Prescribing patterns of oral antiplatelets in Wales: evolving trends from 2005 to 2016.

AIM: Antiplatelets have been used for decades to prevent atherothrombotic disease, but there is limited 'real-life' prescribing data. We hereby report the prescribing patterns for oral antiplatelets in Wales, UK. METHODS/RESULTS: Retrospective analysis of anonymized data in Wales from 2005 to 2016 revealed differences in prescribing patterns of oral antiplatelets. Aspirin and dipyridamole use declined with a corresponding increase in clopidogrel prescription. Costs declined with a sharp decrease coinciding with clopidogrel coming off patent. Prasugrel and ticagrelor have shown significant cost contribution (29% of total) despite only forming 1% of total items prescribed in 2016. CONCLUSION: This first-look analysis of real-life antiplatelet data demonstrates a decrease in the overall prescribing costs with varying patterns. This may aid policy-makers in reviewing funding strategies.

Effect-site concentration of remifentanil during patient-controlled analgesia in labour.

BACKGROUND: Intravenous remifentanil has been described for patient-controlled analgesia in labour. Recently, the application of target-controlled infusion pumps with Minto's pharmacokinetic/pharmacodynamic model has been reported. Hypothetical effect-site remifentanil concentration during patient-controlled analgesia for labour has yet to be examined. The aim of this concept study was to explore characteristics of this parameter. METHODS: We performed a historical cohort study based on our previous randomised cross-over clinical trial and analysed hypothetical effect-site remifentanil concentration. Values at spontaneous vaginal delivery and Apgar scores were tested for correlation. The association between pain score and the corresponding effect-site remifentanil concentration before and after bolus administration, and their relative difference, was examined with a linear mixed-effects model, adjusted for other variables. RESULTS: A series of 23 parturients with uncomplicated singleton pregnancies were included. On average, effect-site remifentanil concentration was highest during the third quarter throughout our recordings (5.5ng/mL; maximum 15.8ng/mL). The mean (median) {IQR} [range] at spontaneous vaginal delivery (n=14) was 2.52 (1.32) {0.95-4.28} [0.65-6.88] ng/mL, all Apgar scores were >7, and no correlation was confirmed. A negative association between effect-site remifentanil concentration before bolus administration and pain score (scale 0-100) was observed (-3.9, 95% CI -5.16 to -2.61, P <0.01). CONCLUSIONS: The residual value of hypothetical effect-site remifentanil concentration before uterine contraction, at the beginning of bolus administration, predicted lower pain scores. Monitoring effect-site remifentanil concentration may be potentially useful when remifentanil is administered for labour analgesia. However, our results need to be confirmed with a pharmacokinetic model optimized for pregnant patients.

Modified patient-controlled remifentanil bolus delivery regimen for labour pain*.

To improve the analgesic efficiency and to simplify the administration of remifentanil for systemic analgesia in labour, we contrived a modified delivery regimen with a specific infusion profile and variable dosing and conducted a single-blind randomised crossover study to compare it with the previous 'classical' regimen. Parturients received both regimens in interchangeable sets, each with five contractions. We compared pain and satisfaction scores, maternal and fetal vital parameters, side-effects and other events. Twenty-three parturients completed the study. No differences in observed parameters were noticed except for slightly lower blood pressure with the modified regimen. Pain estimates were lower in women starting with the modified regimen (p = 0.005), and there were fewer requests for analgesia within the lockout period (31 vs 69, p = 0.041) and bolus adjustments (0 vs 25, p < 0.001) with the modified regimen.

Review of health and health service improvements in Nepal.

Nepal has made great progress regarding maternal and childhood mortality over the past two decades. A visionary leadership, coupled with the implementation of targeted interventions and programmes have resulted in improved MNCH indicators and marked decline in mortality. Maternal deaths have dropped by almost half from 539 per 100,000 live births in 1996 to 281 in 2006. Although neonatal mortality rates have stagnated in recent years, the overall childhood mortality has improved. This article tracks changes made in key indicators (mortality, fertility and service indicators including immunisation, family planning, maternal, neonatal and child over time and provides an overview of successful programmes that have led to this accomplishment.

Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel.

Light transmission aggregometry (LTA) is used worldwide for the investigation of heritable platelet function disorders (PFDs), but interpretation of results is complicated by the feedback effects of ADP and thromboxane A(2) (TxA(2)) and by the overlap with the response of healthy volunteers. Over 5 years, we have performed lumi-aggregometry on 9 platelet agonists in 111 unrelated research participants with suspected PFDs and in 70 healthy volunteers. Abnormal LTA or ATP secretion test results were identified in 58% of participants. In 84% of these, the patterns of response were consistent with defects in Gi receptor signaling, the TxA(2) pathway, and dense granule secretion. Participants with defects in signaling to Gq-coupled receptor agonists and to collagen were also identified. Targeted genotyping identified 3 participants with function-disrupting mutations in the P2Y(12) ADP and TxA(2) receptors. The results of the present study illustrate that detailed phenotypic analysis using LTA and ATP secretion is a powerful tool for the diagnosis of PFDs. Our data also enable subdivision at the level of platelet-signaling pathways and in some cases to individual receptors. We further demonstrate that most PFDs can be reliably diagnosed using a streamlined panel of key platelet agonists and specified concentrations suitable for testing in most clinical diagnostic laboratories.

A novel thromboxane A2 receptor D304N variant that abrogates ligand binding in a patient with a bleeding diathesis.

We investigated the cause of mild mucocutaneous bleeding in a 14-year-old male patient (P1). Platelet aggregation and ATP secretion induced by arachidonic acid and the thromboxane A(2) receptor (TxA(2)R) agonist U46619 were reduced in P1 compared with controls, whereas the responses to other platelet agonists were retained. P1 was heterozygous for a transversion within the TBXA2R gene predictive of a D304N substitution in the TxA(2)R. In Chinese hamster ovary-K1 cells expressing the variant D304N TxA(2)R, U46619 did not increase cytosolic free Ca(2+) concentration, indicating loss of receptor function. The TxA(2)R antagonist [(3)H]-SQ29548 showed an approximate 50% decrease in binding to platelets from P1 but absent binding to Chinese hamster ovary-K1 cells expressing variant D304N TxA(2)R. This is the second naturally occurring TxA(2)R variant to be associated with platelet dysfunction and the first in which loss of receptor function is associated with reduced ligand binding. D304 lies within a conserved NPXXY motif in transmembrane domain 7 of the TxA(2)R that is a key structural element in family A G protein-coupled receptors. Our demonstration that the D304N substitution causes clinically significant platelet dysfunction by reducing ligand binding establishes the importance of the NPXXY motif for TxA(2)R function in vivo.

Testing a scalable community-based approach to improve maternal and neonatal health in rural Nepal.

OBJECTIVE: The aim of the study was to determine the feasibility of improved maternal-neonatal care-seeking and household practices using an approach scalable under Nepal's primary health-care services. STUDY DESIGN: Impact was assessed by pre- and post-intervention surveys of women delivering within the previous 12 months. Each district sample comprised 30 clusters, each with 30 respondents. The intervention consisted primarily of community-based antenatal counseling and dispensing and an early postnatal home visit; most activities were carried out by community-based health volunteers. RESULT: There were notable improvements in most household practice and service utilization indicators, although results regarding care-seeking for danger signs were mixed. CONCLUSION: It is feasible in a Nepal setting to significantly improve utilization of maternal-neonatal services and household practices, using the resources available under the government primary health-care system. This has the potential to significantly reduce neonatal mortality.

Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study.

We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY12) contribute to the bleeding tendency in 92 index cases enrolled in the European MCMDM-1VWD study. A heterozygous mutation, predicting a lysine to glutamate (K174E) substitution in P2Y(12), was identified in one case with mild type 1 von Willebrand disease (VWD) and a VWF defect. Platelets from the index case and relatives carrying the K174E defect changed shape in response to ADP, but showed reduced and reversible aggregation in response to 10 muM ADP, unlike the maximal, sustained aggregation observed in controls. The reduced response was associated with an approximate 50% reduction in binding of [(3)H]2MeS-ADP to P2Y(12), whereas binding to the P2Y(1) receptor was normal. A hemagglutinin-tagged K174E P2Y(12) variant showed surface expression in CHO cells, markedly reduced binding to [(3)H]2MeS-ADP, and minimal ADP-mediated inhibition of forskolin-induced adenylyl cyclase activity. Our results provide further evidence for locus heterogeneity in type 1 VWD.

Reference curves for aggregation and ATP secretion to aid diagnose of platelet-based bleeding disorders: effect of inhibition of ADP and thromboxane A(2) pathways.

Platelet aggregation is widely used in clinical laboratories to evaluate patients with bleeding disorders of suspected platelet aetiology. Simultaneous monitoring of ATP release as a measure of dense granule secretion provides additional information to aid diagnosis. There is, however, no standard way of performing or interpreting these tests. The present study has evaluated aggregation and ATP secretion to eight platelet agonists in healthy donors and has evaluated the reproducibility of response for a number of variables, including platelet number and time after donation. The effect of inhibition of the two major platelet feedback mediators, ADP and thromboxane A(2) (TxA(2)), was investigated using the P2Y(1) and P2Y(12) receptor antagonists, MRS2179 and AR-C67085, and the cyclooxygenase inhibitor, indomethacin. The results demonstrate that, if used within certain boundaries, the investigation of platelet aggregation and secretion is a powerful way to discriminate between differing pathways of platelet activation. The present data-set are an invaluable resource to the clinical laboratory to aid evaluation of patients with suspected platelet-based bleeding disorders.

Mitochondrial gene variation in type 2 diabetes mellitus: detection of a novel mutation associated with maternally inherited diabetes in a Chinese family.

OBJECTIVE: To explore the relationship between type 2 diabetes mellitus and the mutation(s) in mitochondrial DNA. METHODS: According to the previous literature, the fragment of mitochondrial DNA from nucleotide 3153 to 3551, which had shown high frequency of point mutation, was scanned with the technique of polymerase chain reaction--single strand conformation polymorphism (PCR-SSCP) in Chinese normal control, type 2 diabetic population, and 12 families suffered from maternally inherited type 2 diabetes mellitus. Direct sequencing was applied to detect the fragments with abnormal conformation. RESULTS: No special band was found in SSCP electrophoreses in Chinese normal control, and only one subject (No. 81) of diabetic population indicated the abnormality in SSCP study, which was affirmed to be a silent point mutation of T to C at nucleotide 3336 inducing no change in amino acid (ATT-->ATC, Ile). Pedigree 25,001 was the only family that exhibited strongly different SSCP characteristic from the other 11 ones, which was confirmed to be caused by a single point mutation mt3285T-->C/T in the coding region of tRNA(Leu(UUR)) gene by the technique of direct sequencing. CONCLUSIONS: The variation within mt DNA 3153-3551 is not the major cause of type 2 diabetes in Chinese population suffered from this disease in this study. The point mutation T-->C/T at the mitochondrial nucleotide 3285, which was found in pedigree 25,001, is located in the highly conservative region of tRNA(Leu(UUR)) gene. It is strongly suggested that this mutation cause the conversion in the 3-dimentional structure of tRNA(Leu(UUR)), which might disturb the normal translation and lead to the impairment in mitochondrial oxidative phosphorylation characterized by the defects of the polypeptides involved in the respiratory chain. Thus, insulin secretion deficiency and insulin resistance might occur.

Methoxyamine-induced mutagenesis of nucleic acids. A proton NMR study of oligonucleotides containing N4-methoxycytosine paired with adenine or guanine.

We report the solution structure of two heptanucleotides each containing a central N4-methoxycytosine, in one case paired with adenine on the opposite strand and the other with guanine. For the N4-methoxycytosine adenine pair, only the imino form of the N4-methoxycytosine residue is observed and base pairing is in Watson-Crick geometry. However, rotation of the methoxy group about the N-OCH3 bond is not constrained to a particular orientation although it must be anti to the N3 of N4-methoxycytosine. The slow exchange on a proton NMR time scale between the single strand and double strand forms is attributed to the strong preference of the cis conformation of the OCH3 group in the single strand, which inhibits base pair formation. For the N4-methoxycytosine that is base paired with guanine, we observe an amino form in Watson-Crick geometry in slow exchange with a base paired imino form in wobble geometry. The amino form is predominant at low temperature whereas the imino form predominates above 313 K. We have measured the exchange rate between the two forms at 303 K and observed a value of approximately 1 S-1. The relative ratio of amino and imino forms of N4-methoxycytosine is influenced by both the base that is in front and the temperature. Our results explain the preferential replacement of dTTP by N4-methoxycytosine in primer elongation.