Rapid systematic review on risks and outcomes of sepsis: the influence of risk factors associated with health inequalities.

BACKGROUND AND AIMS: Sepsis is a serious and life-threatening condition caused by a dysregulated immune response to an infection. Recent guidance issued in the UK gave recommendations around recognition and antibiotic treatment of sepsis, but did not consider factors relating to health inequalities. The aim of this study was to summarise the literature investigating associations between health inequalities and sepsis. METHODS: Searches were conducted in Embase for peer-reviewed articles published since 2010 that included sepsis in combination with one of the following five areas: socioeconomic status, race/ethnicity, community factors, medical needs and pregnancy/maternity. RESULTS: Five searches identified 1,402 studies, with 50 unique studies included in the review after screening (13 sociodemographic, 14 race/ethnicity, 3 community, 3 care/medical needs and 20 pregnancy/maternity; 3 papers examined multiple health inequalities). Most of the studies were conducted in the USA (31/50), with only four studies using UK data (all pregnancy related). Socioeconomic factors associated with increased sepsis incidence included lower socioeconomic status, unemployment and lower education level, although findings were not consistent across studies. For ethnicity, mixed results were reported. Living in a medically underserved area or being resident in a nursing home increased risk of sepsis. Mortality rates after sepsis were found to be higher in people living in rural areas or in those discharged to skilled nursing facilities while associations with ethnicity were mixed. Complications during delivery, caesarean-section delivery, increased deprivation and black and other ethnic minority race were associated with post-partum sepsis. CONCLUSION: There are clear correlations between sepsis morbidity and mortality and the presence of factors associated with health inequalities. To inform local guidance and drive public health measures, there is a need for studies conducted across more diverse setting and countries.

Clinician acceptability of an antibiotic prescribing knowledge support system for primary care: a mixed-method evaluation of features and context.

BACKGROUND: Overprescribing of antibiotics is a major concern as it contributes to antimicrobial resistance. Research has found highly variable antibiotic prescribing in (UK) primary care, and to support more effective stewardship, the BRIT Project (Building Rapid Interventions to optimise prescribing) is implementing an eHealth Knowledge Support System. This will provide unique individualised analytics information to clinicians and patients at the point of care. The objective of the current study was to gauge the acceptability of the system to prescribing healthcare professionals and highlight factors to maximise intervention uptake. METHODS: Two mixed-method co-design workshops were held online with primary care prescribing healthcare professionals (n = 16). Usefulness ratings of example features were collected using online polls and online whiteboards. Verbal discussion and textual comments were analysed thematically using inductive (participant-centred) and deductive perspectives (using the Theoretical Framework of Acceptability). RESULTS: Hierarchical thematic coding generated three overarching themes relevant to intervention use and development. Clinician concerns (focal issues) were safe prescribing, accessible information, autonomy, avoiding duplication, technical issues and time. Requirements were ease and efficiency of use, integration of systems, patient-centeredness, personalisation, and training. Important features of the system included extraction of pertinent information from patient records (such as antibiotic prescribing history), recommended actions, personalised treatment, risk indicators and electronic patient communication leaflets. Anticipated acceptability and intention to use the knowledge support system was moderate to high. Time was identified as a focal cost/ burden, but this would be outweighed if the system improved patient outcomes and increased prescribing confidence. CONCLUSION: Clinicians anticipate that an eHealth knowledge support system will be a useful and acceptable way to optimise antibiotic prescribing at the point of care. The mixed method workshop highlighted issues to assist person-centred eHealth intervention development, such as the value of communicating patient outcomes. Important features were identified including the ability to efficiently extract and summarise pertinent information from the patient records, provide explainable and transparent risk information, and personalised information to support patient communication. The Theoretical Framework of Acceptability enabled structured, theoretically sound feedback and creation of a profile to benchmark future evaluations. This may encourage a consistent user-focused approach to guide future eHealth intervention development.

A first step towards best practice recommendations for the design and statistical analyses of pragmatic clinical trials: A modified Delphi approach.

AIM: Pragmatic clinical trials (PCTs) are randomized trials implemented through routine clinical practice, where design parameters of traditional randomized controlled trials are modified to increase generalizability. However, this may introduce statistical challenges. We aimed to identify these challenges and discuss possible solutions leading to best practice recommendations for the design and analysis of PCTs. METHODS: A modified Delphi method was used to reach consensus among a panel of 11 experts in clinical trials and statistics. Statistical issues were identified in a focused literature review and aggregated with insights and possible solutions from experts collected through a series of survey iterations. Issues were ranked according to their importance. RESULTS: Twenty-seven articles were included and combined with experts' insight to generate a list of issues categorized into participants, recruiting sites, randomization, blinding and intervention, outcome (selection and measurement) and data analysis. Consensus was reached about the most important issues: risk of participants' attrition, heterogeneity of "usual care" across sites, absence of blinding, use of a subjective endpoint and data analysis aligned with the trial estimand. Potential issues should be anticipated and preferably be addressed in the trial protocol. The experts provided solutions regarding data collection and data analysis, which were considered of equal importance. DISCUSSION: A set of important statistical issues in PCTs was identified and approaches were suggested to anticipate and/or minimize these through data analysis. Any impact of choosing a pragmatic design feature should be gauged in the light of the trial estimand.

Primary Prevention of Cardiovascular and Heart Failure Events With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Their Combination in Type 2 Diabetes.

OBJECTIVE: To assess associations between current use of sodium-glucose cotransporter 2 inhibitors (SGLT2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and their combination and risk for major adverse cardiac and cerebrovascular events (MACCE) and heart failure (HF) in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: In three nested case-control studies involving patients with type 2 diabetes in England and Wales (primary care data from the Clinical Practice Research Datalink and Secure Anonymised Information Linkage Databank with linkage to hospital and mortality records), we matched each patient experiencing an event with up to 20 control subjects. Adjusted odds ratios (ORs) for MACCE and HF among patients receiving SGLT2i or GLP-1RA regimens versus other combinations were estimated using conditional logistic regression and pooled using random-effects meta-analysis. RESULTS: Among 336,334 people with type 2 diabetes and without cardiovascular disease, 18,531 (5.5%) experienced a MACCE. In a cohort of 411,206 with type 2 diabetes and without HF, 17,451 (4.2%) experienced an HF event. Compared with other combination regimens, the adjusted pooled OR and 95% CI for MACCE associated with SGLT2i regimens was 0.82 (0.73, 0.92), with GLP-1RA regimens 0.93 (0.81, 1.06), and with the SGLT2i/GLP-1RA combination 0.70 (0.50, 0.98). Corresponding data for HF were SGLT2i 0.49 (0.42, 0.58), GLP-1RA 0.82 (0.71, 0.95), and SGLT2i/GLP-1RA combination 0.43 (0.28, 0.64). CONCLUSIONS: SGLT2i and SGLT2i/GLP-1RA combination regimens may be beneficial in primary prevention of MACCE and HF and GLP-1RA for HF. These data call for primary prevention trials using these agents and their combination.

Low-dose oral glucocorticoid therapy and risk of osteoporotic fractures in patients with rheumatoid arthritis: a cohort study using the Clinical Practice Research Datalink.

OBJECTIVES: Clinical trials have shown that low-dose glucocorticoid therapy in patients with RA reduces bone loss in hands or hip, but the effect on osteoporotic fractures is not yet clear. Therefore, we investigated the use of low-dose oral glucocorticoids and risk of osteoporotic fractures among patients with RA. METHODS: This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral glucocorticoids was stratified by the most recent prescription in current (<6 months), recent (7-12 months) and past (>1 year) use, and average daily and cumulative doses. Risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, adjusted for lifestyle parameters, comorbidities and comedications. Secondary analyses assessed osteoporotic fracture risk with a combination of average daily and cumulative doses of oral glucocorticoids. RESULTS: Among 15 123 patients with RA (mean age 68.8 years, 68% females), 1640 osteoporotic fractures occurred. Current low-dose oral glucocorticoid therapy (≤7.5 mg prednisolone equivalent dose/day) in patients with RA was not associated with overall risk of osteoporotic fractures (adjusted hazard ratio 1.14, 95% CI 0.98, 1.33) compared with past glucocorticoid use, but was associated with an increased risk of clinical vertebral fracture (adjusted hazard ratio 1.59, 95% CI 1.11, 2.29). Results remained unchanged regardless of a short-term or a long-term use of oral glucocorticoids. CONCLUSION: Clinicians should be aware that even in RA patients who receive low daily glucocorticoid doses, the risk of clinical vertebral fracture is increased.

Implementation of a "real-world" learning health system: Results from the evaluation of the Connected Health Cities programme.

BACKGROUND: The "learning health system" has been proposed to deliver better outcomes for patients and communities by analyzing routinely captured health information and feeding back results to clinical staff. This approach has been piloted in the Connected Health Cities (CHC) programme in four regions in the North of England. This paper presents the results of the evaluation of this program conducted between February and December 2018. METHODS: Fifty nine semistructured interviews were completed with a mix of CHC programme staff and external partners who had contributed to the delivery of the CHC programme. Interviews were audio recorded and transcribed verbatim. This also included the review of project documentation including project reports and minutes of project group meetings, in addition to a short online survey that was completed by 31 members of CHC programme staff. Data were analyzed thematically. RESULTS: Two overarching themes emerged through the thematic analysis of participant interview: (a) challenges in the implementation of learning health system pathways, and (b) benefits to the CHC approach for both staff and patients. In particular, time constraints in delivering an ambitious program of work, data quality, and accessibility, as well as the long-term sustainability of the CHC programme were noted as key challenges in implementing a LHS at scale. CONCLUSIONS: The findings from this evaluation provide valuable insight into creating learning health system at scale, including the potential benefits and likely challenges.

Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study.

BACKGROUND: Patients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs and PPIs and the risk of osteoporotic fractures among patients with RA. METHODS: This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral GCs and PPIs was stratified by the most recent prescription as current use (<6 months), recent use (7-12 months) and past use (>1 year); average daily and cumulative dose; and duration of use. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, statistically adjusted for lifestyle parameters, comorbidities and comedications. RESULTS: Among 12 351 patients with RA (mean age of 68 years, 69% women), 1411 osteoporotic fractures occurred. Concomitant current use of oral GCs and PPIs was associated with a 1.6-fold increased risk of osteoporotic fractures compared with non-use (adjusted HR: 1.60, 95% CI: 1.35 to 1.89). This was statistically different from a 1.2-fold increased osteoporotic fracture risk associated with oral GC or PPI use alone. Most individual fracture sites were significantly associated with concomitant use of oral GCs and PPIs. Among concomitant users, fracture risk did not increase with higher daily dose or duration of PPI use. CONCLUSIONS: There was an interaction in the risk of osteoporotic fractures with concomitant use of oral GCs and PPIs. Fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs.

Developing the infrastructure to support the optimisation of antibiotic prescribing using the learning healthcare system to improve healthcare services in the provision of primary care in England.

INTRODUCTION: The learning healthcare system (LHS) underpinned by data analysis and feedback to clinical care providers is thought to improve quality of care. The work aimed to implement an LHS for antibiotic prescribing in primary care in England. METHOD: Deidentified patient-level data from general practices were processed and analysed at regular intervals (fortnightly increments). A dashboard application was developed and implemented displaying analytical graphics to give periodic feedback to clinicians, tailored to each clinical site. Benchmarking parameters were established by the analysis of two large national primary care datasets allowing peer-to-peer comparisons. To date, the dashboard is available to 70 English practices. CONCLUSIONS: Successful implementation and uptake of the secure technical LHS infrastructure for the analysis and feedback to clinicians of their antibiotic prescribing demonstrate a great appetite for this type of frequent prescribing review in primary care, combining advanced data analytics with tailored feedback.

General practitioners' accounts of negotiating antibiotic prescribing decisions with patients: a qualitative study on what influences antibiotic prescribing in low, medium and high prescribing practices.

BACKGROUND: Antimicrobial resistance (AMR) is high on the UK public health policy agenda, and poses challenges to patient safety and the provision of health services. Widespread prescribing of antibiotics is thought to increase AMR, and mostly takes place in primary medical care. However, prescribing rates vary substantially between general practices. The aim of this study was to understand contextual factors related to general practitioners' (GPs) antibiotic prescribing behaviour in low, high, and around the mean (medium) prescribing primary care practices. METHODS: Qualitative semi-structured interviews were conducted with 41 GPs working in North-West England. Participants were purposively sampled from practices with low, medium, and high antibiotic prescribing rates adjusted for the number and characteristics of patients registered in a practice. The interviews were analysed thematically. RESULTS: This study found that optimizing antibiotic prescribing creates tensions for GPs, particularly in doctor-patient communication during a consultation. GPs balanced patient expectations and their own decision-making in their communication. When not prescribing antibiotics, GPs reported the need for supportive mechanisms, such as regular practice meetings, within the practice, and in the wider healthcare system (e.g. longer consultation times). In low prescribing practices, GPs reported that increasing dialogue with colleagues, having consistent patterns of prescribing within the practice, supportive practice policies, and enough resources such as consultation time were important supports when not prescribing antibiotics. CONCLUSIONS: Insight into GPs' negotiations with patient and public health demands, and consistent and supportive practice-level policies can help support prudent antibiotic prescribing among primary care practices.

Exposure measurement error when assessing current glucocorticoid use using UK primary care electronic prescription data.

PURPOSE: To quantify misclassification in glucocorticoid (GC) exposure defined using UK primary care prescription data. METHODS: A cross-sectional study including patients with rheumatoid arthritis prescribed oral GCs in the past 2 years. Glucocorticoid exposure based on electronic prescription records was compared with participant-reported GC use captured using a paper diary. Prescription data (containing information about prescriptions issued but no dispensing information) was provided by the Clinical Practice Research Datalink. The following variables were defined: current use and dose of oral GCs and if (and when) participants had received a GC injection. For oral GCs, self-reported use was taken to represent "true" exposure. A dataset representing a hypothetical population was generated to assess the impact of the misclassification found for current use. RESULTS: A total of 67 of 78 study participants (86%) were correctly classified as currently on/off oral GCs; 32/38 (84.2%) participants reporting current GC use and 35/40 (87.5%) participants not reporting current use were correctly classified. Estimated values of current dose were imprecise (correlation coefficient 0.46). Concordance between reported and prescribed GC injections was poor (kappa statistic 0.14). Misclassification bias was demonstrated in the hypothetical population: For "true" relative risks of 1.5, 4, and 9, the "observed" relative risks were 1.33, 2.48, and 3.58, respectively. CONCLUSIONS: Misclassification of current use of oral GCs was low but sufficient to lead to significant bias. Researchers should take care to assess the likely impact of exposure misclassification on their analyses.

Protocol for the development of a CONSORT extension for RCTs using cohorts and routinely collected health data.

BACKGROUND: Randomized controlled trials (RCTs) are often complex and expensive to perform. Less than one third achieve planned recruitment targets, follow-up can be labor-intensive, and many have limited real-world generalizability. Designs for RCTs conducted using cohorts and routinely collected health data, including registries, electronic health records, and administrative databases, have been proposed to address these challenges and are being rapidly adopted. These designs, however, are relatively recent innovations, and published RCT reports often do not describe important aspects of their methodology in a standardized way. Our objective is to extend the Consolidated Standards of Reporting Trials (CONSORT) statement with a consensus-driven reporting guideline for RCTs using cohorts and routinely collected health data. METHODS: The development of this CONSORT extension will consist of five phases. Phase 1 (completed) consisted of the project launch, including fundraising, the establishment of a research team, and development of a conceptual framework. In phase 2, a systematic review will be performed to identify publications (1) that describe methods or reporting considerations for RCTs conducted using cohorts and routinely collected health data or (2) that are protocols or report results from such RCTs. An initial "long list" of possible modifications to CONSORT checklist items and possible new items for the reporting guideline will be generated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statements. Additional possible modifications and new items will be identified based on the results of the systematic review. Phase 3 will consist of a three-round Delphi exercise with methods and content experts to evaluate the "long list" and generate a "short list" of key items. In phase 4, these items will serve as the basis for an in-person consensus meeting to finalize a core set of items to be included in the reporting guideline and checklist. Phase 5 will involve drafting the checklist and elaboration-explanation documents, and dissemination and implementation of the guideline. DISCUSSION: Development of this CONSORT extension will contribute to more transparent reporting of RCTs conducted using cohorts and routinely collected health data.

Low salivary cortisol levels in patients with rheumatoid arthritis exposed to oral glucocorticoids: a cross-sectional study set within UK electronic health records.

BACKGROUND: Glucocorticoids (GCs) suppress endogenous cortisol levels which can lead to adrenal insufficiency (AI). The frequency of GC-induced AI remains unclear. In this cross-sectional study, low morning salivary cortisol (MSC) levels were used as a measure of adrenal function. The study aim was to investigate the prevalence of low MSC in patients with rheumatoid arthritis (RA) currently and formerly exposed to oral GCs, and the association with potential risk factors. METHODS: Sample collection was nested within UK primary care electronic health records (from the Clinical Practice Research Datalink). Participants were patients with RA with at least one prescription for oral GCs in the past 2 years. Self-reported oral GC use was used to define current use and current dose; prescription data were used to define exposure duration. MSC was determined from saliva samples; 5 nmol/L was the cut-off for low MSC. The prevalence of low MSC was estimated, and logistic regression was used to assess the association with potential risk factors. RESULTS: 66% of 38 current and 11 % of 38 former GC users had low MSC. Among former users with low MSC, the longest time since GC withdrawal was 6 months. Current GC dose, age and RA duration were significantly associated with increased risk of low MSC. CONCLUSION: The prevalence of low MSC among current GC users is high, and MSC levels may remain suppressed for several months after GC withdrawal. Clinicians should therefore consider the risk of suppressed cortisol and remain vigilant for symptoms of AI following GC withdrawal.

The limitations of using simple definitions of glucocorticoid exposure to predict fracture risk: A cohort study.

PURPOSE: To evaluate the effects of different definitions of glucocorticoid (GC) exposure on the magnitude and pattern of fracture risk using the same dataset. METHODS: Data from patients with rheumatoid arthritis (RA) were extracted from the Clinical Practice Research Datalink, a primary care database with electronic health records in the United Kingdom. Patients exposed to oral GCs were matched to up to two unexposed patients by age, gender and location. The first osteoporotic fracture was identified and adjusted and unadjusted cox proportional hazard ratios (HR) and 95% confidence intervals (CI) produced for fracture risk following GC therapy using different models of risk attribution. These include models demonstrating the effect of dose, duration and recency of GC exposure. RESULTS: There were 16,507 patients included. Exposed patients were older and had more comorbidities. GC therapy was associated with an increased risk of fracture, with the effect size influenced by risk attribution model. The risk of fracture decreased with less recent exposure from HR (95% CI) 1.66 (1.27, 2.16) during the first month of stopping GCs to 1.11 (0.79, 1.57) for between 1 and 3 months. The risk of fracture increased with current daily dose, HR 1.44 (1.17, 1.77) for 5-9.9 mg prednisolone equivalent dose (PEQ) to 3.02 (1.77, 5.15) for 15-19.9 mg PEQ. Risk of fracture increased with cumulative dose, a function of dose and duration, from HR 1.22 (1.03, 1.44) for <1 g to 1.83 (1.35, 2.48) for 7.5-10 g. CONCLUSION: GC exposure was associated with excess fracture risk, with effect size differing according to definition of exposure. This highlights the need to incorporate all exposure dimensions (dose, duration and recency) in these patient's fracture risk assessments.

Protocol for a scoping review to support development of a CONSORT extension for randomised controlled trials using cohorts and routinely collected health data.

INTRODUCTION: Randomised controlled trials (RCTs) conducted using cohorts and routinely collected health data, including registries, electronic health records and administrative databases, are increasingly used in healthcare intervention research. The development of an extension of the CONsolidated Standards of Reporting Trials (CONSORT) statement for RCTs using cohorts and routinely collected health data is being undertaken with the goal of improving reporting quality by setting standards early in the process of uptake of these designs. To develop this extension to the CONSORT statement, a scoping review will be conducted to identify potential modifications or clarifications of existing reporting guideline items, as well as additional items needed for reporting RCTs using cohorts and routinely collected health data. METHODS AND ANALYSIS: In separate searches, we will seek publications on methods or reporting or that describe protocols or results from RCTs using cohorts, registries, electronic health records and administrative databases. Data sources will include Medline and the Cochrane Methodology Register. For each of the four main types of RCTs using cohorts and routinely collected health data, separately, two investigators will independently review included publications to extract potential checklist items. A potential item will either modify an existing CONSORT 2010, Strengthening the Reporting of Observational Studies in Epidemiology or REporting of studies Conducted using Observational Routinely collected health Data item or will be proposed as a new item. Additionally, we will identify examples of good reporting in RCTs using cohorts and routinely collected health data. ETHICS AND DISSEMINATION: The proposed scoping review will help guide the development of the CONSORT extension statement for RCTs conducted using cohorts and routinely collected health data.

Assumptions made when preparing drug exposure data for analysis have an impact on results: An unreported step in pharmacoepidemiology studies.

PURPOSE: Real-world data for observational research commonly require formatting and cleaning prior to analysis. Data preparation steps are rarely reported adequately and are likely to vary between research groups. Variation in methodology could potentially affect study outcomes. This study aimed to develop a framework to define and document drug data preparation and to examine the impact of different assumptions on results. METHODS: An algorithm for processing prescription data was developed and tested using data from the Clinical Practice Research Datalink (CPRD). The impact of varying assumptions was examined by estimating the association between 2 exemplar medications (oral hypoglycaemic drugs and glucocorticoids) and cardiovascular events after preparing multiple datasets derived from the same source prescription data. Each dataset was analysed using Cox proportional hazards modelling. RESULTS: The algorithm included 10 decision nodes and 54 possible unique assumptions. Over 11 000 possible pathways through the algorithm were identified. In both exemplar studies, similar hazard ratios and standard errors were found for the majority of pathways; however, certain assumptions had a greater influence on results. For example, in the hypoglycaemic analysis, choosing a different variable to define prescription end date altered the hazard ratios (95% confidence intervals) from 1.77 (1.56-2.00) to 2.83 (1.59-5.04). CONCLUSIONS: The framework offers a transparent and efficient way to perform and report drug data preparation steps. Assumptions made during data preparation can impact the results of analyses. Improving transparency regarding drug data preparation would increase the repeatability, reproducibility, and comparability of published results.

Pattern of risks of rheumatoid arthritis among patients using statins: A cohort study with the clinical practice research datalink.

We examined the association between statin use and the risk of rheumatoid arthritis (RA), with special focus on describing the patterns of risks of RA during statin exposure in a large population-based cohort in the United Kingdom. In the Clinical Practice Research Datalink, patients aged ≥40 years with at least one prescription of statins (1995-2009) were selected, and matched by age (+/-5 years), sex, practice and date of first prescription of statins to non-users. The follow-up period of statin use was divided into periods of current, recent and past exposure, with patients moving between these three exposure categories over time. Time-dependent Cox models were used to derive hazard ratios (HRs) of RA, adjusted for disease history and previous drug use. The study population included 1,023,240 patients, of whom 511,620 were statin users. No associations were found between RA and current (HRadj,1.06;99%CI:0.88-1.27) or past statin users (HRadj,1.18;99%CI:0.88-1.57). However, in patients who currently used statins, hazard rates were increased shortly after the first prescription of statins and then gradually decreased to baseline level. The risk of developing RA was increased in recent statin users, as compared to non-users (HRadj,1.39;99%CI:1.01-1.90). The risk of RA is substantially increased in the first year after the start of statins and then diminishes to baseline level. These findings may suggest that statins might accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Alternatively, we cannot rule out that confounding by cardiovascular risk factors and ascertainment bias may have influenced the findings.

Supplementing electronic health records through sample collection and patient diaries: A study set within a primary care research database.

PURPOSE: To describe a novel observational study that supplemented primary care electronic health record (EHR) data with sample collection and patient diaries. METHODS: The study was set in primary care in England. A list of 3974 potentially eligible patients was compiled using data from the Clinical Practice Research Datalink. Interested general practices opted into the study then confirmed patient suitability and sent out postal invitations. Participants completed a drug-use diary and provided saliva samples to the research team to combine with EHR data. RESULTS: Of 252 practices contacted to participate, 66 (26%) mailed invitations to patients. Of the 3974 potentially eligible patients, 859 (22%) were at participating practices, and 526 (13%) were sent invitations. Of those invited, 117 (22%) consented to participate of whom 86 (74%) completed the study. CONCLUSIONS: We have confirmed the feasibility of supplementing EHR with data collected directly from patients. Although the present study successfully collected essential data from patients, it also underlined the requirement for improved engagement with both patients and general practitioners to support similar studies.

Quantification of the risk of liver injury associated with flucloxacillin: a UK population-based cohort study.

Background: Flucloxacillin is an established cause of liver injury. Despite this, there are a lack of published data on both the strength of association after adjusting for potential confounders, and the absolute incidence among different subgroups of patients. Objectives: To assess the relative and absolute risks of liver injury following exposure to flucloxacillin and identify subgroups at potentially increased risk. Methods: A cohort study between 1 January 2000 and 1 January 2012 using the UK Clinical Practice Research Datalink, including 1 046 699 people with a first prescription for flucloxacillin (861 962) or oxytetracycline (184 737). Absolute risks of experiencing both symptom-defined (jaundice) and laboratory-confirmed liver injury within 1-45 and 46-90 days of antibiotic initiation were estimated. Multivariable logistic regression was used to estimate 1-45 day relative effects. Results: There were 183 symptom-defined cases (160 prescribed flucloxacillin) and 108 laboratory-confirmed cases (102 flucloxacillin). The 1-45 day adjusted risk ratio for laboratory-confirmed injury was 5.22 (95% CI 1.64-16.62) comparing flucloxacillin with oxytetracycline use. The 1-45 day risk of laboratory-confirmed liver injury was 8.47 per 100 000 people prescribed flucloxacillin (95% CI 6.64-10.65). People who received consecutive flucloxacillin prescriptions had a 1-45 day risk of jaundice of 39.00 per 100 000 (95% CI 26.85-54.77), while those aged >70 receiving consecutive prescriptions had a risk of 110.57 per 100 000 (95% CI 70.86-164.48). Conclusions: The short-term risk of laboratory-confirmed liver injury was >5-fold higher after a flucloxacillin prescription than an oxytetracycline prescription. The risk of flucloxacillin-induced liver injury is particularly high within those aged >70 and those who receive multiple flucloxacillin prescriptions. The stratified risk estimates from this study could help guide clinical care.