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Introduction or background Stratified medicine is an important area of research across all clinical specialties, with far reaching impact in many spheres. Despite recently formulated global policy and research programmes, major challenges for delivering stratified medicine studies persist. Across the globe, clinical research infrastructures have been setup to facilitate high quality clinical research. Sources of data This article reviews the literature and summarizes views collated from a workshop held by the UK Pharmacogenetics and Stratified Medicine Network and the NIHR Clinical Research Network in November 2016. Areas of agreement Stratified medicine is an important area of clinical research and health policy, benefitting from substantial international, cross-sector investment and has the potential to transform patient care. However there are significant challenges to the delivery of stratified medicine studies. Areas of controversy Complex methodology and lack of consistency of definition and agreement on key approaches to the design, regulation and delivery of research contribute to these challenges and would benefit from greater focus. Growing points Effective partnership and development of consistent approaches to the key factors relating to stratified medicine research is required to help overcome these challenges. Areas timely for developing research This paper examines the critical contribution clinical research networks can make to the delivery of national (and international) initiatives in the field of stratified medicine. Importantly, it examines the position of clinical research in stratified medicine at a time when pressures on the clinical and social services are mounting. [ABSTRACT FROM AUTHOR]

What is known and objective Clinical practice in the initiation, prescribing, dosing and monitoring of warfarin in the UK varies, but this has not been adequately documented. The objective was to undertake a survey on current clinical practice in this area, and how it compares with national guidelines that have been developed by the British Committee for Standards in Haematology. Methods A national online survey of anticoagulation clinics was performed using Survey Monkey®. The survey was designed to capture data for prescribing, dosing and monitoring of anticoagulation with warfarin. Results Of 85 clinics who responded to the survey, most were run by secondary care (68%), facilitated by specialist nurses (58%) and followed standard guidelines for the management of warfarin (87%). The majority of clinics indicated their target international normalized ratio (INR) for patients with atrial fibrillation (AF) (69/73; 94·5%) was between 2·0 and 3·0, but the indicated target INR for mechanical heart valves was more variable. Initiation and loading dosing regimens were a major source of variability with uncertainty surrounding individual patient factors such as age, ethnicity and BMI. What is new and conclusions Current practice amongst UK anticoagulation clinics largely follows current national guidelines but better guidance on dosing, taking into account factors that determine interindividual variability in daily warfarin dose requirements would improve and standardize oral anticoagulation with warfarin. [ABSTRACT FROM AUTHOR]

Background Recent data from Western countries indicate that the aetiology of peptic ulcer disease ( PUD) is changing as the prevalence of H elicobacter pylori is decreasing while the use of low-dose aspirin ( LDA, ≤325 mg/day) is increasing. Aim To investigate the changing aetiology and demographics of PUD in a well-characterised patient cohort at a large tertiary hospital in the UK between July 2005 and June 2010. Methods Patients diagnosed with PUD following endoscopy were categorised as non-steroidal anti-inflammatory drug (NSAID)-users or non-users, and their H . pylori status determined. Comparisons between NSAID-users and non-users, and between non-aspirin NSAID-users and LDA-users were summarised using counts and corresponding percentages (for categorical variables) and means and standard deviations (for continuous variables). Results Overall, 386 patients were enrolled; 57% used NSAIDs (51% LDA only) and 43% were non-users. 57% of the whole cohort was H . pylori-positive (including 66% with duodenal ulcers and 47% with gastric ulcers). Compared with non-users, NSAID-users were older (mean age 68 vs. 61 years) and fewer were H . pylori-positive (52% vs. 63%). LDA-users were older (mean age 71 vs. 62 years) and more likely to be H . pylori-positive (61% vs. 41%) than those using non-aspirin NSAIDs. Twelve per cent of the patients were neither using NSAIDs nor were H. pylori-positive. Conclusions The NSAIDs, particularly LDA, were most commonly associated with PUD in this cohort. Our findings are compatible with the decline in the prevalence of H . pylori-positive PUD and increase in non- NSAID, non- H . pylori PUD previously reported. [ABSTRACT FROM AUTHOR]

It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. Prospective observational study over a 2-week period. There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population. [ABSTRACT FROM AUTHOR]

Background: In this pilot study, we have investigated the frequency of adverse drug reaction (ADR)-related admissions to an acute medical assessment unit. Although ADRs are thought to be responsible for 5% of hospital admissions, there have been no recent studies in the U.K. Objective: To pilot such a study for estimating the incidence of ADR-related admissions to an acute medical assessment unit. Method: Data were collected for 200 patients including details of concurrent illness, drug usage and reasons for admission. ADRs were assessed for causality using two previously published classification systems. Results: ADRs were responsible for admission in 15 (7.5%) patients, were present in an additional three (1.5%) patients and may have contributed to the deaths of two (1%) patients. Of the 15 ADRs suspected of causing an admission, three were considered to be ‘possible’ or ‘unlikely’, with the remaining 12 considered to be ‘probable’ or ‘certain’. The proportion of patients identified in this study with ADR-related admissions is either similar to or larger than that found in comparable studies carried out in other hospitals. Nearly all ADRs were Type A reactions in that they were predictable and therefore potentially preventable. Conclusion: This study suggests that the proportion of ADR-related admissions has not decreased in the last decade and, given the increasing numbers of acute medical admissions, the absolute numbers may have actually increased. Furthermore, the nature of drugs causing admissions has not changed substantially over the last 20 years. Strategies to reduce the burden of ADR-related admissions are urgently needed. [ABSTRACT FROM AUTHOR]

Summary: Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, severe, skin blistering conditions in which areas of skin die and detach. They actually represent a single disease with a spectrum of severity: less than 10% body surface area detachment in SJS and more than 30% in TEN. It affects around 500 people in the UK each year and is most commonly caused by a reaction to a wide‐range of commonly prescribed drugs. This study brought together researchers and patients from the U.K., Spain, Taiwan and the U.S.A. and aimed to determine levels of a protein called high mobility group box 1 (HMGB1) in the serum (part of the blood), blister fluid and skin biopsy tissue of SJS/TEN patients. HMGB1 is a protein which is known to be a marker (biological sign) of a) tissue/cell injury and b) activation of the immune response, both of which occur in SJS/TEN. The authors detected elevated serum HMGB1 levels in SJS/TEN patients at the time of reaction in three independent patient populations, and also extremely high levels in patients' blister fluid. Levels of HMGB1 in the epidermal (upper) layer of the skin were considerably decreased in SJS/TEN patients but not healthy control or drug‐induced rash skin. The decrease in HMGB1 levels in the epidermis of the skin appears to occur prior to blistering and may represent an early indicator. In addition, levels of HMGB1 appear to be retained at the junction between the epidermis and the next layer of skin, called the dermis, which may suggest a potential role for HMGB1 in the mechanism by which the layers become detached in SJS/TEN patients. The authors conclude that serum HMGB1 may not represent a good clinical marker of SJS/TEN, but that decreased levels of it in the skin may be a sign of the early onset of skin blistering, and could have a key role in the mechanism by which this occurs. Linked Article: Carr et al. Br J Dermatol 2019; 181:166–174 [ABSTRACT FROM AUTHOR]

Older adults are persistently underrepresented in clinical drug trials worldwide, despite increasing multiple long-term conditions and significant prescribing in this demographic. We discuss systemic challenges such as the exclusion of people with comorbid conditions and the lack of assessment for comorbidities as modifiers of treatment effects and highlight the rising trend of polypharmacy, especially among the oldest age groups, which is linked to a significant percentage of unplanned hospitalizations and medication errors. The consequences of these trends prompted the United Kingdom National Overprescribing review, culminating in a set of recommendations for drug development tailored to older adults. Building on this, two critical reports released in April 2023 by the International Longevity Centre (ILC) and the Nuffield Council on Bioethics (NCOB) are discussed. These reports emphasize the importance of diversity and inclusion in clinical trials, advocating for ethical frameworks and methodologies that cater to the complex needs of older adults. The development of inclusive criteria, innovative statistical methodologies, and the integration of patient-reported outcomes are needed to address the persistent barriers to older adult participation in research, suggesting that pragmatic trials, exemplified by the UK's RECOVERY trial during the COVID-19 pandemic, could pave the way for more inclusive research practices., (© 2024 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide-use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self-reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene-environment interaction (GEI) tests on the significant (P < 2.5 × 10 -9 ) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10 -3 ; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10 -4 ) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9-mediated interaction having been previously reported. In conclusion, we used a two-stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide-associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis., Methods: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239)., Results: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis., Conclusions: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

There is considerable inter-individual variability in the effectiveness and safety of pharmaceutical interventions. This phenomenon can be attributed to a multitude of factors; however, it is widely acknowledged that common genetic variation affecting drug absorption or metabolism play a substantial contributory role. This is a concept known as pharmacogenetics. Understanding how common genetic variants influence responses to medications, and using this knowledge to inform prescribing practice, could yield significant advantages for both patients and healthcare systems. Some health services around the world have introduced pharmacogenetics into routine practice, whereas others are less advanced along the implementation pathway. This chapter introduces the field of pharmacogenetics, the existing body of evidence, and discusses barriers to implementation. The chapter will specifically focus on efforts to introduce pharmacogenetics in the NHS, highlighting key challenges related to scale, informatics, and education., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Spontaneous reporting of suspected adverse drug reactions (ADRs) is the cornerstone of pharmacovigilance. Despite this, it is believed that there is significant under-reporting in the veterinary setting. Low reporting rates delay marketing authorisation holders (MAHs) and regulators taking mitigating action in the case of safety concerns., Method: We designed a survey to explore the perceptions, attitudes and experiences of UK veterinary professionals towards ADR reporting. The survey was advertised widely through conventional and social media and at several conferences., Results: In total, 260 respondents completed the survey, including 210 veterinary surgeons, 49 veterinary nurses and one suitably qualified person. Respondents generally understood the need to report ADRs. The main barrier to reporting was the suspected ADR being well known, and the most popular potential facilitator identified was the ability to report via the practice management system. Facilitation via education in the form of a pharmacovigilance themed continuing professional development event was particularly popular among veterinary nurses, who reported time as being less of a barrier to reporting than their veterinary surgeon counterparts., Conclusions: Our findings suggest that technological interventions to facilitate reporting and empowerment of veterinary nurses to report through a tailored training event should be explored further., (© 2022 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Background: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD., Methods: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls., Findings: The GWAS identified one variant, rs12678747 (p=1·65×10 -7 ) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10 -11 ; OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum., Interpretation: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation., Funding: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF)., Competing Interests: Declaration of Competing Interest MP has received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis); a PhD studentship jointly funded by EPSRC and Astra Zeneca; and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol-Myers Squibb UCB. He has developed a HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. None of these funding sources were used for this study. DMP reports consultancy work from Ipsen pharmaceuticals, Advanced Accelerator Applications, and Mayoly Spindler laboratories, grants from Trio Medicines Ltd, outside the submitted work. All other authors have nothing to declare., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Predictive BRCA testing is offered to asymptomatic individuals to predict future risk where a variant has been identified in a relative. It is uncertain whether all eligible relatives access testing, and whether this is related to health care inequalities. Our aim was to analyse trends and inequalities in uptake of testing, and identify predictors of testing and time-to-receipt of testing. A database from April 2010 to March 2017 was collated. Multivariate analysis explored individual associations with testing. Predictor variables included gender, BRCA test type, cancer history, Index of Multiple Deprivation (IMD) and education status. To evaluate factors associated with time-to-testing, a Cox proportional-hazards (CP) model was used. Of 779 tests undertaken, 336 (43.1%) were identified with a BRCA variant. A total of 537 (68.9%) were female and in 83.4% (387/464) of probands, predictive testing was received by relatives. Analysis identified inequalities since decreased testing was found when the proband was unaffected by cancer (OR 0.14, 95% CI 0.06-0.33). Median time-to-testing was 390 days (range, 0-7090 days) and the CP model also identified inequalities in the hazard ratio (HR) for testing for people aged >40 was higher than for aged <40 (HR 1.41, 95% CI 1.20-1.67) and BRCA2 testing was higher than for BRCA1 testing (HR 1.39, 95% CI 1.18-1.64). Reduced testing was found when probands were unaffected by cancer and time-to-testing was found to vary by age and BRCA1/2 test. Given limited study sample size, further research is recommended to examine inequalities in predictive BRCA testing.

Background: Understanding the relationship between occupation and alcohol use offers opportunities to provide health promotion programmes based on evidence of need. We aimed to determine associations between occupation and heavy alcohol consumption in working individuals aged 40-69 years., Methods: A cross-sectional study was conducted using 100,817 people from the UK Biobank: 17,907 participants categorised as heavy drinkers, defined as > 35 units/week for women and > 50 units/week for men, and 82,910 drinking controls. Prevalence ratios (PRs) and 95% CIs were calculated for gender-specific heavy drinking in 353 occupations using Standard Occupational Classification, V.2000., Results: Seventy-seven occupations were associated with level of alcohol consumption in drinkers. The largest ratios for heavy drinkers were observed for publicans and managers of licenced premises (PR = 2.81, 95%CI 2.52-3.14); industrial cleaning process occupations (PR = 2.09, 1.33-3.28); and plasterers (PR = 2.07, 1.66-2.59). Clergy (PR = 0.20, 0.13-0.32); physicists, geologists and meteorologists (PR = 0.40, 0.25-0.65); and medical practitioners (PR = 0.40, 0.32-0.50) were least likely to be heavy drinkers. There was evidence of gender-specific outcomes with the proportion of jobs associated with heavy drinking accounted for by skilled trade occupations being 0.44 for males and 0.05 for females, and 0.10 for males and 0.40 for females when considering managers and senior officials., Conclusions: In the largest study of its kind, we found evidence for associations between a wider variety of occupations and the risk of heavy alcohol consumption than identified previously, particularly in females, although causality cannot be assumed. These results help determine which jobs and broader employment sectors may benefit most from prevention programmes.

Introduction: Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk., Methods: We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank., Results: The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10-18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10-15). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption., Discussion: If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis., (Copyright © 2020 by The American College of Gastroenterology.)

Objective: To monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects., Methods: Retrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018-2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends., Results: Across nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%-58.6%) and 52.9% (52.2%-53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1-2 weeks before lockdown and fell by 31%-88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93-0.95; total hospital admissions RR 0.96, 0.95-0.97) and after lockdown (attendances RR 0.63, 0.62-0.64; admissions RR 0.59, 0.57-0.60). There was limited recovery towards usual levels of some activities from mid-April 2020., Conclusions: Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite increasing interest in pharmacogenomics, and the potential benefits to improve patient care, implementation into clinical practice has not been widespread. Recently, there has been a drive to implement genomic medicine into the UK National Health Service (NHS), largely spurred on by the success of the 100,000 Genomes Project. 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 challenges of implementing pharmacogenomics into the NHS. This report highlights the discussions of the workshop to provide an overview of the issues that need to be considered to enable pharmacogenomic medicine to become mainstream within the NHS.

Atorvastatin (ATV) is frequently prescribed and generally well  tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L), and 2-OH ATV L was performed in 590 patients who had been hospitalized with a non-ST elevation acute coronary syndrome 1 month earlier and were on high-dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2-OH ATV/ATV (P = 7.25 × 10 -16 ) and 2-OH ATV L/ATV L (P = 3.95 × 10 -15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (P = 6.18 × 10 -7 ), and SLCO1B1 rs4149056 with increased ATV (P = 2.21 × 10 -6 ) and 2-OH ATV (P = 1.09 × 10 -6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (n = 149), all of these associations remained, except for 2-OH ATV and rs4149056 (P = 0.057). Clinically, rs4149056 was associated with increased muscular symptoms (odds ratio (OR) 3.97; 95% confidence interval (CI) 1.29-12.27; P = 0.016) and ATV intolerance (OR 1.55; 95% CI 1.09-2.19; P = 0.014) in patients (n = 870) primarily discharged on high-dose ATV. In summary, both novel and recognized genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high-dose ATV., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 -5 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 -9 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified., (© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

BRCA testing received much publicity following Angelina Jolie's editorial "My Medical Choice" in May 2013 and updated NICE clinical guidance (CG164) in June 2013. We assessed the effect of these two concurrent events on BRCA testing in one UK catchment area and relate this to socioeconomic deprivation. A database of 1393 patients who received BRCA testing was collated. This included individuals with breast/ovarian cancer, and those unaffected by cancer, where a relative has a ≥10% probability of carrying a BRCA variant which affects function. A segmented regression was conducted to estimate changes in testing. To examine the relative distribution of testing by deprivation, the deprivation status of patients who received testing was examined. Between April 2010 and March 2017, testing increased 11-fold and there was an 84% increase (P = 0.006) in BRCA1/2 testing in the month following both publications. In the pre-publication period, there was no statistically significant difference in testing between advantaged and disadvantaged areas (OR 1.21, 95% CI 0.99-1.48; P = 0.06). In the post-publication period helped by a larger sample size, the difference was statistically significant (OR 1.18, 95% CI 1.08-1.29; P = 0.0002) and of a similar magnitude to the pre-publication period. Testing increased following Jolie's editorial and NICE guidance update. However, further research is needed to examine differences in testing by the deprivation group which adjusts for confounders.

Background: Warfarin is a widely used oral anticoagulant. Determining the correct dose required to maintain the international normalised ratio (INR) within a therapeutic range can be challenging. In a previous trial, we showed that a dosing algorithm incorporating point-of-care genotyping information ('POCT-GGD' approach) led to improved anticoagulation control. To determine whether this approach could translate into clinical practice, we undertook an implementation project using a matched cohort design., Methods: At three clinics (implementation group; n = 119), initial doses were calculated using the POCT-GGD approach; at another three matched clinics (control group; n = 93), patients were dosed according to the clinic's routine practice. We also utilised data on 640 patients obtained from routinely collected data at comparable clinics. Primary outcome was percentage time in target INR range. Patients and staff from the implementation group also provided questionnaire feedback on POCT-GGD., Results: Mean percentage time in INR target range was 55.25% in the control group and 62.74% in the implementation group; therefore, 7.49% (95% CI 3.41-11.57%) higher in the implementation group (p = 0.0004). Overall, patients and staff viewed POCT-GGD positively, suggesting minor adjustments to allow smooth implementation into practice., Conclusions: In the first demonstration of the implementation of genotype-guided dosing, we show that warfarin dosing determined using an algorithm incorporating genetic and clinical factors can be implemented smoothly into clinic, to ensure target INR range is reached sooner and maintained. The findings are like our previous randomised controlled trial, providing an alternative method for improving the risk-benefit of warfarin use in daily practice.

What Is Known and Objective: Adverse drug reaction reporting in the UK is lower than expected based on epidemiological data. This study aims to explore (a) nonmedical prescribers' (NMP) confidence in identifying and reporting ADRs, (b) NMP prescribing habits and engagement with the Yellow Card Scheme (YCS) and (c) NMP desire for future training in the identification and reporting of ADRs., Methods: A survey was distributed across NMP networks in the north-west of England using Survey Monkey. Univariate analyses were performed to compare the features of reporters and nonreporters, Kruskal-Wallis H tests for comparisons within multiple subgroups and Spearman's rank correlation coefficient for response associations between answers to ordered-category questions., Results and Discussion: A total of 570 responses were available for analysis, an estimated response rate of 20%. Less than half (n = 219; 38.4%) reported submitting a Yellow Card to the YCS, and the majority of those individuals have submitted five or less Yellow Cards; 28 responders reported more than five submissions. Being professionally qualified for more years (linear regression: B = 0.30, P < 0.0005; 95% CI 1.01 to 1.05) and receiving additional training support about the YCS (chi-squared: χ 2  = 14.7, P < 0.0005) were associated with an increased likelihood of submitting to the YCS. There was a positive linear relationship between confidence in identifying ADRs and likelihood of reporting to YCS. The most common reason given (n = 261) for never having reported to the YCS was "I have never seen an adverse drug reaction." Training appears to give NMPs confidence in reporting ADRs, but there seems to be a gap in actually identifying ADRs given the comment that most had never seen an ADR., What Is New and Conclusion: Strategies for improving the translation of theoretical knowledge about ADRs into practical skills in identifying ADRs, and subsequently reporting them, will be important for improving pharmacovigilance practice., (© 2018 The Authors. Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd.)

Aim: To evaluate drug therapy for alcohol dependence in the 12 months after first diagnosis in UK primary care., Design: Open cohort study., Setting: General practices contributing data to the UK Clinical Practice Research Database., Participants: 39,980 people with an incident diagnosis of alcohol dependence aged 16 years or older between 1 January 1990 and 31 December 2013., Main Outcome Measure: Use of pharmacotherapy (acamprosate, disulfiram, naltrexone, baclofen and topiramate) to promote abstinence from alcohol or reduce drinking to safe levels in the first 12 months after a recorded diagnosis of alcohol dependence., Findings: Only 4,677 (11.7%) of the cohort received relevant pharmacotherapy in the 12 months following diagnosis. Of the 35,303 that did not receive pharmacotherapy, 3,255 (9.2%) received psychosocial support. The remaining 32,048 (80.2%) did not receive either mode of treatment in the first 12 months. Factors that independently reduced the likelihood of receiving pharmacotherapy included: being male (Odds Ratio [OR] 0.74; 95% CI 0.69 to 0.78); older (65-74 years: OR 0.61; 95% CI 0.49 to 0.77); being from a practice based in the most deprived quintile (OR 0.58; 95% CI 0.53 to 0.64); and being located in Northern Ireland (OR 0.78; 95% CI 0.67 to 0.91). The median duration to initiation of pharmacotherapy was 0.80 months (95% CI 0.70 to 1.00) for acamprosate and 0.60 months (95% CI 0.43 to 0.73) for disulfiram. Persistence analysis for those receiving acamprosate and disulfiram revealed that many patients never received a repeat prescription; persistence at 6 months was 27.7% for acomprosate and 33.2% for disulfiram. The median duration of therapy was 2.10 months (95% CI 1.87 to 2.53) for acamprosate and 3.13 months (95% CI 2.77 to 3.36) for disulfiram., Conclusion: Drug therapy to promote abstinence in alcohol dependent patients was low, with the majority of patients receiving no therapy, either psychological or pharmacological. When drug therapy was prescribed, persistence was low with most patients receiving only one prescription. Our data show that treatment for alcohol dependence is haphazard, and there is an urgent need to explore strategies for improving clinical management of this patient group.

Background: Accurate tracking of Clostridium difficile transmission within healthcare settings is key to its containment but is hindered by the lack of discriminatory power of standard genotyping methods. We describe a whole-genome phylogenetic-based method to track the transmission of individual clones in infected hospital patients from the epidemic C. difficile 027/ST1 lineage, and to distinguish between the 2 causes of recurrent disease, relapse (same strain), or reinfection (different strain)., Methods: We monitored patients with C. difficile infection in a UK hospital over a 2-year period. We performed whole-genome sequencing and phylogenetic analysis of 108 strains isolated from symptomatic patients. High-resolution phylogeny was integrated with in-hospital transfers and contact data to create an infection network linking individual patients and specific hospital wards., Results: Epidemic C. difficile 027/ST1 caused the majority of infections during our sampling period. Integration of whole-genome single nucleotide polymorphism (SNP) phylogenetic analysis, which accurately discriminated between 27 distinct SNP genotypes, with patient movement and contact data identified 32 plausible transmission events, including ward-based contamination (66%) or direct donor-recipient contact (34%). Highly contagious donors were identified who contributed to the persistence of clones within distinct hospital wards and the spread of clones between wards, especially in areas of intense turnover. Recurrent cases were identified between 4 and 26 weeks, highlighting the limitation of the standard <8-week cutoff used for patient diagnosis and management., Conclusions: Genome-based infection tracking to monitor the persistence and spread of C. difficile within healthcare facilities could inform infection control and patient management., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

A multigenic classifier based on five single nucleotide polymorphisms (SNPs) was previously reported to predict treatment response in an Australian newly-diagnosed epilepsy cohort using a k-nearest neighbour (kNN) algorithm. We assessed the validity of this classifier in predicting response to initial antiepileptic drug (AED) treatment in two UK cohorts of newly-diagnosed epilepsy and investigated the utility of these five SNPs in predicting seizure control in general. The original Australian cohort constituted the training set for the classifier and was used to predict response to the first well-tolerated AED monotherapy in independently recruited UK cohorts (Glasgow, n=281; SANAD, n=491). A "leave-one-out" cross-validation was also employed, with training sets derived internally from the UK datasets. The multigenic classifier using the Australian cohort as the training set was unable to predict treatment response in either UK cohort. In the "leave-one-out" analysis, the five SNPs collectively predicted treatment response in both Glasgow and SANAD patients prescribed either carbamazepine or valproate (Glasgow OR=3.1, 95% CI=1.4-6.6, p=0.018; SANAD OR=2.8, 95% CI=1.3-6.1, p=0.048), but not those receiving lamotrigine (Glasgow OR=1.3, 95% CI=0.6-2.8, p=1.0; SANAD OR=2.2, 95% CI=0.9-5.4, p=0.36) or other AEDs (Glasgow OR=0.6, 95% CI=0.2-2.0, p=1.0; SANAD OR=1.9, 95% CI=0.9-4.2, p=0.36). The Australian-based multigenic kNN model is not predictive of initial treatment response in UK cohorts of newly-diagnosed epilepsy. However, the five SNPs identified in the original Australian study appear to collectively have a predictive influence in UK patients prescribed either carbamazepine or valproate., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Single-nucleotide polymorphisms (SNPs) in the CYP2C gene cluster have been extensively investigated as predisposing factors for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB). However, results have been inconclusive owing to different study designs, limited genotyping strategies, and small sample sizes. We investigated whether eight functional SNPs in the CYP2C family of genes--CYP2C8*3 (rs11572080 and rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17--are associated with PUD in 1,239 Caucasian patients. Logistic regression analysis showed that only CYP2C19*17 was associated with PUD (odds ratio additive model: 1.47 (95% confidence interval (CI) 1.12 to 1.92); P = 0.005; R(2) 16%), but not UGIB, independent of NSAID use or Helicobacter pylori infection. PUD distribution varied (P = 0.024) according to CYP2C19*17 genotype: *1/*1, 490 (64.3%); *1/*17, 304 (71.7%); and *17/*17, 31 (73.8%). CYP2C19*17, a gain-of-function polymorphism, is associated with PUD irrespective of etiology.

Background: Recent data from Western countries indicate that the aetiology of peptic ulcer disease (PUD) is changing as the prevalence of Helicobacter pylori is decreasing while the use of low-dose aspirin (LDA, ≤325 mg/day) is increasing., Aim: To investigate the changing aetiology and demographics of PUD in a well-characterised patient cohort at a large tertiary hospital in the UK between July 2005 and June 2010., Methods: Patients diagnosed with PUD following endoscopy were categorised as non-steroidal anti-inflammatory drug (NSAID)-users or non-users, and their H. pylori status determined. Comparisons between NSAID-users and non-users, and between non-aspirin NSAID-users and LDA-users were summarised using counts and corresponding percentages (for categorical variables) and means and standard deviations (for continuous variables)., Results: Overall, 386 patients were enrolled; 57% used NSAIDs (51% LDA only) and 43% were non-users. 57% of the whole cohort was H. pylori-positive (including 66% with duodenal ulcers and 47% with gastric ulcers). Compared with non-users, NSAID-users were older (mean age 68 vs. 61 years) and fewer were H. pylori-positive (52% vs. 63%). LDA-users were older (mean age 71 vs. 62 years) and more likely to be H. pylori-positive (61% vs. 41%) than those using non-aspirin NSAIDs. Twelve per cent of the patients were neither using NSAIDs nor were H. pylori-positive., Conclusions: The NSAIDs, particularly LDA, were most commonly associated with PUD in this cohort. Our findings are compatible with the decline in the prevalence of H. pylori-positive PUD and increase in non-NSAID, non-H. pylori PUD previously reported., (© 2012 Blackwell Publishing Ltd.)

Background: Community-associated Clostridium difficile infection (CDI) appears to be an increasing problem. Reported carriage rates by C. difficile are debatable with suggestions that primary asymptomatic carriage is associated with decreased risk of subsequent diarrhoea. However, knowledge of potential reservoirs and intestinal carriage rates in the community, particularly in the elderly, the most susceptible group, is limited. We have determined the presence of C. difficile in the faeces of a healthy elderly cohort living outside of long-term care facilities (LCFs) in the United Kingdom., Methods: Faecal samples from 149 community-based healthy elderly volunteers (median age 81 years) were screened for C. difficile using direct (Brazier's CCEY) and enrichment (Cooked Meat broth) culture methods and a glutamate dehydrogenase (GDH) immunoassay. Isolates were PCR-ribotyped and analysed for toxin production and the presence of toxin genes., Results: Of 149 faecal samples submitted, six (4%) were found to contain C. difficile. One particular sample was positive by both the GDH immunoassay and direct culture, and concurrently produced two distinct strain types: one toxigenic and the other non-toxigenic. The other five samples were only positive by enrichment culture method. Overall, four C. difficile isolates were non-toxigenic (PCR-ribotypes 009, 026 (n = 2) and 039), while three were toxigenic (PCR-ribotypes 003, 005 and 106). All individuals who had a positive culture were symptom-free and none of them had a history of CDI and/or antibiotics use in the 3 month period preceding recruitment., Conclusions: To our knowledge, this is the first study of the presence of C. difficile in healthy elderly community-dwelling individuals residing outside of LCFs. The observed carriage rate is lower than that reported for individuals in LCFs and interestingly no individual carried the common epidemic strain PCR-ribotype 027 (NAP1/BI). Further follow-up of asymptomatic carriers in the community, is required to evaluate host susceptibility to CDI and identify dynamic changes in the host and microbial environment that are associated with pathogenicity.

Background: A strong pharmacogenetic association has been reported in Chinese patients between human leukocyte antigen (HLA)-B*1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)., Methods: We have genotyped the HLA-B alleles in 56 Caucasian patients with varying severities of CBZ hypersensitivity and 43 controls on CBZ without adverse effects., Results: None of our patients (including two with blistering skin rashes) were positive for the HLA-B*1502 allele. HLA-B*0702 allele may protect against severe CBZ hypersensitivity but warrants further study. Of secondary interest, the correlation between HLA-B*0801 and HLA-DR3, DQ2 and TNF -308 alleles (on the ancestral haplotype 8.1) is consistent with our previous findings., Conclusion: HLA-B*1502 does not seem to be a marker for all forms of CBZ-induced hypersensitivity in a Caucasian population.