Scientific
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BACKGROUND: This study sought to evaluate the association between systemic inflammation as measured by C-reactive protein and total joint replacement and the association between change in CRP status (low, < or = 10 mg/L and high, >10 mg/L) measured over one year and total joint replacement in patients diagnosed with rheumatoid arthritis. METHODS: A cohort of patients was selected from The Health Improvement Network (THIN) dataset of anonymised patient-level data from UK general practice with a confirmed chronic rheumatic diagnosis. Surgery-free survival was evaluated using Cox proportional hazards regression models (CPHM). RESULTS: 2,421 cases had at least one CRP measurement of which 125 cases (5.2%) had at least one major joint replacement. In CPHM, each additional unit increase in log mean CRP (range 1 to 6) was associated with a hazard ratio (HR) for major orthopaedic surgery of 1.36 (95% CI 1.10 to 1.67; p = 0.004), after controlling for age at first rheumatoid presentation and average body mass index over the same observation period. Repeated CRP observations around one year apart were recorded in 1,314 subjects. After controlling for confounding factors, in cases whose CRP remained high (>10 mg/L), the HR for joint replacement increased more than two-fold (p = 0.040) relative to cases whose CRP remained low. In patients whose CRP increased from low to high, the HR was 1.86 compared to those who remained in a low state (p = 0.217). By comparison, among those subjects whose CRP was reduced from a high to low state, the hazard ratio was more than halved (1.46) from to those who remained high (p = 0.441). Although underpowered, the trend evident from CRP change corroborates the association of TJR progression with mean CRP. CONCLUSION: CRP level predicts progression to major joint replacement after standardisation for relevant risk factors as did change in CRP status between low and high states observed over one year.

OBJECTIVES: We studied the association between the frequency, dose, and duration of different nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of myocardial infarction (MI) in the general population. We verified whether the degree of inhibition of whole blood cyclooxygenase (COX)-2 by average circulating drug levels can be a surrogate biochemical predictor of the risk of MI by NSAIDs. BACKGROUND: There is evidence that both traditional NSAIDs and selective inhibitors of COX-2 may increase the risk of MI. METHODS: From the THIN (The Health Improvement Network) database, we identified 8,852 cases of nonfatal MI in patients 50 to 84 years old between 2000 and 2005 and conducted a nested case-control analysis. We correlated the risk of MI with the degree of inhibition of platelet COX-1 and monocyte COX-2 in vitro by average therapeutic concentrations of individual NSAIDs. RESULTS: The risk of MI was increased with current use of NSAIDs (relative risk [RR]: 1.35; 95% confidence interval [CI]: 1.23 to 1.48). The risk increased with treatment duration and daily dose. We found a significant correlation between the degree of inhibition in vitro of whole blood COX-2 (r(2) = 0.7458, p = 0.0027), but not whole blood COX-1 (r(2) = 0.0007, p = 0.947), and the risk of MI associated with individual NSAIDs that lacked complete suppression (> or =95%) of platelet COX-1 activity. Individual NSAIDs with a degree of COX-2 inhibition <90% at therapeutic concentrations presented an RR of 1.18 (95% CI: 1.02 to 1.38), whereas those with a greater COX-2 inhibition had an RR of 1.60 (95% CI: 1.41 to 1.81). CONCLUSIONS: Our findings suggest that the variable risk of MI among NSAIDs that do not inhibit platelet COX-1 completely and persistently is largely related to their extent of COX-2 inhibition.

BACKGROUND: Clinical advice to pregnant women with asthma is to maintain optimal therapeutic management; however, potential adverse effects of asthma treatments on fetal development remain uncertain. A study was undertaken to assess the association between maternal asthma and gestational exposure to asthma medications with risk of congenital malformation in offspring. METHODS: A matched case-control study was performed using The Health Improvement Network primary care database. Children with malformations were matched to control children on birth year, general practice and singleton or twin delivery. RESULTS: 5124 cases of liveborn children with major congenital malformations and 30,053 controls were included in the study. The risk of any malformation in children born to women with asthma was marginally higher than that in children born to women without asthma (adjusted OR 1.10, 95% CI 1.01 to 1.20). However, no association was present in children born to mothers receiving asthma treatment in the year before or during pregnancy (OR 1.06, 95% CI 0.94 to 1.20). In assessing teratogenicity of medications, no increased risk of malformation was found with gestational exposures to short- or long-acting beta agonists, inhaled corticosteroids, oral corticosteroids, other bronchodilators or cromones. These findings were similar for each of 11 system-specific malformation groups, except for an increase in musculo-skeletal system malformation associated with cromone exposure. CONCLUSIONS: Gestational exposure to commonly used asthma medications was found to be safe overall, although a moderate teratogenic risk of cromones cannot be excluded. There was some evidence of a small increased risk of congenital malformation in children born to women with asthma, but this was not explained by gestational exposure to asthma drugs.

OBJECTIVE: To explore the hypothesis that medically attended head injury in young children may be causal in the later development of attention deficit hyperactivity disorder. DESIGN: Retrospective cohort study. SETTING: Health improvement network database (1988-2003), a longitudinal UK general practice dataset. PARTICIPANTS: All children registered in the database from birth until their 10th birthday. MAIN OUTCOME MEASURES: Risk of a child with a head injury before age 2 developing attention deficit hyperactivity disorder before age 10 compared with children with a burn injury before age 2 and children with neither a burn nor a head injury. RESULTS: Of the 62 088 children who comprised the cohort, 2782 (4.5%) had a head injury and 1116 (1.8%) had a burn injury. The risk of diagnosis of attention deficit hyperactivity disorder before 10 years of age after adjustment for sex, prematurity, socioeconomic status, and practice identification number was similar in the head injury (relative risk 1.9, 95% confidence interval 1.5 to 2.5) and burn injury groups (1.7, 1.2 to 2.5) compared with all other children. DISCUSSION: Medically attended head injury before 2 years of age does not seem to be causal in the development of attention deficit hyperactivity disorder. Medically attended injury before 2 years of age may be a marker for subsequent diagnosis of attention deficit hyperactivity disorder.

A retrospective cohort study using the data from The Health Improvement Network (THIN) database in the United Kingdom was conducted to examine the incidence rates of seizures across different BMI levels in the adult population aged > or = 18 years. Poisson regression was used to examine the relationship between BMI and seizures. The overall incidence rate of seizures was found to be 31.2 cases per 100,000 person-years. The incidence rate of seizures (cases per 100,000 person-years) in obese patients (BMI > or = 30 kg/m2) was 34.8 (95% confidence interval (CI), 23.1, 46.4), comparable to that in patients with normal weight (BMI between 18.5 and 24.9 kg/m2) (35.8, 95% CI (26.6, 44.9)). In contrast, underweight patients (< 18.5 kg/m2) or extremely obese (> or = 40 kg/m2) patients tended to have higher incidence rates than those with normal weight. After adjustment for age, gender, and smoking status, compared to patients with normal weight, those who were underweight or extremely obese had a rate ratio (RR) for seizures of 1.6 (95% CI (0.7, 3.8)) and 1.7 (95% CI (0.7, 3.9)), respectively. To date, we have not found any study that examines the associations between BMI or obesity and seizures. In this study, the incidence rates of seizures in the extremely obese and underweight patients tended to be higher than that in the normal-weight patients.

BACKGROUND: Between 3% and 40% of patients surviving an episode of upper gastrointestinal bleeding (UGIB) experience a recurrence within 1 year. Aim To characterize further the recurrence rate of UGIB and to investigate the role of long-term acid suppressive therapy in its secondary prevention. METHODS: Recurrent cases of UGIB were identified among patients registered in The Health Improvement Network in the UK. A nested case-control analysis provided relative risk (RR) estimates of factors associated with recurrence. RESULTS: Of 1287 patients included, 67 (5.2%) were identified with a recurrent UGIB episode, corresponding to a recurrence rate of 17.5 per 1000 person-years during a mean follow-up of 3 years. The greatest risk of recurrence was in patients prescribed the oral anticoagulant warfarin (RR: 5.38; 95% confidence interval: 2.02-14.36). Use of a single proton pump inhibitor (PPIs) was associated with a reduced risk of recurrence (RR: 0.51; 95% confidence interval: 0.26-0.99), even in patients taking warfarin, while current use of H(2)-receptor antagonists was not. After the first episode of UGIB, use of nonsteroidal anti-inflammatory drugs and aspirin was greatly reduced, preventing estimation of the risk associated with these drugs. CONCLUSION: Long-term PPI therapy reduces the risk of UGIB recurrence.

PURPOSE: To define periods of acceptable mortality reporting in primary care and to demonstrate through examples the implication for research using automated medical data. METHODS: Annual death counts were obtained for each primary care practice participating in The Health Improvement Network "THIN" (UK). Expected counts were calculated from national death rates, accounting for the practice's age/sex structure. The standardized mortality ratio (SMR) was calculated with 95% confidence intervals (CI). A visual review process was undertaken to assign the year from which the practice had acceptable mortality reporting (AMR). The process involved reviewer pairs who were blinded to each other's decisions. Patterns of death reporting were checked. The AMR year was applied as a filter to THIN data to assess its impact on the SMR. RESULTS: For most practices the SMR was relatively stable and the AMR year was easily identified with 86% agreement between the blinded reviewer pairs. Applying the AMR to THIN removed under-reporting of death. However, the total computerized follow-up reduced from 37 to 32 million patient-years. Problematic death recording patterns included some practices keeping only live patient records when converting their software systems thereby creating 'immortal periods' prior to this moment, and peaks occurring when practices updated the vital status of their patients' records. CONCLUSIONS: This is the first time that an external standard has been used to assess completeness of mortality in automated primary care data. The resulting AMR year provides a natural filter for research and avoids biases associated with 'immortal periods', record updating and under-reporting.