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Stated preferences for attributes of a CYP2C19 pharmacogenetic test among the general population presented with a hypothetical acute coronary syndrome scenario
Background: Pharmacogenetic (PGx) testing identifies pharmacotherapeutic risks to permit personalized therapy. Identifying the genetic profile of patients with acute coronary syndrome (ACS) who are considered for therapy with clopidogrel (P2Y12 receptor blockers) and acetylsalicylic acid (ASA) contributes to the treatment paradigm. Patient preferences would inform a collaborative framework and by extension inform healthcare policy formulation. Purpose: To quantify stated preferences (willingness to pay) for attributes of a novel point-of-care PGx (CYP2C19) test using a discrete choice experiment (DCE) from the general public in Ontario, Canada, and to identify starting point bias of the cost attribute. Methods: A web survey was created and included a questionnaire, decision board, and a DCE. DCE choice sets include the following attributes (levels): sample collection (blood, finger prick, and cheek swab), turnaround time for results (1 hr, 3 days, and 1 week), and cost in additional insurance premiums. The presence of starting point bias (cost attribute levels of 1, 0, 10) in the estimation of willingness to pay (WTP) was tested. Results: Estimates for turnaround time and cost attributes were statistically significant. Coefficients related to the starting point bias were also significant. Approximately 67% of survey participants chose the PGx test compared to status quo treatment options. WTP for a 1 hr turnaround time compared to a 1-week turnaround time was $10.77 (95% CI 9.58-12.25). Conclusion: This translational study shows preference for a point of care PGx test
Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab, and tofacitinib monotherapies in rheumatoid arthritis patients who are naïve to treatment with biologic or conventional synthetic disease-modifying antirheumatic drugs: a matching-adjusted indirect comparison
Objective To compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic (bDMARD)-naïve RA patients using matching-adjusted indirect comparisons (MAICs).
Methods Data were from Phase III trials on patients receiving monotherapy baricitinib, tocilizumab, adalimumab, tofacitinib or MTX. Pain was assessed using a visual analogue scale (0–100 mm) and physical function using the Health Assessment Questionnaire-Disability Index (HAQ-DI). An MAIC based on treatment-arm matching, an MAIC with study-level matching and Bucher’s method without matching compared change in outcomes between therapies. Matching variables included age, gender, baseline disease activity and baseline value of outcome measure.
Results With all methods, greater improvements were observed in pain and HAQ-DI at 6 months for baricitinib compared with adalimumab and tocilizumab (p<0.05). Differences in treatment effects (TEs) favouring baricitinib for pain VAS for treatment-arm matching, study-level matching and Bucher’s method, respectively, were −12, −12 and −12 for baricitinib versus adalimumab and −7, −7 and −9 for baricitinib versus tocilizumab; the difference in TEs for HAQ-DI was −0.28, −0.28 and −0.30 for adalimumab and −0.23, −0.23 and −0.26 for tocilizumab. For baricitinib versus tofacitinib, no statistically significant differences for pain improvement were observed except with one of the three methods (Bucher method) and none for HAQ-DI.
Conclusions Results suggest greater pain reduction and improved physical function for baricitinib monotherapy compared with tocilizumab and adalimumab monotherapy. No statistically significant differences in pain reduction and improved physical function were observed between baricitinib and tofacitinib with the MAIC analyses
Wild-Type Phosphoribosylpyrophosphate Synthase (PRS) from Mycobacterium tuberculosis: A Bacterial Class II PRS?
The 5-phospho-α-D-ribose 1-diphosphate (PRPP) metabolite plays essential roles in several biosynthetic pathways, including histidine, tryptophan, nucleotides, and, in mycobacteria, cell wall precursors. PRPP is synthesized from α-D-ribose 5-phosphate (R5P) and ATP by the Mycobacterium tuberculosis prsA gene product, phosphoribosylpyrophosphate synthase (MtPRS). Here, we report amplification, cloning, expression and purification of wild-type MtPRS. Glutaraldehyde cross-linking results suggest that MtPRS predominates as a hexamer, presenting varied oligomeric states due to distinct ligand binding. MtPRS activity measurements were carried out by a novel coupled continuous spectrophotometric assay. MtPRS enzyme activity could be detected in the absence of Pi. ADP, GDP and UMP inhibit MtPRS activity. Steady-state kinetics results indicate that MtPRS has broad substrate specificity, being able to accept ATP, GTP, CTP, and UTP as diphosphoryl group donors. Fluorescence spectroscopy data suggest that the enzyme mechanism for purine diphosphoryl donors follows a random order of substrate addition, and for pyrimidine diphosphoryl donors follows an ordered mechanism of substrate addition in which R5P binds first to free enzyme. An ordered mechanism for product dissociation is followed by MtPRS, in which PRPP is the first product to be released followed by the nucleoside monophosphate products to yield free enzyme for the next round of catalysis. The broad specificity for diphosphoryl group donors and detection of enzyme activity in the absence of Pi would suggest that MtPRS belongs to Class II PRS proteins. On the other hand, the hexameric quaternary structure and allosteric ADP inhibition would place MtPRS in Class I PRSs. Further data are needed to classify MtPRS as belonging to a particular family of PRS proteins. The data here presented should help augment our understanding of MtPRS mode of action. Current efforts are toward experimental structure determination of MtPRS to provide a solid foundation for the rational design of specific inhibitors of this enzyme