A new concept of gentamicin loaded HAP/TCP bone substitute for prophylactic action: in vivo pharmacokinetic study.

Despite systemic prophylaxis, infection rates after orthopedic surgery can reach more than 1%. A new HAP/TCP bone substitute loaded with 125 mg of gentamicin was designed for prophylactic use. Its aim was to enhance the efficacy of systemic prophylactic treatments by increasing the local antibiotic concentration. The release rate of gentamicin from the bone substitute was investigated after implantation in the femoral condyle of five sheep. In order to investigate the local and systemic gentamicin concentrations, synovial fluids and blood samples were assessed over a 5-day period. The mean gentamicin concentration peak in blood was 4.2 µg/ml and the mean local concentration in synovial fluids during the first 8 h was 305 µg/ml. After 48 h, the concentrations in blood and synovial fluids were less than 0.5 µg/ml. No remaining gentamicin was detected in bone substitutes explanted after 8 days of implantation. The gentamicin release rate from the bone substitutes assessed corresponds to the recommendations for the prophylactic use of antibiotics: high local concentration but limited in time (less than 48 h) not to select antibiotic-resistant bacterial strains. Our results indicated that this implant should be an effective prophylactic tool in orthopedic surgery in combination with systemic prophylaxis.

High incidence of postoperative infections after pancreaticoduodenectomy: A need for perioperative anti-infectious strategies.

OBJECTIVES: Postoperative infections occur frequently after pancreaticoduodenectomy, especially in patients with bile colonization. Recommendations for perioperative anti-infectious treatment are lacking, and clinical practice is heterogenous. We have analyzed the effects of bile colonization and antibiotic prophylaxis on postoperative infection rates, types and therapeutic consequences. METHODS: Retrospective observational study in patients undergoing pancreaticoduodenectomy with intraoperative bile culture. Data on postoperative infections and non-infectious complications, bile cultures and antibiotic prophylaxis adequacy to biliary bacteria were collected. RESULTS: Among 129 patients, 53% had a positive bile culture and 23% had received appropriate antibiotic prophylaxis. Postoperative documented infection rate was over 40% in patients with or without bile colonization, but antibiotic therapy was more frequent in positive bile culture patients (77% vs. 57%, P=0,008). The median duration of antibiotic therapy was 11 days and included a broad-spectrum molecule in 42% of cases. Two-thirds of documented postoperative infections involved one or more bacteria isolated in bile cultures, which was associated with a higher complication rate. While bile culture yielded Gram-negative bacilli (57%) and Gram-positive cocci (43%), fungal microorganisms were scarce. Adequate preoperative antibiotic prophylaxis according to bile culture was not associated with reduced infectious or non-infectious complication rates. CONCLUSION: Patients undergoing pancreaticoduodenectomy experience a high rate of postoperative infections, often involving bacteria from perioperative bile culture when positive, with no preventive effect of an adequate preoperative antibiotic prophylaxis. Increased postoperative complications in patients with bile colonization may render necessary a perioperative antibiotic treatment targeting bile microorganisms. Further prospective studies are needed to improve the anti-infectious strategy in these patients.

Association of transcription factor 7-like 2 gene (TCF7L2) polymorphisms with stress-related hyperglycaemia (SRH) in intensive care and resulting outcomes: The READIAB study.

OBJECTIVE: The study aimed to evaluate the impact of the single nucleotide polymorphism (SNP) rs7903146 on the transcription factor 7-like 2 (TCF7L2) gene in stress-related hyperglycaemia (SRH), defined as blood glucose≥11mmol/L in at least two blood samples during the first 3 days in the intensive care unit (ICU), and on 28-day and 1-year mortality, and incidence of type 2 diabetes (T2D) at 6 months and 1 year in patients hospitalized in the ICU. METHODS: This prospective observational (non-interventional) multicentre READIAB study, carried out during 2012-2016 in six French ICUs, involved adult patients admitted to ICUs for at least two organ failures; patients admitted for<48h were excluded. During the 3-day ICU observational period, genetic testing, blood glucose values and insulin treatment were recorded. MAIN RESULTS: The association of rs7903146 with SRH was assessed using logistic regression models. Cox proportional hazards regression models assessed the associations between rs7903146 and mortality and between SRH and mortality, both at 28 days and 1 year. A total of 991 of the 1000 enrolled patients were included in the READIAB-G4 cohort, but 242 (24.4%) had preexisting diabetes and were excluded from the analyses. SRH occurred within the first 3 days in the ICU for one-third of the non-diabetes patients. The association between the rs7903146 polymorphism and SRH did not reach significance (P=0.078): OR(peroneTcopy): 1.24, 95% CI: 0.98-1.58. A significant association was found between rs7903146 and 28-day mortality after adjusting for severity scores (P=0.026), but was no longer significant at 1 year (P=0.61). At 28 days, mortality was increased in patients with SRH (HR: 2.09, 95% CI: 1.43-3.06; P<0.001), and remained significant at 1 year after adjusting for severity scores (HR: 1.73, 95% CI: 1.32-2.28; P<0.001). On admission, non-diabetes patients with SRH had a higher incidence of T2D at 6 months vs. those without SRH (16.0% vs. 7.6%, RR: 2.11, 95% CI: 1.07-4.20; P=0.030). At 1 year, these figures were 13.4% vs. 9.2%, RR: 1.45, 95% CI: 0.71-2.96; P=0.31). Moreover, the rs7903146 polymorphism was not significantly associated with T2D development at either 6 months (P=0.72) or 1 year (P=0.64). CONCLUSION: This study failed to demonstrate any significant association between rs7903146 and SRH. Nevertheless, the issue remains an important challenge, as SRH may be associated with increased rates of both mortality and T2D development.

[Perioperative management of asplenic patients]. / Prévention du risque infectieux postopératoire chez les patients splénectomisés.

OBJECTIVE: In 2003, asplenia had involved 250000 patients in France. These patients are at risk of severe infection, mostly with capsulated bacteria as pneumococci, meningococci and Haemophilus. The higher mortality and morbidity due to infection in asplenic patient led in June 2003 a French expert committee to propose preventive management based on vaccination and antibioprophylaxis. STUDY DESIGN: Update article. DATA SYNTHESIS: For vaccination, two vaccines against pneumococci are available. The first one, the antipolysaccharide (Pneumo 23) is recommended for adults. It is effective for the majority of the serotypes even if its efficacy can be variable. The second one a conjugated pneumococcal vaccine (Prenevar) is used for children under two years because it has higher activity on antibiotic resistant strains therefore increasing antibiotic prophylaxis efficiency. When splenectomy is required, vaccination against pneumococci, Haemophilus (b type) and C meningococci must be performed at least 15 days before surgery, in order to get better immune stimulation. In case of emergency, vaccines have to be administrated within 30 days after surgery. Antibioprophylaxis is based on cefazolin injection before splenectomy and by postoperative intravenous amoxicillin administration. As soon as oral intake is allowed, antibioprophylaxis is continued for at least two years in adults and five years in children. Both antibiotic and vaccination have been reported to reduce pneumococcus infections.

Verification and validation of a Work Domain Analysis with turing machine task analysis.

While the use of Work Domain Analysis as a methodological framework in cognitive engineering is increasing rapidly, verification and validation of work domain models produced by this method are becoming a significant issue. In this article, we propose the use of a method based on Turing machine formalism named "Turing Machine Task Analysis" to verify and validate work domain models. The application of this method on two work domain analyses, one of car driving which is an "intentional" domain, and the other of a ship water system which is a "causal domain" showed the possibility of highlighting improvements needed by these models. More precisely, the step by step analysis of a degraded task scenario in each work domain model pointed out unsatisfactory aspects in the first modelling, like overspecification, underspecification, omission of work domain affordances, or unsuitable inclusion of objects in the work domain model.

[Cellular culture of osteoblasts and fibroblasts on porous calcium-phosphate bone substitutes]. / Culture cellulaire d'ostéoblastes et de fibroblastes sur substituts osseux poreux en phosphate de calcium.

PURPOSE OF THE STUDY: Calcium phosphate ceramics are synthetic bone substitutes able to fill in bone destruction as a support of the bone growth. This work consisted in an in vitro assessment of osteoblasts and fibroblasts cultures on macroporous calcium-phosphate bone substitutes to analyze the interaction between cells and bone substitute. MATERIALS AND METHODS: The macroporous ceramic was composed of 70% hydroxyapatite and 30% tri-calcium phosphate with known mechanical and physico-chemical properties. Three compounds were processed with different size of macropore and with or without microporosity on their surface. Cells were seeded on discs measuring 10 mm in diameter and 2 mm in thickness. Cellular viability was evaluated by the MTT test for every stage of observation. An histological study to observe the invasion in the depth of discs was performed. Scanning electron microscopy was used to analyze the cellular comportment in contact with the surface of substitutes. RESULTS: An exponential cellular growth was effective on each substitute with the two cellular types. Cells spread on the surface of the compounds covering macropores and colonized the depth of the discs. A size of macropore of 300 microm or more seemed to support this invasion. 15 microm sized interconnections appeared to be effective to allow cell migration between macropores. The cell proliferation was similar on substitutes with or without microporosity. CONCLUSION: Biomaterials currently used as bone substitute are more or less osteoconductive but they have no osteoinductive property. A hybrid association of calcium-phosphate ceramic with osteogenic cells should promote the development of a calcium phosphate compound with osteoinductive capacity.

Effect of micro- and macroporosity of bone substitutes on their mechanical properties and cellular response.

The control of porosity morphology and physico-chemical characteristics of calcium phosphate bone substitutes is a key-point to guaranty healing success. In this work, micro- and macroporosity of materials processed with 70% Hydroxyapatite (HAP) and 30% beta-tricalcium phosphate (beta-TCP) were controlled by sintering temperature and porogen addition, respectively. Porosity was quantified by scanning electron microscopy (pore size) and mercury intrusion porosimetry (interconnection between pores). The content of macrointerconnections and their size were dependent on porogen content, shape, and size. Mechanical properties (compressive strength) were strongly dependent on macroporosity size and content, on the basis of exponential laws, whereas microporosity ratio was less influent. Relying on those results, three types of materials with contrasting porous morphologies were processed and assessed in vitro, in primary culture of human osteoblasts and fibroblasts. With both types of cells, an exponential cellular growth was effective. Cells colonized the surface of the materials, bridging macroporosity, before colonizing the depth of the materials. Cell migration across and into macroporosity occurred via the emission by the cells of long cytoplasmic extensions that hanged on microporosity. Both macroporosity and macrointerconnectivity size influenced the penetration of cells. An interconnection size of 15 microm appeared to be effective to support this invasion without bringing down mechanical strength.