Effect of periodic letters on evidence-based drug therapy on prescribing behaviour: a randomized trial

Background

The effect of regular and expected printed educational materials on physician prescribing behaviour has not been studied. We sought to measure the impact of a series of evidence-based drug therapy letters mailed to physicians in British Columbia on prescribing to newly treated patients.

Methods

A paired, cluster randomized community design was used. The study population included 499 physicians from 24 local health areas in British Columbia. Local health areas were paired by number of physicians, and 1 of each pair was randomly selected and its physicians assigned to an intervention group or a control group. The intervention was 12 issues of an evidence-based series called Therapeutics Letter. Physicians in the control group (n = 241) received the letters 3–8 months after physicians in the intervention group (n = 258). The impact on prescribing to newly treated patients (defined as patients who had not previously made a claim for any medication from the class of drugs profiled in the letter) was analyzed using the drug claims database of BC Pharmacare, a publicly funded drug benefits program that covered all seniors and people receiving social assistance.

Results

The probability of prescribing a drug recommended in the Therapeutics Letter rather than another drug in the same class increased by 30% in the 3 months after the mailing of the letter relative to the preceding 3 months, adjusted for any before–after changes in the control group (relative risk 1.30; 95% confidence interval 1.13–1.52). No letter achieved statistical significance on its own. However, 11 of the 12 letters produced prescribing changes in the predicted direction such that the overall result was significant when their effect was combined.

Interpretation

The combined effect of an ongoing series of printed letters distributed from a credible and trusted source can have a clinically significant effect on prescribing to newly treated patients. Printed letters are regarded as a relatively ineffective method of changing behaviour.^1,2 A systematic review in The Cochrane Library concluded that printed educational materials for health care professionals had negligible impact and were of uncertain clinical significance.³ These conclusions were not based on a quantitative meta-analysis, however, in part because of the poor quality of analysis and reporting of results and in part because the different outcomes could not be easily combined. Although changes in prescribing behaviour as a result of printed materials have tended to be small, printed materials have the potential to be a cost-effective method of education.^4,5 There is also a paucity of studies in Canada on initiatives to change prescribing behaviour.⁶Between 1994 and 1997 the Therapeutics Initiative of the University of British Columbia conducted a randomized controlled trial with its Therapeutics Letter (www.ti.ubc.ca), which is distributed to most practising physicians in British Columbia. We aimed to quantify the publication''s success in producing changes in prescribing behaviour. In 1998 we reported that 2 letters on the treatment of primary hypertension did not produce a statistically significant change in prescribing.⁷ Here we report findings from a combined randomized trial of the impact of 12 of the first 20 issues of the Therapeutics Letter, which were distributed between October 1994 and December 1997. This combined analysis was undertaken to measure the series'' overall impact on prescribing to newly treated patients and to provide evidence of the effectiveness of these interventions in a Canadian setting.     

PEVK domain of titin: an entropic spring with actin-binding properties

The PEVK domain of the giant muscle protein titin is a proline-rich sequence with unknown secondary/tertiary structure. Here we compared the force-extension behavior of cloned cardiac PEVK titin measured by single-molecule atomic force spectroscopy with the extensibility of the PEVK domain measured in intact cardiac muscle sarcomeres. The analysis revealed that cardiac PEVK titin acts as an entropic spring with the properties of a random coil exhibiting mechanical conformations of different flexibility. Since in situ, titin is in close proximity to the thin filaments, we also studied whether the PEVK domain of cardiac or skeletal titin may interact with actin filaments. Interaction was indeed found in the in vitro motility assay, in which recombinant PEVK titin constructs slowed down the sliding velocity of actin filaments over myosin. Skeletal PEVK titin affected the actin sliding to a lesser degree than cardiac PEVK titin. The cardiac PEVK effect was partially suppressed by physiological Ca(2+) concentrations, whereas the skeletal PEVK effect was independent of [Ca(2+)]. Cosedimentation assays confirmed the Ca(2+)-modulated actin-binding propensity of cardiac PEVK titin, but did not detect interaction between actin and skeletal PEVK titin. In myofibrils, the relatively weak actin-PEVK interaction gives rise to a viscous force component opposing filament sliding. Thus, the PEVK domain contributes not only to the extensibility of the sarcomere, but also affects contractile properties.     

Structural Determinants of the β-Selectivity of a Bacterial Aminotransferase

Chiral β-amino acids occur as constituents of various natural and synthetic compounds with potentially useful bioactivities. The pyridoxal 5'-phosphate (PLP)-dependent S-selective transaminase from Mesorhizobium sp. strain LUK (MesAT) is a fold type I aminotransferase that can be used for the preparation of enantiopure β-Phe and derivatives thereof. Using x-ray crystallography, we solved structures of MesAT in complex with (S)-β-Phe, (R)-3-amino-5-methylhexanoic acid, 2-oxoglutarate, and the inhibitor 2-aminooxyacetic acid, which allowed us to unveil the molecular basis of the amino acid specificity and enantioselectivity of this enzyme. The binding pocket of the side chain of a β-amino acid is located on the 3'-oxygen side of the PLP cofactor. The same binding pocket is utilized by MesAT to bind the α-carboxylate group of an α-amino acid. A β-amino acid thus binds in a reverse orientation in the active site of MesAT compared with an α-amino acid. Such a binding mode has not been reported before for any PLP-dependent aminotransferase and shows that the active site of MesAT has specifically evolved to accommodate both β- and α-amino acids.     

Biochemical Properties and Crystal Structure of a β-Phenylalanine Aminotransferase from Variovorax paradoxus

By selective enrichment, we isolated a bacterium that can use β-phenylalanine as a sole nitrogen source. It was identified by 16S rRNA gene sequencing as a strain of Variovorax paradoxus. Enzyme assays revealed an aminotransferase activity. Partial genome sequencing and screening of a cosmid DNA library resulted in the identification of a 1,302-bp aminotransferase gene, which encodes a 46,416-Da protein. The gene was cloned and overexpressed in Escherichia coli. The recombinant enzyme was purified and showed a specific activity of 17.5 U mg⁻¹ for (S)-β-phenylalanine at 30°C and 33 U mg⁻¹ at the optimum temperature of 55°C. The β-specific aminotransferase exhibits a broad substrate range, accepting ortho-, meta-, and para-substituted β-phenylalanine derivatives as amino donors and 2-oxoglutarate and pyruvate as amino acceptors. The enzyme is highly enantioselective toward (S)-β-phenylalanine (enantioselectivity [E], >100) and derivatives thereof with different substituents on the phenyl ring, allowing the kinetic resolution of various racemic β-amino acids to yield (R)-β-amino acids with >95% enantiomeric excess (ee). The crystal structures of the holoenzyme and of the enzyme in complex with the inhibitor 2-aminooxyacetate revealed structural similarity to the β-phenylalanine aminotransferase from Mesorhizobium sp. strain LUK. The crystal structure was used to rationalize the stereo- and regioselectivity of V. paradoxus aminotransferase and to define a sequence motif with which new aromatic β-amino acid-converting aminotransferases may be identified.     

Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma

PURPOSE: Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC) models in mice. The purpose of this study was to determine whether magnetic resonance imaging (MRI) of magnetic iron oxide nanoparticles (MNPs) and micro–positron emission tomography (PET) measurements could respectively detect improvements in tumor vascular parameters and drug uptake in orthotopic PDAC in mice treated with losartan. METHOD AND MATERIALS: All experiments were approved by the local Institutional Animal Care and Use Committee. FVB mice with orthotopic PDAC were treated daily with an i.p. injection of losartan (70 mg/kg) or saline (control vehicle) for 5 days. In order to calculate the fractional blood volume, vessel size index, and vessel density index, MRI was performed at 4.7 T following the injection of 3 mg/kg iron ferumoxytol (i.v.). Dynamic PET images were also acquired for 60 minutes using an ¹⁸F-5FU tracer dose of 200 μCi and analyzed for time activity curves normalized to muscle. Statistical analyses compared both cohorts using an unpaired two-tailed t test. RESULTS: In comparison to the control treatment, the losartan administration significantly increased the fractional blood volume (mean ± SEM) [12.1 ± 1.7 (n = 19) vs 6.7 ± 1.1 (n = 20); P < .02] and vessel size index (128.2 ± 35.6 vs 57.5 ± 18; P < .05). Losartan also induced a significant increase in the intratumoral uptake of ¹⁸F-5FU by 53% (P < .0001). CONCLUSION: MRI using FDA-approved MNPs provides a noninvasive, translatable means of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of ¹⁸F-5FU.     

Adjustment uncertainty in effect estimation

Often there is substantial uncertainty in the selection of confounderswhen estimating the association between an exposure and health.We define this type of uncertainty as `adjustment uncertainty'.We propose a general statistical framework for handling adjustmentuncertainty in exposure effect estimation for a large numberof confounders, we describe a specific implementation, and wedevelop associated visualization tools. Theoretical resultsand simulation studies show that the proposed method providesconsistent estimators of the exposure effect and its variance.We also show that, when the goal is to estimate an exposureeffect accounting for adjustment uncertainty, Bayesian modelaveraging with posterior model probabilities approximated usinginformation criteria can fail to estimate the exposure effectand can over- or underestimate its variance. We compare ourapproach to Bayesian model averaging using time series dataon levels of fine particulate matter and mortality.     

Organic osmolyte permeabilities of the malaria-induced anion conductances in human erythrocytes

Infection of human erythrocytes with the malaria parasite Plasmodium falciparum induces new permeability pathways (NPPs) in the host cell membrane. Isotopic flux measurements demonstrated that the NPP are permeable to a wide variety of molecules, thus allowing uptake of nutrients and release of waste products. Recent patch-clamp recordings demonstrated the infection-induced up-regulation of an inwardly and an outwardly rectifying Cl(-) conductance. The present experiments have been performed to explore the sensitivity to cell volume and the organic osmolyte permeability of the two conductances. It is shown that the outward rectifier has a high relative lactate permeability (P(lactate)/P(Cl) = 0.4). Sucrose inhibited the outward-rectifier and abolished the infection-induced hemolysis in isosmotic sorbitol solution but had no or little effect on the inward-rectifier. Furosemide and NPPB blocked the outward-rectifying lactate current and the sorbitol hemolysis with IC(50)s in the range of 0.1 and 1 microM, respectively. In contrast, the IC(50)s of NPPB and furosemide for the inward-rectifying current were >10 microM. Osmotic cell-shrinkage inhibited the inwardly but not the outwardly rectifying conductance. In conclusion, the parasite-induced outwardly-rectifying anion conductance allows permeation of lactate and neutral carbohydrates, whereas the inward rectifier seems largely impermeable to organic solutes. All together, these data should help to resolve ongoing controversy regarding the number of unique channels that exist in P. falciparum-infected erythrocytes.     

MiRNAs roles in the diagnosis,prognosis and treatment of colorectal cancer

ABSTRACT

Introduction: The liver is the main location for metastasization in stage IV colorectal cancers.

Areas covered: This review intends to comprehensively present the most important studies conducted in the past few years concerning the role of miRNAs in colorectal cancer liver metastases, trying to clarify some aspects regarding tumor biology and favorite liver metastasization site.

Expert commentary: Recent advances in tissue and serum RNA extraction has considerably improved the field of microRNAs studies. These molecules known to play a crucial role in the metastatic stage indicate a starting point in the development of clinical biomarkers with a possible role in the stratification of high-risk patients for adequate treatment.