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• The incidence of Guillain-Barré was 5.4–6.5/106 girl-years in Spain in 2002–2016. • Incidence peaked during the last period of the study (2007–2016) with 11 GBS cases. • Out of 11 GBS cases, 4 (36%) reported infections as the potential triggers. • 3 cases were vaccinated against papillomavirus ever before (7.87/106 girl-years) • The adjusted risk of GBS after HPV vaccination was not different from non-exposed. Studies of the association of Guillain-Barré Syndrome (GBS) with papillomavirus vaccination (HPVv; scheduled from 2007) have provided contradicting results, probably due to the low frequency of this disease. We aimed at estimating that risk relative to non-vaccination among girls, by using the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP). A cohort study of girls aged 9–18 years during 2007–2016 free of GBS or HPVv was selected and followed up to GBS diagnosis. Follow-up time was divided by time-varying HPVv exposure and confounders. Crude Incidence rates (IR per 1,000,000 person-years (py)) and adjusted Hazard Ratios (HR) of GBS were estimated anytime after vaccination compared to non-exposed periods. HRs were also estimated for the first 90 days after HPVv (risk-window) and thereafter. Out of 388,849 girls, of which 154,255 were vaccinated, 6 'confirmed' GBS cases occurred during non-exposure periods (IR of 5.83 per million person-years; 95% CI: 2.62–12.97) and 3 'confirmed' cases anytime after vaccination (IR of 7.87; 95% CI: 2.54–24.39). The resulting adjusted HR anytime after vaccination was 1.24 (95% CI: 0.19–8.00). All three cases occurred after the risk window of 90 days with an HR of 1.77 (95% CI: 0.25–12.54) for post-exposure periods as compared with non-exposure. Since zero cases occurred during the risk window, no HR could be estimated for exposed periods. Incidences of GBS were in line with the range previously reported for young people, supporting the potential of BIFAP for performing studies on GBS. However, a lack of power may be present for quantifying the relative risk of such a rare disease after the vaccination among the study cohort, where we can only exclude an increased risk of 8-times relative to no vaccination. [ABSTRACT FROM AUTHOR]

Objective: As for other auto-immune processes, thyroiditis is monitored after vaccinations. The aim was to estimate the baseline incidence of thyroiditis among girls, before investigating papillomavirus vaccination as a potential risk factor. Methods: Observational cohort study including girls aged 9-18 years and registered between 2002-2016 in the Spanish Primary Care Database for Pharmacoepidemiological Research. Girls were followed until a thyroiditis occurred, 19 years of age, left the cohort, died, or the study ended. Anonymized records were reviewed for diagnosis confirmation (endocrine discharge letter and/or free-text comments) in a random sample. Incidence rate (IR) per 105 person years (/105 py) was estimated. Results: The cohort numbered 480,169 girls, of whom 641 had a record of thyroiditis: 346 autoimmune thyroiditis; 17 thyroiditis of other types; and 278 unspecified. Incidence of recorded thyroiditis increased with age, from 23.96 at age 9 years to 47.91 at age 14 years, and stabilized around 31.06-34.43 among girls aged 15-18 years. Of the 98 records reviewed, 60.2% were 'confirmed' cases, 32.7% 'possible' and 7.1% were discarded. After correction for discarded cases, IR=20.83 'confirmed' cases, increasing to 32.12/105 py when 'confirmed' plus 'possible' cases were included. Between 2002-2005, incidences were lower (16.28 and 20.93 cases/105 py) than in the period 2007-2016 (21.17 and 33.78 cases/105 py) for 'confirmed' and 'confirmed' plus 'possible', respectively. Conclusion: Two-thirds of the recorded thyroiditis included confirmatory evidence. The incidence of thyroiditis among girls increased with age and in the later period, and remained stable among girls aged 15-18 years. [ABSTRACT FROM AUTHOR]

Introduction: A link between the human papillomavirus vaccination (HPVv) and inflammatory bowel disease (IBD) has been suggested. Objective: We aimed to estimate the risk of IBD following HPVv compared with periods not exposed to the vaccines. Methods: Primary healthcare records (Spanish Primary Care Database For Pharmacoepidemiological Research [BIFAP]) were used in a cohort study of girls in Spain aged 9–18 years between 2007 and 2016 free of IBD or HPVv at study entrance. During the follow-up to IBD diagnosis, time-varying HPVv exposure and confounders were assessed in Cox models to estimate the hazard ratio (HRs) of IBD in the 2 years after HPVv (exposed period) and thereafter (post-exposed) compared with the no exposure periods. In a post hoc analysis, we moved the IBD date back 30 days as a theoretical delay in diagnosis confirmation. Results: The cohort comprised 388,669 girls; 154,174 of these received the HPVv, and 88 IBD cases occurred (55 non-exposed, 22 exposed [after first N = 6, second N = 2, or third N = 14 dose] and 11 in post-exposed periods). The adjusted HR was 1.66 (95% confidence interval [CI] 0.68–4.05) for exposed and 1.10 (95% CI 0.37–3.24) for post-exposed periods. The HR for the first dose was 3.94 (95% CI 1.19–13.02). No association was found for the second or third doses. Post hoc, the HR was 1.83 (95% CI 0.72–4.69) for exposed periods (N = 18), and 1.84 (95% CI 0.35–9.83; N = 2), 1.50 (95% CI 0.40–5.63; N = 4) and 1.98 (95% CI 0.71–5.49; N = 12) after the first, second and third doses, respectively. Conclusions: This study did not show an increased risk of IBD following 2 years of HPVv exposure. However, an increased risk of IBD diagnosis was observed following the first vaccination dose (1–34 days), which is likely attributable to the clinical recommendation to vaccinate upon onset of IBD symptoms. [ABSTRACT FROM AUTHOR]

Background: In Spain, girls are vaccinated against human papillomavirus (HPV) in the primary care setting, according to a national vaccination programme. Vaccination is voluntary and is covered by the public health system. Objectives: The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in primary care in Spain. Methods: A cohort study was performed using the information recorded in the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP) from 7.9 million patients from seven Spanish regions, between 2001 and 2016 (56.6% of the regional population). Data available in BIFAP include patient age, sex, life-style factors, clinical events, specialist referrals, prescriptions, and vaccinations as recorded by the primary care physician (PCP) or administering nurse. The study cohort comprised all girls aged 9–18 years registered in BIFAP between 1st January of 2007 and 31st December of 2016 who had at least 1 year of clinical record information with their PCP (inclusion criteria). The date the inclusion criteria were met was designated as the start date to the study cohort contribution. In order to estimate the incidence of HPV vaccination (initiation of vaccination schedule), girls with an HPV vaccination recorded before the start date or without vaccination date were excluded. Girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, end of available information, or 31st December 2016. The person-time of all patients forming the study cohort was reckoned in the incidence estimations. The follow-up was replicated yearly from 2007 to 2016. The cumulative incidence (CuIn) of vaccination by birth cohort, year and region, was estimated using life tables (proportion of vaccination by intervals in which the denominator is the initial population corrected for losses). Results: Of 388,690 girls forming the study population, 154,211 initiated the vaccination during 2007–2016. Ages ranged from 12 to 14 years at first dose in 84.5% of vaccinated girls, 42.79% received a quadrivalent vaccine, 21.86% a bivalent vaccine, and 35.35% an unknown type. Of the vaccinated population, 48.0% were completely vaccinated with a three-dose schedule and 28.9% with a two-dose schedule, 20.2% received one dose and 3.0% two doses in a three-dose schedule, at a maximum of 10 years of follow-up. The CuIn was highest among girls aged either 13 or 14 years over all regions (reaching 92.8% and 89.7%, respectively), and aged 12 in some regions/years (up to 89.8%). Girls aged 15 years were also vaccinated (although showing lower yearly incidence, i.e. < 69.1%) in two regions. The coverage was broadened to younger girls (11 years) during the last years of the study period in some regions. Conclusions: According to BIFAP primary care data, a high incidence of vaccination among girls aged 13–14 years was observed. Vaccination among younger and older girls were less common, although they reached high incidence in some regions and/or years. Most vaccination patterns adjusted to a complete vaccination regimen, as recommended posology. [ABSTRACT FROM AUTHOR]

Background: In Spain, girls and women are vaccinated against human papillomavirus (HPV) in the primary care setting, according to a national vaccination program. Vaccination is voluntary and the cost is covered by the public health system. Objectives: The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in Spain. Methods: A cohort study was performed using the information recorded in the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP) from 7.4 million patients from eight Spanish regions, between 2001 and 2013 (56% of the regional population). Data available in BIFAP include patient age, sex, lifestyle factors, clinical events, specialist referrals, prescriptions, and vaccinations as recorded by the primary care physician (PCP) or administering nurse. The study cohort comprised all girls aged 11–18 years registered in BIFAP between 1 January 2007 and 31 December 2013 who had at least 1 year of clinical record information with their PCP (inclusion criteria). The date the inclusion criteria were met was designated as the start date of the study cohort contribution. In order to estimate the incidence of HPV vaccination, girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, the end of available information, or 31 December 2013. The person-time of all patients forming the study cohort was taken into account in the incidence estimations. The cumulative incidence (CuIn) of vaccination by birth cohort, year and region was estimated using life-tables (proportion of vaccination by intervals in which the denominator is the initial population corrected for losses). Results: Out of 273,098 girls forming the study population, 81,461 were vaccinated during 2007–2013. Age ranged from 12 to 14 years at first dose in 86.0% of vaccinated girls; 54.1% received a quadrivalent vaccine, 21.9% a bivalent vaccine, and 24.0% an unknown type. Out of the vaccinated population, 87.9% received three doses, 8.2% two and 3.9% one dose, at a maximum of 7 years of follow-up. By calendar year and region, the CuIn reached 70.0–95.8% for birth cohorts between 1993 and 1999, 28.6–99.0% for births cohorts between 1990 and 1992, and exceptionally, 70.6–99.8% for births cohorts between 2000 and 2002 in three regions. Conclusions: According to BIFAP primary care data, a high incidence of vaccination among girls aged 13–15 years was observed. Vaccination among younger and older girls was less common although they reached high incidence in those regions that included girls aged 11–18 years in mass programs. Most vaccination patterns adjusted to a three-dose regimen, as recommended. [ABSTRACT FROM AUTHOR]

Objective Different regulatory actions for anti-osteoporotic medication (AOM) were taken during the last years, including marketing of new drugs, safety warnings, or restrictions on the indications. We aimed to characterise the secular trends of AOM use in Spain from 2001 to 2013. Methods A cohort study using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP), was performed. BIFAP includes anonym records for 4 million patients. Participants entered the study when aged ≥ 50 years in 2001–2013 and after 1 year of data available, and were followed to an AOM prescription (including alendronate, other bisphosphonates, SERM (selective estrogen receptor modulators), strontium ranelate, teriparatide or denosumab), death, lost or the end of December 2013. Prevalence (%) and incidence rate (IR/1000 person-years (py)) of AOM users were computed by years and sex. Results Out of 1.5 million participants, 135,410 received AOM treatment during 2001–2013. Prevalence was 6.1% (women) and 1.1% (men), that increased from 2001 (2.0%) to 2009 (7.6%) to decrease thereafter. Out of them, 95,057 were incident. The IR was 24.90 (women) and 2.77 (men), that increased from 2001 (21.25 and 1.96) to 2007 (35.84 and 3.64), and decreased to 12.48 and 1.81 (2013). IRs were highest for bisphosphonates along the years (ranging 3.70–14.73 and 0.57–1.75 in women and men respectively), followed by SERM up to 2005 (6.51–9.02 and 0.06–0.07), and strontium ranelate from 2006 (4.66 and 0.45) to 2012 (2.05 and 0.26). IR for teriparatide increased from marketing in 2004 (0.10–1.01 and 0.02–0.29), as was denosumab from marketing in 2011 (0.03–2.64 and 0.09–0.15). Conclusions Population-based estimates of AOM use in Spain peaked in 2007–2009 and decreased thereafter, irrespective of age and sex. New treatments were ten times higher in women than men. Bisphosphonates were the most frequently prescribed class, followed by SERM in women before 2006, strontium otherwise till 2012, and denosumab in women or teriparatide in men in 2013. Changes in the osteoporosis criteria, fracture risk assessment strategies, and regulatory actions for AOM around the time, may explain that trend. [ABSTRACT FROM AUTHOR]

Background: Uterine fibroids (UFs) are the most common benign tumour in women, and many undergo hysterectomy or uterus-preserving procedures (UPPs) to manage their symptoms. We aimed to validate the recording of UFs in a primary care database, The Health Improvement Network (THIN), and to determine the incidence of UFs in the UK.Methods: In this observational study, women in THIN aged 15-54 years between January 2000 and December 2009 with no previous record of UFs, hysterectomy or UPPs were identified. Individuals were followed up until there was a Read code indicating UFs, they reached 55 years of age or died, or the study ended. Among those without a UF code, women were identified with a code for hysterectomy, UPPs or heavy menstrual bleeding (HMB). Anonymized patient profiles from each category were randomly selected and reviewed. Subsequently, primary care physicians were asked to complete questionnaires to verify the diagnosis for a randomly selected subgroup.Results: In total, 737,638 women were identified who met the initial inclusion criteria. The numbers of women with a code for UFs, hysterectomy, UPPs and HMB were 9380, 11,002, 3220 and 60,915, respectively; the proportions of confirmed cases of UFs were 88.8, 29.7, 57.7 and 15.9 %. The estimated number of women with UFs was 23,140 (64.0 % without a recorded UF diagnosis). The overall incidence of UFs was 5.8 per 1000 woman-years.Conclusions: UFs were confirmed in a high proportion of women with UF Read codes. However, almost two-thirds of cases were identified among women with a code for hysterectomy, UPPs or HMB. These results show that UFs are under-recorded in UK primary care, and suggest that primary care physicians tend to code the symptoms of UFs more often than the diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To determine the incidence of hysterectomy and uterus-preserving procedures (UPPs) among women with uterine fibroids (UFs) and the incidence of further procedures after a UPP.Study Design: This was an observational study using a primary care database, The Health Improvement Network (THIN). Women in THIN with UFs aged 15-54 years between January 2000 and December 2009 were eligible for study. The UPPs examined were myomectomy, endometrial ablation (EA) and uterine artery embolization (UAE). Using Read codes, women were followed up until one of the following was met: there was a record of hysterectomy or UPPs, they died or the study ended (end of 2010).Results: The cumulative incidence of hysterectomy or UPPs was 23.6% at 1 year, and 40.9% after the follow-up period (median 3.6 years). At the end of the follow-up period, the cumulative incidences of hysterectomy, myomectomy, EA and UAE were 33.0%, 3.9%, 6.4% and 1.9%, respectively. For women initially treated with a UPP, the cumulative incidence of second procedures was 11.5% at 1 year. At the end of the follow-up period (median 2.7 years), the cumulative incidence of further procedures was 26.1%, and the cumulative incidences of women undergoing hysterectomy, myomectomy, EA and UAE were 19.0%, 4.3%, 3.4% and 1.4%, respectively.Conclusions: Women considering UPPs for the management of UFs should be made aware that the incidence of further treatments is high, with hysterectomy being the most frequent procedure undergone. [ABSTRACT FROM AUTHOR]

Purpose: We aim to estimate the incidence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) among tetrazepam users and compare it with benzodiazepine users in a Spanish primary care database (BIFAP). The incidence in the general population (GenPop) and among phenytoin new users (as a positive control) was also estimated. Methods: We identified a cohort of GenPop free of SJS/TEN ( N = 3,155,364). Cohort entry was the date after 1 year of register with the physician during 2001-2011. No age restrictions were applied. Patients were followed from entry up to the first of the following: a record of SJS/TEN (potential cases), death, end of information, or December 2011. History of potential cases were manually reviewed blinded to exposure and considered 'probable' when diagnosed in referral reports. Three cohorts of patients newly prescribed with benzodiazepines ( N = 531,813), tetrazepam ( N = 343,568), or phenytoin ( N = 4993) were extracted from the GenPop cohort. Incidence rate (cases per million person-years (py)) for the GenPop and cumulative incidence (per million new users) during the first 9 weeks after each drug prescription were computed. Results: In the GenPop, 48 probable cases (38 SJS and 10 TEN) were identified (3.21/million py; 3.37 in men and 2.94 in women). In the benzodiazepines cohort, 2 probable TEN cases was identified (3.76/mill.). In the tetrazepam cohort, 1 probable SJS/TEN case was identified (2.91/mill.). In the phenytoin cohort, 4 probable cases (2 SJS and 2 TEN) were identified (801.12/mill.). Conclusions: The incidence of SJS/TEN in tetrazepam users was very rare and similar to benzodiazepines users. The incidence in the GenPop and among users of phenytoin agreed with the literature. [ABSTRACT FROM AUTHOR]

In this retrospective database study, carried out using The Health Improvement Network, a UK primary care database, we followed up patients who were prescribed low-dose acetylsalicylic acid (ASA) (75-300 mg/day) for the secondary prevention of cardiovascular disease in 2000-2007, and who discontinued therapy for a period of at least 90 days during that time ( n = 11,565). We assessed the incidence of, and factors associated with, ASA represcription. Patients were followed up from the first day after their initial 90-day period of discontinuation (start date) until ASA represcription, death, or the end of the study period (31 December 2010). Hazard ratios for factors associated with represcription were calculated using Cox regression models. The cumulative incidence of ASA represcription was 85.2 % over the entire follow-up period, and 63.5 % of all represcriptions were received in the first 6 months after patients' start dates. Factors significantly associated with a reduced likelihood of ASA represcription included being aged 75-84 years, cardiovascular and gastrointestinal comorbidities (in particular, atrial fibrillation and high overall gastrointestinal risk), adverse drug reactions experienced during therapy, and use of gastroprotective or cardiovascular medications (most notably warfarin). Factors significantly associated with an increased likelihood of ASA represcription included obesity, diabetes mellitus, stable angina, depression, and use of non-steroidal anti-inflammatory drugs. In conclusion, approximately 85 % of patients who discontinued low-dose ASA therapy were subsequently represcribed ASA during the study period. Comorbidities and comedication use affected represcription rates. [ABSTRACT FROM AUTHOR]

Purpose: We aimed at estimating the incidence of diabetic retinopathy (DR) and maculopathy (DMP) among newly diagnosed type 1 (t1DM) and type 2 diabetic patients (t2DM) in the United Kingdom primary care system. The incidence of DMP among patients with DR was also estimated. Method: We conducted a cohort study using The Health Improvement Network database. The cohort included 64,983 incident diabetic patients (97.3% were t2DM) aged 1–84 years diagnosed between 2000 and 2007. This cohort was followed from the date of diabetes diagnosis until recording of DR or DMP in two separate follow-ups. Follow-up was censored at 85 years of age, death, or end of 2008. An additional follow-up was conducted from DR to DMP diagnosis using similar censoring reasons. DR and DMP cumulative incidences were calculated as well as incidence rates (IR; cases per 1,000 person-years) per calendar period (2000–2001 and 2006–2007). Results: Follow-up for DR: 9 years after diabetes diagnosis, 28% of t2DM and 24% of t1DM patients had developed DR (7,899 incident DR cases). During the first 2 years with diabetes, the IR was almost 2 times higher in patients diagnosed with diabetes in 2006–2007 (47.7) than among those diagnosed in 2000–2001 (24.5). Follow-up for DMP: 9 years after diabetes diagnosis, 3.6% of t2DM and 4.4% of t2DM patients had developed DMP (912 incident DMP cases). During the first 2 years with diabetes, the IR was three times higher in patients diagnosed with diabetes in 2006–2007 (5.8) than among those diagnosed in 2000–2001 (1.8). Macular oedema occurred in 0.8% of patients. Conclusions: In a cohort of incident diabetes, 28% of patients developed retinopathy and 4% maculopathy within the first 9 years. The 2-year IRs of DR and DMP were higher in patients diagnosed with diabetes during the period 2006–2007 than in those diagnosed during the 2000–2001 period. [ABSTRACT FROM AUTHOR]

For patients at high cardiovascular and high gastrointestinal (GI) risk, coprescription of a proton pump inhibitor (PPI) with low-dose aspirin is recommended. We aimed to quantify the extent to which low-dose aspirin discontinuation in patients at high cardiovascular risk is affected by PPI use and baseline GI risk. Patients aged 50 to 84 years who had evidence of ischemic heart disease or cardiovascular disease and who were new users of low-dose aspirin in 2000 to 2007 were identified using The Health Improvement Network (n = 35,604). Aspirin discontinuation was defined as a period of at least 90 days after completion of the last prescribed course during which no repeat prescription was issued. The incidence of low-dose aspirin discontinuation was 26.8 per 100 person-years (95% confidence interval [CI] 26.2 to 27.4). The age-, gender-, and indication-adjusted risk of aspirin discontinuation was 15% less among continuous PPI users than among PPI nonusers (hazard ratio [HR] 0.85, 95% CI 0.78 to 0.92); after further adjusting for number of coprescribed medications, the HR was 0.95 (95% CI 0.87 to 1.03). Continuous PPI use was associated with a reduced risk of aspirin discontinuation among patients at high GI risk (HR 0.83; 95% CI 0.74 to 0.93) but not among those at low GI risk (HR 1.08; 95% CI 0.96 to 1.21). In conclusion, among patients at high GI risk, concomitant users of aspirin and PPI showed a greater aspirin adherence than aspirin users not on PPI. Further studies need to confirm factors with the potential to increase adherence to long-term aspirin. [ABSTRACT FROM AUTHOR]

Background: Few studies have evaluated the prevention of upper gastrointestinal complications (UGIC; bleeding or perforation) in patients with uncomplicated peptic ulcer (PU). We assessed the effect of proton pump inhibitors (PPI) in a non-randomized setting. To maximize exchangeability of exposed and unexposed groups we restricted the study to patients with a new diagnosis of PU, i.e., a clear indication. To minimize selection bias we mimicked an intention to treat approach by assessing the effect of PPI prescription after PU diagnosis. Methods: Within a population of subjects aged 40-84 years from The Health Improvement Network database, 1997-2006, we identified 3,850 patients with incident PU. Among them, we confirmed 74 first UGIC episodes during a mean follow-up of 4 years. Exposure was prescription coverage during the month following PU diagnosis. We performed a nested case-control analysis and compared UGIC cases with 400 controls matched for age, sex, year and duration of follow-up. Relative risks (RR) and 95 % confidence intervals (CI) were estimated. Results: The overall incidence of UGIC was 4.6 cases/1,000 person-years; it was highest during the months after PU diagnosis, increased with age, and it was higher in men and subjects with Helicobacter pylori infection, anemia, and alcohol use at PU diagnosis. The RR for UGIC associated with PPI prescriptions during the month after PU diagnosis was 0.56 (95 % CI 0.31-1.0). The RR for NSAIDs with and without a PPI was 1.72 (0.68-4.45) and 3.27 (0.85-12.67), respectively. Conclusions: Findings suggest that prescription of PPIs after a PU diagnosis is associated with a reduced risk of UGIC. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To describe the validity of recorded diabetic retinopathy (DR) and diabetic maculopathy (DMP) diagnoses, including edema (DMO) in The Health Improvement Network (THIN) database. RESEARCH DESIGN AND METHODS--In two independent computer searches, we detected 20,838 patients with diabetes aged 1-84 years with a first DR computer Read entry in 2000-2008 and 4,064 with a first DMP entry. A two-step strategy was used to validate both outcomes as follows: 1) review of patient profiles including free-text comments from primary care practitioners (PCPs) (containing referral information and test results) of a random sample of 500 DR and all DMP computer-detected patients.We classified them in probable, possible, and noncase according to the diagnosis plausibility based on the manual review of the computerized information; and 2) review of questionnaires sent by PCPs and medical records in a random sample (N = 200 for each outcome including 36 diabetic macular edema [DMO]). Gold standard was PCPs' confirmation. RESULTS--After profiles review, we categorized 418 as probable/possible DR. In addition, 3,676 DMP were categorized as probable/possible (including 711 DMO). After review of information sent by PCPs, confirmation rateswere 87.3 and 87.2%, respectively (90.3%for DMO). When we applied them to the whole sample of computer-detected patients, the weighted confirmation rate was 78.0% for DR and 78.8% for DMP (86.2% for DMO). CONCLUSIONS--Read codes for DR, DM, and DMO are moderately accurate in identifying incident case subjects of these ophthalmologic complications. The validity improved when incorporating PCPs' text comments to the patient's profile. THIN database proved to be a valuable resource to study ophthalmological diabetes complications. [ABSTRACT FROM AUTHOR]

Background: Discontinuation of low-dose acetylsalicylic acid (ASA) leads to an increased risk of cardiovascular and cerebrovascular events in patients taking low-dose ASA for secondary cardiovascular prevention. However, little is known about the rate of discontinuation in everyday clinical practice. Objectives: To assess the rate of low-dose ASA discontinuation in primary care, and identify factors that predict discontinuation. Methods: The Health Improvement Network, a large UK primary care database, was used to identify patients aged 50-84 years who received at least two consecutive prescriptions for lowdose ASA for secondary cardiovascular or cerebrovascular prevention in 2000-2007 (n = 35,639). Discontinuation was defined as a period of at least 90 days after completion of the last prescribed course of ASA during which no repeat prescription was issued. Results: During the study, 11,729 patients (32.9%) discontinued ASA therapy (mean follow-up 2.5 years). The discontinuation rate was lower in patients with ASA indicated for myocardial infarction than for other indications. The diagnosis of gastrointestinal disorders during the study (overall odds ratio: 1.74; 95% confidence interval: 1.61-1.88) was associated with increased rates of ASA discontinuation, whereas co-prescription of a proton pump inhibitor from the start of ASA therapy was associated with a decreased rate of discontinuation (odds ratio: 0.80; 95% confidence interval: 0.75-0.86). Co-prescription of several other cardioprotective medications was also associated with a reduced risk of discontinuation, as were increasing age, prior hospitalization and overall number of co-medications. Conclusion: Continuous co-prescription of a PPI with low-dose ASA may improve adherence and outcomes, particularly in patients at both cardiovascular and gastrointestinal risk. [ABSTRACT FROM AUTHOR]

Background. Anxiety disorders are common and can cause substantial quality of life impairment. [ABSTRACT FROM PUBLISHER]

The authors have retracted the original article because it contains an error that has made the data unreliable. The authors have been invited to resubmit a revised version of the article. All authors agree to this retraction. [ABSTRACT FROM AUTHOR]

Background Single-dose vaccination was widely recommended in the pre-Omicron era for persons with previous SARS-CoV-2 infection. The effectiveness of a second vaccine dose in this group in the Omicron era is unknown. Methods We linked nationwide population registries in Spain to identify community-dwelling individuals aged 18–64, with a positive SARS-CoV-2 test before single-dose mRNA vaccination (mRNA-1273 or BNT162b2). Every day between 3 January and 6 February 2022 we matched 1:1 individuals receiving a second mRNA vaccine dose and controls on sex, age, province, first dose type and time, month of primary infection, and number of previous tests. We then estimated Kaplan–Meier risks of confirmed SARS-CoV-2 reinfection. We performed a similar analysis in a Delta-dominant period, between 19 July and 30 November 2021. Results In the Omicron period, estimated effectiveness (95% CI) of a second dose was 62.2% (58.2–66.4%) 7–34 days after administration, similar across groups defined by age, sex, type of first vaccine, and time since the first dose. Estimated effectiveness was 65.4% (61.1–69.9%) for mRNA-1273 and 52.0% (41.8–63.1%) for BNT162b2. Estimated effectiveness was 78.5% (67.4–89.9%), 66.1% (54.9–77.5%), and 60.2% (55.5–64.8%) when primary infection had occurred in the Delta, Alpha, and pre-Alpha periods, respectively. In the Delta period, the estimated effectiveness of a second dose was 8.8% (−55.3% to 81.1%). Conclusions Our results suggest that, over 1 month after administration, a second dose of mRNA vaccine increases protection against SARS-CoV-2 reinfection with the Omicron variant among individuals with single-dose vaccination and previously infected with another variant. [ABSTRACT FROM AUTHOR]

Background: The omicron (B.1.1.529) variant of SARS-CoV-2 has increased capacity to elude immunity and cause breakthrough infections. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters (third dose) against infection with the omicron variant by age, sex, time since complete vaccination, type of primary vaccine, and type of booster.Methods: In this nationwide cohort study, we linked data from three nationwide population registries in Spain (Vaccination Registry, Laboratory Results Registry, and National Health System registry) to select community-dwelling individuals aged 40 years or older, who completed their primary vaccine schedule at least 3 months before the start of follow-up, and had not tested positive for SARS-CoV-2 since the start of the pandemic. On each day between Jan 3, and Feb 6, 2022, we matched individuals who received a booster mRNA vaccine and controls of the same sex, age group, postal code, type of vaccine, time since primary vaccination, and number of previous tests. We estimated risk of laboratory-confirmed SARS-CoV-2 infection using the Kaplan-Meier method and compared groups using risk ratios (RR) and risk differences. Vaccine effectiveness was calculated as one minus RR.Findings: Between Jan 3, and Feb 6, 2022, 3 111 159 matched pairs were included in our study. Overall, the estimated effectiveness from day 7 to 34 after a booster was 51·3% (95% CI 50·2-52·4). Estimated effectiveness was 52·5% (51·3-53·7) for an mRNA-1273 booster and 46·2% (43·5-48·7) for a BNT162b2 booster. Effectiveness was 58·6% (55·5-61·6) if primary vaccination had been with ChAdOx1 nCoV-19 (Oxford-AstraZeneca), 55·3% (52·3-58·2) with mRNA-1273 (Moderna), 49·7% (48·3-51·1) with BNT162b2 (Pfizer-BioNTech), and 48·0% (42·5-53·7) with Ad26.COV2.S (Janssen). Estimated effectiveness was 43·6% (40·0-47·1) when the booster was administered between 151 days and 180 days after complete vaccination and 52·2% (51·0-53·3) if administered more than 180 days after primary scheduled completion.Interpretation: Booster mRNA vaccine-doses were moderately effective in preventing infection with the omicron variant of SARS-CoV-2 for over a month after administration, which indicates their suitability as a strategy to limit the health effects of COVID-19 in periods of omicron variant domination. Estimated effectiveness was higher for mRNA-1273 compared with BNT162b2 and increased with time between completed primary vaccination and booster.Funding: None. [ABSTRACT FROM AUTHOR]

Previous studies have suggested a relationship between human papillomavirus vaccine and autoimmune diseases, including thyroiditis. Thus, we aimed to evaluate the risk of thyroiditis associated with HPV vaccination among girls using the Primary Care Database For Pharmacoepidemiological Research (BIFAP) in Spain. In this retrospective cohort study, girls in BIFAP aged 9–18 years from 2007 to 2016, free of past thyroiditis and HPV vaccination, were included. Hazard Ratios (HRs; 95% CI) of thyroiditis were calculated within exposed periods (up to 2 years of vaccination) and post-exposed periods (from 2 years after vaccination onwards) compared with non-exposed periods, overall, by dose and by type of vaccine, adjusted for potential confounders collected at different times. In a post-hoc analysis, we moved back the thyroiditis date (30 days) as a theoretical delay in diagnosis. Out of the 388,411 girls included in the cohort, 153,924 were vaccinated against HPV and 480 thyroiditis (253 autoimmune) cases were identified (334 non-exposed; 103 exposed; 43 post-exposed). Adjusted HR was 1.18 [95% CI: 0.79–1.76] for exposed (1.25 [0.77–2.04] for bi- and 1.15 [0.76–1.76] for quadri-valent vaccines) and 1.26 [0.74–2.14] for post-exposed periods. HR was 1.50 [0.87–2.59] for the 1st dose, 1.13 [0.66–1.91] for the 2nd and 1.11 [0.71–1.72] for the 3rd one. When the diagnosis date was moved back, the risk was 1.14 [0.76–1.70] for exposed period, being 1.80 [0.86–3.76] and 1.40 [0.74–2.66] after 1st dose of bi- and quadri-valent, respectively. We did not observe an increased risk of thyroiditis following HPV vaccination (whether bi- or quadri-valent). Even though the point estimate was higher after 1st HPV vaccination dose than after subsequent doses, a dose–effect was not confirmed. Results remained similar after applying a lag time. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs).A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005–2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before).The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37–40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92–26.99] and 4.40 [0.90–21.57] versus NSAID, and 3.31 [1.17–9.34] and 2.45 [0.68–8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57–5.65] versus NSAID.Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.Methods: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs).A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005–2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before).The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37–40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92–26.99] and 4.40 [0.90–21.57] versus NSAID, and 3.31 [1.17–9.34] and 2.45 [0.68–8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57–5.65] versus NSAID.Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.Results: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs).A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005–2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before).The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37–40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92–26.99] and 4.40 [0.90–21.57] versus NSAID, and 3.31 [1.17–9.34] and 2.45 [0.68–8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57–5.65] versus NSAID.Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.Conclusions: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs).A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005–2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before).The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37–40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92–26.99] and 4.40 [0.90–21.57] versus NSAID, and 3.31 [1.17–9.34] and 2.45 [0.68–8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57–5.65] versus NSAID.Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded. [ABSTRACT FROM AUTHOR]

The article explores the association between diagnoses of chronic obstructive pulmonary disease (COPD) and gastroesophageal reflux disease (GERD) in primary care. Results reveal the relative risk (RR) of an incident COPD diagnosis in patients with a diagnosis of GERD was 1.17, while the RR of an incident GERD diagnosis among patients with a diagnosis of COPD was 1.46. The study concludes that patients with COPD are at an increased risk of a diagnosis of GERD compared with people without COPD.

Introduction: The public–private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data. Methods: Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell's palsy, Guillain–Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. Results: Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell's palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6–24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6–0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. Conclusion: A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data. [ABSTRACT FROM AUTHOR]

• Incidence rates of events following vaccination can be derived when exposure data is missing. • Incidence rate ratios from databases with complete exposure data can be used to derive IRs. • Type of database and event reporting methods determines bias for derived IRs. • Background incidence can be used to derive risk period incidence if the risk period is short. The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public–private collaboration aiming to develop and test a system for rapid vaccine benefit-risk monitoring using existing European healthcare databases. Incidence rate (IR) estimates of vaccination-associated adverse events that are needed to model vaccination risks can be calculated from existing healthcare databases when vaccination (exposure) data are available. We assessed different methods to derive IRs in risk periods following vaccination when exposure data are missing in one database, using estimated IRs and IRRs from other databases for febrile seizures, fever and persistent crying. IRs were estimated for children aged 0–5 years in outcome-specific risk and non-risk periods following the first dose of acellular pertussis (aP) vaccination in four primary care databases and one hospital database. We compared derived and observed IRs in each database using three methods: 1) multiplication of non-risk period IR for database i by IR ratio (IRR) obtained from meta -analysis of IRRs estimated using the self-controlled case-series method, from databases other than i ; 2) same method as 1, but multiplying with background IR; and 3) meta -analyses of observed IRs from databases other than i. IRs for febrile seizures were lower in primary care databases than the hospital database. The derived IR for febrile seizures using data from primary care databases was lower than that observed in the hospital database, and using data from the hospital database gave a higher derived IR than that observed in the primary care database. For fever and persistent crying the opposite was observed. We demonstrated that missing IRs for a post-vaccination period can be derived but that the type of database and the method of event data capture can have an impact on potential bias. We recommend IRs are derived using data from similar database types (hospital or primary care) with caution as even this can give heterogeneous results. [ABSTRACT FROM AUTHOR]

• This paper describes 9 electronic healthcare datasources covering more than 40 million persons. • Background rates for 11 events of interest and pertussis vaccine coverage were benchmarked. • All datasources were fit-for-purpose to generate reliable evidence on vaccine coverage, benefits and risks. The public-private ADVANCE consortium (Accelerated development of vaccine benefit-risk collaboration in Europe) aimed to assess if electronic healthcare databases can provide fit-for purpose data for collaborative, distributed studies and monitoring of vaccine coverage, benefits and risks of vaccines. To evaluate if European healthcare databases can be used to estimate vaccine coverage, benefit and/or risk using pertussis-containing vaccines as an example. Characterisation was conducted using open-source Java-based (Jerboa) software and R scripts. We obtained: (i) The general characteristics of the database and data source (meta-data) and (ii) a detailed description of the database population (size, representatively of age/sex of national population, rounding of birth dates, delay between birth and database entry), vaccinations (number of vaccine doses, recording of doses, pattern of doses by age and coverage) and events of interest (diagnosis codes, incidence rates). A total of nine databases (primary care, regional/national record linkage) provided data on events (pertussis, pneumonia, death, fever, convulsions, injection site reactions, hypotonic hypo-responsive episode, persistent crying) and vaccines (acellular pertussis and whole cell pertussis) related to the pertussis proof of concept studies. The databases contained data for a total population of 44 million individuals. Seven databases had recorded doses of vaccines. The pertussis coverage estimates were similar to those reported by the World Health Organisation (WHO). Incidence rates of events were comparable in magnitude and age-distribution between databases with the same characteristics. Several conditions (persistent crying and somnolence) were not captured by the databases for which outcomes were restricted to hospital discharge diagnoses. The database characterisation programs and workflows allowed for an efficient, transparent and standardised description and verification of electronic healthcare databases which may participate in pertussis vaccine coverage, benefit and risk studies. This approach is ready to be used for other vaccines/events to create readiness for participation in other vaccine related studies. [ABSTRACT FROM AUTHOR]

The Accelerated Development of VAccine benefit-risk Collaboration in Europe (ADVANCE), a public-private consortium, implemented and tested a distributed network system for the generation of evidence on the benefits-risks of marketed vaccines in Europe. We tested the system by estimating the incidence rate (IR) of pertussis and pertussis-related complications in children vaccinated with acellular (aP) and whole-cell (wP) pertussis vaccine. Data from seven electronic databases from four countries (Denmark: AUH and SSI, Spain: SIDIAP and BIFAP, UK: THIN and RCGP RSC and Italy: Pedianet) were included in a retrospective cohort analysis. Exposure was defined as any pertussis vaccination (aP or wP). The follow-up time started 14 days after the first dose. Children who had received any pertussis vaccine from January 1990 to December 2015 were included (those who switched type, or had unknown type were excluded). The outcomes of interest were confirmed or suspected pertussis and pertussis-related pneumonia and generalised convulsions within one month of pertussis diagnosis and death within three months of pertussis diagnosis. The cohort comprised 2,886,367 children ≤5 years of age. Data on wP and aP vaccination were available in three and seven databases, respectively. The IRs (per 100,000 person-years) for pertussis varied largely and ranged between 0.15 (95% CI: 0.12; 0.19) and 1.15 (95% CI: 1.07; 1.23), and the trends over time was consistent with those observed from national surveillance databases for confirmed pertussis. The pertussis IRs decreased as the number of wP and aP vaccine doses increased. Pertussis-related complications were rare (89 pneumonia, 7 generalised convulsions and no deaths) and their relative risk (vs. non-pertussis) could not be reliably estimated. The study demonstrated the feasibility of the ADVANCE system to estimate the change in pertussis IRs following pertussis vaccination. Larger sample sizes would provide additional power to compare the risk for complications between children with and without pertussis. The feasibility of vaccine-type specific effectiveness studies may be considered in the future. [ABSTRACT FROM AUTHOR]

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using electronic health record (eHR) databases in Europe. Proof-of-concept studies were designed to assess the proposed processes and system for generating the required evidence to perform B/R assessment and near-real time monitoring of vaccines. We aimed to test B/R methodologies for vaccines, using the comparison of the B/R profiles of whole-cell (wP) and acellular pertussis (aP) vaccine formulations in children as an example. We used multi-criteria decision analysis (MCDA) to structure the B/R assessment combined with individual-level state transition modelling to build the B/R effects table. In the state transition model, we simulated the number of events in two hypothetical cohorts of 1 million children followed from first pertussis dose till pre-school-entry booster (or six years of age, whichever occurred first), with one cohort receiving wP, and the other aP. The benefits were reductions in pertussis incidence and complications. The risks were increased incidences of febrile convulsions, fever, hypotonic-hyporesponsive episodes, injection-site reactions and persistent crying. Most model parameters were informed by estimates (coverage, background incidences, relative risks) from eHR databases from Denmark (SSI), Spain (BIFAP and SIDIAP), Italy (Pedianet) and the UK (RCGP-RSC and THIN). Preferences were elicited from clinical and epidemiological experts. Using state transition modelling to build the B/R effects table facilitated the comparison of different vaccine effects (e.g. immediate vaccine risks vs long-term vaccine benefits). Estimates from eHR databases could be used to inform the simulation model. The model results could be easily combined with preference weights to obtain B/R scores. Existing B/R methodology, modelling and estimates from eHR databases can be successfully used for B/R assessment of vaccines. [ABSTRACT FROM AUTHOR]

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European healthcare databases. Event misclassification can result in biased estimates. Using different algorithms for identifying cases of Bordetella pertussis (BorPer) infection as a test case, we aimed to describe a strategy to quantify event misclassification, when manual chart review is not feasible. Four participating databases retrieved data from primary care (PC) setting: BIFAP: (Spain), THIN and RCGP RSC (UK) and PEDIANET (Italy); SIDIAP (Spain) retrieved data from both PC and hospital settings. BorPer algorithms were defined by healthcare setting, data domain (diagnoses, drugs, or laboratory tests) and concept sets (specific or unspecified pertussis). Algorithm- and database-specific BorPer incidence rates (IRs) were estimated in children aged 0–14 years enrolled in 2012 and 2014 and followed up until the end of each calendar year and compared with IRs of confirmed pertussis from the ECDC surveillance system (TESSy). Novel formulas were used to approximate validity indices, based on a small set of assumptions. They were applied to approximately estimate positive predictive value (PPV) and sensitivity in SIDIAP. The number of cases and the estimated BorPer IRs per 100,000 person-years in PC, using data representing 3,173,268 person-years, were 0 (IR = 0.0), 21 (IR = 4.3), 21 (IR = 5.1), 79 (IR = 5.7), and 2 (IR = 2.3) in BIFAP, SIDIAP, THIN, RCGP RSC and PEDIANET respectively. The IRs for combined specific/unspecified pertussis were higher than TESSy, suggesting that some false positives had been included. In SIDIAP the estimated IR was 45.0 when discharge diagnoses were included. The sensitivity and PPV of combined PC specific and unspecific diagnoses for BorPer cases in SIDIAP were approximately 85% and 72%, respectively. Retrieving BorPer cases using only specific concepts has low sensitivity in PC databases, while including cases retrieved by unspecified concepts introduces false positives, which were approximately estimated to be 28% in one database. The share of cases that cannot be retrieved from a PC database because they are only seen in hospital was approximately estimated to be 15% in one database. This study demonstrated that quantifying the impact of different event-finding algorithms across databases and benchmarking with disease surveillance data can provide approximate estimates of algorithm validity. [ABSTRACT FROM AUTHOR]

• We tested the ADVANCE system workflows and methods for assessing vaccine benefit-risk. • We evaluated the use of European healthcare databases to assess pertussis vaccine reactogenicity. • Estimates differed based on where the data originate, i.e. in a primary care or hospital setting. • Primary care databases were more suited for milder reactogenicity events than hospital databases. • European healthcare databases can be used to generate reliable estimates for vaccine safety events. The Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster. The study population comprised almost 5.1 million children aged 1 month to <6 years vaccinated with wP or aP vaccines during the study period from 1 January 1990 to 31 December 2015. Data from two Danish hospital (H) databases (AUH and SSI) and five primary care (PC) databases from, UK (THIN and RCGP RSC), Spain (SIDIAP and BIFAP) and Italy (Pedianet) were analysed. Database-specific IRRs between risk vs. non-risk periods were estimated in a self-controlled case series study and pooled using random-effects meta-analyses. The overall IRs were: fever, 58.2 (95% CI: 58.1; 58.3), 96.9 (96.7; 97.1) for PC DBs and 8.56 (8.5; 8.6) for H DBs; convulsions, 7.6 (95% CI: 7.6; 7.7), 3.55 (3.5; 3.6) for PC and 12.87 (12.8; 13) for H; persistent crying, 3.9 (95% CI: 3.8; 3.9) for PC, injection-site reactions, 2.2 (95% CI 2.1; 2.2) for PC, hypotonic hypo-responsive episode (HHE), 0.4 (95% CI: 0.4; 0.4), 0.6 (0.6; 0.6) for PC and 0.2 (0.2; 0.3) for H; and somnolence: 0.3 (95% CI: 0.3; 0.3) for PC. The pooled IRRs for persistent crying, fever, and ISR, adjusted for age and healthy vaccinee period were higher after wP vs. aP vaccination, and lower for convulsions, for all doses. The IRR for HHE was slightly lower for wP than aP, while wP was associated with somnolence only for dose 1 and dose 3 compared with aP. The estimated IRs and IRRs were comparable with published data, therefore demonstrating that the ADVANCE system was able to combine several European healthcare databases to assess vaccine safety data for wP and aP vaccination. [ABSTRACT FROM AUTHOR]

• Feasibility of estimating pertussis vaccination covering using 7 European healthcare databases. • The majority of children were vaccinated at the recommended age of vaccination. • Two estimation methods provided comparable coverage estimates. • Benchmarking using national coverage estimates showed comparable results. • The approached used provided reliable estimates for pertussis vaccination coverage. The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines, using existing healthcare databases in Europe. The objective of this paper was to assess the feasibility of using electronic healthcare databases to estimate dose-specific acellular pertussis (aP) and whole cell pertussis (wP) vaccine coverage. Seven electronic healthcare databases in four European countries (Denmark (n = 2), UK (n = 2), Spain (n = 2) and Italy (n = 1)) participated in this study. Children were included from birth and followed up to age six years. Vaccination exposure was obtained from the databases and classified by type (aP or wP), and dose 1, 2 or 3. Coverage was estimated using period prevalence. For the 2006 birth cohort, two estimation methods for pertussis vaccine coverage, period prevalence and cumulative incidence were compared for each database. The majority of the 2,575,576 children included had been vaccinated at the country-specific recommended ages. Overall, the estimated dose 3 coverage was 88–97% in Denmark (birth cohorts from 2003 to 2014), 96–100% in the UK (2003–2014), 95–98% in Spain (2004–2014) and 94% in Italy (2006–2007). The estimated dose 3 coverage per birth cohort in Denmark and the UK differed by 1–6% compared with national estimates, with our estimates mostly higher. The estimated dose 3 coverage in Spain differed by 0–2% with no consistent over- or underestimation. In Italy, the estimates were 3% lower compared with the national estimates. Except for Italy, for which the two coverage estimation methods generated the same results, the estimated cumulative incidence coverages were consistently 1–10% lower than period prevalence estimates. This study showed that it was possible to provide consistent estimates of pertussis immunisation coverage from the electronic healthcare databases included, and that the estimates were comparable with the national estimates. [ABSTRACT FROM AUTHOR]

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public–private collaboration aiming to develop and test a system for rapid benefit-risk monitoring of vaccines using existing healthcare databases in Europe. We estimated vaccine coverage from electronic healthcare databases as part of a fit-for-purpose assessment for vaccine benefit-risk studies. A retrospective dynamic cohort study was conducted through a distributed network approach. Coverage with measles-vaccine for birth year 2006, human papillomavirus (HPV)-vaccine for birth years 1990–2000 and influenza-vaccine for birth years 1920–1950 was estimated using period-prevalence and inverse probability weighting methods. Seven databases from four countries participated: Italy (Pedianet, Val Padana), Spain (BIFAP, SIDIAP), UK (RCGP-RSC, THIN), Denmark (SSI/AUH). Database access providers extracted the data, transformed it into a common structure and ran an R-script locally. The created output tables were shared and pooled at a central server. The total study population comprised 274,616 persons for measles-vaccine, 2,011,666 persons for HPV-vaccine and 14,904,033 persons for influenza-vaccine. Measles-vaccine coverage varied from 84.3% (Denmark) to 96.5% (Italy, Val Padana) for the first dose and from 82.8% (Italy, Val Padana) to 90.9% (UK) for the second dose at the age of 7 years. The HPV-vaccine coverage, aggregated over birth years 1997–2000, ranged from 60% (UK) to 88.3% (Denmark) at the age of 15 years. The influenza-vaccine coverage for the influenza seasons from 2009 to 2015 for persons aged 65 years and more was roughly stable around 43% in Denmark and around 68% in the UK while a decrease from 58 to 50% was observed in Catalonia (Spain). We obtained detailed, age-specific coverage estimates though a common procedure. We discussed between database comparability and comparability to published national estimates. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the specific incidences of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among new users of drugs frequently reported to be associated with this serious event.Methods: We performed a case-population approach, which combined data from a registry of SJS/TEN cases from the Madrid region (numerator) during the study period 2005-2015 and a primary healthcare database from the same catchment population. The proportion of new users of drugs estimated in the primary healthcare database was stratified by calendar year, sex and age (5-year bands), and then applied to the same strata of Madrid's population census to compute the number of new users (denominator). Incidences were re-estimated using only cases in which the concerned drug had a probable or very probable causal relationship.Results: A total of 44 SJS/TEN cases aged > 14 years were registered during the study period. The highest SJS/TEN incidence was found for phenytoin with 68.9 per 100,000 new users (95% CI 27.7-141.9), followed by dexamethasone (5.48; 1.49-14.03), allopurinol (3.29; 1.07-7.67) and cotrimoxazole (3.19; 0.87-8.16). Considering only probable and very probable cases, the incidences hardly changed, except for dexamethasone, which was left without cases. Pantoprazole, levofloxacin and lorazepam showed incidences between 1 per 100,000 and 1 per 1,000,000 new users. Ibuprofen, amoxicillin-clavulanic acid, metamizole, amoxicillin, paracetamol and omeprazole showed incidences around 1 per one million new users.Conclusions: Phenytoin was the drug with the highest incidence of SJS/TEN, followed by allopurinol and cotrimoxazole. For the rest of the drugs, the estimated incidences were below 1 in 100,000 new users. [ABSTRACT FROM AUTHOR]

We aimed to develop and validate a fracture risk algorithm for the automatic identification of subjects at high risk of imminent and long-term fracture risk. A cohort of subjects aged 50–85, between 2007 and 2017, was extracted from the Catalan information system for the development of research in primary care database (SIDIAP). Participants were followed until the earliest of death, transfer out, fracture, or 12/31/2017. Potential risk factors were obtained based on the existing literature. Cox regression was used to model 1 and 5-year risk of hip and major fracture. The original cohort was randomly split in 80:20 for development and internal validation purposes respectively. External validation was explored in a cohort extracted from the Spanish database for pharmaco-epidemiological research in primary care. A total of 1.76 million people were included from SIDIAP (50.7 % women with mean age of 65.4 years). Hip and major fracture incidence rates were 3.57 [95%CI 3.53 to 3.60] and 11.61 [95%CI 11.54 to 11.68] per 1000 person-years, respectively. The derived model included 19 risk factors. Internal validity showed good results on calibration and discrimination. The 1-year C-statistic for hip and major fracture were 0.851 (95%CI 0.853 to 0.864), and 0.717 (95%CI 0.742 to 0.749) respectively. The 5-year C-statistic for hip and major fracture were 0.849 (95%CI 0.847 to 0.852) and 0.724 (95%CI 0.721 to 0.727) respectively. External validation showed good performance for hip and major fracture risk prediction. We have developed and validated a clinical prediction tool for 1- and 5-year hip and major osteoporotic fracture risks using electronic primary care data. The proposed algorithm can be automatically estimated at the population level using the available primary care records. Future work is needed on the cost-effectiveness of its use for population-based screening and targeted prevention of osteoporotic fractures. • A prediction model for hip and major fracture imminent risk and long-term risk is presented. • The algorithm can be estimated at population level using available primary care records for identification of subjects at high risk of fracture. • The tool was externally validated and has good external calibration and discrimination. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) is used to delay tumour development and improve survival in patients with prostate cancer. However, several randomized controlled trials and observational studies have suggested that ADT may increase the risk of cardiovascular events.Objective: The aim of the study was to evaluate the risk of coronary heart disease (CHD) and heart failure (HF) in patients with prostate cancer receiving ADT in UK primary care, and to evaluate the risks associated with individual ADT and combination ADT.Methods: The UK General Practice Research Database was used to identify a cohort of patients with a first prostate cancer diagnosis during 1999-2005. These patients were followed up to assess the occurrence of acute myocardial infarction (AMI), death from CHD, incident HF and hospitalization due to acute decompensated HF. Nested case-control analyses were performed to assess the risk of these outcomes associated with anti-androgen therapy, as well as different types of ADT and combinations of ADT.Results: Current anti-androgen use was associated with a significant increase in the risk of hospitalization due to HF (odds ratio [OR] 2.15; 95% CI 1.08, 4.29), but not of incident HF, CHD or AMI. When assessed individually, there was no significant association of bicalutamide or cyproterone use with the risk of AMI or CHD. Current use of bicalutamide 50 mg/day was associated with a significant increase in the risk of HF (OR 3.28; 95% CI 1.31, 8.18); however, this increased risk of HF was only found in patients taking bicalutamide 50 mg/day in combination with luteinizing hormone-releasing hormone (LHRH) receptor agonists. There were no cases of hospitalized HF in patients taking bicalutamide 50 mg/day as monotherapy and there was no significant association between current use of bicalutamide 150 mg/day and the risk of hospitalized HF. Combination therapy with LHRH agonists and anti-androgens was associated with a significant increase in the risk of CHD (OR 4.35; 95% CI 1.94, 9.75), AMI (OR 3.57; 95% CI 1.44, 8.86), incident HF (OR 3.19; 95% CI 1.10, 9.27) and hospitalized HF (OR 3.39; 95% CI 1.07, 10.70) compared with non-use of these drugs.Conclusions: In men with prostate cancer, combination therapy with LHRH agonists and anti-androgens is associated with significant increases in the risk of CHD, AMI, incident HF and hospitalized HF. Individual therapies do not appear to increase the risk of these outcomes. [ABSTRACT FROM AUTHOR]

The exact mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may increase coronary risk is not completely understood. The aim of this study was to quantify the risk for each type of acute coronary syndrome (ACS) associated using NSAIDs and the role played by dose, duration, and patient characteristics. A prospective case-control study was performed, interviewing 2,954 patients hospitalized for ACS at 32 Spanish hospitals and a similar number of age-matched controls using a structured questionnaire collecting information on the use of NSAIDs, risk factors, and cardiovascular history. Odds ratios (ORs) for any type and each ACS type were calculated adjusted for gender, body mass index, other risk factors, and concomitant medications by conditional logistic regression. The adjusted OR of ACS associated with the current use of NSAIDs was 1.16 (95% confidence interval [CI] 0.95 to 1.42). The risk was increased in patients consuming high doses (OR 1.64, 95% CI 1.06 to 2.53) and those with previous ischemic heart disease (OR 1.84, 95% CI 1.13 to 3.00). The hazard was driven mostly by the increase in the risk for non-ST-segment elevation ACS (OR 1.20, 95% CI 0.99 to 1.47), whereas NSAIDs did not increase the risk for ST-segment elevation myocardial infarction (OR 1.00, 95% CI 0.80 to 1.26). In conclusion, the use of NSAIDs was associated with a small, nonsignificant overall coronary risk that was more apparent for non-ST-segment elevation ACS. This risk was stronger when NSAIDs were used at high doses or in patients with previous ischemic heart disease. [Copyright &y& Elsevier]