Perceived barriers for treatment of chronic heart failure in general practice; are they affecting performance?

BACKGROUND: The aim of this study is to determine to what extent barriers perceived by general practitioners (GPs) for prescribing angiotensin-converting enzyme inhibitors (ACE-I) in chronic heart failure (CHF) patients are related to underuse and underdosing of these drugs in actual practice. METHODS: Barriers were assessed with a semi-structured questionnaire. Prescribing data were extracted from GPs' computerised medical records for a random sample of their CHF patients. Relations between barriers and prescribing behaviour were assessed by means of Spearman rank correlation and multivariate regression modelling. RESULTS: GPs prescribed ACE-I to 45% of their patients and had previously initiated such treatment in an additional 3.5%, in an average standardised dose of 13.5 mg. They perceived a median of four barriers in prescribing ACE-I or optimising ACE-I dose. Many GPs found it difficult to change treatment initiated by a cardiologist. Furthermore, initiating ACE-I in patients already using a diuretic or stable on their current medication was perceived as barrier. Titrating the ACE-I dose was seen as difficult by more than half of the GPs. No significant relationships could be found between the barriers perceived and actual ACE-I prescribing. Regarding ACE-I dosing, the few GPs who did not agree that the ACE-I should be as high as possible prescribed higher ACE-I doses. CONCLUSION: Variation between GPs in prescribing ACE-I for CHF cannot be explained by differences in the barriers they perceive. Tailor-made interventions targeting only those doctors that perceive a specific barrier will therefore not be an efficient approach to improve quality of care

Ficolin-2 Levels and FCN2 Haplotypes Influence Hepatitis B Infection Outcome in Vietnamese Patients

Human Ficolin-2 (L-ficolins) encoded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity and is mainly expressed in the liver. Ficolin-2 serum levels and FCN2 single nucleotide polymorphisms were associated to several infectious diseases. We initially screened the complete FCN2 gene in 48 healthy individuals of Vietnamese ethnicity. We genotyped a Vietnamese cohort comprising of 423 clinically classified hepatitis B virus patients and 303 controls for functional single nucleotide polymorphisms in the promoter region (-986G>A, -602G>A, -4A>G) and in exon 8 (+6424G>T) by real-time PCR and investigated the contribution of FCN2 genotypes and haplotypes to serum Ficolin-2 levels, viral load and liver enzyme levels. Haplotypes differed significantly between patients and controls (P = 0.002) and the haplotype AGGG was found frequently in controls in comparison to patients with hepatitis B virus and hepatocellular carcinoma (P = 0.0002 and P<0.0001) conferring a protective effect. Ficolin-2 levels differed significantly between patients and controls (p<0.0001). Patients with acute hepatitis B had higher serum Ficolin-2 levels compared to other patient groups and controls.The viral load was observed to be significantly distributed among the haplotypes (P = 0.04) and the AAAG haplotype contributed to higher Ficolin-2 levels and to viral load. Four novel single nucleotide polymorphisms in introns (-941G>T, -310G>A, +2363G>A, +4882G>A) and one synonymous mutation in exon 8 (+6485G>T) was observed. Strong linkage was found between the variant -986G>A and -4A>G. The very first study on Vietnamese cohort associates both Ficolin-2 serum levels and FCN2 haplotypes to hepatitis B virus infection and subsequent disease progression

Functional Analysis of Ficolin-3 Mediated Complement Activation

The recognition molecules of the lectin complement pathway are mannose-binding lectin and Ficolin -1, -2 and -3. Recently deficiency of Ficolin-3 was found to be associated with life threatening infections. Thus, we aimed to develop a functional method based on the ELISA platform for evaluating Ficolin-3 mediated complement activation that could be applicable for research and clinical use. Bovine serum albumin (BSA) was acetylated (acBSA) and chosen as a solid phase ligand for Ficolins in microtiter wells. Binding of Ficolins on acBSA was evaluated, as was functional complement activation assessed by C4, C3 and terminal complement complex (TCC) deposition. Serum Ficolin-3 bound to acBSA in a calcium dependent manner, while only minimal binding of Ficolin-2 and no binding of Ficolin-1 were observed. No binding to normal BSA was seen for any of the Ficolins. Serum C4, C3 and TCC deposition on acBSA were dependent only on Ficolin-3 in appropriate serum dilutions. Deposition of down stream complement components correlated highly significantly with the serum concentration of Ficolin-3 but not with Ficolin-2 in healthy donors. To make the assay robust for clinical use a chemical compound was applied to the samples that inhibited interference from the classical pathway due to the presence of anti-BSA antibodies in some sera. We describe a novel functional method for measuring complement activation mediated by Ficolin-3 in human serum up to the formation of TCC. The assay provides the possibility to diagnose functional and genetic defects of Ficolin-3 and down stream components in the lectin complement pathway

Reliable and rapid characterization of functional <it>FCN2</it> gene variants reveals diverse geographical patterns

<p>Abstract</p> <p>Background</p> <p>Ficolin-2 coded by <it>FCN2</it> gene is a soluble serum protein and an innate immune recognition element of the complement system. <it>FCN2</it> gene polymorphisms reveal distinct geographical patterns and are documented to alter serum ficolin levels and modulate disease susceptibility.</p> <p>Methods</p> <p>We employed a real-time PCR based on Fluorescence Resonance Energy Transfer (FRET) method to genotype four functional SNPs including <it>-986 G > A</it> (#rs3124952), <it>-602 G > A</it> (#rs3124953), <it>-4A > G</it> (#rs17514136) and <it>+6424 G > T</it> (#rs7851696) in the ficolin-2 (<it>FCN2)</it> gene. We characterized the <it>FCN2</it> variants in individuals representing Brazilian (n = 176), Nigerian (n = 180), Vietnamese (n = 172) and European Caucasian ethnicity (n = 165).</p> <p>Results</p> <p>We observed that the genotype distribution of three functional SNP variants (−<it>986 G > A, -602 G > A</it> and <it>-4A > G</it>) differ significantly between the populations investigated (<it>p</it> < 0.0001). The SNP variants were highly linked to each other and revealed significant population patterns. Also the distribution of haplotypes revealed distinct geographical patterns (<it>p</it> < 0.0001).</p> <p>Conclusions</p> <p>The observed distribution of the <it>FCN2</it> functional SNP variants may likely contribute to altered serum ficolin levels and this may depend on the different disease settings in world populations. To conclude, the use of FRET based real-time PCR especially for <it>FCN2</it> gene will benefit a larger scientific community who extensively depend on rapid, reliable method for <it>FCN2</it> genotyping.</p

Personalizing health care: feasibility and future implications

Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer’s perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients

Development and Initial Validation of a Patient-Reported Adverse Drug Event Questionnaire

<p>Background Direct patient reporting of adverse drug events (ADEs) is relevant for the evaluation of drug safety. To collect such data in clinical trials and postmarketing studies, a valid questionnaire is needed that can measure all possible ADEs experienced by patients.</p><p>Objective Our aim was to develop and test a generic questionnaire to identify ADEs and quantify their nature and causality as reported by patients.</p><p>Methods We created a draft list of common ADEs in lay-terms, which were classified in body categories and mapped to the Medical Dictionary for Regulatory Activities (MedDRA (R)) terminology. Questions about the nature and causality were derived from existing questionnaires and causality scales. Content validity was tested through cognitive debriefing, revising the questionnaire in an iterative process. Feasibility and reliability were assessed using a Web-based version of the questionnaire. Patients received the questionnaire twice. Feasibility was assessed by the reported time needed for completion and ease of use. Reliability was calculated using Cohen's kappa and proportion of positive agreement (PPA) on: (1) any AIDE at patient level; (2) similar ADEs at MedDRA (R) System Organ Class level; and (3) the same AIDE at AIDE-specific level.</p><p>Results In the development phase, 28 patients with type 2 diabetes or asthma/chronic obstructive pulmonary disease (COPD) participated. Questions and answer options were rephrased, layout was improved, and changes were made in the classification of ADEs. The final questionnaire consisted of 252 ADEs organized in 16 body categories, and included 14 questions per reported AIDE. A total of 135 patients using a median of five different drugs completed the Web-based questionnaire twice. The median completion time was 15 mm for patients not reporting any AIDE, and 30 mm for patients reporting at least one AIDE. Three quarters of the patients found the questionnaire easy to use. Test-retest reliability was acceptable at patient level (kappa = 0.50, PPA 0.64) and at MedDRA (R) System Organ Class level (kappa = 0.52, PPA 0.54), but was low at ADE-specific level (kappa = 0.38, PPA 0.38).</p><p>Conclusion We developed a generic patient-reported AIDE questionnaire and confirmed its content validity. The questionnaire was feasible and reliable for reporting any AIDE and similar ADEs at MedDRA (R) System Organ Class level. Additional work is, however, needed to reliably quantify specific ADEs reported by patients.</p>