The Interface of Therapeutics and Genomics in Cardiovascular Medicine.

Pharmacogenomics has a burgeoning role in cardiovascular medicine, from warfarin dosing to antiplatelet choice, with recent developments in sequencing bringing the promise of personalised medicine ever closer to the bedside. Further scientific evidence, real-world clinical trials, and economic modelling are needed to fully realise this potential. Additionally, tools such as polygenic risk scores, and results from Mendelian randomisation analyses, are only in the early stages of clinical translation and merit further investigation. Genetically targeted rational drug design has a strong evidence base and, due to the nature of genetic data, academia, direct-to-consumer companies, healthcare systems, and industry may meet in an unprecedented manner. Data sharing navigation may prove problematic. The present manuscript addresses these issues and concludes a need for further guidance to be provided to prescribers by professional bodies to aid in the consideration of such complexities and guide translation of scientific knowledge to personalised clinical action, thereby striving to improve patient care. Additionally, technologic infrastructure equipped to handle such large complex data must be adapted to pharmacogenomics and made user friendly for prescribers and patients alike.

Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

BACKGROUND: The number of patients living with co-existing diseases is growing. This study aimed to assess the extent of multimorbidity, medication use, and drug- and gene-based interactions in patients following a non-ST elevation acute coronary syndrome (NSTE-ACS). METHODS: In 1456 patients discharged from hospital for a NSTE-ACS, comorbidities and multimorbidity (≥ 2 chronic conditions) were assessed. Of these, 698 had complete drug use recorded at discharge, and 652 (the 'interaction' cohort) had drug use and actionable genotypes available for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, SLCO1B1, TPMT, UGT1A1, and VKORC1. The following drug interactions were investigated: pharmacokinetic drug-drug (DDIs) involving CYPs (CYPs above, plus CYP1A2, CYP2C8, CYP3A4), SLCO1B1, and P-glycoprotein; drug-gene (DGIs); drug-drug-gene (DDGIs); and drug-gene-gene (DGGIs). Interactions predicted to be 'substantial' were defined as follows: DDIs due to strong inhibitors/inducers, DGIs due to variant homozygous/compound heterozygous genotypes, and DDGIs/DGGIs where the constituent DDI/DGI(s) both influenced the victim drug in the same direction. RESULTS: In the whole cohort, 727 (49.9%) patients had multimorbidity. Non-linear relationships between age and increasing comorbidities and decreasing coronary intervention were observed. There were 98.1% and 39.8% patients on ≥ 5 and ≥ 10 drugs, respectively (from n = 698); women received more non-cardiovascular drugs than men (median (IQR) 3 (1-5) vs 2 (1-4), p = 0.014). Overall, 98.7% patients had at least one actionable genotype. Within the interaction cohort, 882 interactions were identified in 503 patients (77.1%), of which 346 in 252 patients (38.7%) were substantial: 59.2%, 11.6%, 26.3%, and 2.9% substantial interactions were DDIs, DGIs, DDGIs, and DGGIs, respectively. CYP2C19 (49.5% of all interactions) and SLCO1B1 (18.4%) were involved in the largest number of interactions. Multimorbidity (p = 0.019) and number of drugs (p = 9.8 × 10-10) were both associated with patients having ≥ 1 substantial interaction. Multimorbidity (HR 1.76, 95% CI 1.10-2.82, p = 0.019), number of drugs (HR 1.10, 95% CI 1.04-1.16, p = 1.2 × 10-3), and age (HR 1.05, 95% CI 1.03-1.07, p = 8.9 × 10-7), but not drug interactions, were associated with increased subsequent major adverse cardiovascular events. CONCLUSIONS: Multimorbidity, polypharmacy, and drug interactions are common after a NSTE-ACS. Replication of results is required; however, the high prevalence of DDGIs suggests integrating co-medications with genetic data will improve medicines optimisation.

Working together to deliver stratified medicine research effectively.

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.

Serum and blister-fluid elevation and decreased epidermal content of high-mobility group box 1 protein in drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND: High-mobility group box 1 (HMGB1) is a damage-associated molecular-pattern protein. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are serious, immune-mediated skin-blistering conditions. OBJECTIVES: To determine serum and/or blister-fluid total HMGB1 levels in SJS/TEN cohorts, and HMGB1 expression in formalin-fixed, paraffin-embedded (FFPE) SJS/TEN skin vs. healthy and maculopapular exanthema (MPE) skin. Methods Serum HMGB1 was quantified in Malawian nevirapine-induced hypersensitivity, Taiwanese SJS/TEN and Spanish SJS/TEN cohorts. FFPE skin (healthy skin, MPE, SJS/TEN) was stained and assessed for HMGB1 expression. RESULTS: Serum total HMGB1 was not significantly elevated in patients with nevirapine-induced SJS/TEN (3·98 ± 2·17 ng mL-1 ), MPE (3·92 ± 2·75 ng mL-1 ) or drug reaction with eosinophilia and systemic symptoms (4·73 ± 3·00 ng mL-1 ) vs. tolerant controls (2·97 ± 3·00 ng mL-1 ). HMGB1 was significantly elevated in Taiwanese patients with SJS/TEN, highest during the acute phase (32·6 ± 26·6 ng mL-1 ) vs. the maximal (19·7 ± 23·2 ng mL-1 ; P = 0·007) and recovery (24·6 ± 25·3 ng mL-1 ; P = 0·027) phases. In blister fluid from Spanish patients with SJS/TEN, HMGB1 (486·8 ± 687·9 ng mL-1 ) was significantly higher than in serum (8·8 ± 7·6 ng mL-1 ; P <0·001). Preblistered SJS/TEN skin showed decreased epidermal nuclear HMGB1 expression in upper epidermis vs. healthy or MPE skin but retained basal/suprabasal expression. CONCLUSIONS: Epidermal HMGB1 expression was decreased in SJS/TEN skin. Retained basal/suprabasal epidermal HMGB1 expression may exacerbate localized injury in SJS/TEN.

Zoonotic Transfer of Clostridium difficile Harboring Antimicrobial Resistance between Farm Animals and Humans.

The emergence of Clostridium difficile as a significant human diarrheal pathogen is associated with the production of highly transmissible spores and the acquisition of antimicrobial resistance genes (ARGs) and virulence factors. Unlike the hospital-associated C. difficile RT027 lineage, the community-associated C. difficile RT078 lineage is isolated from both humans and farm animals; however, the geographical population structure and transmission networks remain unknown. Here, we applied whole-genome phylogenetic analysis of 248 C. difficile RT078 strains from 22 countries. Our results demonstrate limited geographical clustering for C. difficile RT078 and extensive coclustering of human and animal strains, thereby revealing a highly linked intercontinental transmission network between humans and animals. Comparative whole-genome analysis reveals indistinguishable accessory genomes between human and animal strains and a variety of antimicrobial resistance genes in the pangenome of C. difficile RT078. Thus, bidirectional spread of C. difficile RT078 between farm animals and humans may represent an unappreciated route disseminating antimicrobial resistance genes between humans and animals. These results highlight the importance of the "One Health" concept to monitor infectious disease emergence and the dissemination of antimicrobial resistance genes.

Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden.

We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0.0039 and 0.0015 in the United Kingdom and Sweden, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were £6 702 and 253 848 SEK per QALY gained. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 93% of the simulations in the United Kingdom and below 500 000 SEK in 67% of the simulations in Sweden. Our data suggest that pharmacogenetic-guided dosing of warfarin is a cost-effective strategy to improve outcomes of patients with AF treated with warfarin in the United Kingdom and in Sweden.

The role of Clostridium difficile in the paediatric and neonatal gut - a narrative review.

Clostridium difficile is an important nosocomial pathogen in adults. Its significance in children is less well defined, but cases of C. difficile infection (CDI) appear to be increasingly prevalent in paediatric patients. This review aims to summarize reported Clostridium difficile carriage rates across children of different age groups, appraise the relationship between CDI and factors such as method of delivery, type of infant feed, antibiotic use, and co-morbidities, and review factors affecting the gut microbiome in children and the host immune response to C. difficile. Searches of PubMed and Google Scholar using the terms 'Clostridium difficile neonates' and 'Clostridium difficile children' were completed, and reference lists of retrieved publications screened for further papers. In total, 88 papers containing relevant data were included. There was large inter-study variation in reported C. difficile carriage rates. There was an association between CDI and recent antibiotic use, and co-morbidities such as immunosuppression and inflammatory bowel disease. C. difficile was also found in stools of children with diarrhoea attributed to other pathogens (e.g. rotavirus). The role of C. difficile in the paediatric gut remains unclear; is it an innocent bystander in diarrhoeal disease caused by other organisms, or a pathogen causing subclinical to severe symptoms? Further investigation of the development of serological and local host response to C. difficile carriage may shed new light on disease mechanisms. Work is underway on defining a framework for diagnosis and management of paediatric CDI.

Personalized medicine approaches in epilepsy.

Epilepsy affects 50 million persons worldwide, a third of whom continue to experience debilitating seizures despite optimum anti-epileptic drug (AED) treatment. Twelve-month remission from seizures is less likely in female patients, individuals aged 11-36 years and those with neurological insults and shorter time between first seizure and starting treatment. It has been found that the presence of multiple seizures prior to diagnosis is a risk factor for pharmacoresistance and is correlated with epilepsy type as well as intrinsic severity. The key role of neuroinflammation in the pathophysiology of resistant epilepsy is becoming clear. Our work in this area suggests that high-mobility group box 1 isoforms may be candidate biomarkers for treatment stratification and novel drug targets in epilepsy. Furthermore, transporter polymorphisms contributing to the intrinsic severity of epilepsy are providing robust neurobiological evidence on an emerging theory of drug resistance, which may also provide new insights into disease stratification. Some of the rare genetic epilepsies enable treatment stratification through testing for the causal mutation, for example SCN1A mutations in patients with Dravet's syndrome. Up to 50% of patients develop adverse reactions to AEDs which in turn affects tolerability and compliance. Immune-mediated hypersensitivity reactions to AED therapy, such as toxic epidermal necrolysis, are the most serious adverse reactions and have been associated with polymorphisms in the human leucocyte antigen (HLA) complex. Pharmacogenetic screening for HLA-B*15:02 in Asian populations can prevent carbamazepine-induced Stevens-Johnson syndrome. We have identified HLA-A*31:01 as a potential risk marker for all phenotypes of carbamazepine-induced hypersensitivity with applicability in European and other populations. In this review, we explore the currently available key stratification approaches to address the therapeutic challenges in epilepsy.

HLA-DQ allele-restricted activation of nitroso sulfamethoxazole-specific CD4-positive T lymphocytes from patients with cystic fibrosis.

BACKGROUND: For certain HLA allele-associated drug hypersensitivity reactions, the parent drug has been shown to associate directly with the risk allele. In other forms of hypersensitivity, HLA risk alleles have not been identified and T cells are activated in an allele unrestricted manner. Chemically reactive drug metabolites bind to multiple proteins; thus, it is assumed that the derived peptide antigens interact with a number of HLA molecules to activate T cells; however, HLA restriction of the drug metabolite-specific T-cell response has not been studied. OBJECTIVE: To utilize T cells from sulfamethoxazole (SMX) hypersensitive patients with cystic fibrosis to examine the HLA molecules that interact with nitroso SMX (SMX-NO)-derived antigens. METHODS: T-cell clones were generated from 4 hypersensitive patients. Drug-specific proliferative responses and cytokine secretion were measured. Anti-human class I and class II antibodies were used to analyse HLA restriction. Antigen-presenting cells expressing different HLA molecules were used to determine the alleles involved in the presentation of SMX-NO-derived antigens to T cells. RESULTS: A total of 976 clones were tested for SMX-NO reactivity. Thirty-nine CD4+ clones were activated with SMX-NO and found to proliferate and secrete cytokines. The SMX-NO-specific response was blocked with an antibody against HLA-DQ. SMX-NO-specific responses were detected with antigen-presenting cells expressing HLA-DQB1*05:01 (patient 1) and HLA-DQB1*02:01 (patient 2), but not other HLA-DQB1 alleles. CONCLUSION AND CLINICAL RELEVANCE: HLA-DQ plays an important role in the activation of SMX-NO-specific CD4+ T cells. Detection of HLA-DQ allele-restricted responses suggests that T cells are activated by a limited repertoire of SMX-NO-modified peptides.

Management of allergy to penicillins and other beta-lactams.

The Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) and an expert panel have prepared this guidance for the management of immediate and non-immediate allergic reactions to penicillins and other beta-lactams. The guideline is intended for UK specialists in both adult and paediatric allergy and for other clinicians practising allergy in secondary and tertiary care. The recommendations are evidence based, but where evidence is lacking, the panel reached consensus. During the development of the guideline, all BSACI members were consulted using a Web-based process and all comments carefully considered. Included in the guideline are epidemiology of allergic reactions to beta-lactams, molecular structure, formulations available in the UK and a description of known beta-lactam antigenic determinants. Sections on the value and limitations of clinical history, skin testing and laboratory investigations for both penicillins and cephalosporins are included. Cross-reactivity between penicillins and cephalosporins is discussed in detail. Recommendations on oral provocation and desensitization procedures have been made. Guidance for beta-lactam allergy in children is given in a separate section. An algorithm to help the clinician in the diagnosis of patients with a history of penicillin allergy has also been included.

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Variation in warfarin prescribing and dosing in the UK: a national survey of anticoagulation clinics.

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.

A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine.

At the blood-brain barrier, overexpression of the drug efflux transporter ABCC2 (also known as MRP2) has been proposed as a mechanism for impaired carbamazepine (CBZ) treatment response in epilepsy. However, investigation of the impact of ABCC2 polymorphisms on CBZ treatment efficacy has produced conflicting and inconclusive results. A series of in vitro cell efflux and plasma membrane vesicle uptake assays were undertaken to investigate whether CBZ was an ABCC2 substrate. In addition, the effect of three common ABCC2 polymorphisms, -24C>T, c.1249G>A and c.3972C>T, on the efficacy of CBZ in epilepsy (assessed using the clinical end points time to first seizure and time to 12-month remission from the SANAD (Standard and New Antiepileptic Drugs) trial) was determined. CBZ was found not to be a substrate for human ABCC2 in vitro. Clinically, no significant association was observed for the ABCC2 genetic variants and CBZ treatment outcomes. This comprehensive analysis does not support a role for ABCC2 in CBZ treatment efficacy.

Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects.

Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first 6 months' treatment time spent within the target International Normalised Ratio (INR) range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (odds ratio (OR; per additional copy) 4.18, 95% confidence interval (CI) 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR (heterozygotes vs homozygotes) 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population.

Dexamethasone and haemorrhage risk in paediatric tonsillectomy: a systematic review and meta-analysis.

Summary In children undergoing tonsillectomy, dexamethasone is recommended to reduce the risk of postoperative nausea and vomiting while non-steroidal anti-inflammatory drugs (NSAIDs) are used for pain relief. We aimed to determine whether children who receive dexamethasone or dexamethasone with NSAID are more likely to experience haemorrhage post-tonsillectomy. Randomized and non-randomized studies in which children undergoing tonsillectomy received dexamethasone or dexamethasone and NSAID were sought within bibliographic databases and selected tertiary sources. The risk of bias assessment and evaluation of haemorrhage rate data collection and reporting were assessed using the Cochrane Risk of Bias Tool and McHarm tool. Synthesis methods comprised pooled estimate of the effect of dexamethasone on the risk of haemorrhage rate using the Peto odds ratio (OR) method. The pooled estimate for haemorrhage rate in children who received dexamethasone was 6.2%, OR 1.41 (95% confidence interval 0.89-2.25, P=0.15). There was risk of bias and inconsistent data collection and reporting rates of haemorrhage in many of the included studies. Clinical heterogeneity was observed between studies. The pooled analysis did not demonstrate a statistically significant increase in the risk of post-tonsillectomy haemorrhage with dexamethasone with/without NSAID use in children. However, the majority of the included studies were not designed to investigate this endpoint, and thus large studies which are specifically designed to collect data on haemorrhage rate are needed.

Recording of suspected adverse drug reaction reporting in veterinary free-text clinical narratives.

OBJECTIVES: To use text mining approaches to identify instances of suspected adverse drug reactions recorded in first opinion veterinary free-text clinical narratives, and to evaluate whether these were also reported to either the Veterinary Medicines Directorate or the relevant Marketing Authorisation holder in order to derive an estimate of the suspected adverse drug reaction (sADR) minimum under-reporting rate. To characterise sADR reports and explore whether particular features are associated with report submission. MATERIALS AND METHODS: Two regular expressions were developed to identify mentions of "adverse drug reactions" and "side effects" in the free-text clinical narratives of electronic health records contained within the Small Animal Veterinary Surveillance Network database. Consultations containing a match for the developed regular expressions were manually reviewed for inclusion and further classified to determine the suspected product, seriousness and expectedness of the event, and an indication of whether the event had been reported. The associations between event characteristics and reporting were explored using Fisher's exact tests. RESULTS: A total of 10,565 records were manually reviewed from which 827 sADRs were identified. Approximately 90% of these sADRs were not recorded as reported. Suspected adverse drug reactions that were not considered "expected" were recorded as reported more frequently than "expected" sADRs. However, clinical severity did not appear to impact on whether there was a record of reporting. CLINICAL SIGNIFICANCE: This is the first estimate of under reporting sADRs based on real world evidence from veterinary clinical records. The under-reporting rate implied by this study highlights that further interventions are required to improve reporting rate within the veterinary profession in order to support pharmacovigilance activities and improve drug safety.

Genome-wide association study of serious blistering skin rash caused by drugs.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe, potentially life threatening adverse drug reactions characterized by skin blistering. Previous studies have identified drug-specific and population-specific genetic risk factors with large effects. In this study, we report the first genome-wide association study (GWAS) of SJS/TEN induced by a variety of drugs. Our aim was to identify common genetic risk factors with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 96 retrospective cases and 198 controls with a panel of over one million single-nucleotide polymorphisms (SNPs). We further improved power with about 4000 additional controls from publicly available datasets. No genome-wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a role in predisposing to drug-induced SJS/TEN. Our GWAS did not find common, highly penetrant genetic risk factors responsible for SJS/TEN events in the cases selected.