Epidemiology of moderately severe and severe non-proliferative diabetic retinopathy in South West England.

AIMS: To estimate the incidence of early treatment diabetic retinopathy study (ETDRS) level 47 and 53 and progression to treatment with panretinal photocoagulation (PRP) for proliferative DR (PDR). METHODS: Log-linear regression was used to estimate the incidence of level 47-53 or worse for 33,009 people with diabetes (PWD) in Gloucestershire during 2013-2016 by calendar year and diabetes type, based on the first recording. Progression was analysed in Gloucestershire and Bristol with a parametric survival analysis examining the association of baseline and time-varying demographic and clinical factors on time to PRP after the first recording of level 47-53. RESULTS: Incidence decreased from 0.57 (95% confidence intervals (CI) 0.48-0.67) per 100 PWD in 2013 to 0.35 (95% CI 0.29-0.43) in 2016 (p < 0.001). For progression, 338 eligible PWD from Gloucestershire and 418 from Bristol were followed for a median of 1.4 years; 78 and 83% had Type 2 diabetes and a median (interquartile range) of 15 (10-22) and 17 (11-25) years duration of diagnosed diabetes respectively. Three years from the incident ETDRS 47-53, 18.9% and 17.2% had received PRP respectively. For Gloucestershire, severe IRMA and updated mean HbA1c were associated with an increase in the risk of initiating PRP (hazard ratio 3.14 (95% CI: 1.60-6.15) and 1.21 (95% CI: 1.06-1.38 per 10 mmol/mol) respectively). CONCLUSION: This study provides additional understanding of this population and shows that a high proportion of patients with ETDRS levels 47-53 need to be monitored as they are at high risk of progressing to PDR.

Prevalence and incidence of diabetic retinopathy (DR) in the UK population of Gloucestershire.

PURPOSE: To estimate prevalence and incidence of diabetic retinopathy (DR) in a UK region by severity between 2012 and 2016 and risk factors for progression to proliferative DR (PDR). METHODS: Electronic medical records from people with diabetes (PWD) ≥18 years seen at the Gloucestershire Diabetic Eye Screening Programme (GDESP) and the hospital eye clinic were analysed (HEC). Prevalence and incidence of DR per 100 PWD (%) by calendar year, grade and diabetes type were estimated using log-linear regression. Progression to PDR and associated risk factors were estimated using parametric survival analyses. RESULTS: Across the study period, 35 873 PWD had at least one DR assessment. They were aged 66 (56-75) years (median (interquartile range)), 57% male, 5 (1-10) years since diabetes diagnosis, 93% Type 2 diabetes. Prevalence of DR decreased from 38.9% (95% CI: 38.1%, 39.8%) in 2012 to 36.6% (95% CI: 35.9%, 37.3%) in 2016 (p < 0.001). Incidence of any DR decreased from 10.9% (95% CI: 10.4%, 11.5%) in 2013 to 8.5% (95% CI: 8.1%, 9.0%) in 2016 (p < 0.001). Prevalence of PDR decreased from 3.5% (95% CI: 3.3%, 3.8%) in 2012 to 3.1% (95% CI 2.9%, 3.3%) in 2016 (p = 0.008). Incidence of PDR did not change over time. HbA1c and bilateral moderate-severe NPDR were statistically significant risk factors associated with progression to PDR. CONCLUSIONS: Incidence and prevalence of DR decreased between 2012 and 2016 in this well-characterized population of the UK.

Real world management of pregestational diabetes not achieving glycemic control for many patients in the UK.

PURPOSE: Our goal was to describe the management of pregestational diabetes in pregnant women in the United Kingdom. METHODS: We used electronic medical records from The Health Improvement Network database between January 1995 and June 2012 to identify the first pregnancy in women 15 to 45 years of age with pregestational diabetes type 1 or type 2. Information on lifestyle factors, demographic characteristics, prescription of specific antidiabetic medications, and glycemic control measures (HbA1c) was obtained from primary care provider records. We evaluated treatment patterns and HbA1c levels within 90 days before the last menstrual period (prepregnancy period) and within each trimester of pregnancy. RESULTS: In a cohort of 1511 pregnant women with pregestational diabetes, 60% had type 1 and 40% type 2 diabetes. Among women with type 1 diabetes, 90% received antidiabetic medication (primarily insulin) prepregnancy and 92% during the first trimester. Among women with type 2 diabetes, 54% received antidiabetic medication (primarily metformin) during the prepregnancy period and 60% during the first trimester. Among women with nontreated diabetes type 2 before pregnancy, 22% initiated treatment by the first trimester (primarily insulin); those on noninsulin antidiabetic medications often switched to insulin. The proportion of women with at least 1 HbA1c value recorded within the prepregnancy period was 33% for type 1 (n = 299) and 31% for type 2 diabetes (n = 189); the corresponding proportions within the first trimester were 48% and 40%, respectively. Among women with recorded HbA1c, the prevalence of HbA1c > 7% prepregnancy was 70% for type 1 and 52% for type 2 diabetes; the proportions within the first trimester were 73% and 46%, respectively. CONCLUSIONS: Management of pregnant women with diabetes seems to follow recommendations for pharmacological treatment. However, there is substantial room for improvement in HbA1c control, that is, in the planning of pregnancy in women with diabetes, in the initiation of antidiabetic medication among women with diabetes type 2 who may need it, and likely in the compliance with treatments in women with type 2 and type 1 diabetes.

Safety of non-insulin glucose-lowering drugs in pregnant women with pre-gestational diabetes: A cohort study.

AIMS: To evaluate the association between use of non-insulin antidiabetics in early pregnancy and the risk of miscarriages, stillbirths and major structural malformations. MATERIALS AND METHODS: A cohort of 1511 pregnant women with pre-gestational diabetes linked to live births was identified using electronic medical records from The Health Improvement Network (THIN) for the period 1995 to 2012. Information on prescriptions, foetal outcomes and potential confounders was ascertained from both codes and free text in the THIN database. Odds ratios (OR) and 95% confidence intervals (CI) of adverse foetal outcomes in women treated with non-insulin antidiabetics during the first trimester compared to those on insulin were estimated using logistic regression to adjust for type of diabetes, glycaemic control and other maternal characteristics. RESULTS: Among 311 pregnant women on non-insulin antidiabetics, 21.9% had a miscarriage and 1.6% a stillbirth; 1.9% of live births had major malformations. The corresponding frequencies for the 883 women on insulin were 13.3%, 1.7% and 9.6%. Insulin users more often had type 1 diabetes and poor glycaemic control. Compared to women with type 1 diabetes, those with type 2 diabetes had a higher risk of miscarriages (20.5% vs 12.8%) but a lower prevalence of malformations (4.0% vs 9.2%). Compared to women with HbA1c ≤7%, those with HbA1c >7% had a higher prevalence of malformations (12.6% vs 2.7%). After adjustment for diabetes type and glycaemic control, compared to insulin, non-insulin antidiabetic patients were associated with an OR for miscarriage of 1.19 (95% CI, 0.75-1.89), for stillbirths of 0.65 (95% CI, 0.16-2.58), and for major malformations of 0.25 (95% CI, 0.08-0.84). CONCLUSION: Among women with diabetes, use of non-insulin antidiabetics early in pregnancy was not associated with greater risks of foetal losses or major malformations than was insulin.

Claims-based studies of oral glucose-lowering medications can achieve balance in critical clinical variables only observed in electronic health records.

AIM: To evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from linked electronic health records (EHR) data. METHODS: Within a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase-4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims-EHR-linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances. RESULTS: From a claims-based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims-based characteristics in the EHR-linked and EHR-unlinked patients were similar (SD < 0.1), confirming the representativeness of the EHR-linked subset. The balance of claims-based and EHR-based patient characteristics appeared to be reasonable before PS-matching and generally improved in the PS-matched population, to be SD < 0.1 for most patient characteristics and SD < 0.2 for select laboratory results and body mass index categories, which was not large enough to cause meaningful confounding. CONCLUSION: In the context of pharmacoepidemiological research on diabetes therapy, choosing appropriate comparison groups paired with a new-user design and 1:1 PS matching on many proxies of diabetes severity and duration improves balance in covariates typically unmeasured in administrative claims datasets, to the extent that residual confounding is unlikely.

Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations.

BACKGROUND: Recent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved. METHODS: We reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges. RESULTS: From the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods. CONCLUSIONS/INTERPRETATION: Observational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.

Achievement of lipoprotein goals among patients with metabolic syndrome at high cardiovascular risk across Europe. The EURIKA study.

OBJECTIVE: To examine for the first time the achievement of lipoprotein treatment goals in patients with metabolic syndrome and lipid abnormalities who are at elevated cardiovascular risk in Europe. METHODS: Cross-sectional study conducted in 2009-2010 in 12 European countries among outpatients aged ≥50 years free of clinical cardiovascular disease. We assessed achievement of American Diabetes Association/American College of Cardiology lipid treatment goals in those with metabolic syndrome at highest risk (diabetes plus ≥1 additional major cardiovascular risk factor beyond lipid abnormalities) or high risk (no diabetes but ≥2 additional major cardiovascular risk factors). RESULTS: Among 1431 highest-risk patients, 64.6% (between-country range [BCR] 40-84.5%) were on lipid-lowering medication. Of them, 13.4% (BCR: 2.5-28.6%) had LDL-cholesterol<70 mg/dl, non-HDL-cholesterol<100mg/dl, and apolipoprotein B<80 mg/dl. Among 832 high-risk patients, 38.7% BCR: 27.5-55.3%) were on lipid-lowering medication. Of them, 20.5% (BCR: 5.5-57.6%) had LDL-cholesterol<100mg/dl, non-HDL-cholesterol<130 mg/dl, and apolipoprotein B<90 mg/dl. About 96% of highest-risk patients and 94% of high-risk patients were given at least one lifestyle advice (weight reduction, healthy diet, physical activity, no-smoking), but only 1.3% of the former and 4.9% of the latter reached all three lipid goals. CONCLUSION: There is a substantial gap between clinical guidelines and medical practice since only one in 5-7 patients met all treatment targets. Although most patients received lifestyle advice, the effectiveness of counseling was very low. Large between-country differences in outcomes suggest considerable room for improvement.

Survey of physicians' practices in the control of cardiovascular risk factors: the EURIKA study.

OBJECTIVES: To assess the practices of physicians in 12 European countries in the primary prevention of cardiovascular disease (CVD). METHODS: In 2009, 806 physicians from 12 European countries answered a questionnaire, delivered electronically or by post, regarding their assessment of patients with cardiovascular risk factors, and their use of risk calculation tools and clinical practice guidelines (ClinicalTrials.gov number: NCT00882336). Approximately 60 physicians per country were selected (participation rate varied between 3.1% in Sweden and 22.8% in Turkey). RESULTS: Among participating physicians, 85.2% reported using at least one clinical guideline for CVD prevention. The most popular were the ESC guidelines (55.1%). Reasons for not using guidelines included: the wide choice available (47.1%), time constraints (33.3%), lack of awareness of guidelines (27.5%), and perception that guidelines are unrealistic (23.5%). Among all physicians, 68.5% reported using global risk calculation tools. Written charts were the preferred method (69.4%) and the most commonly used was the SCORE equation (35.4%). Reasons for not using equations included time constraints (59.8%), not being convinced of their usefulness (21.7%) and lack of awareness (19.7%). Most physicians (70.8%) believed that global risk-equations have limitations; 89.8% that equations overlook important risk factors, and 66.5% that they could not be used in elderly patients. Only 46.4% of physicians stated that their local healthcare framework was sufficient for primary prevention of CVD, while 67.2% stated that it was sufficient for secondary prevention of CVD. CONCLUSIONS: A high proportion of physicians reported using clinical guidelines for primary CVD prevention. However, time constraints, lack of perceived usefulness and inadequate knowledge were common reasons for not using CVD prevention guidelines or global CVD risk assessment tools.

Excess risk attributable to traditional cardiovascular risk factors in clinical practice settings across Europe - The EURIKA Study.

BACKGROUND: Physicians involved in primary prevention are key players in CVD risk control strategies, but the expected reduction in CVD risk that would be obtained if all patients attending primary care had their risk factors controlled according to current guidelines is unknown. The objective of this study was to estimate the excess risk attributable, firstly, to the presence of CVD risk factors and, secondly, to the lack of control of these risk factors in primary prevention care across Europe. METHODS: Cross-sectional study using data from the European Study on Cardiovascular Risk Prevention and Management in Daily Practice (EURIKA), which involved primary care and outpatient clinics involved in primary prevention from 12 European countries between May 2009 and January 2010. We enrolled 7,434 patients over 50 years old with at least one cardiovascular risk factor but without CVD and calculated their 10-year risk of CVD death according to the SCORE equation, modified to take diabetes risk into account. RESULTS: The average 10-year risk of CVD death in study participants (N = 7,434) was 8.2%. Hypertension, hyperlipidemia, smoking, and diabetes were responsible for 32.7 (95% confidence interval 32.0-33.4), 15.1 (14.8-15.4), 10.4 (9.9-11.0), and 16.4% (15.6-17.2) of CVD risk, respectively. The four risk factors accounted for 57.7% (57.0-58.4) of CVD risk, representing a 10-year excess risk of CVD death of 5.66% (5.47-5.85). Lack of control of hypertension, hyperlipidemia, smoking, and diabetes were responsible for 8.8 (8.3-9.3), 10.6 (10.3-10.9), 10.4 (9.9-11.0), and 3.1% (2.8-3.4) of CVD risk, respectively. Lack of control of the four risk factors accounted for 29.2% (28.5-29.8) of CVD risk, representing a 10-year excess risk of CVD death of 3.12% (2.97-3.27). CONCLUSIONS: Lack of control of CVD risk factors was responsible for almost 30% of the risk of CVD death among patients participating in the EURIKA Study.

Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study.

AIMS: Most studies on the primary prevention of cardiovascular disease (CVD) have been limited to patients at high CVD risk. We assessed the achievement of treatment goals for CVD risk factors among patients with a substantial variation in CVD risk. METHODS AND RESULTS: This study was conducted with 7641 outpatients aged ≥50 years, free of clinical CVD and with at least one major CVD risk factor, selected from 12 European countries in 2009. Risk factor definition and treatment goals were based on the 2007 European guidelines on CVD prevention. Cholesterol fractions and glycated haemoglobin (HbA1c) were measured in a central laboratory. Cardiovascular disease risk was estimated with the SCORE equation. Patients' mean age was 63 years (48% men), and 40.1% had a high CVD risk. Among treated hypertensives (94.2%), only 38.8% achieved the blood pressure target of <140/90 mmHg [between-country range (BCR): 32.1-47.5%]. Among treated dyslipidaemic patients (74.4%), 41.2% attained both the total- and LDL-cholesterol target of <5 and <3 mmol/L, respectively (BCR: 24.3-68.4%). Among treated type 2 diabetic patients (87.2%), 36.7% achieved the <6.5% HbA1c target (BCR: 23.4-48.4%). Among obese patients on non-pharmacological treatment (92.2%), 24.7% reached the body mass index target of <30 kg/m(2) (BCR: 12.7-37.1%). About one-third of controlled patients on treatment were still at high remaining CVD risk. Although most patients were advised to reduce excess weight and to follow a low-calorie diet, less than half received written recommendations. CONCLUSIONS: In Europe, a large proportion of patients in primary prevention have CVD risk factors that remain uncontrolled, and lifestyle counselling is not well implemented; moreover, there is substantial between-country variation, which indicates additional room for improvement. Raised residual CVD risk is relatively frequent among patients despite control of their primary risk factors and should be addressed.

Rationale and methods of the European Study on Cardiovascular Risk Prevention and Management in Daily Practice (EURIKA).

BACKGROUND: The EURIKA study aims to assess the status of primary prevention of cardiovascular disease (CVD) across Europe. Specifically, it will determine the degree of control of cardiovascular risk factors in current clinical practice in relation to the European guidelines on cardiovascular prevention. It will also assess physicians' knowledge and attitudes about CVD prevention as well as the barriers impeding effective risk factor management in clinical practice. METHODS/DESIGN: Cross-sectional study conducted simultaneously in 12 countries across Europe. The study has two components: firstly at the physician level, assessing eight hundred and nine primary care and specialist physicians with a daily practice in CVD prevention. A physician specific questionnaire captures information regarding physician demographics, practice settings, cardiovascular prevention beliefs and management. Secondly at the patient level, including 7641 patients aged 50 years or older, free of clinical CVD and with at least one classical risk factor, enrolled by the participating physicians. A patient-specific questionnaire captures information from clinical records and patient interview regarding sociodemographic data, CVD risk factors, and current medications. Finally, each patient provides a fasting blood sample, which is sent to a central laboratory for measuring serum lipids, apolipoproteins, hemoglobin-A1c, and inflammatory biomarkers. DISCUSSION: Primary prevention of CVD is an extremely important clinical issue, with preventable circulatory diseases remaining the leading cause of major disease burden. The EURIKA study will provide key information to assess effectiveness of and attitudes toward primary prevention of CVD in Europe. A transnational study creates opportunities for benchmarking good clinical practice across countries and improving outcomes. (ClinicalTrials.gov number, NCT00882336).

Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding.

OBJECTIVE: Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. METHODS: We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. RESULTS: The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82-5.31) for traditional NSAIDs and 1.88 (95% CI 0.96-3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17-3.33]), rofecoxib (2.12 [95% CI 1.59-2.84]), aceclofenac (1.44 [95% CI 0.65-3.2]), and celecoxib (1.42 [95% CI 0.85-2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87-36.04]) and piroxicam (9.94 [95% CI 5.99-16.50). Estimated RRs were 5.63 (95% CI 3.83-8.28) for naproxen, 5.57 (95% CI 3.94-7.87) for ketoprofen, 5.40 (95% CI 4.16-7.00) for indomethacin, 4.15 (95% CI 2.59-6.64) for meloxicam, and 3.98 (95% CI 3.36-4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r(2) = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. CONCLUSION: The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation.

Do oral antimuscarinic drugs carry an increased risk of acute urinary retention?

PURPOSE: We determined whether men treated with oral antimuscarinics are at increased risk for acute urinary retention. MATERIALS AND METHODS: In this population based, retrospective cohort study using a nested case-control design we analyzed data from a large primary care database containing patient information entered by general practitioners in the United Kingdom. Our study cohort comprised men 20 to 84 years old. Cases of acute urinary retention were identified by reviewing diagnostic codes and were confirmed in a random sample through questionnaires sent to the treating physician. RESULTS: The overall incidence of acute urinary retention in the study cohort (1,844) was 1.0 per 1,000 person-years, with the incidence rate increasing with age. The first 30 days (early treatment) of antimuscarinic use was associated with a relative risk of acute urinary retention of 8.3 (95% CI 4.8-14.2) and with longer term use (more than 30 days) the relative risk was 2.0 (95% CI 1.2-3.1). The relative risk of acute urinary retention was similar for low/medium and high antimuscarinic doses (relative risk 2.8 vs 3.0, 95% CI 2.1-3.8 and 1.3-6.8, respectively). The relative risk of acute urinary retention was highest during early treatment for a urogenital indication (relative risk 14.2, 95% CI 6.8-29.6). The risk of acute urinary retention was not increased when antimuscarinics were used as antispasmodics or for drug induced parkinsonism. CONCLUSIONS: Men prescribed antimuscarinics, particularly for a urogenital condition, should be closely monitored during the first 30 days of treatment for signs or symptoms of urinary retention.

Natural antioxidants protect against lead-induced damage during pregnancy and lactation in rat's pups.

The aim of this study was to add further evidence to the biochemical changes produced in lead-exposed pups and to investigate the potential role of natural antioxidants against the lead-induced damage. Pregnant Wistar rats received treatments with drinking water, divided into four groups, as follows: (1) distilled water; (2) lead (300mg/L); (3) lead+Zn (20mg/L)+vitamins A (50,000U/L), C (2g/L), E (500mg/L) and B(6) (500mg/L); and (4) vitamins+Zn solution. We found a significant decrease in haemoglobin and haematocrit values as well and an increase in haemolysis among lead-exposed pups. Vitamins and zinc supplementation were effective in restoring delta-aminolevulinic acid dehydratase, inhibited by lead in erythrocytes, but did not reach control values. Lead exposure increased the production of thiobarbituric acid reactive substances (TBARS) and catalase activity in kidneys and liver that were reduced by the co-administration of vitamins and zinc. Our findings suggest that administration of antioxidants during gestation and lactation could prevent some of the negative effects of lead.

Chest pain without established ischaemic heart disease in primary care patients: associated comorbidities and mortality.

BACKGROUND: Ischaemic heart disease (IHD) can be excluded in the majority of patients with unspecific chest pain. The remainder have what is generally referred to as non-cardiac chest pain, which has been associated with gastrointestinal, neuromusculoskeletal, pulmonary, and psychiatric causes. AIM: To assess morbidity and mortality following a new diagnosis of non-specific chest pain in patients without established IHD. DESIGN OF STUDY: Population-based cohort study with nested case-control analysis. SETTING: UK primary care practices contributing to the General Practice Research Database. METHOD: Patients aged 20-79 years with chest pain who had had no chest pain consultation before 2000 and no IHD diagnosis before 2000 or within 2 weeks after the index date were selected from the General Practice Research Database. The selected 3028 patients and matched controls were followed-up for 1 year. RESULTS: The incidence of chest pain in patients without established IHD was 12.7 per 1000 person-years. In the year following the index date, patients who had chest pain but did not have established IHD were more likely than controls to receive a first IHD diagnosis (hazard ratio [HR] = 18.2, 95% confidence interval [CI] = 11.6 to 28.6) or to die (HR = 2.3, 95% CI = 1.3 to 4.1). Patients with chest pain commonly had a history of gastro-oesophageal reflux disease (GORD; odds ratio [OR] = 2.0, 95% CI = 1.5 to 2.7) or went on to be diagnosed with GORD (risk ratio 4.5, 95% CI = 3.1 to 6.4). CONCLUSION: Patients with chest pain but without established IHD were found to have an increased risk of being diagnosed with IHD. Chest pain in patients without established IHD was also commonly associated with GORD.

Toxic effects of perinatal lead exposure on the brain of rats: involvement of oxidative stress and the beneficial role of antioxidants.

The aim of this study was to determine whether changes in the activities of antioxidant enzymes occur in the brain of lead-exposed rats (300mgPb/L in drinking water) and to investigate the potential benefit of the administration of some natural antioxidants (Zn 20mg/L+vitamins A 50.000U/L, C 2g/L, E 500mg/L and B6 500mg/L) during pregnancy and lactation. Lead exposure caused a significant increase in brain TBARS (23%) vs. control, whereas co-administration of antioxidants+lead was effective in reducing TBARS levels. The catalase activity in brain samples of the lead group was enhanced 99% vs. control, but no changes were found in the remainder of the groups. No statistically significant effect of lead and/or antioxidants in brain SOD activity was noted. Acid phosphatase activity was enhanced in both lead groups but no changes were found in alkaline phosphatase activity. Finally, a statistically significant decrease (-35%) of acetylcholinesterase activity was noted in the lead+antioxidants group. This study provides evidence of the beneficial role of antioxidants in early status of brain development in rats against lead exposure.

The safety of rosuvastatin in comparison with other statins in over 100,000 statin users in UK primary care.

PURPOSE: To compare mortality and the incidence of hospitalization for myopathy, rhabdomyolysis, acute renal failure and acute liver injury in patients receiving rosuvastatin and those taking other statins. METHODS: Patients prescribed a statin that they had not used before were selected from the UK General Practice Research Database (GPRD) and followed up from 1 April 2003 to 31 December 2005. RESULTS: We studied 10 289 patients on rosuvastatin and 117 102 taking other statins. No cases of myopathy, rhabdomyolysis or acute liver injury occurred among rosuvastatin users. In those taking statins other than rosuvastatin, the incidence of myopathy was 0.4 (95% confidence interval (CI): 0.1-0.9), of rhabdomyolysis was 0.4 (95%CI: 0.1-0.9) and of acute liver injury was 0.4 (95%CI: 0.2-1.0), per 10 000 person-years. Fourteen cases of acute renal failure were identified (two among rosuvastatin users and 12 among other statin users). Among current users, the relative risk (RR) of acute renal failure in rosuvastatin users compared with other statin users was 1.16 (95%CI: 0.15-9.03).We identified 3232 deaths during the study period (173 in the rosuvastatin-treated group and 3059 in the other statin group). The RR of death associated with current use of rosuvastatin compared with other statins was 0.55 (95%CI: 0.44-0.68). CONCLUSIONS: We found no evidence that patients prescribed rosuvastatin were at greater risk of these outcomes than patients prescribed other statins. There was no evidence of increased mortality among patients taking rosuvastatin, even after allowing for age, sex and prior statin use.