology department received either miconazole MBT (60 patients) or conventional oral amphotericin B suspensions three times a day (44 patients) in order to prevent or decrease chemotherapy-induced mucositis. The use of miconazole MBT is associated with less infectious complications as indicated by shorter antibiotic use (7.8 vs. 12.3 days; p < 0.0001), shorter intravenous antifungal use (1.4 vs. 3.6 days; p = 0.02), and a trend towards less yeast contamination in stool samples. Less patients required any analgesic drugs during hospitalization in the miconazole MBT group (18 vs. 7 %; p = 0.09). Indirect indicators of chemotherapy-induced mucositis (duration of hospitalization, morphine use) were in favor of miconazole MBT in patients with multiple myeloma (MM) but not for those with lymphoma. This study suggests that miconazole MBT provides a valid alternative to oral amphotericin B suspensions in regards to mucositis-related complications. A prospective and randomized study is warranted to establish the definite role of miconazole MBT.

In vivo evaluation of lipid nanocapsules as a promising colloidal carrier for paclitaxel.

Paclitaxel-loaded lipid nanocapsules (PX-LNC) exhibit interesting in vitro characteristics with improved antitumoral activity compared with free PX formulation. Biodistribution studies were realized with the use of (14)C-trimyristin ((14)C-TM) or (14)C-phosphatidylcholine ((14)C-PC) whereas antitumoral activity of PX-LNC formulations was based on the animal survival in a chemically induced hepatocellular carcinoma (HCC) model in Wistar rats. Blood concentration-time profiles for both labeled (14)C-TM-LNC and (14)C-PC-LNC were similar; the t(1/2) and MRT values (over 2h and close to 3h, respectively, for both formulations) indicated the long circulating properties of the LNC carrier with a slow distribution and elimination phase. Survival curves of paclitaxel treated groups showed a statistical significant difference compared to the control survival curve (P=0.0036 and 0.0408). Animals treated with 4x 70 mg/m(2) of PX-LNC showed the most significant increase in mean survival times compared to the controls (IST(mean) 72%) and cases of long-term survivors were preferentially observed in the PX-LNC treated group (37.5%; 3/8). These results demonstrate the great interest to use LNC as drug delivery system for paclitaxel, permitting with an equivalent therapeutic efficiency to avoid the use of excipients such as polyoxyethylated castor oil for its formulation.

Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease.

Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR.

Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4.

Studies of genetically engineered flies and mice have revealed the role that orthologs of the human LIM homeobox LHX4 have in the control of motor-neuron-identity assignment and in pituitary development. Remarkably, these mouse strains, which bear a targeted modification of Lhx4 in the heterozygous state, are asymptomatic, whereas homozygous animals die shortly after birth. Nevertheless, we have isolated the human LHX4 gene, as well as the corresponding cDNA sequence, to test whether it could be involved in developmental defects of the human pituitary region. LHX4, which encodes a protein 99% identical to its murine counterpart, consists of six coding exons and spans >45 kb of the q25 region of chromosome 1. We report a family with an LHX4 germline splice-site mutation that results in a disease phenotype characterized by short stature and by pituitary and hindbrain (i.e., cerebellar) defects in combination with abnormalities of the sella turcica of the central skull base. This intronic mutation, which segregates in a dominant and fully penetrant manner over three generations, abolishes normal LHX4 splicing and activates two exonic cryptic splice sites, thereby predicting two different proteins deleted in their homeodomain sequence. These findings, which elucidate the molecular basis of a complex Mendelian disorder, reveal the fundamental pleiotropic role played by a single factor that tightly coordinates brain development and skull shaping during head morphogenesis.

New method of cardiac output measurement using ultrasound velocity dilution in rats.

The aim of this study was to validate a new technique for the measurement of cardiac output (CO) based on ultrasound and dilution (COUD) in anesthetized rats. A transit time ultrasound (TTU) probe was placed around the rat carotid artery, and ultrasound velocity dilution curves were generated on intravenous injections of saline. CO by COUD were calculated from the dilution curves for normal and portal hypertensive rats in which CO was known to be increased. COUD was compared with the radiolabeled microsphere method and with direct aortic TTU flowmetry for baseline CO and drug-induced CO variations. CO in direct aortic TTU flowmetry was the ascending aorta blood flow measured directly by TTU probe (normal use of TTU flowmetry). The reproducibility of COUD within the same animal was also determined under baseline conditions. COUD detected the known CO increase in portal hypertensive rats compared with normal rats. CO values by COUD were correlated with those provided by microsphere technique or direct aortic TTU flowmetry (adjusted r = 0.76, P < 10(-4) and r = 0.79, P < 0.05, respectively). Baseline CO values and terlipressin-induced CO variations were detected by COUD and the other techniques. Intra- and interobserver agreements for COUD were excellent (intraclass r = 0.99 and 0.98, respectively). COUD was reproducible at least 10 times in 20 min. COUD is an accurate and reproducible method providing low-cost, repetitive CO measurements without open-chest surgery. It can be used in rats as an alternative to the microsphere method and to direct aortic flowmetry.

Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease.

Hirschsprung disease (HD) has been described in association with microcephaly, mental retardation and characteristic facial features, delineating a syndrome possibly caused by mutations localized at chromosome 2q22--q23. We have analyzed a de novo translocation breakpoint at 2q22 in one patient presenting with this syndrome, and identified a gene, SIP1, which is disrupted by this chromosomal rearrangement. SIP1 encodes Smad interacting protein 1, a new member of the delta EF1/Zfh-1 family of two-handed zinc finger/homeodomain transcription factors. We determined the genomic structure and expression of the human SIP1 gene. Further analysis of four independent patients showed that SIP1 is altered by heterozygous frameshift mutations causing early truncation of the protein. SIP1, among other functions, seems to play crucial roles in normal embryonic development of neural structures and neural crest. Its deficiency, in altering function of the TGF beta/BMP/Smad-mediated signalling cascade, is consistent with some of the dysmorphic features observed in this syndrome, in particular the enteric nervous system defect that underlies HD.

Spleno-renal shunt blood flow is an accurate index of collateral circulation in different models of portal hypertension and after pharmacological changes in rats.

BACKGROUND/AIMS: Recently, we developed a new method to measure collateral blood flow in rats: splenorenal shunt (SRS) blood flow (BF). The aims were to evaluate the reproducibility of SRSBF measurement in different models of portal hypertension, and to investigate the ability of SRSBF to disclose pharmacological changes. METHODS: Hemodynamics were determined in anesthetized rats with secondary biliary, CCl4 or DMNA cirrhosis and portal vein ligation (PVL) under baseline and pharmacological (octreotide, vapreotide) conditions. The main measurements performed were: SRSBF by the transit time ultrasound (TTU) method and % portosystemic shunts (PSS) by the microsphere method. RESULTS: SRSBF was 6 to 10 times higher in portal hypertensive rats and was similar in the different models of cirrhosis but was higher in portal vein ligated rats than in cirrhotic rats (1.1+/-0.7 vs 0.6+/-0.7 ml x min(-1) x 100 g(-1), p=0.01). SRSBF was correlated with mesenteric %PSS (r=0.61, p<0.01), splenic %PSS (r=0.54, p<0.05), portal pressure (r= 0.32, p<0.05) and the area of liver fibrosis (r=0.33, p<0.05). Octreotide significantly decreased SRSBF (-23+/-20%, p<0.01 vs placebo: -6+/-8%, NS). Vapreotide significantly decreased SRSBF but not mesenteric or splenic %PSS compared to placebo. The variations in SRSBF (-26+/-32%) and in splenic %PSS (0+/-15%) with vapreotide were significantly different (p<0.05) and not correlated (r=-0.1, NS). CONCLUSIONS: Determination of SRSBF by TTU is an accurate way to measure collateral blood flow in different models of intra- and extra-hepatic portal hypertension in rats. Its sensitivity provides accurate measurement of pharmacological changes, unlike the traditional estimation of %PSS by the microsphere method.

Measurement of collateral circulation blood flow in anesthetized portal hypertensive rats.

AIMS: The aim of this study was to develop a technique to measure collateral blood flow in portal hypertensive rats. METHODS: Morphological techniques included inspection, casts and angiographies of portosystemic shunts. The main hemodynamic measurements were splenorenal shunt blood flow (transit time ultrasound method), percentage of portosystemic shunts and regional blood flows (microsphere method). In study 1, a model of esophageal varices was developed by ligating the splenorenal shunt. In study 2, morphological studies of the splenorenal shunt were performed in rats with portal vein ligation. In study 3, the relationship between splenorenal shunt blood flow with percentage of portosystemic shunts was evaluated in dimethylnitrosamine cirrhosis. In study 4, secondary biliary, CCl4 and dimethylnitrosamine cirrhosis were compared. In study 5, rats with portal vein ligation received acute administration of octreotide. In study 6, rats with dimethylnitrosamine cirrhosis received acute administration of vapreotide. RESULTS: Blood flow of para-esophageal varices could not be measured. SRS blood flow was correlated with the mesenteric percentage of portosystemic shunts (r = 0.74, P < 0.05), splenic percentage of portosystemic shunts (r = 0.54, P < 0.05) and estimated portosystemic blood flow (r = 0.91, P < 0.01). Splenorenal shunt blood flow was 6 to 12 times higher in portal hypertensive rats, e.g., in portal vein ligated rats: 2.8 +/- 2.7 vs 0.3 +/- 0.1 mL.min-1 in sham rats (P < 0.01), and was similar in the different cirrhosis models but was higher in portal vein ligated rats than in cirrhotic rats (1.2 +/- 0.7 vs 0.6 +/- 0.6 mL.min-1.100 g-1, P = 0.05). Octreotide significantly decreased splenorenal shunt blood flow: -23 +/- 20% (P < 0.01) vs -6 +/- 8% (not significant) in placebo rats. The variation of splenorenal shunt blood flow after vapreotide was significant but not that of the splenic percentage of portosystemic shunts compared to placebo. CONCLUSIONS: The splenorenal shunt is the main portosystemic shunt in rats. The measurement of splenorenal shunt blood flow is easy, accurate and reproducible and should replace the traditional measurement of the percentage of portosystemic shunts in pharmacological studies.

Splenorenal shunt blood flow by transit-time ultrasound as an index of collateral circulation in portal hypertensive rats.

The aim of this study was to develop a technique that could serve as an index of portosystemic shunt (PSS) blood flow in portal hypertensive rats whose main shunt is the splenorenal shunt (SRS). The main hemodynamic measurements performed were: SRS blood flow by the transit-time ultrasound (TTU) method, percentage of PSS, and regional blood flows by the microsphere method. We determined the accuracy and reproducibility of SRS blood flow measurements under baseline and pharmacological (octreotide) conditions. SRS blood flow was compared with other hemodynamic characteristics. Two models of portal hypertension were used: secondary biliary and dimethylnitrosamine cirrhosis. The SRS blood flow was correlated with mesenteric (r = .76; P < .001) and splenic (r = .67; P < .01) PSS percentages. The intra- and interobserver agreements for SRS blood flow were excellent: ric = .99 and ric = .98, respectively. SRS blood flow was six times higher in portal hypertensive rats (0.6 +/- 0.7 mL . min-1 . 100 g-1) than in sham rats (0.1 +/- 0.1 mL . min-1 . 100 g-1 [P < .01]). Octreotide significantly decreased SRS blood flow but not mesenteric or splenic PSS percentages. SRS is the main PSS in rats. The measurement of SRS blood flow by TTU is accurate and reproducible. This method can be used to identify new mechanisms in hemodynamic studies that differ from those identified by the measurement of the percentage of PSS by the microsphere method, especially in pharmacological studies.