Pharmacogenomics in the UK National Health Service: opportunities and challenges

There is increasing interest in pharmacogenomics. However, it is also widely acknowledged that implementation of pharmacogenomics into clinical practice has been slow. Implementation is being undertaken in many centres in the US, but this is not nationwide and often focused on highly specialised academic centres, driven by champions. To date, there has been no implementation on a whole country basis. The UK National Health Service (NHS) is a single integrated healthcare system, which provides free care to all patients at the point of need. Recently, there has been a drive to implement genomic medicine into the NHS, largely spurred on by the success of the 100,000 genomes project. This represents an unprecedented opportunity to implement pharmacogenomics for over 60 million people. In order to discuss the potential for implementing pharmacogenomics into the NHS, the UK Pharmacogenetics and Stratified Medicine Network, NHS England and Genomics England invited experts from academia, the healthcare sector, industry and patient representatives to come together to discuss the opportunities and challenges1. This report highlights the discussions of the workshop with the aim of providing an overview of the issues that need to be considered to enable pharmacogenomic medicine to become mainstream within the NHS

Influences on condom use: A secondary analysis of women's perceptions from the Australian Contraceptive ChOice pRoject (ACCORd) trial.

Background and objectives Women’s ability to negotiate condom use helps prevent sexually transmissible infections (STIs) and unintended pregnancies. The aim of this study was to assess the relationship between substance use, risk perception and the certainty of using condoms in several hypothetical situations. Methods This is a secondary analysis from the Australian Contraceptive ChOice pRoject (ACCORd) cluster randomised controlled trial. Descriptive statistics and logistic regression were used for the analysis. Results At baseline, contraceptive questions were answered by 698 women attending 57 general practices in Melbourne, Australia. Condom use was reported by 47%. Of those using condoms as the sole form of contraception (n = 137), 20% used them inconsistently. Dual protection was used by 58% of women (188/325). Condoms and the pill were more frequently used than condoms and longer-acting contraceptives. Women were less likely to be confident negotiating condom use when using substances. Discussion Substance use and the concurrent use of other forms of contraception impact use of condoms. Even when condoms are the sole form of contraception with willing partners, use is inconsistent, leaving women at risk of pregnancy and STI

Increasing the uptake of long-acting reversible contraception in general practice: the Australian Contraceptive ChOice pRoject (ACCORd) cluster randomised controlled trial longitudinal follow-up protocol.

IntroductionThrough addressing main barriers to the uptake of long-acting reversible contraceptives (LARCs) among Australian women, the Australian Contraceptive ChOice pRoject (ACCORd) trialled an educational intervention targeting general practitioners (GPs) and provided those in the intervention group with a rapid referral service for quick insertion. The cluster randomised controlled trial resulted in greater uptake of LARC in the intervention group. This protocol paper describes a longitudinal follow-up to the ACCORd Study to assess the long-term efficacy and cost-effectiveness of the intervention.Methods and analysisWomen participants (patients of ACCORd GPs) completed a baseline, 6-month and 12-month survey. These participants will be invited to complete an additional follow-up survey 3 years post completion of their baseline interview. Based on the original ACCORd Study tools, the online survey will address long-term outcomes including contraceptive continuation rates and reproductive history, any unintended pregnancies, satisfaction and concerns with their current contraceptive method, and an assessment of quality of life. We will analyse data using binary regression models with generalised estimating equations and robust standard errors to account for clustering.DiscussionDemonstration of sustained use, effectiveness at reducing unwanted pregnancies and cost-effectiveness of this strategy among this cohort of Australian primary care patients, will strengthen the policy and programme urgency of addressing wider dissemination of these strategies and replicating the study elsewhere.Ethics and disseminationThe ACCORd Study received approval from the Monash University Human Research Ethics Committee: CF16/188-201000080. Additionally, an amendment to conduct this 3-year longitudinal follow-up survey has been approved. The trial follow-up outcomes will be disseminated through formal academic pathways, including journal articles, national and international conferences and reports as well as using more 'mainstream' strategies such as seminars, workshops and media engagement. Additionally, outcomes will be communicated through policy briefs to Australian state and federal governments.Trail registration numberThis trial is registered with the Australian and New Zealand Trials Registry ACTRN12615001346561. Recruitment and data collection have been completed for the baseline, 6-month and 12-month surveys. Data collection for the 3-year survey commenced in August 2019

Cost-effectiveness of a complex intervention in general practice to increase uptake of long-acting reversible contraceptives in Australia.

Objective The aim of this study was to evaluate the cost-effectiveness of the Australian Contraceptive ChOice pRoject (ACCORd) intervention. Methods An economic evaluation compared the costs and outcomes of the ACCORd intervention with usual care (UC). Data from the ACCORd trial were used to estimate costs and efficacy in terms of contraceptive uptake and quality of life. Rates of contraceptive failure and pregnancy were sourced from the literature. Using a Markov model, within-trial results were extrapolated over 10 years and subjected to univariate sensitivity analyses. Model outputs were expressed as the cost per quality-adjusted life years (QALY) gained and cost per unintended pregnancy resulting in birth (UPB) avoided. Results Over 10 years, compared with UC, initiating contraception through the ACCORd intervention resulted in 0.02 fewer UPB and higher total costs (A$2505 vs A$1179) per woman. The incremental cost-effectiveness of the ACCORd intervention versus UC was A$1172 per QALY gained and A$7385 per UPB averted. If the start-up cost of the ACCORd intervention was removed, the incremental cost-effectiveness ratio was A$81 per QALY gained and A$511 per UPB averted. The results were most sensitive to the probability of contraceptive failure, the probability of pregnancy-related healthcare service utilisation or the inclusion of the costs of implementing the ACCORd intervention. Conclusions From a health system perspective, if implemented appropriately in terms of uptake and reach, and assuming an implicit willingness to pay threshold of A$50 000 the ACCORd intervention is cost-effective. What is known about the topic? The uptake of long-active reversible contraceptives (LARC) in Australia is low. The ACCORd trial assessed the efficacy of providing structured training to general practitioners (GPs) on LARC counselling, together with access to rapid referral to insertion clinics. What does this paper add? This study is the first to assess the cost-effectiveness of a complex intervention in the general practice setting aimed at increasing the uptake of LARC in Australia. What are the implications for practitioners? The results show that implementing a complex intervention in general practice involving GP education and the availability of rapid referral to LARC insertion clinics is a cost-effective approach to increase LARC use and its attending efficacy. If the majority of Australian GPs were able to deliver effectiveness-based contraceptive counselling and either insert LARC or use a rapid referral process to a LARC insertion clinic, the additional cost associated with the purchase of LARC products and their insertion would be offset by reductions to health system costs as a result of fewer UPB and abortions. Moreover, the benefits to women's physical and psychological health of avoiding such events is substantial

Diet-Induced Obesity Impairs Endothelium-Derived Hyperpolarization via Altered Potassium Channel Signaling Mechanisms

BACKGROUND: The vascular endothelium plays a critical role in the control of blood flow. Altered endothelium-mediated vasodilator and vasoconstrictor mechanisms underlie key aspects of cardiovascular disease, including those in obesity. Whilst the mechanism of nitric oxide (NO)-mediated vasodilation has been extensively studied in obesity, little is known about the impact of obesity on vasodilation to the endothelium-derived hyperpolarization (EDH) mechanism; which predominates in smaller resistance vessels and is characterized in this study. METHODOLOGY/PRINCIPAL FINDINGS: Membrane potential, vessel diameter and luminal pressure were recorded in 4(th) order mesenteric arteries with pressure-induced myogenic tone, in control and diet-induced obese rats. Obesity, reflecting that of human dietary etiology, was induced with a cafeteria-style diet (∼30 kJ, fat) over 16-20 weeks. Age and sexed matched controls received standard chow (∼12 kJ, fat). Channel protein distribution, expression and vessel morphology were determined using immunohistochemistry, Western blotting and ultrastructural techniques. In control and obese rat vessels, acetylcholine-mediated EDH was abolished by small and intermediate conductance calcium-activated potassium channel (SK(Ca)/IK(Ca)) inhibition; with such activity being impaired in obesity. SK(Ca)-IK(Ca) activation with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) and 1-ethyl-2-benzimidazolinone (1-EBIO), respectively, hyperpolarized and relaxed vessels from control and obese rats. IK(Ca)-mediated EDH contribution was increased in obesity, and associated with altered IK(Ca) distribution and elevated expression. In contrast, the SK(Ca)-dependent-EDH component was reduced in obesity. Inward-rectifying potassium channel (K(ir)) and Na(+)/K(+)-ATPase inhibition by barium/ouabain, respectively, attenuated and abolished EDH in arteries from control and obese rats, respectively; reflecting differential K(ir) expression and distribution. Although changes in medial properties occurred, obesity had no effect on myoendothelial gap junction density. CONCLUSION/SIGNIFICANCE: In obese rats, vasodilation to EDH is impaired due to changes in the underlying potassium channel signaling mechanisms. Whilst myoendothelial gap junction density is unchanged in arteries of obese compared to control, increased IK(Ca) and Na(+)/K(+)-ATPase, and decreased K(ir) underlie changes in the EDH mechanism

Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis

Background: Inflammation is an essential component of arthritis pain. Nerve growth factor (NGF) plays a key role in acute and chronic pain states especially those associated with inflammation. NGF acts through tropomyosin-receptor-kinase A (TrkA). NGF blockade has reduced arthritis pain in clinical trials. We explored the mechanisms within the joint which may contribute to the analgesic effects of NGF by selectively inhibiting TrkA in carrageenan-induced or collagen-induced joint pain behaviour. The goal of the current study was to elucidate whether inflammation is central to the efficacy for NGF blockade. Methods: Rats were injected in their left knees with 2 % carrageenan or saline. Collagen-induced arthritis (CIA) was induced by intradermal injections of a mixture of bovine type II collagen (0.2 mg) and incomplete Freund’s adjuvant (0.2 mg). Oral doses (30 mg/kg) of AR786 or vehicle control were given twice daily after arthritis induction. Ibuprofen-treated (35 mg/kg, orally, once daily) rats with CIA were used as positive analgesic controls. Pain behaviour was measured as hind-limb weight-bearing asymmetry and hind-paw withdrawal thresholds to von Frey hair stimulation (carrageenan synovitis), or withdrawal to joint compression using a Randall Selitto device (CIA). Inflammation was measured as increased knee joint diameter and by histopathological analysis. Results: Intra-articular injections of carrageenan or induction of CIA was each associated with pain behaviour and synovial inflammation. Systemic administration of the TrkA inhibitor AR786 reduced carrageenan-induced or CIA-induced pain behaviour to control values, and inhibited joint swelling and histological evidence of synovial inflammation and joint damage. Conclusions: By using two models of varying inflammation we demonstrate for the first time that selective inhibition of TrkA may reduce carrageenan-induced or CIA-induced pain behaviour in rats, in part through potentially inhibiting synovial inflammation, although direct effects on sensory nerves are also likely. Our observations suggest that inflammatory arthritis causes pain and the presence of inflammation is fundamental to the beneficial effects (reduction in pain and pathology) of NGF blockade. Further research should determine whether TrkA inhibition may ameliorate human inflammatory arthritis

Possible involvement of integrin-mediated signalling in oocyte activation: evidence that a cyclic RGD-containing peptide can stimulate protein kinase C and cortical granule exocytosis in mouse oocytes

BACKGROUND: Mammalian sperm-oocyte interaction at fertilization involves several combined interactions between integrins on the oocyte and integrin ligands (disintegrins) on the sperm. Recent research has indicated the ability of peptides containing the RGD sequence that characterized several sperm disintegrins, to induce intracellular Ca2+ transients and to initiate parthenogenetic development in amphibian and bovine oocytes. In the present study, we investigate the hypothesis that an integrin-associated signalling may participate in oocyte activation signalling by determining the ability of a cyclic RGD-containing peptide to stimulate the activation of protein kinase C (PKC) and the exocytosis of cortical granules in mouse oocytes. METHODS: An In-Vitro-Fertilization assay (IVF) was carried in order to test the condition under which a peptide containing the RGD sequence, cyclo(Arg-Gly-Asp-D-Phe-Val), was able to inhibit sperm fusion with zona-free mouse oocytes at metaphase II stage. PKC activity was determined by means of an assay based on the ability of cell lysates to phosphorylate MARKS peptide, a specific PKC substrate. Loss of cortical granules was evaluated by measuring density in the oocyte cortex of cortical granules stained with LCA-biotin/Texas red-streptavidin. In all the experiments, effects of a control peptide containing a non RGD sequence, cyclo(Arg-Ala-Asp-D-Phe-Val), were evaluated. RESULTS: The IVF assay revealed that the fusion rate declined significantly when insemination was carried out in the presence of cyclic RGD peptide at concentrations > or = 250 microM (P < 0.05, Student-Newman-Keuls Method). When the peptide was applied to the oocytes at these concentrations, a dose-dependent increase of PKC activity was observed, in association with a loss of cortical granules ranging from 38+/-2.5 % to 52+/-5.4 %. Evaluation of meiotic status revealed that cyclic RGD peptide was ineffective in inducing meiosis resumption under conditions used in the present study. CONCLUSION: The presents results provide evidence that a cyclic RGD peptide highly effective in inhibiting sperm-oocyte interaction stimulates in mouse oocytes the activation of PKC and the exocytosis of cortical granules. These data support the view that RGD-binding receptors may function as signalling receptors giving rise integrated signalling not sufficient for a full oocyte activation response. This study may contribute to the understanding of possible negative effects of skipping gamete interaction in IVF techniques

CpG-island methylation study of liver fluke-related cholangiocarcinoma

Background: Genetic changes have been widely reported in association with cholangiocarcinoma (CCA), while epigenetic changes are poorly characterised. We aimed to further evaluate CpG-island hypermethylation in CCA at candidate loci, which may have potential as diagnostic or prognostic biomarkers. Methods: We analysed methylation of 26 CpG-islands in 102 liver fluke related-CCA and 29 adjacent normal samples using methylation-specific PCR (MSP). Methylation of interest loci was confirmed using pyrosequencing and/or combined bisulfite restriction analysis, and protein expression by immunohistochemistry. Results: A number of CpG-islands (OPCML, SFRP1, HIC1, PTEN and DcR1) showed frequency of hypermethylation in >28% of CCA, but not adjacent normal tissues. The results showed that 91% of CCA were methylated in at least one CpG-island. The OPCML was the most frequently methylated locus (72.5%) and was more frequently methylated in less differentiated CCA. Patients with methylated DcR1 had significantly longer overall survival (Median; 41.7 vs 21.7 weeks, P=0.027). Low-protein expression was found in >70% of CCA with methylation of OPCML or DcR1. Conclusion: Aberrant hypermethylation of certain loci is a common event in liver fluke-related CCA and may potentially contribute to cholangiocarcinogenesis. The OPCML and DcR1 might serve as methylation biomarkers in CCA that can be readily examined by MSP

Children’s rights online: challenges, dilemmas and emerging directions

In debates over internet governance, the interests of children figure unevenly, and only partial progress has been made in supporting children’s rights online globally. This chapter examines how the UN Convention on the Rights of the Child is helpful in mapping children’s rights to provision, protection and participation as they apply online as well as offline. However, challenges remain. First, opportunities and risks are positively linked, policy approaches are needed to resolve the potential conflict between protection on the one hand, and provision and participation on the other. Second, while parents may be relied on to some degree to balance their child’s rights and needs, the evidence suggests that a minority of parents are ill-equipped to manage this. Third, resolution is needed regarding the responsibility for implementing digital rights, since many governments prefer self-regulation in relation to internet governance. The chapter concludes by calling for a global governance body charged with ensuring the delivery of children’s rights