Comparison of drug survival rates for tumor necrosis factor antagonists in rheumatoid arthritis.

BACKGROUND Persistence of anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis (RA) is an overall marker of treatment success. OBJECTIVE To assess the survival of anti-TNF treatment and to define the potential predictors of drug discontinuation in RA, in order to verify the adequacy of current practices. DESIGN An observational, descriptive, longitudinal, retrospective study. SETTING The Hospital Clínico Universitario de Valladolid, Valladolid, Spain. PATIENTS RA patients treated with anti-TNF therapy between January 2011 and January 2012. MEASUREMENTS Demographic information and therapy assessments were gathered from medical and pharmaceutical records. Data is expressed as means (standard deviations) for quantitative variables and frequency distribution for qualitative variables. Kaplan-Meier survival analysis was used to assess persistence, and Cox multivariate regression models were used to assess potential predictors of treatment discontinuation. RESULTS In total, 126 treatment series with infliximab (n = 53), etanercept (n = 51) or adalimumab (n = 22) were administered to 91 patients. Infliximab has mostly been used as a first-line treatment, but it was the drug with the shortest time until a change of treatment. Significant predictors of drug survival were: age; the anti-TNF agent; and the previous response to an anti-TNF drug. LIMITATION The small sample size. CONCLUSION The overall efficacy of anti-TNF drugs diminishes with time, with infliximab having the shortest time until a change of treatment. The management of biologic therapy in patients with RA should be reconsidered in order to achieve disease control with a reduction in costs.

Pivotal role for a tail subunit of the RNA polymerase II mediator complex CgMed2 in azole tolerance and adherence in Candida glabrata.

Antifungal therapy failure can be associated with increased resistance to the employed antifungal agents. Candida glabrata, the second most common cause of invasive candidiasis, is intrinsically less susceptible to the azole class of antifungals and accounts for 15% of all Candida bloodstream infections. Here, we show that C. glabrata MED2 (CgMED2), which codes for a tail subunit of the RNA polymerase II Mediator complex, is required for resistance to azole antifungal drugs in C. glabrata. An inability to transcriptionally activate genes encoding a zinc finger transcriptional factor, CgPdr1, and multidrug efflux pump, CgCdr1, primarily contributes to the elevated susceptibility of the Cgmed2Δ mutant toward azole antifungals. We also report for the first time that the Cgmed2Δ mutant exhibits sensitivity to caspofungin, a constitutively activated protein kinase C-mediated cell wall integrity pathway, and elevated adherence to epithelial cells. The increased adherence of the Cgmed2Δ mutant was attributed to the elevated expression of the EPA1 and EPA7 genes. Further, our data demonstrate that CgMED2 is required for intracellular proliferation in human macrophages and modulates survival in a murine model of disseminated candidiasis. Lastly, we show an essential requirement for CgMed2, along with the Mediator middle subunit CgNut1 and the Mediator cyclin-dependent kinase/cyclin subunit CgSrb8, for the high-level fluconazole resistance conferred by the hyperactive allele of CgPdr1. Together, our findings underscore a pivotal role for CgMed2 in basal tolerance and acquired resistance to azole antifungals.

Factors associated with beliefs about adherence to non-pharmacological treatment of patients with heart failure

This study aimed at assessing beliefs about the benefits and barriers to adherence to daily self-monitoring of weight/edema in patients with heart failure, and the influence of demographic and clinical variables on those beliefs. 105 patients were interviewed. The mean of the subscales Benefits and Barriers were 20.2 (± 5.7) and 30.1 (±7.1), respectively. Patients perceived that adherence to daily self-monitoring of weight/edema could keep them healthy, improve their quality of life and decrease the chances of readmission. Approximately half of patients (46.7%) reported forgetting this measure. Those who controlled weight once a month were more likely to have barriers to adherence (OR= 6.6; IC 95% 1.9-13.8; p=0.01), showing this measure to be the main factor related to perceived barriers. Education in health can contribute with the development of strategies aimed at lowering barriers and increasing benefits of this control.

Exploring the implementation of a medication adherence programme by community pharmacists : a qualitative study

Background Medication adherence has been identified as an important factor for clinical success. Twenty-four Swiss community pharmacists participated in the implementation of an adherence support programme for patients with hypertension, diabetes mellitus and/or dyslipidemia. The programme combined tailored consultations with patients about medication taking (expected at an average of one intervention per month) and the delivery of each drug in an electronic monitoring system (MEMS6?). Objective To explore pharmacists' perceptions and experiences with implementation of the medication adherence programme and to clarify why only seven patients were enrolled in total. Setting Community pharmacies in French-speaking Switzerland. Method Individual in-depth interviews were audio-recorded, with 20 of the pharmacists who participated in the adherence programme. These were transcribed verbatim, coded and thematically analysed. Process quality was ensured by using an audit trail detailing the development of codes and themes; furthermore, each step in the coding and analysis was verified by a second, experienced qualitative researcher. Main outcome measure Community pharmacists' experiences and perceptions of the determining factors influencing the implementation of the adherence programme. Results Four major barriers were identified: (1) poor communication with patients resulting in insufficient promotion of the programme; (2) insufficient collaboration with physicians; (3) difficulty in integrating the programme into pharmacy organisation; and (4) insufficient pharmacist motivation. This was related to the remuneration perceived as insufficient and to the absence of clear strategic thinking about the pharmacist position in the health care system. One major facilitator of the programme's implementation was pre-existing collaboration with physicians. Conclusion A wide range of barriers was identified. The implementation of medication adherence programmes in Swiss community pharmacies would benefit from an extended training aimed at developing communication and change management skills. Individualised onsite support addressing relevant barriers would also be necessary throughout the implementation process.

Fibronectin-binding proteins and clumping factor A in Staphylococcus aureus experimental endocarditis: FnBPA is sufficient to activate human endothelial cells.

Surface molecules of Staphylococcus aureus are involved in the colonization of vascular endothelium which is a crucial primary event in the pathogenesis of infective endocarditis (IE). The ability of these molecules to also launch endothelial procoagulant and proinflammatory responses, which characterize IE, is not known. In the present study we investigated the individual capacities of three prominent S. aureus surface molecules; fibronectin-binding protein A (FnBPA) and B (FnBPB) and clumping factor A (ClfA), to promote bacterial adherence to cultured human endothelial cells (ECs) and to activate phenotypic and functional changes in these ECs. Non-invasive surrogate bacterium Lactococcus lactis, which, by gene transfer, expressed staphylococcal FnBPA, FnBPB or ClfA molecules were used. Infection of ECs increased 50- to 100-fold with FnBPA- or FnBPB-positive recombinant lactococci. This coincided with EC activation, interleukin-8 secretion and surface expression of ICAM-1 and VCAM-1 and concomitant monocyte adhesion. Infection with ClfA-positive lactococci did not activate EC. FnBPA-positive L. lactis also induced a prominent tissue factor-dependent endothelial coagulation response that was intensified by cell-bound monocytes. Thus S. aureus FnBPs, but not ClfA, confer invasiveness and pathogenicity to non-pathogenic L. lactis organisms indicating that bacterium-EC interactions mediated by these adhesins are sufficient to evoke inflammation as well as procoagulant activity at infected endovascular sites.

Role of Staphylococcus aureus coagulase and clumping factor in pathogenesis of experimental endocarditis.

The pathogenic role of staphylococcal coagulase and clumping factor was investigated in the rat model of endocarditis. The coagulase-producing and clumping factor-producing parent strain Staphylococcus aureus Newman and a series of mutants defective in either coagulase, clumping factor, or both were tested for their ability (i) to attach in vitro to either rat fibrinogen or platelet-fibrin clots and (ii) to produce endocarditis in rats with catheter-induced aortic vegetations. In vitro, the clumping factor-defective mutants were up to 100 times less able than the wild type strain to attach to fibrinogen and also significantly less adherent than the parents to platelet-fibrin clots. Coagulase-defective mutants, in contrast, were not altered in their in vitro adherence phenotype. The rate of in vivo infection was inoculum dependent. Clumping factor-defective mutants produced ca. 50% less endocarditis than the parent organisms when injected at inoculum sizes infecting, respectively, 40 and 80% (ID40 and ID80, respectively) of rats with the wild-type strain. This was a trend at the ID40 but was statistically significant at the ID80 (P < 0.05). Coagulase-defective bacteria were not affected in their infectivity. Complementation of a clumping factor-defective mutant with a copy of the wild-type clumping factor gene restored both its in vitro adherence and its in vivo infectivity. These results show that clumping factor plays a specific role in the pathogenesis of S. aureus endocarditis. Nevertheless, the rate of endocarditis with clumping factor-defective mutants increased with larger inocula, indicating the contribution of additional pathogenic determinants in the infective process.

Risk factor profile and management of cerebrovascular patients in the REACH Registry.

BACKGROUND: Cerebrovascular disease (CVD) is a global public health problem. CVD patients are at high risk of recurrent stroke and other atherothrombotic events. Prevalence of risk factors, comorbidities, utilization of secondary prevention therapies and adherence to guidelines all influence the recurrent event rate. We assessed these factors in 18,992 CVD patients within a worldwide registry of stable outpatients. METHODS: The Reduction of Atherothrombosis for Continued Health Registry recruited >68,000 outpatients (44 countries). The subjects were mainly recruited by general practitioners (44%) and internists (29%) if they had symptomatic CVD, coronary artery disease, peripheral arterial disease (PAD) and/or >or=3 atherothrombotic risk factors. RESULTS: The 18,992 CVD patients suffered a stroke (53.7%), transient ischemic attack (TIA) (27.7%) or both (18.5%); 40% had symptomatic atherothrombotic disease in >or=1 additional vascular beds: 36% coronary artery disease; 10% PAD and 6% both. The prevalence of risk factors at baseline was higher in the TIA subgroup than in the stroke group: treated hypertension (83.5/82.0%; p = 0.02), body mass index >or=30 (26.7/20.8%; p < 0.0001), hypercholesterolemia (65.1/52.1%; p < 0.0001), atrial fibrillation (14.7/11.9%; p < 0.0001) and carotid artery disease (42.3/29.7%; p < 0.0001). CVD patients received antiplatelet agents (81.7%), oral anticoagulants (17.3%), lipid-lowering agents (61.2%) and antihypertensives (87.9%), but guideline treatment targets were frequently not achieved (54.5% had elevated blood pressure at baseline, while 4.5% had untreated diabetes). CONCLUSIONS: A high percentage of CVD patients have additional atherothrombotic disease manifestations. The risk profile puts CVD patients, especially the TIA subgroup, at high risk for future atherothrombotic events. Undertreatment is common worldwide and adherence to guidelines needs to be enforced.

Exploring the implementation of a medication adherence programme by community pharmacists: a qualitative study

BACKGROUND: Medication adherence has been identified as an important factor for clinical success. Twenty-four Swiss community pharmacists participated in the implementation of an adherence support programme for patients with hypertension, diabetes mellitus and/or dyslipidemia. The programme combined tailored consultations with patients about medication taking (expected at an average of one intervention per month) and the delivery of each drug in an electronic monitoring system (MEMS6?). OBJECTIVE: To explore pharmacists' perceptions and experiences with implementation of the medication adherence programme and to clarify why only seven patients were enrolled in total. SETTING: Community pharmacies in French-speaking Switzerland. METHOD: Individual in-depth interviews were audio-recorded, with 20 of the pharmacists who participated in the adherence programme. These were transcribed verbatim, coded and thematically analysed. Process quality was ensured by using an audit trail detailing the development of codes and themes; furthermore, each step in the coding and analysis was verified by a second, experienced qualitative researcher. MAIN OUTCOME MEASURE: Community pharmacists' experiences and perceptions of the determining factors influencing the implementation of the adherence programme. RESULTS: Four major barriers were identified: (1) poor communication with patients resulting in insufficient promotion of the programme; (2) insufficient collaboration with physicians; (3) difficulty in integrating the programme into pharmacy organisation; and (4) insufficient pharmacist motivation. This was related to the remuneration perceived as insufficient and to the absence of clear strategic thinking about the pharmacist position in the health care system. One major facilitator of the programme's implementation was pre-existing collaboration with physicians. CONCLUSION: A wide range of barriers was identified. The implementation of medication adherence programmes in Swiss community pharmacies would benefit from an extended training aimed at developing communication and change management skills. Individualised onsite support addressing relevant barriers would also be necessary throughout the implementation process.

The mediterranean diet pattern and its main components are associated with lower plasma concentrations of tumor necrosis factor receptor 60 in patients at high risk for cardiovascular disease

Adherence to aMediterranean diet (MD) is associated with a reduced risk of coronary heart disease. However, themolecular mechanisms involved are not fully understood. The aim of this studywas to compare the effects of 2MD with those of a lowfat- diet (LFD) on circulating inflammatory biomarkers related to atherogenesis. A total of 516 participants included in the PreventionwithMediterraneanDiet Studywere randomized into 3 intervention groups [MD supplementedwith virgin olive oil (MD-VOO); MD supplemented with mixed nuts (MD-Nuts); and LFD]. At baseline and after 1 y, participants completed FFQ and adherence to MD questionnaires, and plasma concentrations of inflammatory markers including intercellular adhesion molecule-1(ICAM-1), IL-6, and 2 TNF receptors (TNFR60 and TNFR80) were measured by ELISA. At 1 y, the MD groups had lower plasma concentrations of IL-6, TNFR60, and TNFR80 (P , 0.05), whereas ICAM-1, TNFR60, and TNFR80 concentrations increased in the LFD group (P , 0.002). Due to between-group differences, participants in the 2 MD groups had lower plasma concentrations of ICAM-1, IL-6, TNFR60, and TNFR80 compared to those in the LFD group (P # 0.028). When participants were categorized in tertiles of 1-y changes in the consumption of selected foods, those in the highest tertile of virgin olive oil (VOO) and vegetable consumption had a lower plasma TNFR60 concentration compared with those in tertile 1 (P,0.02).Moreover, the only changes in consumption thatwere associated with 1-y changes in the geometricmean TNFR60 concentrations were those of VOO and vegetables (P = 0.01). This study suggests that a MD reduces TNFR concentrations in patients at high cardiovascular risk.

von Willebrand factor antigen levels in plasma of patients with malignant breast disease

von Willebrand factor (vWF) is a protein that mediates platelet adherence to the subendothelium during primary hemostasis. High plasma vWF concentrations have been reported in patients with various types of cancer, such as head and neck, laryngeal and prostatic cancer, probably representing an acute phase reactant. In the present study we determined the plasma levels of vWF antigen (vWF:Ag) by quantitative immunoelectrophoresis in 128 female patients with breast cancer as well as in 47 women with benign breast disease and in 27 healthy female controls. The levels of vWF:Ag were 170.7 ± 78 U/dl in patients with cancer, 148.4 ± 59 U/dl in patients with benign disease and 130.6 ± 45 U/dl in controls (P<0.005). We also detected a significant increase in the levels of vWF:Ag (P<0.0001) in patients with advanced stages of the disease (stage IV = 263.3 ± 113 U/dl, stage IIIB = 194.0 ± 44 U/dl) as compared to those with earlier stages of the disease (stage I = 155.3 ± 65 U/dl, stage IIA = 146.9 ± 75 U/dl). In conclusion, vWF levels were increased in plasma of patients with malignant breast disease, and these levels correlated with tumor progression.

The role of SEF14 and SEF17 fimbriae in the adherence of Salmonella enterica serotype Enteritidis to inanimate surfaces

To gain an understanding of the role of fimbriae and flagella in the adherence of Salmonella enterica serotype Enteritidis to inanimate surfaces, the extent of adherence of viable wild-type strains to a polystyrene microtitration plate was determined by a crystal violet staining assay, Elaboration of surface antigens by adherent bacteria was assayed by fimbriae- and flagella-specific ELISAs, Wild-type Enteritidis strains adhered well at 37 degrees C and 25 degrees C when grown in microtitration wells in Colonisation Factor Antigen broth, but not in other media tested, At 37 degrees C, adherent bacteria elaborated copious quantities of SEF14 fimbrial antigen, whereas at 25 degrees C adherent bacteria elaborated copious quantities of SEF17 fimbrial antigen. Non-fimbriate and non-flagellate knock-out mutant strains were also assessed in the adherence assay. Mutant strains unable to elaborate SEF14 and SEF17 fimbriae adhered poorly at 37 degrees C and 25 degrees C, respectively, but adherence was not abolished. Non-motile mutant strains showed reduced adherence whilst type-1, PEF and LPF fimbriae appeared not to contribute to adherence in this assay. These data indicate that SEF17 and SEF14 fimbriae mediate bacterial cell aggregation on inanimate surfaces under appropriate growth conditions.

Adherence and intracellular parasitism of Paracoccidioides brasiliensis in Vero cells

Paracoccidioides brasiliensis is a dimorphic fungus known to produce invasive systemic disease in humans. The 43-kDa glycoprotein of P, brasiliensis is the major diagnostic antigen of paracoccidioidomycosis and may act as a virulence factor, since it is a receptor for laminin. Very little is known about early interact-ions between this fungus and the host cells, so we developed in vitro a model system employing cultured mammalian cells (Vero cells), in order to investigate the factors and virulence mechanisms of P. brasiliensis related to the adhesion and invasion process. We found that there is a permanent interaction after 30 min of contact between the fungus and the cells. The yeasts multiply in the cells for between 5 and 24 h. Different strains of P, brasiliensis were compared, and strain 18 thigh virulence) was the most strongly adherent, followed by strain 113 (virulent), 265 (considered of low virulence) and 113M(mutant obtained by ultraviolet radiation, deficient in gp43). P. brasiliensis adhered to the epithelial cells by a narrow tube, while depressions were noticed in the cell surface, suggesting an active cavitation process. An inhibition assay was performed and it was verified that anti-gp43 serum and a pool of sera from individuals with paracoccidioidomycosis were able to inhibit the adhesion of P. brasiliensis to the Vero cells. Glycoprotein 43 (gp43) antiserum abolished 85 % of the binding activity of P. brasiliensis. This fungus can also invade the Vero cells, and intraepithelial parasitism could be an escape mechanism in paracoccidioidomycosis. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

In vitro adherence of Candida albicans isolated from patients with chronic periodontitis

Adherence is considered an extremely important virulence factor in yeast. Objective: The aim of this study was to analyze the adherence to epithelial cells of C. albicans isolated from patients with chronic periodontitis in comparison to healthy patients. Material and methods: Candida albicans cells isolated from individuals with chronic periodontitis (n=25) and healthy controls (n=25) were included in this study. Suspensions of C. albicans (10(6) cells/rnL) and epithelial cells (10(5) cells/mL) were mixed and incubated at 37 degrees C for 1 h. The number of yeasts adhered to 25 epithelial cells was counted. Results: The number of C. albicans cells adhered to epithelial cells was statistically higher in the chronic periodontitis group than in the control group (Student's t-test, p=0.000). Conclusion: The results of the present study suggest a higher Candida adherence of samples isolated from patients with chronic periodontitis.

Medication adherence in frail elderly outpatients with dementia

Since drug therapy in the elderly is complex and longterm and aged people commonly present some level of impairment and disability, medication adherence tend to decrease with age. Cognitive function is a key factor associated with medication adherence and professional or caregiver assistance may be necessary to maintain correct drug use. This study aims to analyze frail elderly outpatients aged 80 years or over diagnosed with dementia. The study is cross-sectional and is being conducted at the Ambulatory of Frailty of the University Hospital of the University of São Paulo (AF-UH). It is being based on information collected through an interview conducted with the patient or its caregiver. Medication adherence is assessed by the proportion of the prescribed drugs used in concordance with the prescription. Here it is presented the results of a pilot study. Thirty patients were included in the pilot study of which 23 (76.7%) were female and 7 (23.3%) males. The mean(SD) age, number of dwelling relatives, living children and prescribed drugs was, respectively, 86(5) years, 3(2), 3(2) and 6(3). The AF-UH consultation is the only regular physician encounter for 60.7% of the patients. Out of 30 patients, 5 (16.7%) live alone. Medication is a caregiver responsibility in 22 (73.4%) patients; the others (26.6%) self-administer their medicines. 13 (43.3%) of patients regularly use at least one drug not prescribed. Dementia was present in 8 patients all of which have a caregiver responsible for the management and,or the administration of the medicines; on the other hand, only 4 of the 22 nondemented patients (18.2%) have assistance of a caregiver (p<.001). The mean(SD) number of prescribed drugs was higher in nondemented patients [6.5(2.4)] than in those with dementia[3.5(2.3)] (p=.004). Educational level was similar between caregivers and patients (p=.503) as well as between caregivers of demented and non demented patients (p=.582). Among patients without dementia, those with caregiver assistance pre-presented the same mean(SD) medication adherence [0.93(0.14)] than those without it [0.78(0.28)] (p=.305). When compared to nondemented patients without caregivers, demented patients showed higher medication adherence [1.00(0.00)] (p=.013) since all of them used their drugs as recommended. The lower number of prescribed drugs and caregiver assistance seem to play an important role in the adherence of pharmacotherapy of demented patients in the studied population.

Effects of adherence to guidelines for the control of major cardiovascular risk factors on outcomes in the REduction of Atherothrombosis for Continued Health (REACH) Registry Europe

To examine the impact of cardiovascular risk factor control on 3-year cardiovascular event rates in patients with stable symptomatic atherothrombotic disease in Europe.