Adherence to the evidence-based heart failure drug treatment: Are there sex-specific differences among new users?

BACKGROUND: The evidence-based heart failure (HF) drug treatment is made of a ß-blocker and an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, or hydralazine + isosorbide dinitrate. Little is known about sex-based difference in adherence to the evidence-based HF drug treatment. OBJECTIVES: To assess among new users of the evidence-based HF drug treatment, the association between sex and 1) persistence with the treatment 1 year after its initiation, 2) implementation of the treatment among those who persisted, and 3) overall adherence to treatment in the year following its initiation. METHODS: A cohort study was conducted among new users of this treatment using Quebec medico-administrative data. Patients still on the evidence-based HF drug treatment one year after initiation were considered persistent. Among persistent users, those with ≥88% of days covered by the treatment were deemed to have adequately implemented it. Persistent patients who have adequately implemented the treatment were considered adherent. To measure the association between, on one hand sex, and on the other persistence, implementation and adherence, adjusted proportion ratios (APR) with their 95% confidence intervals (CI) were calculated. RESULTS: Among 13,453 women, 72.1% were persistent, 72.2% adequately implemented the treatment, and 52.8% were adherent. Among the 14,614 men, these proportions were 73.6%, 67.9% and 50.1%, respectively. Men were less likely than women to be adherent to their treatment (APR: 0.96, 95% CI: 0.94-0.99). CONCLUSION: Among individuals initiating an evidence-based multi-drug treatment for HF, men are less likely than women to be adherent to this treatment.

The impact of incident depression on medication adherence in patients with type 2 diabetes.

BACKGROUND: Depression has been correlated with suboptimal adherence to antidiabetic drugs (ADs). Most studies on this topic were cross-sectional; thus, the directionality of this relationship could not be established. The objective of this study was to measure the association between incident depression and AD nonadherence among newly treated patients with diabetes. METHODS: We performed a population-based cohort study among new AD users using the Quebec public health insurance data. To avoid immortal time bias, we carried out depression diagnosis-time distribution matching by assigning a date of depression diagnosis to individuals without depression. Nonadherence (i.e.,<90% of days covered by≥1 AD) during the year following depression diagnosis (real or assigned date) was the outcome. Multivariate logistic regression analyses that adjusted for baseline adherence and other confounders were used to estimate the adjusted effect of depression on AD nonadherence. RESULTS: Between 2000 and 2006, we identified 3,106 new AD users with a subsequent diagnosis of depression and 70,633 without depression, of which 52% and 49% became non-adherent to AD treatment, respectively. Among patients with depression, 52.0% were considered AD non-adherent in the year after depression diagnosis compared with 49.0% of matched patients without depression. Depression was associated with AD nonadherence after accounting for baseline adherence and other confounders with an adjusted odds ratio of 1.24 (95% confidence interval: 1.13-1.37). CONCLUSIONS: The results suggest that depression is an independent risk factor for AD nonadherence. Patients with type 2 diabetes and depression might benefit from adherence-enhancing interventions.

Underexposure of Seniors to Heart Failure Drug Therapy.

BACKGROUND: Little is known about exposure to heart failure (HF) treatment among seniors with ischemic heart disease. OBJECTIVES: In a population of seniors, we: 1) estimated the association between age and exposure to HF drug therapy at 6, 12, 36 and 60 month intervals after HF diagnosis, and 2) determined the influence of the passage of time on exposure to drug therapy. METHODS: Using the Quebec provincial administrative databases, we conducted a population-based inception cohort study that included all individuals aged ≥ 65 with a first HF diagnosis between 2000 and 2009 and an ischemic heart disease diagnosis in the year before HF diagnosis. We assessed exposure to HF drug therapy and to drug therapy at target doses at 6, 12, 36 and 60 month intervals after HF diagnosis. Adjusted prevalence ratios (aPR) between age at diagnosis and exposure to drug therapy and the influence of time (6-month periods) were assessed using multivariate modified Poisson regressions. RESULTS: Among the 86,428 seniors, those who were older were less likely to be exposed to both HF drug therapy and drug therapy at target doses at each time point, than were the younger ones (aged 65-69). The aPRs for exposure to drug therapy for the 90+ age group were 0.64, 0.64, 0.56 and 0.53 at the 6, 12, 36 and 60 month intervals, respectively. After HF diagnosis, exposure increased by a maximum of 8% per 6-month period. CONCLUSION: Increasing age is associated with a decrease in exposure to drug therapy, with only slight improvement in exposure after HF diagnosis.

Comparative effectiveness of cardioprotective drugs in elderly individuals with type 2 diabetes.

AIMS: Although many elderly individuals suffer from type 2 diabetes, the effectiveness of cardioprotective drugs in primary prevention of cardiovascular events in clinical practice in this population has rarely been evaluated. We aimed to assess the effectiveness of, (i) angiotensin converting enzyme inhibitors or angiotensin receptor blockers, (ii) statins, (iii) antiplatelet drugs and (iv) the combination of these three drugs, in the prevention of myocardial infarction (MI) and stroke in elderly individuals with type 2 diabetes. METHODS: Using Quebec administrative databases, we conducted nested case-control analyses among a cohort of 17,384 individuals without a history of cardiovascular disease. Individuals were aged ≥ 66 years, newly treated with oral antidiabetes drugs and had not used any of the three above classes of cardioprotective drugs in the year before cohort entry. For each case (MI/stroke during follow-up), five controls were matched for age, year of cohort entry and sex. Use of each drug and of their combination was defined as current, past or no use. We calculated adjusted odds ratios (AOR) of MI/stroke. RESULTS: We observed no reduction in the MI/stroke risk for users of ACEI/ARB nor for users of the three drugs combination. Longer exposure to statins was associated with a lower risk (AOR for every 30 days of therapy: 0.97; 95% CI: 0.96-0.99). By contrast, current use of antiplatelet drugs was associated with an increased risk of MI/stroke (1.40; 1.12-1.75). CONCLUSION: The benefit of cardioprotective drugs in primary prevention was not clear in this cohort of elderly individuals with type 2 diabetes. A short duration of exposure to these drugs might explain the lack of benefit.

Difficulty adhering to antidiabetic treatment: factors associated with persistence and compliance.

AIMS: This study aimed to assess the 1-year treatment persistence and compliance of new oral antidiabetic drug (OAD) users with their treatment, and to identify the factors associated with both persistence and compliance. METHODS: This population-based cohort study of new OAD users aged 18 years or above used the Quebec health insurance board databases. Those having a prescription filled for antidiabetic treatment during the period leading up to the 1-year anniversary of their first claim were considered to be persistent with their antidiabetic treatment. Of these patients, individuals with a medication possession ratio (MPR) greater or equal to 80% for OAD or insulin were deemed compliant. Also identified were the characteristics associated with both outcomes, using a multivariate logistic regression model. RESULTS: Our cohort consisted of 151,173 individuals, 119,832 (79.3%) of whom were considered persistent. Of these, 93,418 (78.0%) were also deemed compliant. Persistence and compliance were associated with older ages, living in a rural region, low socioeconomic status, having the first OAD prescribed by a general practitioner and a history of using five different drugs or more. People were less likely to be persistent and compliant if their initial OAD was a secretagogue and if they had consulted a physician eight times or more during the year prior to starting treatment. CONCLUSION: One year after OAD treatment initiation, 21% had discontinued their treatment and 22% of those still being treated were non-compliant. These results could help to tailor interventions aimed at optimizing the use of OAD treatments.

Underuse of cardioprotective treatment by the elderly with type 2 diabetes.

AIMS: To assess whether elderly patients with type 2 diabetes use a comprehensive cardioprotective regimen (CCR) of antihypertensive, lipid-lowering and antiplatelet drugs in the year following oral antidiabetic drug initiation and, if so, to identify the determinants of such use. METHODS: Using the Quebec Diabetes Surveillance System administrative database, we carried out an inception cohort study of individuals aged 66 years and over who began oral antidiabetic therapy between 1998 and 2002. Those individuals with at least one claim in the year after starting antidiabetic treatment for an antihypertensive, a lipid-lowering and an antiplatelet drugs were deemed to be using a CCR. A multivariate logistic regression model was built to identify the characteristics associated with CCR use. RESULTS: Of the 48,505 individuals included in the study, 9912 (20.4%) used a CCR during the year following the first antidiabetic claim. Those more likely to use a CCR were men (odds ratio [OR]: 1.2; 99% confidence intervals [CI]: 1.1-1.3), those who had used an antihypertensive (1.6; 1.4-1.7), lipid-lowering (7.4; 6.8-8.0) or antiplatelet (7.3; 6.7-7.9) drug in the year before the first antidiabetic claim and those with a preexisting diagnosis of cardiovascular disease (1.9; 1.8-2.1). The odds of using a CCR increased every year. CONCLUSIONS: CCR use by the elderly with type 2 diabetes in the year following antidiabetic initiation is low, and prior use of individual cardioprotective drugs is a strong predictor of its use. These findings suggest that the treatment of important modifiable risk factors for cardiovascular disease is suboptimal.

Toll-like receptors, cytokines and the immunotherapeutics of asthma.

Asthma is a complex disease caused by a poorly characterized set of genetic and environmental factors whose pathology is a result of immune dysregulation. Toll-like receptors are pathogen associated molecular pattern receptors expressed by many airway and pulmonary tissues as well as cells of the innate and adaptive immune system. Ligation of toll-like receptors can lead to a change in the expression levels of multiple inflammatory and anti-inflammatory mediators which are involved in the pathogenesis of asthma. These ligands and their receptors are therefore prime candidates in the search for immunotherapeutic treatments of asthma. The use of murine models of allergic asthma as tools for the genetic dissection of this disease should allow the molecular mechanisms underlying asthma to be identified and possibly used as further immunotherapeutic targets.

TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway.

Asthma is one of the leading causes of childhood hospitalization, and its incidence is on the rise throughout the world. Currently, the standard treatment for asthma is the use of corticosteroids to try to suppress the inflammatory reaction taking place in the bronchial tree. Using a murine model of atopic allergic asthma employing a methacholine-hyperresponsive (A/J) as well as a hyporesponsive (C57BL/6) strain of mice sensitized and challenged with ovalbumin, we show that treatment with a synthetic Toll-like receptor 7 (TLR7) ligand (S-28463, a member of the imidazoquinoline family) prevents development of the asthmatic phenotype. Treatment with S-28463 resulted in a reduction of airway resistance and elastance following ovalbumin sensitization and challenge. This was accompanied by a dramatic reduction in infiltration of leukocytes, especially eosinophils, into the lungs of both C57BL/6 and A/J mice following OVA challenge. Treatment with S-28463 also abolished both the elevation in serum IgE level as well as the induction of IL-4, IL-5, and IL-13 by OVA challenge. The protective effects of S-28463 were also observed in MK2 knockout, but not MYD88 knockout, mice. We did not observe a switch in cytokine profile from T(H)2 to T(H)1, as both IL-12p70 and IFN-gamma levels were reduced following S-28463 treatment. These results clearly demonstrate the anti-inflammatory effect of imidazoquinolines in an allergic asthma model as well as the clinical potential of TLR7 ligands in the treatment of allergic diseases.

Genetic diversity of KIR natural killer cell markers in populations from France, Guadeloupe, Finland, Senegal and Réunion.

Killer cell immunoglobulin-like receptors (KIRs) belong to a diverse family of natural killer (NK) cell receptors recognizing human leukocyte antigen (HLA) class I molecules. Due to this functional link, KIR molecules are expected to display a high polymorphism, such as their HLA ligands. Moreover, many studies conducted in mouse and human models have shown that NK-KIR receptors play an important role in haematopoietic stem cell transplantation (HSCT). A beneficial impact of peculiar KIR ligand (HLA) mismatching has been reported suggesting a role to this combinatory HLA-KIR polymorphism. It is thus important to investigate KIR diversity in various human populations. To this end, we used polymerase chain reaction-sequence-specific primers to evaluate KIR gene in five selected populations (France, Guadeloupe, Senegal, Finland and Réunion). Genotypic and haplotypic frequencies were computed, as well as genetic distances and dendrogram (phylip package). These data illustrate the genetic relationship of these five populations through the KIR polymorphism. Results revealed a wide diversity in KIR gene frequencies in Guadeloupe and Réunion, and a high specificity in Senegal. The obtained dendrogram indicated small genetic distances between France, Guadeloupe and Réunion as well as between France and Finland. Senegal showed a distant genetic relationship with the other countries and, interestingly, an inverted ratio of coding/non-coding (KIR2DS4/1D) alleles compared with Caucasians. These data expose the broad diversity in KIR genes worldwide and show that KIR genes are pertinent tools in human population genetics. If the role of KIR donor-recipient incompatibilities is confirmed, KIR diversity according to ethnicity should be taken into account during the selection of HSCT donors.

[Acrodermatitis enteropathica in full-term breast-fed infant]. / Acrodermatite entéropathique chez un nourrisson né à terme nourri exclusivement au sein.

BACKGROUND: Acrodermatitis enteropathica is a rare autosomal recessive disorder, caused by impaired absorption of zinc from the gastrointestinal tract. Symptoms of acrodermatitis enteropathica occur within the first few months after birth and tend to appear shortly after discontinuation of breast-feeding. We report a breast-fed infant with acrodermatitis enteropathica. CASE REPORT: A full term, 4-month-old girl, consulted in dermatologic department for persistent and refractory anogenital lesions since the age of 1 month, with progressive erythematous, vesiculous and squamous lesions, sometimes erosive in a peri orificial and acral pattern. She was calm and healthy baby. She was breast feeding. The diagnosis of acrodermatitis enteropathica was confirmed by decreased plasma zinc level (14 microg/100 ml). Breast milk zinc levels was low (46 microg/100 ml), as plasma zinc level of the mother (94 microg/100 ml). A genetic study showed that she was homozygous for the mutation, whereas her brother and parents were heterozygous. She was given zinc sulphate, and her condition has improved significantly. DISCUSSION: Acrodermatitis enteropathica is characterized by a characteristic clinical feature and the diagnosis is confirmed by decreased plasma zinc level. Acrodermatitis enteropathica in exclusively breast fed infant is rare, it was essentially reported in premature babies. Our case report is particular because it's concerning a full-term breast-fed infant, with zinc deficiency in breast milk and mother's decreased plasma zinc level.

Health-related quality of life in hypertension: impact of a pharmacy intervention programme.

BACKGROUND AND OBJECTIVE: In a previous study, we observed that a pharmacy-based intervention programme decreased the blood pressure of hypertensive patients. The objective of the present study was to assess the effect of this pharmacy programme on the health-related quality of life (HRQOL) of individuals treated for hypertension. METHODS: In a quasi-experimental cohort pilot study, we recruited 91 participants from nine pharmacies in the Quebec City area. We offered the intervention programme over a 9-month period to participants enrolled at four of the pharmacies. The other participants were not exposed to pharmaceutical services other than those usually given by their pharmacists. We used the SF-36 to evaluate HRQOL. Covariance analysis was used to test for significant differences of HRQOL scores between participants exposed and not exposed to the programme. RESULTS AND DISCUSSION: When compared with the non-exposed participants, those receiving the intervention and with high income had an improvement in vitality score (P=0.05). On the contrary, low-income exposed participants did not show this benefit and had a decline in mental health score (P=0.01). Improvement in vitality is likely due to increased physical activity and to a reduction in systolic blood pressure in the high-income exposed group. The negative effect of the programme on the mental health of those exposed in the low-income group might be due to the fact that the programme was not effective in reducing blood pressure and may therefore have caused anxiety. CONCLUSION: Pharmacists' interventions can have both a positive and negative impact on the HRQOL of individuals, treated with antihypertensive agents, depending on income level.

In-line ultrasonic monitoring of semi-solid magnesium die casting process.

Ultrasonic velocity and attenuation measurements in AZ91D magnesium (Mg) alloy with dendritic, rosette and globular microstructures were performed at elevated temperatures using a non-contact laser-ultrasonic technique. It was found that the ultrasonic velocity in the globular microstructure and the ultrasonic attenuation in the dendritic microstructure are the highest among the three microstructures. An ultrasonic clad steel buffer rod sensor embedded in the die has been used to monitor the semi-solid die casting process in-line for the AZ91D Mg alloy. This probe monitored the completion of the die filling, the release of the pressure, the opening of the die, part detachment, solidification of the part, the averaged temperature of the die and the part.

Mutation analysis of the zinc transporter gene SLC30A4 reveals no association with periodic catatonia on chromosome 15q15.

The zinc transporter gene SLC30A4, located on chromosome 15q15-q21, has previously been reported to show altered expression patterns in post mortem analysis of the brains of schizophrenic patients. As a positional candidate we investigated SLC30A4 in the chromosome 15q15-linked schizophrenic phenotype periodic catatonia (MIM 605419), by means of a systematic mutation screening in affected individuals from exceptionally large pedigrees with perfect co-segregation of a chromosomal segment between marker D15S1042 and D15S659 in all affected individuals. The mutation scan revealed no genetic variants within the coding and the putative promoter region of SLC30A4 and, thus, excludes a genetic association of SLC30A4 with catatonic schizophrenia.

Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1.

In the present study, we report a kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits. Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies. Two patients were diagnosed with vestibular pathology. All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis. No individual in this family met diagnostic criteria for any previously described clinical syndrome. A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein. JAG1 is a cell-surface ligand in the Notch signaling pathway. Mutations in JAG1 have been identified in patients with Alagille syndrome. Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred, which demonstrates that mutation in JAG1 can cause hearing loss.

Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.

BACKGROUND: The SCN5A gene encoding the human cardiac sodium channel alpha subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease). METHODS AND RESULTS: In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na(+) current but normal protein trafficking. CONCLUSIONS: We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation.