Costs and management of patients with hemophilia A in France: the Hemraude study.

OBJECTIVE: The Hemraude study was conducted to describe the profile of patients with HA, disease management, and economic burden in a collective perspective. METHODS: This retrospective study was conducted using the French administrative healthcare claims database SNIIRAM/SNDS. Male patients treated for hemophilia A with a long-term illness (ALD) status or invalidity were included in the study between January 1, 2016 and December 31, 2017. Patients were classified in six treatment groups: no treatment, on-demand FVIII, prophylactic FVIII, FVIII in immune tolerance induction (ITI) protocol, on-demand bypassing agents, and prophylactic bypassing agents. Patients treated with FVIII in ITI protocol and those treated with bypassing agents are deemed to have developed inhibitors. HA patients were compared to a control population without coagulation disorder and matched (ratio 1:3) on age and sex. RESULTS: A total of 4172 patients were included in the analysis, aged on average 35.2 years, 5.3% had HIV infection, and 8.8% had hepatitis B or C. In 2017, half of the patients received no treatment for HA, 46.7% were treated with FVIII (25% on demand, 20.6% with prophylaxis, and 1.1% ITI), 1.5% with bypassing agents. Patients treated with prophylactic treatments, either inhibitor or non-inhibitor, were less likely to be hospitalized for severe bleeding compared to patients receiving on-demand treatments. The average annual costs for HA management per patient were 72,209.60 €. The highest costs were observed in patients treated with FVIII in ITI protocol and those receiving prophylactic bypassing agents. CONCLUSION: Direct costs of HA treatments for HA may be very high especially in the small percentage of patients developing inhibitors or treated with ITI protocol.

[Optimising drug dispensation by pharmacy technicians: A quality approach]. / Optimisation des dispensations réalisées par les préparateurs en pharmacie : démarche qualité en rétrocession.

INTRODUCTION: In a context of continuity of quality improvement, we are committed to enhancing the care management and medication management of outpatients in the drug dispensation unit of our pharmacy. An audit was carried out to assess the training needs of pharmacy technicians (PTs). MATERIALS AND METHODS: All drug dispensations done over a 9-week period by the units PTs were audited. Data collected were: PTs' presentation to the patient, duration of drug dispensation, notion of introduction or renewal, the tools used during retrocession, and the explanations given to the patient about her/his treatment. PT perceptions and patient satisfaction were evaluated on a Likert scale from 1 to 5 and on a scale from 1 to 4, respectively. RESULTS: One hundred drug dispensation were audited: 21 introductions and 79 renewals. Tools were used in 52% of introductions and 11% of renewals. Administration modalities were explained for all introductions but for only 57% of renewals, 47% of adverse events and 9.5% of storage methods. Tolerance was discussed in 34% of drug dispensations and compliance in 19%. The scores of PT perception and patient satisfaction were 4.4/5 and between 3/4 and 3.9/4 depending on the items, respectively. CONCLUSION: Several areas for improvement are highlighted in this survey. PTs' complementary should include communication with outpatients. This approach is an integral part of the ISO 9001 certification obtained in 2019 in our drug dispensation unit.

The impact of an in-department pharmacist on the prevention of drug iatrogenesis in a rheumatology department.

INTRODUCTION/OBJECTIVES: The primary objective was to evaluate the impact of an in-department pharmacist on the prevention of drug iatrogenesis in a rheumatology department. Secondary objectives were to determine (i) if medication history discrepancies were detected more frequently in the elderly or not, and (ii) if the mean number of treatments at admission had an impact on the number of medication history discrepancies. METHODS: Implementation of a clinical-pharmacy program based on medication reconciliation and medication review of prescription for all patients admitted to a rheumatology department between January and June 2017. The analytical approach was mainly descriptive and data were expressed as mean ± standard deviation (i.e., number of treatments at admission, number of medication reconciliations) and as proportions (i.e., acceptance rate, impact). Chi-squared tests and Student's test were performed to determine if there was a significant difference in outcomes. RESULTS: Three hundred twelve patients were included in the study, 517 medication history discrepancies in 243 (77.8%) patients and 196 pharmaceutical interventions in 133 (42.6%) patients. A significant difference was found in the number of medication history discrepancies and pharmaceutical interventions between the two age groups and in the mean number of treatments at admission between patients with or without medication history discrepancies. 15.4% of study patients had major medication history discrepancies and major pharmaceutical interventions. All patients and practitioners reported the usefulness of an in-department pharmacist. CONCLUSION: This program was found effective in terms of safety and improvement in the continuity of care. Key Points • This clinical-pharmacy program with an in-department pharmacist had a positive impact on the prevention of drug iatrogenesis in one rheumatology department. • 15.4% (n = 48) of study patients had major medication history discrepancies and major pharmaceutical interventions. • All practitioners and patients were satisfied with this clinical-pharmacy program.

The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells.

Voltage-gated Na+ channels (VGSCs) are highly expressed in several types of carcinomas including breast, prostate and lung cancers as well as in mesothelioma and cervical cancers. Although the VGSCs activity is considered crucial for the potentiation of cancer cell migration and invasion, the mechanisms responsible for their functional expression and regulation in cancer cells remain unclear. In the present study, the role of the small GTPase RhoA in the regulation of expression and function of the Nav1.5 channel in the breast cancer cell lines MDA-MB 231 and MCF-7 was investigated. RhoA silencing significantly reduced both Nav1.5 channel expression and sodium current indicating that RhoA exerts a stimulatory effect on the synthesis of an active form of Nav1.5 channel in cancer cells. The inhibition of Nav1.5 expression dramatically reduced both cell invasion and proliferation. In addition, a decrease of RhoA protein levels induced by Nav1.5 silencing was observed. Altogether, these findings revealed: i) the key role of the small GTPase RhoA in upregulation of Nav1.5 channel expression and tumor aggressiveness, and ii) the existence of a positive feedback of Nav1.5 channels on RhoA protein levels.

[Crushing drugs in geriatric units: an "handicraft" practice with frequent errors which imposed recommendations]. / L'écrasement des médicaments en gériatrie: une pratique « artisanale ¼ avec de fréquentes erreurs qui nécessitait des recommandations.

PURPOSE: Swallowing disorders or psycho-behavioural distress frequently interfere on drug administration in elderly inpatients. Crushing drugs is a common although non validated practice. The objective of this first prospective study, performed in all geriatric units of the Rouen university hospital by a multidisciplinary group, was to assess the crushing practice, from the prescription to the administration of the drugs in order to elaborate corrective measures. METHODS: A survey was performed in June 2009 and included 683 inpatients, 65 years and above, in 23 geriatric units. If a patient received drugs after crushing, we recorded the reason for crushing, what drugs were crushed, the galenic presentations and the technique used for preparation and administration. RESULTS: Two hundred and twenty-one patients (32.3%) (85.5 ± 6.5 years, females 74.2%) received 1528 drugs (6.9 ± 4 per patient) including 966 drugs (63.2%) after crushing (crushed pills or crushed content of opened capsules), mainly in the morning (50.4%). The main reasons for crushing drugs were swallowing disorders and psycho-behavioural distress. Forty-two percent of crushed drugs had a galenic presentation which did not allow crushing. The patient's drugs were crushed together three out of four times and mixed with different vehicules for administration. The material used for crushing (a mortar, 92.6%) was often the same for several patients (59.4%); 83.5% of crushed drugs were immediately administered to the patients, though there were important variations about schedules of administration. CONCLUSION: Crushing drugs expose both to iatrogenic hazards and professional risks. Regional and national recommendations were developed in order to correct the errors linked to this practice.

[An update on the use of tissue adhesives in ophthalmology]. / Mise au point sur l'utilisation des colles tissulaires en ophtalmologie.

Tissue adhesives have a long history of use in almost all surgical disciplines, both as an alternative and a complement to sutures. Nevertheless, ophthalmologists have restricted knowledge of their potential applications; consequently, tissue adhesives have been underutilized so far. This review discusses the most relevant clinical and experimental advances in the use of tissue adhesives in ophthalmology and details the characteristics and properties of the glues. Among the currently available adhesives, synthetic glues are mainly represented by cyanoacrylates and biologic glues by fibrin-based adhesives. Cyanoacrylate-based glues are especially useful for treating perforated or preperforated corneal ulcers and performing temporary tarsorrhaphy. Fibrin-based glues have the largest field of application, as they can be used in corneal perforations and are being widely used in pterygium surgery and conjunctival surgery. We also reviewed other anecdotic applications of these adhesives. Novel biomaterials such as biodendrimers, polyethylene glycols, modified chondroitin sulfates, and acrylic copolymers show promising results in the experimental field, and one product has been on the market for a short period of time.

Vasculogenic mimicry of acute leukemic bone marrow stromal cells.

Angiogenesis is thought to be involved in the development of acute leukemia (AL). We investigated whether bone marrow stromal cells (BMSCs) derived from stem cells might be responsible for the increase in microvascular density (MVD), and compared 13 bone marrow samples from AL patients with 23 samples from patients in complete remission (controls). We demonstrated that AL-derived BMSC secreted more insulin growth factor-1 (IGF-1) and SDF-1alpha than controls. In addition, in contrast to normal adherent BMSCs, adherent BMSCs derived from CD133+/CD34+ stem cells from AL patients were able to form capillary-like structures ('vasculogenic mimicry') on Matrigel. The increase in vasculogenic mimicry occurred through PI3 kinase and rho GTPase pathway as inhibitors of these signaling pathways (wortmannin and GGTI-298, respectively) were able to reduce or prevent capillary tube formation. In normal BMSC, addition of exogenous IGF-1 generated capillary-like tubes through the same pathway as observed spontaneously in AL-derived BMSC. The involvement of IGF-1 in the mimicry process was confirmed by the addition of a neutralizing antibody against IGF-1R or a IGF-1R pathway inhibitor (picropodophyllin). In conclusion, AL-derived BMSC present functional abnormalities that may explain the increase in MVD in the bone marrow of AL patients.

[Transfusions of rhesus-incompatible platelet concentrates in Rouen University Hospital: procedures and consequences]. / Transfusions de concentrés plaquettaires Rhésus incompatible au CHU de Rouen: pratiques et conséquences.

INTRODUCTION: Guidelines for distribution and use of blood products have been established for both blood transfusion institution and hospitals, in particular for the use of Rh (D)-incompatible platelet concentrates. The aim of this study was to evaluate: 1) the rate of attribution for the Rh (D)-incompatible platelets concentrates, 2) the immunisation prophylaxis practices, 3) the immunological consequences using short and medium term follow-up of transfused patients. METHODS: Patients with Rh (D)-incompatible platelets concentrate administered during the year 2003 at Rouen University Hospital were retrospectively selected. Patients on transfusion were described. The relationship of various factors with the injection as well as the appearance of allo-immunization was statistically tested. RESULTS: During a year, 280 Rh (D)-incompatible platelets concentrates were administered to 67 patients. Immunisation prophylaxis by injection of Ig anti-D was not systematically performed. Four immunizations in the Rhesus group system were identified: 2 against D antigen (Ag), 1 against E Ag and 1 against C Ag. Immunisations against D Ag occurred for two younger women considered as immunodeficient. Immunization prophylaxis was more frequent in poly-transfused patients. However no difference was observed for the other factors. CONCLUSION: Compatibility concerning Rhesus (D) is not always possible. The immunization against red cells persists, in particular against the antigens of the Rhesus group system and moreover for the immunodeficient patients. Recommendations for immunization prophylaxis by injection of specific anti-D immune-globulin (Ig) could be reconsidered.

Feasibility study of the direct mechano-chemical synthesis of nanostructured magnesium tetrahydroaluminate (alanate) [Mg(AlH(4))(2)] complex hydride.

The present work reports a feasibility study of the direct mechano-chemical synthesis by controlled reactive mechanical alloying (CRMA) in a magneto-ball mill of the nanostructured magnesium tetrahydroaluminate (magnesium alanate) Mg(AlH(4))(2) complex hydride. Three stoichiometric Mg-2Al mixtures, (a) elemental Mg and Al powders, (b) elemental Al powder and commercial AZ91 alloy (Mg-Al-Zn alloy) and (c) powder of as-cast Mg-2Al alloy, have been used. No successful synthesis of Mg(AlH(4))(2) has been achieved. The only nanocrystalline hydride formed up to 270 h of CRMA is beta-MgH(2), and it does not react with Al and H(2) to form Mg(AlH(4))(2). It has been found that there is strong competition between formation of Al(Mg) solid solution and the beta-MgH(2) hydride occurring to a various extent up to approximately 10 h of CRMA in all three Mg-2Al mixtures. It is hypothesized that the presence of Al(Mg) solid solution inhibits the reaction of beta-MgH(2), Al and H(2) to form Mg(AlH(4))(2). Furthermore, despite the fact that after prolonged milling the Al(Mg) solution eventually decomposes into secondary Al(s) (derived from solid solution), the latter retains its physico-chemical characteristics of the former solid solution which still inhibits the reaction to form Mg(AlH(4))(2). Experimental evidence from DSC measurements shows increasing ranges of the melting enthalpy with increasing amounts of Al(Mg) solid solution and consequently the secondary Al(s) for all the three Mg-2Al mixtures. This strongly supports the hypothesis about the different nature of Al(Mg) and the secondary Al(s) as compared to the primary elemental Al powder.

Adverse effect of polyvalent immunoglobulin in the treatment of Guillain-Barre syndrome.

BACKGROUND: Acute polyradiculoneuropathy or Guillain-Barre syndrome is a neurological disease which may present with severe forms which have a poor prognosis. The patient's management requires multidisciplinary specialised care. Morbidity has been reported to be significantly improved with initial therapy using high-dose intravenous immunoglobulin (IVIG). However, this therapy represent an immunological risk which has remained overlooked by clinicians in the majority of cases and is not clearly stated by the pharmaceutical companies. Therefore, the use of IVIG in the intensive care unit can cause some problems. CASE REPORT: A 32-year-old woman presented with clinical signs of Guillain-Barre syndrome. The patient received high-dose intravenous immunoglobulin (TEGELINE). Nine days after beginning therapy, she presented with severe immunological hemolytic anaemia; the IVIG was suspected as the cause. The blood cell count returned to normal approximately two months after the onset of the hemolytic syndrome. CONCLUSION: Despite the effectiveness of IVIG therapy in the management of various diseases, intensive care clinicians should be aware of possible major adverse effects which make a careful assessment of the patient necessary before treatment. It may also be important to consider the patient's ABO blood group before initiating IVIG treatment, particularly in patients bearing A and/or B blood group antigens.

[Oxidative stress and endothelial dysfunction in heart failure]. / Stress oxydant et dysfonction endothéliale dans l'insuffisance cardiaque.

Chronic heart failure is characterized by increased vascular systemic resistances secondary to activation of various vasoconstrictor systems and to decreased endothelium-dependent vasodilatation. Endothelial dysfunction, described both in animals and in humans, may be caused by an increased inactivation of nitric oxide (NO) by reactive oxygen species, leading to decreased NO bioavailability and impaired vasodilatation. Increased levels of free radicals in heart failure may result either from increased production or a decrease in the cellular antioxidant reserves. Free radicals are produced by three enzymatic systems: NADH/NADPH oxidase (after stimulation by angiotensin II or TNF-alpha), xanthine oxidase or endothelial NO-synthase (NOS) itself. However, oxidative stress alone cannot explain endothelial dysfunction. Other mechanisms involved in the regulation of the production of NO (e.g. decreased expression and/or activity of the NOS) and/or changes in production of vasoconstrictors may participate in this impaired endothelium-dependent vasodilatation in heart failure.

Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure : role of nitric oxide, prostanoids, oxidant stress, and bradykinin.

BACKGROUND-Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved. METHODS AND RESULTS-FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg. kg(-1). day(-1) for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor N(W)-nitro-L-arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor-treated CHF rats was abolished by N(W)-nitro-L-arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor-treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF. CONCLUSIONS-In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.

Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress.

BACKGROUND: Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown. METHODS AND RESULTS: FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 microL/min flow: sham, 42+/-5%; CHF, -4+/-3%; P<0.05). Exercise partially restored FMD (18+/-3%; P<0.05 versus CHF). In sham rats, FMD was abolished by the nitric oxide-synthase inhibitor Nomega-nitro-L-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise. CONCLUSIONS: CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.

[Endothelial dysfunction in cardial failure: potential mechanisms]. / Dysfonction endothéliale dans l'insuffisance cardiaque: mécanismes potentiels.

From the vascular point of view, cardiac failure is characterised by increased systemic resistances secondary to an increased concentration of a number of vasoconstrictor substances and also to decreased endothelium dependent vasodilatation. Endothelial dysfunction has been described both in man and in animal models, but its causes are not well understood. Such dysfunction could be due to a decrease in the production of nitric oxide, a decrease in its vasodilator effect due to an increased degradation or an increased vasoconstrictor tone. Recent data suggests an improvement or prevention of this endothelial dysfunction observed in cardiac failure by physical training and by chronic treatment with an angiotensin converting enzyme inhibitor. The improvement or preservation of endothelial function induced by exercise or ACE inhibitor could explain some of the benefits of these treatments in terms of tissue perfusion and haemodynamic conditions.

A clinical study of quazepam in hospitalized patients with insomnia.

The efficacy of quazepam (Sch-16134) 15 mg capsules as a hypnotic has been compared with that of placebo in a 9-day study, using a parallel-group design. The physician's global evaluation numerically favoured quazepam 63% (nineteen of thirty) over placebo 50% (fifteen of thirty). Furthermore, it demonstrated greater improvement in Hypnotic Activity Index and Sleep Quality Index from baseline scores, and caused no adverse reactions.