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Alejandro Arana,1 Anton Pottegård,2 Josephina G Kuiper,3 Helen Booth,4 Johan Reutfors,5 Brian Calingaert,6 Lars Christian Lund,2 Elizabeth Crellin,4 Marcus Schmitt-Egenolf,5,7 James A Kaye,8 Karin Gembert,5 Kenneth J Rothman,8 Helle Kieler,5 Daniel Dedman,4 Eline Houben,3 Lia Gutiérrez,1 Jesper Hallas,2 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, 08028, Spain; 2Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense C, 5000, Denmark; 3The PHARMO Institute, Utrecht, 3528 AE, the Netherlands; 4Clinical Practice Research Datalink (CPRD), The Medicines and Healthcare Products Regulatory Agency, London, E14 4PU, UK; 5Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, 171 76, Stockholm, Sweden; 6Department of Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 27709-2194, USA; 7Department of Public Health and Clinical Medicine, Umeå University, Umeå, 901 87, Sweden; 8Department of Epidemiology, RTI Health Solutions, Waltham, MA, 02451-1623, USACorrespondence: Alejandro AranaDepartment of Epidemiology, RTI Health Solutions, Av. Diagonal 605, 9-1, Barcelona, 08028, SpainTel +34 93 362 2805Fax +34 93 414 2610Email aarana@rti.orgPurpose: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately.Patients and Methods: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids.Results: The study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥ 10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were < 1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25– 2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were < 1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin’s lymphoma; and 1.21 (1.03– 1.41) for melanoma; and 1.28 (1.20– 1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥ 5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses.Conclusion: Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.Keywords: tacrolimus, pimecrolimus, cutaneous T-cell lymphoma, malignant melanoma, non-melanoma skin cancer, database study

Purpose To assess the feasibility of using Clinical Practice Research Datalink (CPRD) data for identifying populations of patients with chronic obstructive pulmonary disease (COPD) eligible for a hypothetical pragmatic trial. Methods A retrospective multidatabase cohort study using CPRD primary care and linked secondary care data to describe the characteristics of populations of patients with COPD. Patients' demographic and lifestyle factors, comorbidity profile, spirometry measurements and treatment changes were evaluated, as was the distribution of follow‐up time and types of losses during follow‐up. Characteristics were evaluated using descriptive statistics. Results A total of 322 991 patients from 1148 primary care practices in the United Kingdom across two CPRD primary care databases, CPRD GOLD and CPRD Aurum, were potentially eligible to participate in a hypothetical trial using CPRD, starting on 31 December 2017. Patients with COPD in CPRD GOLD and CPRD Aurum were comparable in terms of age (median age 70 vs. 68 years), gender (50% vs. 52% male), disease severity (e.g., 25% vs. 24% Medical Research Council [MRC] dyspnoea score grades 3–5) and history of respiratory conditions (e.g., 43% vs. 38% asthma). High proportions of patients with COPD in CPRD GOLD and CPRD Aurum were available on 31 December 2012 for follow‐up at 1, 2, and 5 years (92%, 85% and 67%, respectively). Conclusions Patients and data from CPRD GOLD and CPRD Aurum were comparable across key aspects relevant to COPD trials. A pragmatic trial using CPRD to recruit patients with COPD is scientifically feasible.

Purpose\ud UK primary care provides a rich data source for research. The impact of proposed data collection restrictions is unknown. This study aimed to assess the impact of restricting the scope of electronic health record (EHR) data collection on the ability to conduct research. The study estimated the consequences of restricted data collection on published Clinical Practice Research Datalink studies from high impact journals or referenced in clinical guidelines.\ud \ud Methods\ud A structured form was used to systematically analyse the extent to which individual studies would have been possible using a database with data collection restrictions in place: (1) retrospective collection of specified diseases only; (2) retrospective collection restricted to a 6‐ or 12‐year period; (3) prospective and retrospective collection restricted to non‐sensitive data. Outcomes were categorised as unfeasible (not reproducible without major bias); compromised (feasible with design modification); or unaffected.\ud \ud Results\ud Overall, 91% studies were compromised with all restrictions in place; 56% studies were unfeasible even with design modification. With restrictions on diseases alone, 74% studies were compromised; 51% were unfeasible. Restricting collection to 6/12 years had a major impact, with 67 and 22% of studies compromised, respectively. Restricting collection of sensitive data had a lesser but marked impact with 10% studies compromised.\ud \ud Conclusion\ud EHR data collection restrictions can profoundly reduce the capacity for public health research that underpins evidence‐based medicine and clinical guidance. National initiatives seeking to collect EHRs should consider the implications of restricting data collection on the ability to address vital public health questions.

PURPOSE: It is not clear whether all deaths are recorded in the Clinical Practice Research Datalink (CPRD) or how accurate a recorded date of death is. Individual-level linkage with national data from the Office for National Statistics (ONS) and Hospital Episode Statistics (HES) in England offers the opportunity to compare death information across different data sources. METHODS: Age-standardised mortality rates (ASMRs) standardised to the European Standard Population (ESP) 2013 for CPRD were compared with figures published by the ONS, and crude mortality rates were calculated for a sample population with individual linkage between CPRD, ONS, and HES data. Agreement on the fact of death between CPRD and ONS was assessed and presented over time from 1998 to 2013. RESULTS: There were 33 997 patients with a record of death in the ONS data; 33 389 (98.2%) of these were also identified in CPRD. Exact agreement on the death date between CPRD and the ONS was 69.7% across the whole study period, increasing from 53.4% in 1998 to 78.0% in 2013. By 2013, 98.8% of deaths were in agreement within ±30 days. CONCLUSIONS: For censoring follow-up and calculating mortality rates, CPRD data are likely to be sufficient, as a delay in death recording of up to 1 month is unlikely to impact results significantly. Where the exact date of death or the cause is important, it may be advisable to include the individually linked death registration data from the ONS.

Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.This was a new-user cohort study design with propensity score matching.Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4.Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of 45 ml/minute/1.73 mBisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure.Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data.This study is registered as EUPAS10029.This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inBisphosphonates are used to prevent fractures in people with fragile bones. People with chronic kidney disease have a high risk of fracturing, but the safety and effectiveness of bisphosphonates in severe chronic kidney disease is unclear. The aim of this study was to assess the benefits (e.g. bone strength improvement and fracture prevention) and the risks of unwanted effects associated with bisphosphonates for people with moderate to severe chronic kidney disease.Anonymised primary and secondary care electronic medical records data from the UK NHS were used, as well as a Danish equivalent that included bone density scans. Anyone in these databases with a measure of reduced kidney function that suggested moderate to severe chronic kidney disease was eligible, which was 220,000 people from the UK. Over 20,000 of them used bisphosphonates. Bisphosphonate users were matched to non-users with similar age, sex and other characteristics.Bisphosphonate users had a 12% higher risk of their chronic kidney disease getting worse than non-users. Their risks of other side effects, such as acute kidney injuries and gastrointestinal problems, did not change. Bisphosphonate users had a 25% higher risk of fractures than non-users in the UK database, probably because the matching methods did not create similar-enough groups of users and non-users. However, it was found that bisphosphonate improved bone density in the Danish database. Bone density is a proxy for bone strength, so better bone density should mean fewer fractures.These results suggest that bisphosphonate therapy may make moderate to severe chronic kidney disease worse. More studies are needed on how bisphosphonates affect milder chronic kidney disease. Bisphosphonates were associated with better bone strength, but it could not be demonstrated that they reduced fracture risk. More data are required, probably from a placebo-controlled trial, to determine whether or not bisphosphonates prevent fractures in people with moderate to severe chronic kidney disease and whether or not this is worth the risk of their chronic kidney disease worsening.

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m2 , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).

ObjectiveTo identify observational studies which used data from more than one primary care electronic health record (EHR) database, and summarise key characteristics including: objective and rationale for using multiple data sources; methods used to manage, analyse and (where applicable) combine data; and approaches used to assess and report heterogeneity between data sources.DesignA systematic review of published studies.Data sourcesPubmed and Embase databases were searched using list of named primary care EHR databases; supplementary hand searches of reference list of studies were retained after initial screening.Study selectionObservational studies published between January 2000 and May 2018 were selected, which included at least two different primary care EHR databases.Results6054 studies were identified from database and hand searches, and 109 were included in the final review, the majority published between 2014 and 2018. Included studies used 38 different primary care EHR data sources. Forty-seven studies (44%) were descriptive or methodological. Of 62 analytical studies, 22 (36%) presented separate results from each database, with no attempt to combine them; 29 (48%) combined individual patient data in a one-stage meta-analysis and 21 (34%) combined estimates from each database using two-stage meta-analysis. Discussion and exploration of heterogeneity was inconsistent across studies.ConclusionsComparing patterns and trends in different populations, or in different primary care EHR databases from the same populations, is important and a common objective for multi-database studies. When combining results from several databases using meta-analysis, provision of separate results from each database is helpful for interpretation. We found that these were often missing, particularly for studies using one-stage approaches, which also often lacked details of any statistical adjustment for heterogeneity and/or clustering. For two-stage meta-analysis, a clear rationale should be provided for choice of fixed effect and/or random effects or other models.

Summary Background Clostridioides difficile infection (CDI) increases the risk of complications and mortality. We assessed the magnitude of these outcomes in a large cohort of English patients with initial and recurrent CDI. Aim To compare the risk of complications and all-cause mortality, within 12 months, among hospitalized patients ≥18 years old with hospital-associated- (HA-) CDI and recurrent CDI. Methods Patients with HA-CDI during 2002–2013 were identified using inpatient hospital data linked to primary care and death data. Each HA-CDI case was frequency matched to two hospitalized patients without CDI on age group, sex, calendar year of admission, admission method and number of hospital care episodes. A second CDI episode starting on days 13–56 was defined as recurrence. Risks of mortality and complications at 12 months were analysed using Cox proportional hazard models. Findings We included 6862 patients with HA-CDI and 13,724 without CDI. Median age was 81.0 years (IQR 71.0–87.0). Patients with HA-CDI had more comorbidities than those without CDI, and significantly higher risks of mortality (adjusted hazard ratio (95% confidence interval) 1.77 (1.67–1.87)) and complications (1.66 (1.46–1.88)) within 12 months from hospital admission. Of those with HA-CDI, 1140 (16.6%) experienced CDI recurrence. Patients with recurrent versus non-recurrent CDI also had significantly increased risk of mortality (1.32 (1.20–1.45)) and complications (1.37 (1.01–1.84)) in the 12 months from the initial CDI. Conclusions HA-CDI (versus no CDI) and recurrent CDI are both associated with significantly higher risks of complications or death within 12 months of the initial CDI episode.

Edith M Heintjes,1 Irene D Bezemer,1 Daniel Prieto-Alhambra,2,3 Elisabeth Smits,1 Helen P Booth,4 Daniel Dedman,4 Ying He,3 Fabian Hoti,5 Minna Vehkala,5 Stefan de Vogel,6 Noah Jamie Robinson,6 Kwame Appenteng,7 Fernie JA Penning-van Beest1 1PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 2Idiap Jordi Gol Primary Care Research Institute and CIBERFes, Universitat Autonoma de Barcelona and Instituto de Salud Carlos III, Barcelona, Catalonia, Spain; 3Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, England, UK; 4Clinical Practice Research Datalink (CPRD), London, UK; 5Statfinn - EPID Research, Espoo, Finland; 6Astellas Pharma Europe B.V., Leiden, Netherlands; 7Astellas Pharma Global Development, Inc., Northbrook, IL, USACorrespondence: Edith M HeintjesPHARMO Institute for Drug Outcomes Research, Van Deventerlaan 30-40, Utrecht, AE 3528, the NetherlandsTel +31 30 7440 800Email pharmo@pharmo.nlBackground: Mirabegron, indicated for the treatment of overactive bladder, is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg). In September 2015, a Direct Healthcare Professional Communication (DHPC) letter was disseminated as an additional risk minimisation measure.Purpose: To assess the effectiveness of the DHPC in reducing the proportions of patients with severe or non-severe uncontrolled hypertension at mirabegron initiation.Methods: An observational multi-database cohort study was undertaken using routinely collected healthcare data (December 2012–December 2016) from the PHARMO Database Network (Netherlands), SIDIAP database (Spain), CPRD (United Kingdom, UK) and national healthcare registers and electronic medical records from Finland. DHPC effectiveness was evaluated using interrupted time series analyses comparing trends and changes in monthly proportions of severe or non-severe uncontrolled hypertensive mirabegron initiations relative to the timing of the DHPC dissemination.Results: The study population comprised 52,078 patients. Prior to DHPC dissemination, across the four databases, 0.3– 1.3% had severe uncontrolled hypertension. Estimated absolute changes (EAC) in proportions of severe uncontrolled hypertension post-DHPC indicated a tendency towards a lower proportion in the Netherlands (EAC − 0.36%, p=0.053), unchanged proportions in Spain and the UK and a higher proportion in Finland (EAC +0.73%, p=0.016). For non-severe uncontrolled hypertension (13– 16% pre-DHPC), post-DHPC proportions tended to be lower in the Netherlands (EAC − 2.02%, p=0.038) and Spain (EAC − 1.04%, p=0.071), and unchanged in the UK and Finland.Conclusion: Severe uncontrolled hypertension prior to mirabegron initiation was uncommon in these four European countries even before DHPC dissemination. This suggests that other risk minimisation communications (prior to the DHPC dissemination) had worked adequately with respect to minimising mirabegron use among patients with severe uncontrolled hypertension. No strong and consistent evidence of further risk minimisation after the DHPC dissemination was observed in this study.Keywords: drug utilisation study, direct healthcare professional communication, risk minimization, interrupted time series analysis

Background: Although contraindicated in patients with severe chronic kidney disease (CKD) due to a lack of safety data, bisphosphonates are commonly used to prevent or treat bone fragility in these patients. We studied the safety of bisphosphonates in patients with moderate-to-severe CKD. Methods: Patients with stage 3b+ CKD based on 2+ estimated glomerular filtration rate (eGFR) measures were identified in two primary-care records databases, the UK CPRD GOLD during 1997-2016 and the Catalan (Spain) SIDIAP during 2007-2015. New bisphosphonate users were propensity-scorematched with up to five non-users to minimise confounding, and followed until treatment discontinuation, switching, dropout, death, or 10 years. The primary outcome was CKD stage worsening (eGFR decline or renal replacement therapy). Secondary outcomes included hospitalised acute kidney injury (AKI), gastrointestinal bleeding/ulcers (GIE), and hypocalcaemia. Hazard ratios (HRs) were estimated using Cox regression for SIDIAP participants, and sub-HRs (sHRs) calculated using Fine-Gray models for CPRD. Findings: We matched 2,447 bisphosphonate users with 8,931 non-users from CPRD, and 1,399 users with 6,547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in both CPRD (HR [95% CI]: 1·14 [1·04, 1·26]) and SIDIAP (HR: 1·16 [1·04, 1·29]). No statistically significant risk differences were found for AKI, GIE, or hypocalcaemia. Interpretation: A modest (10%-15%) increased risk of CKD progression was identified in association with bisphosphonate use amongst patients with moderate-severe disease. No other safety concerns were identified. Our findings should be considered in combination with effectiveness data before prescribing bisphosphonates to patients with moderate-severe CKD. Funding Statement: Funding was provided by the National Institute of Health Research Health Technology Assessment project number 14/36/02. The project was partially funded by CIBERFES, Instituto Carlos III, Spain. JP and MJP-S are supported by PI16/00619 (Spanish Ministry of Health ISCIII FIS-FEDER) and RD16/0009/0013 (ISCIII FEDER RedinRen). Declaration of Interests: B Abrahamsen reports research grants from UCB and Novartis. NK Arden reports personal fees from Flexion, Freshfields, Janssen, Merck, and Regeneron. C Cooper reports lecture fees and honoraria from the Alliance for Better Bone Health Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda, and UCB. A Judge is a subpanel member of the NIHR PGfAR, has received consultancy fees from Freshfields Bruckhaus Deringer, and has held advisory board positions (which involved receipt of fees) at Anthera Pharmaceuticals, INC. MK Javaid reports research support and speaker fees from Amgen. D Prieto-Alhambra reports research grants from UCB, Amgen, and Les Laboratoires Servier, and departmental (not personal) speaker and consultancy fees from UCB and Amgen. D Prieto-Alhambra is a member of the NIHR HTA CET panel since November 2017. DE Robinson, MS Ali, VY Strauss, L Elhussein, Y Ben-Shlomo, F Caskey, D Dedman, and A Delmestri have nothing to disclose. Ethics Approval Statement: This study was approved by the CPRD Independent Scientific Advisory Committee (protocol number 15_ 53R2A).

Background: Despite the concerns about a potential increased risk of skin cancer and lymphoma with the use of topical tacrolimus and pimecrolimus, no population-based studies have given an overview of the use of these drugs in Europe. Objective: To assess the use of topical tacrolimus and pimecrolimus in children and adults in Europe. Methods: Multicentre database cohort study comprising data from the Netherlands, Denmark, Sweden and the UK. We analysed users of topical tacrolimus and pimecrolimus starting from the date of first availability (between 2002 and 2003) or start establishment of the prescription database in Sweden (2006) through 2011. Use was assessed separately for children (≤ 18 years) and adults. Results: 32,052 children and 104,902 adults were treated with topical tacrolimus, and 32,125 children and 58,280 adults were treated with topical pimecrolimus. The number of users increased rapidly after first availability, especially for topical tacrolimus. Topical tacrolimus was more frequently used in all countries except Denmark. For both drugs, there was a decrease in users after 2004 in the Netherlands and Denmark and after 2005 in the UK, especially among children. This decrease was largest in Denmark. The decrease in the number of users was temporary for topical tacrolimus, while use remained relatively low for topical pimecrolimus. Conclusions: The number of topical tacrolimus and pimecrolimus users increased rapidly after regulatory approval. A transient reduction in topical tacrolimus use and a persistent reduction in topical pimecrolimus use was seen after 2004 in the Netherlands and Denmark and after 2005 in the UK.

Jordi Castellsague,1 Josephina G Kuiper,2 Anton Pottegård,3 Ingegärd Anveden Berglind,4 Daniel Dedman,5 Lia Gutierrez,1 Brian Calingaert,6 Myrthe PP van Herk-Sukel,2 Jesper Hallas,3 Anders Sundström,4 Arlene M Gallagher,5 James A Kaye,7 Carolina Pardo,8 Kenneth J Rothman,7 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, Spain; 2Department Research, PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 3Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; 4Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, London, UK; 6Department Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 7Department of Epidemiology, RTI Health Solutions, Waltham, MA, USA; 8Pharmacovigilance Department, Astellas Pharma Europe B.V., Leiden, the Netherlands Background: There is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children.Objective: The aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects.Methods: This is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel–Haenszel methods for stratified analysis.Results: We included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00–14.06) in children and 1.27 (0.94–1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58–17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81–3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33–5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60–43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer.Conclusion: Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results. Keywords: topical calcineurin inhibitors, cutaneous T-cell lymphoma, malignant melanoma skin cancer, database study

Purpose We examined the association between childhood respiratory infections and adult lung function and how this association varies depending on the age at infection. Methods The Barry Caerphilly Growth study collected information on childhood upper and lower respiratory tract infections (URTI, LRTI) from birth to 5 years on 14 occasions. Subjects were traced prospectively and had lung function measured at age 25 years. Results A total of 581 subjects had acceptable data for both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Childhood LRTIs (0–5 years) but not URTIs were negatively associated with all lung function measures except FVC and showed a dose–response effect. In the first year of life, a two-fold increase in the number of LRTIs experienced was associated with a reduction in FEV1 (78 mL; 95% confidence interval [95% CI], 3–153), FEV1/FVC (1.23%; 95% CI 0.25–2.22), forced expiratory flow 25%–75% (0.25 l/sec; 95% CI 0.08–0.41), and peak expiratory flow (0.30 l/sec; 95% CI 0.11–0.49) after adjustment for confounders. Few associations were found after the first year of life. There was evidence that age at infection effect modifies the association between LRTIs and FEV1, forced expiratory flow 25%–75%, and peak expiratory flow. Conclusions LRTIs are associated with an obstructive lung function deficit. Furthermore, the first year of life may be a sensitive period for experiencing LRTIs.

OBJECTIVE: To examine whether a single repeat prostate-specific antigen (PSA) helps discriminate cancer from non-cancer-related PSA elevation. METHODS: Men aged 50-70 yr (n=54,087) in a multicentre randomised controlled trial comparing treatments for localised prostate cancer were tested. A total of 4102 (7.6%) with an initial PSA in the range of 3-19.9 ng/ml had repeat measurement (median interval: 50 d) followed by prostate biopsy. The decision to biopsy was based on the first PSA level. The outcome was the presence of prostate cancer on biopsy. RESULTS: Men with a 20% drop in PSA had a lower risk of cancer (odds ratio [OR]=0.43; 95% confidence interval [CI], 0.35-0.52; p60 yr. (OR for any cancer=1.6; 95%CI, 1.0-2.4; p=0.05; OR for high-grade cancer=2.9; 95%CI, 1.2-6.7; p=0.014). This equated to a risk reduction of high-grade cancer from 4% to 0.5%, 6% to 2%, and 15% to 2% in men < or =60 yr with an initial PSA of 3.0-3.99, 4.0-5.99, and > or =6 ng/ml, respectively. No level of repeat PSA confidently predicted absence of cancer. CONCLUSION: Following an initial PSA of 3.0-19.99 ng/ml in men aged 50-70 yr, repeat PSA within 7 wk allows more accurate risk prediction that may assist in the decision-making as to whether or not to proceed with prostate biopsy.

Aim To obtain insight into the perceived quality of electronic records received by GP2GP transfer, from the perspective of staff within the receiving practice. Methods A pilot study using a self-completion online survey.We used textual analysis and descriptive statistics to report the findings. Results Respondents considered a significantly higher proportion of their own records to be accurate, complete and useful compared with records transferred from other practices (PConclusion The results suggest that respondents value the GP2GP record transfer system. They perceive issues with record quality, which require significant resources to rectify. Textual analysis suggests that difficulties in mapping data structures between systems may underlie some of the perceived issues. Further research is needed to confirm these initial findings on differential perception and explore their underlying causes.

SummaryBackgroundProstate cancer is a major public health problem with considerable uncertainties about the effectiveness of population screening and treatment options. We report the study design, participant sociodemographic and clinical characteristics, and the initial results of the testing and diagnostic phase of the Prostate testing for cancer and Treatment (ProtecT) trial, which aims to investigate the effectiveness of treatments for localised prostate cancer.MethodsIn this randomised phase 3 trial, men aged 50–69 years registered at 337 primary care centres in nine UK cities were invited to attend a specialist nurse appointment for a serum prostate-specific antigen (PSA) test. Prostate biopsies were offered to men with a PSA concentration of 3·0 μg/L or higher. Consenting participants with clinically localised prostate cancer were randomly assigned to active monitoring (surveillance strategy), radical prostatectomy, or three-dimensional conformal external-beam radiotherapy by a computer-generated allocation system. Randomisation was stratified by site (minimised for differences in participant age, PSA results, and Gleason score). The primary endpoint is prostate cancer mortality at a median 10-year follow-up, ascertained by an independent committee, which will be analysed by intention to treat in 2016. This trial is registered with ClinicalTrials.gov, number NCT02044172, and as an International Standard Randomised Controlled Trial, number ISRCTN20141297.FindingsBetween Oct 1, 2001, and Jan 20, 2009, 228 966 men were invited to attend an appointment with a specialist nurse. Of the invited men, 100 444 (44%) attended their initial appointment and 82 429 (82%) of attenders had a PSA test. PSA concentration was below the biopsy threshold in 73 538 (89%) men. Of the 8566 men with a PSA concentration of 3·0–19·9 μg/L, 7414 (87%) underwent biopsies. 2896 men were diagnosed with prostate cancer (4% of tested men and 39% of those who had a biopsy), of whom 2417 (83%) had clinically localised disease (mostly T1c, Gleason score 6). With the addition of 247 pilot study participants recruited between 1999 and 2001, 2664 men were eligible for the treatment trial and 1643 (62%) agreed to be randomly assigned (545 to active monitoring, 545 to radiotherapy, and 553 to radical prostatectomy). Clinical and sociodemographic characteristics of randomly assigned participants were balanced across treatment groups.InterpretationThe ProtecT trial randomly assigned 1643 men with localised prostate cancer to active monitoring, radiotherapy, or surgery. Participant clinicopathological features are more consistent with contemporary patient characteristics than in previous prostate cancer treatment trials.FundingUK National Institute for Health Research Health Technology Assessment Programme.

BACKGROUND: An algorithm that detects errors in diagnosis, classification or coding of diabetes in primary care computerised medial record (CMR) systems is currently available. However, this was developed on CMR systems that are episode orientated medical records (EOMR); and do not force the user to always code a problem or link data to an existing one. More strictly problem orientated medical record (POMR) systems mandate recording a problem and linking consultation data to them. OBJECTIVE: To compare the rates of detection of diagnostic accuracy using an algorithm developed in EOMR with a new POMR specific algorithm. METHOD: We used data from The Health Improvement Network (THIN) database (N = 2,466,364) to identify a population of 100,513 (4.08%) patients considered likely to have diabetes. We recalibrated algorithms designed to classify cases of diabetes to take account of that POMR enforced coding consistency in the computerised medical record systems [In Practice Systems (InPS) Vision] that contribute data to THIN. We explored the different proportions of people classified as having type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and with diabetes unclassifiable as either T1DM or T2DM. We compared proportions using chi-square tests and used Tukey's test to compare the characteristics of the people in each group. RESULTS: The prevalence of T1DM using the original EOMR algorithm was 0.38% (9,264/2,466,364), and for T2DM 3.22% (79,417/2,466,364). The prevalence using the new POMR algorithm was 0.31% (7,750/2,466,364) T1DM and 3.65% (89,990/2,466,364) T2DM. The EOMR algorithms also left more people unclassified 11,439 (12%), as to their type of diabetes compared with 2,380 (2.4%), for the new algorithm. Those people who were only classified by the EOMR system differed in terms of older age, and apparently better glycaemic control, despite not being prescribed medication for their diabetes (p < 0.005). CONCLUSION: Increasing the degree of problem orientation of the medical record system can improve the accuracy of recording of diagnoses and, therefore, the accuracy of using routinely collected data from CMRs to determine the prevalence of diabetes mellitus; data processing strategies should reflect the degree of problem orientation.

Hospital laboratory reports of parainfluenza virus (PIV) infections from England and Wales between 1975 and 1997 were analysed with regard to PIV type and seasonality, and in addition, those between 1985–1997 with regard to age, sex and clinical features. Laboratory-based surveillance data highlight striking differences in the seasonality of different PIV types. PIV-3 reports demonstrated a clear annual epidemic cycle, with a peak usually occurring in late spring or summer, whereas peaks of PIV-1 and PIV-2 occurred at one or two year intervals, in the late autumn or early winter. PIV-4 also occurred most frequently in the late autumn or early winter, but a clear epidemic cycle could not be identified. Laboratory surveillance data also provide insight into the age and disease distribution of PIV infection in children and indicate severity of PIV infection in immunosuppressed adults. Of 8221 PIV reports received between 1985–1997, PIV-3 accounted for 70.8, PIV-1 for 17.2, PIV-2 for 7.5, and PIV-4 for 1.1; 64.1 of reports came from infants under one year, 24.4 from children aged 1–4 years and 7.2 from individuals aged 5 years or older, with an excess of males in all age groups. Bronchiolitis, croup and pneumonia occurred in association with all PIV types. In children under 1 year, PIV-2 infections were more likely to be associated with bronchiolitis than infections with other PIV types. In children under 15 years, croup was more frequently associated with PIV-1 and PIV-2 than with PIV-3 or PIV-4. In 392 (7.2) of the reported PIV infections between 1989 and 1997 an underlying condition was implicated, which included immunosuppression or chronic cardiac or pulmonary disease. Considerable morbidity is associated with PIV infections in infants and young children and would make the widescale use of a vaccine a valuable public health intervention. Surveillance information is essential to guide the development and use of preventive measures as well as to monitor their effectiveness.

OBJECTIVE: To evaluate the psychosocial impact of participation in a population-based prostate-specific antigen (PSA) testing programme, akin to screening, and to explore the relationship between urinary symptoms reported before PSA testing and the response to the subsequent PSA result. PATIENTS AND METHODS: This prospective questionnaire study was nested within the case-finding component of the ProtecT (prostate testing for cancer and treatment) feasibility study (ISRCTN20141297). Men aged 50-69 years from 18 general practices in three cities in the UK completed the Hospital Anxiety and Depression Scale (HADS), the Short Form-12 (SF-12) Health Survey, and the International Continence Society 'male' (ICSmale) questionnaires before giving consent for a PSA test in a community clinic (baseline). Men with an 'abnormal' PSA result returned for further investigation (including biopsy) and repeated these questionnaires before biopsy. RESULTS: At baseline, study participants had similar levels of anxiety and depression to the general male population. There was no increase in the HADS scores, or reduction in the SF-12 mental health component summary score, on attendance at the biopsy clinic after receiving an 'abnormal' PSA result. Urinary symptoms were associated with levels of anxiety and depression before receiving a PSA result (baseline), but were not associated with anxiety and depression at biopsy independently of baseline scores. Therefore changes in anxiety or depression at biopsy did not appear to differ between those with and without urinary symptoms. CONCLUSIONS: This study confirms the findings of other studies that the deleterious effects of receiving an abnormal PSA result during population screening are not identified by generic health-status questionnaires. Comparisons with outcomes of studies measuring cancer-specific distress and using qualitative research methods raise the question of whether a prostate cancer screening-specific instrument is required. However, a standardized measure of anxiety identified differences at baseline between those who did and did not report urinary symptoms. These findings suggest that it might be advisable to better inform men undergoing PSA testing about the uncertain relationship between urinary symptoms and prostate cancer, to minimize baseline levels of psychological distress.

Objectives a) To review reported barriers to, and facilitators of, occupational epidemiological research in the UK; b) To explore perceptions of these and related issues among key UK-based researchers. Methods A systematic literature search (1990–2010) was performed to identify studies that reported barriers and/or facilitators. Bibliographies and grey literature were also searched, and key journals were hand-searched for relevant original studies carried out in the UK and published in 2010. A narrative synthesis was undertaken. In-depth interviews of a purposive sample of 10–12 key UK-based researchers will be carried out to explore their perceptions of these issues, and the strategies they have employed to address them. Results The systematic search revealed no empirical studies that specifically examined barriers and/or facilitators in occupational epidemiology research. These issues were mentioned in a small number of reports and expert opinion articles. Detailed results will be presented, along with results from the qualitative study. Conclusions The systematic review reveals a gap in the literature related to occupational epidemiology research barriers and facilitators in the UK. Results from the review and the qualitative study will inform the design of the subsequent phases of the project. These include a questionnaire survey of UK researchers and stakeholders, and a multiple observational case study of 4 researchers/teams at different stages of their projects.