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Abstract Background Despite the growing interest in the use of human genomic data for drug target identification and validation, the extent to which the spectrum of human disease has been addressed by genome-wide association studies (GWAS), or by drug development, and the degree to which these efforts overlap remain unclear. Methods In this study we harmonize and integrate different data sources to create a sample space of all the human drug targets and diseases and identify points of convergence or divergence of GWAS and drug development efforts. Results We show that only 612 of 11,158 diseases listed in Human Disease Ontology have an approved drug treatment in at least one region of the world. Of the 1414 diseases that are the subject of preclinical or clinical phase drug development, only 666 have been investigated in GWAS. Conversely, of the 1914 human diseases that have been the subject of GWAS, 1121 have yet to be investigated in drug development. Conclusions We produce target-disease indication lists to help the pharmaceutical industry to prioritize future drug development efforts based on genetic evidence, academia to prioritize future GWAS for diseases without effective treatments, and both sectors to harness genetic evidence to expand the indications for licensed drugs or to identify repurposing opportunities for clinical candidates that failed in their originally intended indication.

Abstract Vaccination has proven to be a valuable tool to combat SARS-CoV-2. However, reports of rare adverse reactions such as thrombosis/thrombocytopenia syndrome after ChAdOx1 nCoV-19 vaccination have caused scientific, public and media concern. ChAdOx1 was vectorised from the Y25 chimpanzee adenovirus, which was selected due to low human seroprevalence to circumvent pre-existing immunity. In this study, we aimed to explore patterns of T-cell activation after SARS-CoV-2 COVID-19 vaccine exposure in vitro using PBMCs collected from pre-pandemic ChAdOx1 nCoV-19 naïve healthy donors (HDs), and ChAdOx1 nCoV-19 and Pfizer vaccinated controls. PBMCs were assessed for T-cell proliferation using the lymphocyte transformation test (LTT) following exposure to SARS-CoV-2 COVID-19 vaccines. Cytokine analysis was performed via intracellular cytokine staining, ELISpot assay and LEGENDplex immunoassays. T-cell assays performed in pre-pandemic vaccine naïve HDs, revealed widespread lymphocyte stimulation after exposure to ChAdOx1 nCoV-19 (95%), ChAdOx-spike (90%) and the Ad26.COV2. S vaccine, but not on exposure to the BNT162b2 vaccine. ICS analysis demonstrated that CD4+ CD45RO+ memory T-cells are activated by ChAdOx1 nCoV-19 in vaccine naïve HDs. Cytometric immunoassays showed ChAdOx1 nCoV-19 exposure was associated with the release of proinflammatory and cytotoxic molecules, such as IFN-γ, IL-6, perforin, granzyme B and FasL. These studies demonstrate a ubiquitous T-cell response to ChAdOx1 nCoV-19 and Ad26.COV2. S in HDs recruited prior to the SARS-CoV-2 pandemic, with T-cell stimulation also identified in vaccinated controls. This may be due to underlying T-cell cross-reactivity with prevalent human adenoviruses and further study will be needed to identify T-cell epitopes involved.

Abstract Background Asthma is routinely treated with inhaled corticosteroids (ICS). Asthma patients on ICS are at increased risk of adrenal suppression, a potentially serious effect of long‐term glucocorticoid exposure; however, this relationship is poorly understood. Therefore, this study aims to identify metabolite biomarkers related to adrenal suppression in asthma patients taking ICS. Methods A total of 571 urine metabolites from 200 children with asthma on ICS in the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) cohort were profiled. Samples were grouped by peak plasma cortisol measurement as adrenal sufficient (>350 nmol/L) or insufficient (≤350 nmol/L) (outcome). Regression and discriminant‐based statistical models combined with network analyses were utilized to assess relationships between metabolites and the outcome. Finally, prioritized metabolites were validated using data from an ancillary study of the Childhood Asthma Management (CAMP) cohort with similar characteristics to PASS. Results Ninety metabolites were significantly associated with adrenal suppression, of which 57 also could discriminate adrenal status. While 26 metabolites (primarily steroids) were present at lower levels in the adrenal insufficient patients, 14 were significantly elevated in this group; the top metabolite, mannitol/sorbitol, was previously associated with asthma exacerbations. Network analyses identified unique clusters of metabolites related to steroids, fatty acid oxidation, and nucleoside metabolism, respectively. Four metabolites including urocanic acid, acetylcarnitine, uracil, and sorbitol were validated in CAMP cohort for adrenal suppression. Conclusions Urinary metabolites differ among asthma patients on ICS, by adrenal status. While steroid metabolites were reduced in patients with poor adrenal function, our findings also implicate previously unreported metabolites involved in amino acid, lipid, and nucleoside metabolism.

Objectives Pharmacovigilance databases play a critical role in monitoring drug safety. The duplication of reports in pharmacovigilance databases, however, undermines their data integrity. This scoping review sought to provide a comprehensive understanding of duplication in pharmacovigilance databases worldwide.Design A scoping review.Data sources Reviewers comprehensively searched the literature in PubMed, Web of Science, Wiley Online Library, EBSCOhost, Google Scholar and other relevant websites.Eligibility criteria Peer-reviewed publications and grey literature, without language restriction, describing duplication and/or methods relevant to duplication in pharmacovigilance databases from inception to 1 September 2023.Data extraction and synthesis We used the Joanna Briggs Institute guidelines for scoping reviews and conformed with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. Two reviewers independently screened titles, abstracts and full texts. One reviewer extracted the data and performed descriptive analysis, which the second reviewer assessed. Disagreements were resolved by discussion and consensus or in consultation with a third reviewer.Results We screened 22 745 unique titles and 156 were eligible for full-text review. Of the 156 titles, 58 (47 peer-reviewed; 11 grey literature) fulfilled the inclusion criteria for the scoping review. Included titles addressed the extent (5 papers), prevention strategies (15 papers), causes (32 papers), detection methods (25 papers), management strategies (24 papers) and implications (14 papers) of duplication in pharmacovigilance databases. The papers overlapped, discussing more than one field. Advances in artificial intelligence, particularly natural language processing, hold promise in enhancing the efficiency and precision of deduplication of large and complex pharmacovigilance databases.Conclusion Duplication in pharmacovigilance databases compromises risk assessment and decision-making, potentially threatening patient safety. Therefore, efficient duplicate prevention, detection and management are essential for more reliable pharmacovigilance data. To minimise duplication, consistent use of worldwide unique identifiers as the key case identifiers is recommended alongside recent advances in artificial intelligence.

Abstract Raynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP (p

Background & Aims: Population screening for non-alcoholic fatty liver disease (NAFLD) and associated comorbidities remains an unaddressed clinical need. We aimed to assess the utility of the fatty liver index (FLI) for risk stratification of NAFLD and related comorbidities using the UK Biobank. Methods: Electronic health records and liver MRI-proton density fat fraction (PDFF) were used to define NAFLD cases. FLI was calculated and individuals with high alcohol intake and other liver diseases were excluded. Using listwise deletion analysis, the area under receiver-operating characteristic curve (AUROC) of FLI for NAFLD risk was determined. Thereafter, time-dependent covariate-adjusted Cox regression models were used to estimate FLI’s risk stratification potential for comorbidities of interest. Results: FLI was derived for 327,800 individuals with a median age of 58 (IQR 51.5-64.5), of whom 59.8% were females. Using Perspectum Diagnostics and AMRA protocols as references, FLI identified the risk of NAFLD with AUROCs (95% CI, n) of 0.858 (0.848-0.867, n = 7,566) and 0.851 (0.844-0.856, n = 10,777), respectively. Intermediate and high-risk FLI was associated with increased cardiometabolic and malignant disease. In the first 3 years, high-risk FLI conferred an increased risk (adjusted hazard ratio, 95% CI) of ischaemic heart disease (2.14, 1.94-2.36), hypertension (2.84, 2.70-2.98), type 2 diabetes mellitus (4.55, 4.04-5.12), dyslipidaemia (2.48, 2.32-2.64), ischaemic stroke (1.31, 1.20-1.42) and hepatic malignancy (1.69, 1.23-2.30). FLI was not associated with risk of extrahepatic malignancy but was associated with a higher risk of specific cancers (colon, upper gastrointestinal and breast). All-cause mortality was similarly stratified by FLI, independently of non-invasive fibrosis scores. Conclusions: FLI identifies NAFLD and holds potential for the risk stratification of cardiometabolic and malignant disease outcomes (including some extrahepatic malignancies), as well as all-cause mortality. Its use in population screening for primary and secondary prevention of NAFLD should be considered. Impact and implications: Our analysis using the UK Biobank study shows the potential of the fatty liver index as a risk stratification tool for identifying the risk of developing NAFLD, ischaemic heart disease, ischaemic stroke, type 2 diabetes mellitus, hypertension, hyperlipidaemia, hepatic malignancy, specific metabolism-related malignancies and all-cause mortality. These results suggest that the fatty liver index should be considered as a non-invasive steatosis score that may help guide primary prevention strategies for NAFLD and related outcomes.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15–20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1–5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28–29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

BackgroundThe quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. ObjectiveThis study aims to evaluate the implementation of the “warfarin bundle,” a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. MethodsPatients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. ResultsWe started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. ConclusionsWe anticipate that the “bundle of care,” which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. International Registered Report Identifier (IRRID)DERR1-10.2196/46710

Background: Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory.Methods: A systematic review identified 12 pharmacogenetic studies investigating genetic variation in CYP3A4*22 and CYP3A5*3 and TIPN. In our candidate gene study, 288 eligible participants (211 taxane participants receiving docetaxel or paclitaxel, and 77 control participants receiving oxaliplatin) were successfully genotyped for CYP3A4*22 and CYP3A5*3. Genotyping data was transformed into a combined CYP3A metaboliser phenotype: Poor metabolisers, intermediate metabolisers and extensive metabolisers. Individual genotypes and combined CYP3A metaboliser phenotypes were assessed in relation to neurotoxicity, including by meta-analysis where possible.Results: In the systematic review, no significant association was found between CYP3A5*3 and TIPN in seven studies, with one study reporting a protective association. For CYP3A4*22, one study has reported an association with TIPN, while four other studies failed to show an association. Evaluation of our patient cohort showed that paclitaxel was found to be more neurotoxic than docetaxel (p < 0.001). Diabetes was also significantly associated with the development of TIPN. The candidate gene analysis showed no significant association between either SNP (CYP3A5*3 and CYP3A4*22) and the development of TIPN overall, or severe TIPN. Meta-analysis showed no association between these two variants and TIPN. Transformed into combined CYP3A metaboliser phenotypes, 30 taxane recipients were poor metabolisers, 159 were intermediate metabolisers, and 22 were extensive metabolisers. No significant association was observed between metaboliser status and case-control status.Summary: We have shown that the risk of peripheral neuropathy during taxane chemotherapy is greater in patients who have diabetes. CYP3A genotype or phenotype was not identified as a risk factor in either the candidate gene analysis or the systematic review/meta-analysis, although we cannot exclude the possibility of a minor contribution, which would require a larger sample size.

Diagnostics require precision and predictive ability to be clinically useful. Integration of multi-omic with clinical data is crucial to our understanding of disease pathogenesis and diagnosis. However, interpretation of overwhelming amounts of information at the individual level requires sophisticated computational tools for extraction of clinically meaningful outputs. Moreover, evolution of technical and analytical methods often outpaces standardisation strategies. RNA is the most dynamic component of all -omics technologies carrying an abundance of regulatory information that is least harnessed for use in clinical diagnostics. Gene expression-based tests capture genetic and non-genetic heterogeneity and have been implemented in certain diseases. For example patients with early breast cancer are spared toxic unnecessary treatments with scores based on the expression of a set of genes (e.g., Oncotype DX). The ability of transcriptomics to portray the transcriptional status at a moment in time has also been used in diagnosis of dynamic diseases such as sepsis. Gene expression profiles identify endotypes in sepsis patients with prognostic value and a potential to discriminate between viral and bacterial infection. The application of transcriptomics for patient stratification in clinical environments and clinical trials thus holds promise. In this review, we discuss the current clinical application in the fields of cancer and infection. We use these paradigms to highlight the impediments in identifying useful diagnostic and prognostic biomarkers and propose approaches to overcome them and aid efforts towards clinical implementation.

Measurement(s) Adverse Event Technology Type(s) digital curation Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.16681933

Abstract Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond.

Abstract Warfarin remains the most widely prescribed oral anticoagulant in sub‐Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine‐learning techniques in predicting stable warfarin dose in sub‐Saharan Black‐African patients and (b) externally validated a previously developed Warfarin Anticoagulation in Patients in Sub‐Saharan Africa (War‐PATH) clinical dose–initiation algorithm. The development cohort included 364 patients recruited from eight outpatient clinics and hospital departments in Uganda and South Africa (June 2018–July 2019). Validation was conducted using an external validation cohort (270 patients recruited from August 2019 to March 2020 in 12 outpatient clinics and hospital departments). Based on the mean absolute error (MAE; mean of absolute differences between the actual and predicted doses), random forest regression (12.07 mg/week; 95% confidence interval [CI], 10.39–13.76) was the best performing machine‐learning technique in the external validation cohort, whereas the worst performing technique was model trees (17.59 mg/week; 95% CI, 15.75–19.43). By comparison, the simple, commonly used regression technique (ordinary least squares) performed similarly to more complex supervised machine‐learning techniques and achieved an MAE of 13.01 mg/week (95% CI, 11.45–14.58). In summary, we have demonstrated that simpler regression techniques perform similarly to more complex supervised machine‐learning techniques. We have also externally validated our previously developed clinical dose–initiation algorithm, which is being prospectively tested for clinical utility.

BackgroundPolypharmacy can be a consequence of overprescribing that is prevalent in older adults with multimorbidity. Polypharmacy can cause adverse reactions and result in hospital admission. This study predicted risks of adverse drug reaction (ADR)-related and emergency hospital admissions by medicine classes.MethodsWe used electronic health record data from general practices of Clinical Practice Research Datalink (CPRD GOLD) and Aurum. Older patients who received at least five medicines were included. Medicines were classified using the British National Formulary sections. Hospital admission cases were propensity-matched to controls by age, sex, and propensity for specific diseases. The matched data were used to develop and validate random forest (RF) models to predict the risk of ADR-related and emergency hospital admissions. Shapley Additive eXplanation (SHAP) values were calculated to explain the predictions.ResultsIn total, 89,235 cases with polypharmacy and hospitalised with an ADR-related admission were matched to 443,497 controls. There were over 112,000 different combinations of the 50 medicine classes most implicated in ADR-related hospital admission in the RF models, with the most important medicine classes being loop diuretics, domperidone and/or metoclopramide, medicines for iron-deficiency anaemias and for hypoplastic/haemolytic/renal anaemias, and sulfonamides and/or trimethoprim. The RF models strongly predicted risks of ADR-related and emergency hospital admission. The observed Odds Ratio in the highest RF decile was 7.16 (95% CI 6.65-7.72) in the validation dataset. The C-statistics for ADR-related hospital admissions were 0.58 for age and sex and 0.66 for RF probabilities.ConclusionsPolypharmacy involves a very large number of different combinations of medicines, with substantial differences in risks of ADR-related and emergency hospital admissions. Although the medicines may not be causally related to increased risks, RF model predictions may be useful in prioritising medication reviews. Simple tools based on few medicine classes may not be effective in identifying high risk patients.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value

Since the first polygenic risk score (PRS) in 2007, research in this area has progressed significantly. The increasing number of SNPs that have been identified by large scale GWAS analyses has fuelled the development of a myriad of PRSs for a wide variety of diseases and, more recently, to PRSs that potentially identify differential response to specific drugs. PRSs constitute a composite genomic biomarker and potential applications for PRSs in clinical practice encompass risk prediction and disease screening, early diagnosis, prognostication, and drug stratification to improve efficacy or reduce adverse drug reactions. Nevertheless, to our knowledge, no PRSs have yet been adopted into routine clinical practice. Beyond the technical considerations of PRS development, the major challenges that face PRSs include demonstrating clinical utility and circumnavigating the implementation of novel genomic technologies at scale into stretched healthcare systems. In this review, we discuss progress in developing disease susceptibility PRSs across multiple medical specialties, development of pharmacogenomic PRSs, and future directions for the field.

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p < 3.21E-04) for warfarin/metabolite ratios. In an exploratory GWAS analysis, 373 unique SNPs in 13 genes, including CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p < 3.846E-9), with 325 (87%, all located on chromosome 10) SNPs being associated with the S-warfarin/R-warfarin outcome (top SNP rs11188082, CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.

Abstract Background There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods/design AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registration EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183 19 February 2021 ISRCTN reference: 27106947

Introduction Combination antiretroviral therapy (cART) has massively reduced HIV mortality. However, long-term cART increases the risk of adverse drug reactions (ADRs), which can lead to higher morbidity, mortality and healthcare costs for people living with HIV (PLHIV).Pharmacovigilance—monitoring the effects of medicines—is essential for understanding real-world drug safety. In Uganda, pharmacovigilance systems have only recently been developed, and rates of ADR reporting for cART are very low. Thus, the safety profile of medicines currently used to treat HIV and tuberculosis in our population is poorly understood.The Med Safety mobile application has been developed through the European Union’s Innovative Medicines Initiative WEB-Recognising Adverse Drug Reactions project to promote digital pharmacovigilance. This mobile application has been approved for ADR-reporting by Uganda’s National Drug Authority. However, the barriers and facilitators to Med Safety uptake, and its effectiveness in improving pharmacovigilance, are as yet unknown.Methods and analysis A pragmatic cluster-randomised controlled trial will be implemented over 30 months at 191 intervention and 191 comparison cART sites to evaluate Med Safety. Using a randomisation sequence generated by the sealed envelope software, we shall randomly assign the 382 prescreened cART sites to the intervention and comparison arms. Each cART site is a cluster that consists of healthcare professionals and PLHIV receiving dolutegravir-based cART and/or isoniazid preventive therapy. Healthcare professionals enrolled in the intervention arm will be trained in the use of mobile-based, paper-based and web-based reporting, while those in the comparison arm will be trained in paper-based and web-based reporting only.Ethics and dissemination Ethical approval was given by the School of Biomedical Sciences Research and Ethics Committee at Makerere University (SBS-REC-720), and administrative clearance was obtained from Uganda National Council for Science and Technology (HS1366ES). Study results will be shared with healthcare professionals, policymakers, the public and academia.Trial registration number PACTR202009822379650.

Abstract The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

Understanding the immune response to SARS-CoV-2 is dependent on being able to distinguish COVID-19 immune responses from cross-reactive immune responses to other coronaviruses. Here the authors show that choice of antigens and whether an ICS, ELISPOT or T cell proliferation assay is used has a major effect on this discriminatory ability.

Abstract 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.

Objectives To examine the socioeconomic and demographic drivers associated with polypharmacy (5–9 medicines), extreme polypharmacy (9–20 medicines) and increased medication count.Design, setting and participants A total of 5509 participants, from two waves of the English North West Coast, Household Health Survey were analysedOutcome measures Logistic regression modelling was used to find associations with polypharmacy and extreme polypharmacy. A negative binomial regression identified associations with increased medication count. Descriptive statistics explored associations with medication management.Results Age and number of health conditions account for the greatest odds of polypharmacy. ORs (95% CI) were greatest for those aged 65+ (3.87, 2.45 to 6.13) and for those with ≥5 health conditions (10.87, 5.94 to 19.88). Smaller odds were seen, for example, in those prescribed cardiovascular medications (3.08, 2.36 to 4.03), or reporting >3 emergency attendances (1.97, 1.23 to 3.17). Extreme polypharmacy was associated with living in a deprived neighbourhood (1.54, 1.06 to 2.26). The greatest risk of increased medication count was associated with age, number of health conditions and use of primary care services. Relative risks (95% CI) were greatest for those aged 65+ (2.51, 2.23 to 2.82), those with ≥5 conditions (10.26, 8.86 to 11.88) or those reporting >18 primary care visits (2.53, 2.18 to 2.93). Smaller risks were seen in, for example, respondents with higher levels of income deprivation (1.35, 1.03 to 1.77). Polypharmic respondents were more likely to report medication management difficulties associated with taking more than one medicine at a time (p

BackgroundAdult chronic heart failure mainly affects an elderly population with multiple comorbidities that often require frequent medical visits to prevent poor health outcomes. However, the heart failure disease process reduces their independence by reducing mobility, exercise tolerance, and cognitive decline. Remote care technologies can bridge the gap in care for these patients by allowing them to be followed up within the comfort of their home and encourage their self-care. However, patients, carers, and health care professionals need to engage with the technology for it to be useful. ObjectiveThis systematic review explores qualitative primary studies of remote care technologies used in heart failure, to determine the factors that affect user engagement with the technology. This is explored from the perspective of patients, carers, and health care professionals. MethodsRelevant studies published between January 1, 1990, and September 19, 2020, were identified from EMBASE, Ovid MEDLINE, PubMed, Cochrane Library, and Scopus. These studies were then synthesized using thematic analysis. Relevant user experiences with remote care were extracted using line-by-line coding. These codes were summarized into secondary codes and core concepts, which were further merged into overarching themes that encapsulate user experience with remote care. ResultsThe review included 47 studies, which led to the generation of 5 overarching themes that affect engagement: (1) “Convenience” relates to time saved by the intervention; (2) “Clinical Care” relates to perceived quality of care and health outcomes; (3) “Communication” involves feedback and interaction between patients, staff, and carers; (4) “Education” concerns the tailored information provided; and (5) “Ease of Use” relates to accessibility and technical barriers to engagement. Each theme was applied to each user base of patient, carer, and health care professional in a different manner. ConclusionsThe 5 themes identified highlight aspects of remote care that facilitate engagement, and should be considered in both future design and trials evaluating these technologies.

Warfarin has remained the most commonly prescribed vitamin K oral anticoagulant worldwide since its approval in 1954. Dosing challenges including having a narrow therapeutic window and a wide interpatient variability in dosing requirements have contributed to making it the most studied drug in terms of genotype-phenotype relationships. However, most of these studies have been conducted in Whites or Asians which means the current pharmacogenomics evidence-base does not reflect ethnic diversity. Due to differences in minor allele frequencies of key genetic variants, studies conducted in Whites/Asians may not be applicable to underrepresented populations such as Blacks, Hispanics/Latinos, American Indians/Alaska Natives and Native Hawaiians/other Pacific Islanders. This may exacerbate health inequalities when Whites/Asians have better anticoagulation profiles due to the existence of validated pharmacogenomic dosing algorithms which fail to perform similarly in the underrepresented populations. To examine the extent to which individual races/ethnicities are represented in the existing body of pharmacogenomic evidence, we review evidence pertaining to published pharmacogenomic dosing algorithms, including clinical utility studies, cost-effectiveness studies and clinical implementation guidelines that have been published in the warfarin field.

Abstract Background The Household Health Survey (HHS) was developed to understand the socioeconomic determinants of mental and physical health, and health inequalities in health and social care. This paper aims to provide a detailed rationale of the development and implementation of the survey and explore socio-economic variations in physical and mental health and health care. Methods This comprehensive longitudinal public health survey was designed and piloted in a disadvantaged area of England, comprising questions on housing, physical health, mental health, lifestyle, social issues, environment, work, and finances. After piloting, the HHS was implemented across 28 neighbourhoods – 10 disadvantaged neighbourhoods for learning (NfLs), 10 disadvantaged comparator sites, and eight relatively advantaged areas, in 2015 and 2018. Participants were recruited via random sampling of households in pre-selected neighbourhoods based on their areas of deprivation. Results 7731 residents participated in Wave 1 (N = 4319) and 2 (n = 3412) of the survey, with 871 residents having participated in both. Mental health, physical health, employment, and housing quality were poorer in disadvantaged neighbourhoods than in relatively advantaged areas. Conclusions This survey provides important insights into socio-economic variations in physical and mental health, with findings having implications for improved care provision to enable residents from any geographical or socio-economic background to access suitable care.

Introduction: Immune checkpoint inhibitors can lead to thyroid dysfunction. However, the understanding of the clinical phenotype of ICI-induced thyroid dysfunction in the real-world population is limited. The purpose of this study was to characterise the clinical patterns of dysfunction and evaluate the demographic, biochemical and immunological features associated with this patient cohort. Materials and methods: To characterise the longitudinal clinical course of thyroid dysfunction in patients from a single, UK regional cancer centre, a retrospective review of patients was conducted. Inclusion criteria included all patients treated with antiPD-1 checkpoint inhibitors (ICI), either as monotherapy (pembrolizumab/nivolumab) or in combination with a CTLA-4 inhibitor (ipilimumab). Patterns of toxicity were evaluated together with assessment of antibody titres. Results: Over 16 months, thyroid dysfunction was seen in 13/90 and 3/13 patients treated with anti-PD1 monotherapy and in combination with ipilimumab, respectively. Patients either developed hyperthyroidism followed by hypothyroidism (12/16) or de novo hypothyroidism (4/16). Most patients were female (n = 11). All patients required thyroid replacement therapy. There was no relationship between clinical pattern of dysfunction and the presence of thyroid autoantibodies. Conclusions: There are two distinct patterns of thyroid dysfunction in ICI-treated patients. Patients with thyroiditis develop subsequent hypothyroidism in the vast majority of cases. The potential benefit from steroids or other therapy to manage t he hyperthyroid phase remains unclear. Early detection of these patients through appropriate monitoring will improve clinical management and early hormone replacement, reducing the symptomatic burden of hypothyroidism.

Background The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT infrastructures. We report results of CDS implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites in the Netherlands, Spain, Slovenia, Italy, Greece, United Kingdom and Austria, covering a wide variety of healthcare settings. Methods We evaluated the CDS implementation process through qualitative and quantitative process indicators. Quantitative indicators included statistics on generated PGx reports, median time from sampled upload until report delivery and statistics on report retrievals via the mobile-based CDS tool. Adoption of different CDS tools, uptake and usability were further investigated through a user survey among healthcare providers. Results of a risk assessment conducted prior to the implementation process were retrospectively analyzed and compared to actual encountered difficulties and their impact. Results As of March 2021, personalized PGx reports were produced from 6884 genotyped samples with a median delivery time of twenty minutes. Out of 131 invited healthcare providers, 65 completed the questionnaire (response rate: 49.6%). Overall satisfaction rates with the different CDS tools varied between 63.6% and 85.2% per tool. Delays in implementation were caused by challenges including institutional factors and complexities in the development of required tools and reference data resources, such as genotype-phenotype mappings. Conclusions We demonstrated the feasibility of implementing a standardized PGx decision support solution in a multinational, multi-language and multi-center setting. Remaining challenges for future wide-scale roll-out include the harmonization of existing PGx information in guidelines and drug labels, the need for strategies to lower the barrier of PGx CDS adoption for healthcare institutions and providers, and easier compliance with regulatory and legal frameworks.

ABSTRACT: 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)

Abstract 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.

HLA-B*13:01 allele has been identified as the genetic determinant of dapsone hypersensitivity syndrome (DHS) among leprosy and non-leprosy patients in several studies. Dapsone hydroxylamine (DDS-NHOH), an active metabolite of dapsone, has been believed to be responsible for DHS. However, studies have not highlighted the importance of other genetic polymorphisms in dapsone-induced severe cutaneous adverse reactions (SCAR). We investigated the association of HLA alleles and cytochrome P450 (CYP) alleles with dapsone-induced SCAR in Thai non-leprosy patients. A prospective cohort study, 16 Thai patients of dapsone-induced SCARs (5 SJS-TEN and 11 DRESS) and 9 Taiwanese patients of dapsone-induced SCARs (2 SJS-TEN and 7 DRESS), 40 dapsone-tolerant controls, and 470 general Thai population were enrolled. HLA class I and II alleles were genotyped using polymerase chain reaction-sequence specific oligonucleotides (PCR-SSOs). CYP2C9, CYP2C19, and CYP3A4 genotypes were determined by the TaqMan real-time PCR assay. We performed computational analyses of dapsone and DDS-NHOH interacting with HLA-B*13:01 and HLA-B*13:02 alleles by the molecular docking approach. Among all the HLA alleles, only HLA-B*13:01 allele was found to be significantly associated with dapsone-induced SCARs (OR = 39.00, 95% CI = 7.67–198.21, p = 5.3447 × 10−7), SJS-TEN (OR = 36.00, 95% CI = 3.19–405.89, p = 2.1657 × 10−3), and DRESS (OR = 40.50, 95% CI = 6.38–257.03, p = 1.0784 × 10−5) as compared to dapsone-tolerant controls. Also, HLA-B*13:01 allele was strongly associated with dapsone-induced SCARs in Asians (OR = 36.00, 95% CI = 8.67–149.52, p = 2.8068 × 10−7) and Taiwanese (OR = 31.50, 95% CI = 4.80–206.56, p = 2.5519 × 10−3). Furthermore, dapsone and DDS-NHOH fit within the extra-deep sub pocket of the antigen-binding site of the HLA-B*13:01 allele and change the antigen-recognition site. However, there was no significant association between genetic polymorphism of cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) and dapsone-induced SCARs (SJS-TEN and DRESS). The results of this study support the specific genotyping of the HLA-B*13:01 allele to avoid dapsone-induced SCARs including SJS-TEN and DRESS before initiating dapsone therapy in the Asian population.

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab. Causality was confirmed by a positive re-challenge with amidotrizoate and laboratory investigations that implicated T cells. Importantly, the introduction of atezolizumab appears to have altered the immunologic response to amidotrizoate in terms of the tolerance–elicitation continuum. Proof of concept studies demonstrated enhancement of recall responses to a surrogate antigen panel following in-vitro (healthy donors) and in-vivo (ICI patients) administrations of ICIs. Our findings highlight the importance of considering all concomitant medications in patients on ICIs who develop immune-mediated adverse reactions. In the event of some immune-related adverse reactions, it may be critical to identify the culprit antigen-forming entity that the ICIs have altered the perception of rather than simply attribute causality to the ICI itself in order to optimize both patient safety and treatment of malignancies.

HLA-B*13:01-positive patients in Thailand can develop frequent co-trimoxazole hypersensitivity reactions. This study aimed to characterize drug-specific T cells from three co-trimoxazole hypersensitive patients presenting with either Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms. Two of the patients carried the HLA allele of interest, namely HLA-B*13:01. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones were generated from T cell lines of co-trimoxazole hypersensitive HLA-B*13:01-positive patients. Clones were characterized for antigen specificity and cross-reactivity with structurally related compounds by measuring proliferation and cytokine release. Surface marker expression was characterized via flow cytometry. Mechanistic studies were conducted to assess pathways of T cell activation in response to antigen stimulation. Peripheral blood mononuclear cells from all patients were stimulated to proliferate and secrete IFN-γ with nitroso sulfamethoxazole. All sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones expressed the CD4+ phenotype and strongly secreted IL-13 as well as IFN-γ, granzyme B and IL-22. No secretion of IL-17 was observed. A number of nitroso sulfamethoxazole-specific clones cross-reacted with nitroso dapsone but not sulfamethoxazole whereas sulfamethoxazole specific clones cross-reacted with nitroso sulfamethoxazole only. The nitroso sulfamethoxazole specific clones were activated in both antigen processing-dependent and -independent manner, while sulfamethoxazole activated T cell responses via direct HLA binding. Furthermore, activation of nitroso sulfamethoxazole-specific, but not sulfamethoxazole-specific, clones was blocked with glutathione. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones from hypersensitive patients were CD4+ which suggests that HLA-B*13:01 is not directly involved in the iatrogenic disease observed in co-trimoxazole hypersensitivity patients.

INTRODUCTION:Warfarin is the most commonly prescribed oral anticoagulant in sub-Saharan Africa and requires ongoing monitoring. The burden of both infectious diseases and non-communicable diseases is high and medicines used to treat comorbidities may interact with warfarin. We describe service provision, patient characteristics, and anticoagulation control at selected anticoagulation clinics in Uganda and South Africa. METHODS:We evaluated two outpatient anticoagulation services in Kampala, Uganda and three in Cape Town, South Africa between 1 January and 31 July 2018. We collected information from key staff members about the clinics' service provision and extracted demographic and clinical data from a sample of patients' clinic records. We calculated time in therapeutic range (TTR) over the most recent 3-month period using the Rosendaal interpolation method. RESULTS:We included three tertiary level, one secondary level and one primary level anticoagulation service, seeing between 30 and 800 patients per month. Care was rendered by nurses, medical officers, and specialists. All healthcare facilities had on-site pharmacies; laboratory INR testing was off-site at two. Three clinics used warfarin dose-adjustment protocols; these were not validated for local use. We reviewed 229 patient clinical records. Most common indications for warfarin were venous thrombo-embolism in 112/229 (49%), atrial fibrillation in 74/229 (32%) and valvular heart disease in 30/229 (13%). Patients were generally followed up monthly. HIV prevalence was 20% and 5% at Ugandan and South African clinics respectively. Cardiovascular comorbidity predominated. Furosemide, paracetamol, enalapril, simvastatin, and tramadol were the most common concomitant drugs. Anticoagulation control was poor at all included clinics with median TTR of 41% (interquartile range 14% to 69%). CONCLUSIONS:TTR was suboptimal at all included sites, despite frequent patient follow-up. Strategies to improve INR control in sub-Saharan patients taking warfarin are needed. Locally validated warfarin dosing algorithms in Uganda and South Africa may improve INR control.

Background: Combination antiretroviral therapy (cART) is the standard for human immunodeficiency virus (HIV) infection treatment but can result in metabolic abnormalities, such as insulin resistance, dyslipidaemia and lipodystrophy, which can increase the risk of cardiovascular disease. Objective: The objective of the trial was to evaluate whether or not telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ partial agonist, could reduce insulin resistance in HIV-positive individuals on cART, and affect blood and imaging biomarkers of cardiometabolic disease. Design: A Phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan over a period of 48 weeks with an adaptive design comprising two stages was used to identify the optimal dose of telmisartan. Participants were randomised to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control). Setting: Recruitment was from 19 HIV specialist centres in the UK. Participants: A total of 377 patients infected with HIV who met the prespecified inclusion/exclusion criteria. Interventions: 20-, 40- and 80-mg tablets of telmisartan. Main outcome measures: The primary outcome measure was reduction in the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, at 24 weeks. Secondary outcome measures were changes in plasma lipid profile; Quantitative Insulin Sensitivity Check Index (QUICKI) and revised QUICKI, alternative markers of insulin resistance, plasma adipokines (adiponectin, leptin, interleukin 8, tumour necrosis factor alpha, resistin); high-sensitivity C-reactive protein (hs-CRP); body fat redistribution, as measured by magnetic resonance imaging/proton magnetic resonance spectroscopy; changes in renal markers (albumin-to-creatinine ratio, neutrophil gelatinase-associated lipocalin); and tolerability to telmisartan. Results: At the interim analysis, 80 mg of telmisartan was taken forward into the second stage of the study. Baseline characteristics were balanced across treatment arms. There were no differences in HOMA-IR [0.007, standard error (SE) 0.106], QUICKI (0.001, SE 0.001) and revised QUICKI (0.002, SE 0.002) at 24 weeks between the telmisartan (80 mg; n = 106) and non-intervention (n = 105) arms. Longitudinal analysis over 48 weeks showed that there was no change in HOMA-IR, lipid or adipokine levels; however, but there were significant, but marginal, improvements in revised QUICKI [0.004, 95% confidence interval (CI) 0.000 to 0.008] and plasma hs-CRP (–0.222, 95% CI –0.433 to –0.011) over 48 weeks. Substudies also showed a significant reduction in the liver fat content at 24 weeks (1.714, 95% CI –2.787 to –0.642; p = 0.005) and urinary albumin excretion at 48 weeks (–0.665, 95% CI –1.31 to –0.019; p = 0.04). There were no differences in serious adverse events between the telmisartan and control arms. Limitations: The patients had modest elevations of HOMA-IR at baseline, and our trial could have been under-powered to detect smaller improvements in insulin resistance over time. Conclusions: Using a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals. Future work: The mechanistic basis of adipocyte regulation will be studied to allow for development of biomarkers and interventions. Trial registration: Current Controlled Trials ISRCTN51069819. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

AimsStatin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.Methods and resultsSRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.ConclusionsIn this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

Improved serodiagnostic tests for typhoid fever (TF) are needed for surveillance, to facilitate patient management, curb antibiotic resistance, and inform public health programs. To address this need, IgA, IgM and IgG ELISAs using Salmonella enterica serovar Typhi (S. Typhi) lipopolysaccharide (LPS) and hemolysin E (t1477) protein were conducted on 86 Nigerian pediatric TF and 29 non-typhoidal Salmonella (NTS) cases, 178 culture-negative febrile cases, 28 "other" (i.e., non-Salmonella) pediatric infections, and 48 healthy Nigerian children. The best discrimination was achieved between TF and healthy children. LPS-specific IgA and IgM provided receiver operator characteristic areas under the curve (ROC AUC) values of 0.963 and 0.968, respectively, and 0.978 for IgA+M combined. Similar performance was achieved with t1477-specific IgA and IgM (0.968 and 0.968, respectively; 0.976 combined). IgG against LPS and t1477 was less accurate for discriminating these groups, possibly as a consequence of previous exposure, although ROC AUC values were still high (0.928 and 0.932, respectively). Importantly, discrimination between TF and children with other infections was maintained by LPS-specific IgA and IgM (AUC = 0.903 and 0.934, respectively; 0.938 combined), and slightly reduced for IgG (0.909), while t1477-specific IgG performed best (0.914). A similar pattern was seen when comparing TF with other infections from outside Nigeria. The t1477 may be recognized by cross-reactive antibodies from other acute infections, although a robust IgG response may provide some diagnostic utility in populations where incidence of other infections is low, such as in children. The data are consistent with IgA and IgM against S. Typhi LPS being specific markers of acute TF.

Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. CYP4F2 is part of the CYP4F gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the CYP4F gene cluster on expression of the individual CYP4F genes and warfarin response. mRNA levels of the CYP4F gene cluster were quantified in human liver samples (n = 149) obtained from a well-characterized liver bank and fine mapping of the CYP4F gene cluster encompassing CYP4F2, CYP4F11, and CYP4F12 was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients (n = 711) was also analyzed for genetic variations across the CYP4F gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between CYP4F genes were explored in silico using publicly available data repositories. We found that SNPs in CYP4F2, CYP4F11, and CYP4F12 were associated with mRNA expression in the CYP4F gene cluster. In particular, CYP4F2 rs2108622 was associated with increased CYP4F2 expression while CYP4F11 rs1060467 was associated with decreased CYP4F2 expression. Interestingly, these CYP4F2 and CYP4F11 SNPs showed similar effects with warfarin stable dose where CYP4F11 rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, Pc = 0.017), an effect opposite to that previously reported with CYP4F2 (rs2108622). However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI), gender, baseline clotting factor II level, CYP2C9∗2 rs1799853, CYP2C9∗3 rs1057910, and VKORC1 rs9923231 improved warfarin dose variability only by 0.5–0.7% with an improvement in dose prediction accuracy of ∼1–2%. Although there is complex regulation across the CYP4F gene cluster, the opposing effects between the two SNPs in the CYP4F gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.

AimTo evaluate drug therapy for alcohol dependence in the 12 months after first diagnosis in UK primary care.DesignOpen cohort study.SettingGeneral practices contributing data to the UK Clinical Practice Research Database.Participants39,980 people with an incident diagnosis of alcohol dependence aged 16 years or older between 1 January 1990 and 31 December 2013.Main outcome measureUse 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.FindingsOnly 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.ConclusionDrug 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.

This study aims to investigate the incidence and annual presentation rates of alcohol dependence in general practice in the UK, and examine age-, gender-, socioeconomic-, and region-specific variation. We conducted a retrospective 'open' cohort study using the Clinical Practice Research Datalink (CPRD), an anonymised primary care database. Prior to data extraction, a case definition for alcohol dependence in CPRD was established using 47 Read codes, which included primary alcohol dependence and consequences of alcohol dependence. Directly standardised rates for incidence and annual presentation were calculated for each year between 1990 and 2013. Rates were compared by gender, age, UK home nation, and practice-level Index of Multiple Deprivation. The directly standardised annual incidence rates were 8.3 and 3.7 per 10,000 male and female patients, respectively. The estimated annual rates of presentation per 10,000 were 17.1 for males and 7.6 for females. Female to male rate ratios were: 0.40 (95% CI: 0.39-0.41) for incident cases; and 0.37 (95% CI: 0.36-0.39) for annual presentation. Rates were highest in those aged 35-54 for both measures and across genders, and lowest in those aged over 75 years. With England as the reference nation, Northern Ireland and Scotland had significantly higher rates for both measures. Patients from the most deprived areas had the highest incidence and annual presentation rates. There is unequal distribution of patients with severe alcohol dependence across population subgroups in general practice. Given the health and economic burden associated with dependent drinking, these data will be useful in informing future public health initiatives.

To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings.The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the 'gold standard' (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist).Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories.Preliminary work-Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52-90%. Phase 3: Percentage exact agreement ranged from 35-70%. Overall, individuals had better agreement with the 'gold standard'.Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups.

Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP.Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups.Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16-16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC.We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.

Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity.

Background: Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. Objectives: (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism. Design: FolATED (Folate Augmentation of Treatment – Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost–utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a ‘small’ effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453. Settings: Clinical – Three centres in Wales – North East Wales, North West Wales and Swansea. Trial management – North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis – University Hospital of Wales, Cardiff. Genetic analysis – University of Liverpool. Participants: Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research. Interventions: Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners. Main outcome measures: Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by ‘area under curve’ (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health – BDI-II (primary), Clinical Global Impression (CGI), Montgomery–Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health – UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale – 5 Dimensions (EQ-5D); Biochemistry – serum folate, B12, homocysteine; Adherence – Morisky Questionnaire; Economics – resource use. Results: Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from –12.7 to 7.0 days] and saved a mean of just £48 (95% CI from –£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from –5.2% to –0.8%). Conclusions: The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM. Trial registration: Current Controlled Trials ISRCTN37558856. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.

Background: Pragmatic trials compare the effects of different decisions in usual clinical practice. Objectives: To develop and evaluate methods to implement simple pragmatic trials using routinely collected electronic health records (EHRs) and recruiting patients at the point of care; to identify the barriers and facilitators for general practitioners (GPs) and patients and the experiences of trial participants. Design: Two exemplar randomised trials (Retropro and eLung) with qualitative evaluations. Setting: Four hundred and fifty-nine English and Scottish general practices contributing EHRs to a research database, of which 17 participated in the trials. Participants: Retropro aimed to recruit 300 patients with hypercholesterolaemia and high cardiovascular risk and eLung aimed to recruit 150 patients with a chronic obstructive pulmonary disease exacerbation. Interventions: Retropro randomised between simvastatin and atorvastatin and eLung between immediate antibiotics and deferred or non-use. eLung recruited during an unscheduled consultation using EHR flagging. Main outcome measure: Successful trial completion with implementation of information technology (IT) system for flagging and data processing and documentation of operational and scientific experiences. Data sources: EHR research database. Results: The governance approval process took over 3 years. A total of 58.8% of the practices (n = 270) expressed interest in participating. The number of interested practices dropped substantially with each stage of the governance process. In Retropro, 6.5% of the practices (n = 30) were eventually approved and 3.7% (n = 17) recruited patients; in eLung, these numbers were 6.8% (n = 31) and 1.3% (n = 6) respectively. Retropro successfully completed recruitment (301 patients) whereas eLung recruited 31 patients. Retropro recruited 20.6% of all statin starters in recruiting practices and 1.1% in the EHR database; the comparable numbers for eLung were 32.3% and 0.9% respectively. The IT system allowed for complex eligibility criteria with central on and off control of recruitment and flagging at a practice. Good Clinical Practice guidelines, governance and consent procedures were found to have substantially affected the intended simple nature of the trials. One qualitative study of 13 clinicians found that clinicians were generally positive about the principle of computerised trial recruitment (flagging during consultation). However, trials which did not include patients with acute illness were favoured. The second qualitative process evaluation interviewed 27 GPs about their actual experiences, including declining, recruiting and non-recruiting GPs. Opportunistic patient recruitment during a routine GP consultation was found to be the most controversial element. The actual experiences of recruiting patients during unscheduled consultation were generally more positive than the hypothetical views of GPs. Several of the recruiting GPs reported the process took 5 minutes and was straightforward and feasible on most occasions. Almost all GPs expressed their strong support for the use of EHRs for trials. Ten eLung participants were interviewed, all of whom considered it acceptable to be recruited during a consultation and to use EHRs for trials. Conclusions: EHR point-of-care trials are feasible, although the recruitment of clinicians is a major challenge owing to the complexity of trial approvals. These trials will provide substantial evidence on clinical effectiveness only if trial interventions and participating clinicians and patients are typical of usual clinical care and trials are simple to initiate and conduct. Recommendations for research include the development of evidence and implementation of risk proportionality in trial governance and conduct. Trial registration: Current Controlled Trials ISRCTN33113202 and ISRCTN72035428. Funding: This project was funded by the NIHR Health Technology Assessment programme and the Wellcome Trust and will be published in full in Health Technology Assessment; Vol. 18, No. 43. See the NIHR Journals Library website for further project information.

Aims: To comprehensively investigate the incidence, nature and risk factors of adverse drug reactions (ADRs) in a hospital-based population of children, with rigorous assessment of causality, severity and avoidability, and to assess the consequent impact on children and families. We aimed to improve the assessment of ADRs by development of new tools to assess causality and avoidability, and to minimise the impact on families by developing better strategies for communication. Review methods: Two prospective observational studies, each over 1 year, were conducted to assess ADRs in children associated with admission to hospital, and those occurring in children who were in hospital for longer than 48 hours. We conducted a comprehensive systematic review of ADRs in children. We used the findings from these studies to develop and validate tools to assess causality and avoidability of ADRs, and conducted interviews with parents and children who had experienced ADRs, using these findings to develop a leaflet for parents to inform a communication strategy about ADRs. Results: The estimated incidence of ADRs detected in children on admission to hospital was 2.9% [95% confidence interval (CI) 2.5% to 3.3%]. Of the reactions, 22.1% (95% CI 17% to 28%) were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44 out of 249 (17.7%) of ADRs, the remainder originating from hospital. A total of 120 out of 249 (48.2%) reactions resulted from treatment for malignancies. Off-label and/or unlicensed (OLUL) medicines were more likely to be implicated in an ADR than authorised medicines [relative risk (RR) 1.67, 95% CI 1.38 to 2.02; p 48 hours, the overall incidence of definite and probable ADRs based on all admissions was 15.9% (95% CI 15.0 to 16.8). Opiate analgesic drugs and drugs used in general anaesthesia (GA) accounted for > 50% of all drugs implicated in ADRs. The odds ratio of an OLUL drug being implicated in an ADR compared with an authorised drug was 2.25 (95% CI 1.95 to 2.59; p