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Background: Complication rates of medical therapy for secondary stroke prevention derived from clinical trials may or may not be applicable to patients with cerebrovascular disease in the general population.Objective: To determine complication rates for aspirin, warfarin, and intravenous heparin administered for secondary stroke prevention after first episodes of ischemic stroke, transient ischemic attack, or amaurosis fugax in a community.Design: Population-based historical cohort study.Setting: Rochester, Minnesota.Patients: All residents of Rochester who, between 1985 and 1989, received aspirin (n = 339) or warfarin (n = 145) within 2 years after first ischemic stroke, transient ischemic attack, or amaurosis fugax or received intravenous heparin (n = 201) within 2 weeks after first ischemic stroke, transient ischemic attack, or amaurosis fugax.Measurements: Occurrence of major complications caused by therapy.Results: Twenty aspirin-associated complications (1 fatal) occurred during an average 1.7 years of treatment, 8 warfarin-associated complications occurred during an average 0.7 years of treatment, and 3 heparin-associated complications (1 fatal) occurred during an average 5.1 days of treatment. Complication rates were 3.5 per 100 person-years (95% CI, 2.1 to 5.4) for aspirin, 7.9 per 100 person-years (CI, 3.4 to 15.6) for warfarin, and 0.30 (CI, 0.06 to 0.86) per 100 person-days for heparin. Rates of fatal complications were 0.2 per 100 person-years (CI, 0 to 1.0) for aspirin, 0 per 100 person-years (CI, 0 to 3.6) for warfarin, and 0.10 per 100 person-days (0 to 0.55) for heparin.Conclusions: Complication rates for warfarin and intravenous heparin given as therapy for secondary stroke prevention in Rochester, Minnesota, were lower than rates reported from earlier trials and observational studies. However, complication rates for warfarin were higher than in more recent referral-based studies and multicenter randomized trials. After adjustment for duration of therapy, complication rates for heparin were higher than those for aspirin or warfarin. These rates can be used to judge the applicability of complication rates derived from ongoing clinical trials. [ABSTRACT FROM AUTHOR]

The relation of antioxidant nutrients to the incidence of nuclear cataracts was investigated in a cohort of adults aged 43-84 years in the Beaver Dam Eye Study (Beaver Dam, Wisconsin). Nuclear opacity was assessed on a five-point ordinal scale using lens photographs taken at baseline (1988-1990) and at follow-up (1993-1995). Of the 1,354 persons eligible, 246 developed a nuclear cataract (level 4 or 5 opacity) in at least one eye. Antioxidant intakes were assessed using a food frequency questionnaire administered at baseline for time points corresponding to intake during the year preceding baseline and 10 years before baseline (the distant past). Lutein-zeaxanthin was the only carotenoid, out of five examined, that was associated with nuclear cataracts. Persons in the highest quintile of lutein intake in the distant past were half as likely to have an incident cataract as persons in the lowest quintile of intake (95% confidence interval 0.3-0.8). In the overall group, nuclear cataracts were not significantly related to intake of vitamin C or vitamin E. However, vitamins C and E were inversely associated with opacities in persons who had some other risk factors for cataracts. While results of this short term follow-up study are consistent with a possible protective influence of lutein and vitamins E and C on the development of nuclear cataracts, the evidence in the present study provides weak support for these associations. [ABSTRACT FROM AUTHOR]

Objective: We updated our incidence study by identifying Rochester, Minnesota, residents diagnosed with anorexia nervosa during 1985 through 1989. Method: From a community-based epidemiologic resource, 2,806 medical records with diagnoses including anorexia nervosa, eating disorder, bulimia, amenorrhea and other conditions were screened to identify new cases of anorexia nervosa. Results: Two hundred eight (193 females and 15 males) residents fulfilled standard diagnostic criteria for anorexia nervosa. The overall age-sex-adjusted incidence rate was 8.3 per 100,000 person-years. The age-adjusted incidence among females was 15.0 per 100,000 person-years compared to 1.5 per 100,000 among males. The long-term linear increase for 15 to 24-year-old females noted during the first 50 years of the study continued. The disorder remained less frequent among older females. Discussion: Anorexia nervosa remains a relatively common disorder among young females. While there are short-term fluctuations in incidence, the long-term increasing trend for 15 to 24-year-old females has continued. [ABSTRACT FROM AUTHOR]

Objective: To assess the validity of the suggestion that protruding atheromatous material in the thoracic aorta is an important cause of cerebrovascular ischemic events (CIEs) (ie, transient ischemic attack or ischemic stroke). Methods: This case-control study of Olmsted County, Minnesota, residents who underwent transesophageal echocardiography (TEE) from 1993 to 1997 included controls without CIE randomly selected from the population, controls without CIE referred for TEE because of cardiac disease, cases with incident CIE of obvious cause (noncryptogenic), and cases with incident CIE of uncertain cause (cryptogenic). Results: Of the 1135 subjects, 520 were randomly selected controls without CIE, 329 were controls without CIE referred for TEE, 159 were noncryptogenic CIE cases, and 127 were cryptogenic CIE cases. Complex atherosclerotic aortic debris in ascending and transverse segments of the arch was detected in 8 randomly selected controls (1.5%), 13 referred controls (4.0%), and 15 noncryptogenic (9.4%) and 4 cryptogenic (3.1%) CIE cases. After adjusting for age, sex, hypertension, smoking, atrial fibrillation, valvular heart disease, congestive heart failure, and atherosclerosis other than in the thoracic aorta, complex atherosclerotic aortic debris was not significantly associated with group status. With randomly selected controls as the referent group, odds ratios (95% confidence intervals) were 1.72 (0.61-4.87) for referred controls, 3.16 (1.18-8.51) for noncryptogenic CIE cases, and 1.39 (0.39-4.88) for cryptogenic CIE cases. Conclusions: Complex atherosclerotic aortic debris is not a risk factor for cryptogenic ischemic stroke or transient ischemic attack but is a marker for generalized atherosclerosis and well-established atherosclerotic and cardioembolic mechanisms of cerebral ischemia. Embolization from the aorta is not a common mechanism of ischemic stroke or transient ischemic attack. [ABSTRACT FROM AUTHOR]

Objective: To determine whether patent foramen ovale (PFO) is a risk factor for a cryptogenic cerebrovascular ischemic event (CIE). Methods: This case-control study of 1072 residents of Olmsted County, Minnesota, who underwent contrast transesophageal echocardiography between 1993 and 1997 included 519 controls without CIE randomly selected from the population, 262 controls without CIE referred for transesophageal echocardiography because of cardiac disease, 158 cases with incident CIE of obvious cause (noncryptogenic), and 133 cases with incident CIE of uncertain cause (cryptogenic). Results: Large PFOs were detected in 108 randomly selected controls (20.8%), 22 referred controls (8.4%), 17 noncryptogenic CIE cases (10.8%), and 22 cryptogenic CIE cases (16.5%). After adjustment for age, sex, hypertension, smoking, atrial fibrillation, ischemic heart disease, and number of contrast injections, the presence of a large PFO was not significantly associated with group status (P=.07). Using the odds of the presence of large PFO in the randomly selected controls as the reference, the odds ratio (95% confidence interval) of the presence of large PFO was 0.47 (0.26-0.87) for referred controls, 0.69 (0.37-1.29) for noncryptogenic CIE cases, and 1.10 (0.63-1.90) for cryptogenic CIE cases. Conclusions: Patent foramen ovale is not a risk factor for cryptogenic ischemic stroke or transient ischemic attack in the general population. The PFO's importance in the genesis of cryptogenic CIE may have been overestimated in previous studies because of selective referral of cases and underascertainment of PFO among comparison groups of patients referred for echocardiography for clinical indications other than cryptogenic CIE. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate the rates and predictors of survival and recurrence among residents of Olmsted County, Minnesota, who received an Initial diagnosis based on 2-dimensional color Doppler echocardiography of moderate or severe mitral or aortic stenosis or regurgitation and who experienced a first ischemic stroke, transient ischemic attack (TIA), or amaurosis fugax. PATIENTS AND METHODS: At the Mayo Clinic in Rochester, Minn, we used the resources of the Rochester Epidemiology Project to identify Individuals who met the criteria for inclusion in the study and to verify exclusion criteria. The study included all residents of Olmsted County, Minnesota, who experienced a first Ischemic stroke, TIA, or amaurosis fugax within 30 days of or subsequent to receiving a first-time 2-dimensional color Doppler echocardlography-based diagnosis of moderate or severe mitral or aortic stenosis or regurgitation between January 1, 1985, and December 31, 1992. The Kaplan-Meier product-limit method was used to estimate the rates of subsequent stroke and death after the ischemic stroke, TIA, or amaurosis fugax. The Cox proportional hazards model was used to assess the effect of several potential risk factors on subsequent stroke occurrence and death. RESULTS: For the 125 patients in the study, the Kaplan-Meier estimates of the risk of death and the risk of stroke at 2-year follow-up were 38.6% (95% confidence interval [CI], 29.9%-47.5%) and 18.5% (95% CI, 10.0%-27.0%), respectively. Compared with the general population, death rates were significantly Increased (standardized mortality ratio = 1.75; 95% CI, 1.38-2.19; P < .001) but rates of subsequent stroke occurrence were not (standardized morbidity ratio = 1.20; 95% CI, 0.75-1.84; P = .40). After adjustment for age, sex, and cardiac comorbidity, neither the type nor severity of valvular heart disease was an independent determinant of survival or subsequent stroke occurrence. CONCLUSIONS: Patients with mitral or aortic valvular heart disease who experience Ischemic stroke, TIA, or amaurosis fugax have Increased rates of death, but not recurrent stroke, compared with expected rates. Other cardiovascular risk factors are more important determinants of survival In these patients than the type or echocardiographic severity of the valvular heart disease. [ABSTRACT FROM AUTHOR]

Objectives: The study determined, in a population-based setting, whether dilatation of the thoracic aorta is an atherosclerosis-related process.Background: The role of atherosclerosis in thoracic aortic dilatation and aneurysm formation is poorly defined.Methods: The dimensions of the thoracic aorta were measured with transesophageal echocardiography in 373 subjects participating in a population-based study (median age 66 years; 52% men). The associations between clinical and laboratory atherosclerosis risk factors, aortic atherosclerotic plaques, and aortic dimensions were examined.Results: Age, male gender, and body surface area (BSA) jointly accounted for 41%, 31%, 38%, and 47% of the variability in diameters of the sinuses of Valsalva, ascending aorta, aortic arch, and descending aorta, respectively. Adjusting for age, gender, and BSA: 1) smoking was associated with a greater aortic arch diameter, and diastolic blood pressure and diabetes were each associated with a greater descending aorta diameter (p < 0.05); 2) atherosclerotic plaques in the descending aorta were associated with a greater descending aorta diameter (0.18 +/- 0.08-mm increase in diameter per 1-mm increase in plaque thickness; p = 0.02); and 3) minor negative associations were noted between atherosclerotic plaques and risk factors for atherosclerosis and the dimensions of the proximal thoracic aorta. Notably, atherosclerosis risk factors and plaque variables each accounted for <2% of the variability in aortic dimensions, adjusting for age, gender, and BSA.Conclusions: Age, gender, and BSA are major determinants of thoracic aortic dimensions. Atherosclerosis risk factors and aortic atherosclerotic plaques are weakly associated with distal aortic dilatation, suggesting that atherosclerosis plays a minor role in aortic dilatation in the population. [ABSTRACT FROM AUTHOR]

Objectives: We sought evidence of a change in the prevalence of atrial fibrillation (AF) over a 30-year period among residents of Rochester, Minnesota.Background: Atrial fibrillation is increasingly encountered in clinical practice, but there is limited data on secular trends of AF over time.Methods: Within a longitudinal case-control study of ischemic stroke, the prevalence of AF and of selected comorbid conditions among incident stroke cases and age- and gender-matched controls between 1960 and 1989 was determined.Results: The mean age +/- standard deviation for the 1,871 stroke cases (45% men) and matched controls was 75 +/- 11 years. For cases, age-adjusted estimates of AF prevalence for 1960 to 1969, 1970 to 1979, and 1980 to 1989 were 11%, 13%, and 16%, respectively, for men, and 13%, 16%, and 20% for women. For controls, the rates were 5%, 8%, and 12%, respectively, for men, and 4%, 6%, and 8% for women. Increasing AF prevalence was associated with increasing age (doubling of odds per decade of age in both cases and controls) and calendar time adjusted for age and gender (cases: odds ratio [OR] per 5 years 1.13, 95% confidence interval [CI], 1.05 to 1.22; controls: OR per 5 years 1.24, 95% CI 1.12 to 1.37). The rates of increase with calendar time were significant for cases (p = 0.001) and controls (p < 0.001) and comparable between the genders.Conclusions: The prevalence of AF increased significantly in ischemic stroke patients and their controls from 1960 to 1989 in Rochester, Minnesota, independent of age and gender. The rate of increase did not differ significantly between men and women. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the overall risk of breast cancer and breast cancer characteristics in women given supradiaphragmatic radiation therapy for Hodgkin lymphoma. PATIENTS AND METHODS: Medical records of 653 female patients who received supradiaphragmatic radiation therapy for Hodgkin lymphoma at the Mayo Clinic in Rochester, Minn, between 1950 and 1993 were abstracted, and follow-up questionnaires were mailed. In 4 patients, breast cancer was diagnosed before Hodgkin lymphoma was discovered. RESULTS: The median age of 649 patients at supradiaphragmatic radiation therapy was 31.8 years (range, 2.6-86.5 years). The median duration of follow-up was 8.7 years (range, < 1-47.9 years). In 30 patients, breast cancer developed (bilaterally in 4 patients) after supradiaphragmatic radiation therapy; the median interval was 19.9 years (range, 0.7-423 years). The median age at breast cancer diagnosis was 44.4 years (range, 27.5-70.8 years). The standardized morbidity ratio for breast cancer after supradiaphragmatic radiation therapy was 2.9 (95 % confidence interval [CI], 2.0-4.2) (P < .001). Breast cancer risk significantly increased 15 to 30 years after patients received supradiaphragmatic radiation therapy, and risk was inversely related to age at supradiaphragmatic radiation therapy until age 30 years. The standardized morbidity ratio for patients younger than 30 years at supradiaphragmatic radiation was 8.5 (95% CI, 53-13.1) vs 1.2 (95% CI, 0.5-2.2) for those aged 30 years or older (P < .001). Splenectomy increased breast cancer risk (P = .01). Breast cancer detection was by self-examination in 15 cancers, by mammography in 13, and by clinical examination in 4; in 2 cancers, the mode of detection was unknown. Modified radical mastectomy was used to treat breast cancer. CONCLUSION: The increased risk of breast cancer in survivors of Hodgkin lymphoma given supradiaphragmatic radiation therapy appears to be limited to patients who are younger than 30 years at radiation therapy or to those who have undergone splenectomy. [ABSTRACT FROM AUTHOR]

Objective: To compare the frequency of traditional cardiovascular (CV) risk factors in rheumatoid arthritis (RA) compared to non-RA subjects, and examine their impact on the risk of developing selected CV events (myocardial infarction (MI), heart failure (HF) and CV death) in these two groups., Methods: We examined a population-based incidence cohort of subjects with RA (defined according to the 1987 American College of Rheumatology criteria), and an age- and sex-matched non-RA cohort. All subjects were followed longitudinally through their complete community medical records, until death, migration, or 1 January 2001. Clinical CV risk factors and outcomes were defined using validated criteria. The chi2 test was used to compare the frequency of each CV risk factor at baseline. Person-years methods were used to estimate the rate of occurrence of each CV risk factor during follow-up. Cox models were used to examine the influence of CV risk factors on the development of CV outcomes., Results: A total of 603 RA and 603 non-RA subjects (73% female; mean age 58 years) were followed for a mean of 15 and 17 years (total: 8842 and 10,101 person-years), respectively. At baseline, RA subjects were significantly more likely to be former or current smokers when compared to non-RA subjects (p<0.001). Male gender, smoking, and personal cardiac history had weaker associations with CV events among RA subjects, compared to non-RA subjects. There was no significant difference between RA and non-RA subjects in the risk imparted with respect to the other CV risk factors (ie, family cardiac history, hypertension, dyslipidaemia, body mass index, or diabetes mellitus)., Conclusion: While some traditional CV risk factors imparted similar risk among RA compared with non-RA subjects, others (ie, male gender, smoking and personal cardiac history) imparted significantly less risk for the development of CV disease. These differences in the overall impact of traditional CV risk factors suggest that strategies to prevent CV disease and mortality focused solely on controlling traditional CV risk factors may be relatively less beneficial in RA subjects than in the general population. Further research is needed to determine optimal approaches to reducing CV morbidity and mortality in persons with RA.

It is unclear how often patients with very mild aortic stenosis (gradients < 25 mmHg) need interval follow-up. The purpose of this study was to define the determinants of disease severity progression and to propose appropriate management strategies. It is known that congenital aortic stenosis is a progressive disease that requires long-term follow-up at consistent intervals. We studied 89 patients with very mild aortic stenosis. Cox proportional hazard modeling was performed to ascertain predictors of morbidity and mortality. Events were defined as valve surgery or death. Of the original 89 patients, 7 died (92% survival); one death was sudden and unexplained and six were noncardiac. Eighteen individuals were lost to follow-up (10 not located and 8 refused participation). Twelve (17%) had valve surgery. The minimum time interval between initial diagnosis of very mild aortic stenosis and surgery was 4.6 years (mean, 14.0). Age at diagnosis, gender, initial gradient, initial gradient/age, and aortic regurgitation were found not to be predictive of outcome. However, the slope of the transaortic gradient [change of gradient/time (years)] was predictive of outcome (hazard ratio of 1.69; confidence interval, 1.4-2.2). At least 17% of these patients progress to require operation. For patients with a gradient slope < 1.1, evaluation every 4 or 5 years is recommended. For patients with a gradient slope > 1.2, evaluation every 1 or 2 years seems prudent.

Objective: A major challenge in management of rheumatoid arthritis (RA) is prediction of longterm response to disease-modifying antirheumatic drug (DMARD) treatment. Our objective was to identify the predictors of DMARD discontinuation in an incidence cohort of patients with RA followed continuously from their incidence date., Methods: Members of a population-based incidence cohort of Rochester, Minnesota, residents aged > or = 18 years diagnosed with RA (by 1987 American College of Rheumatology criteria) from January 1, 1955, to January 1, 1995, were followed longitudinally through their complete medical records until January 1, 2001. Detailed drug exposure data were collected on all DMARD and glucocorticoid regimens. Subjects were considered exposed to a DMARD if duration of use was > or = 30 days. Time to discontinuation of DMARD was estimated using survival analysis techniques. Andersen-Gill models with multiple events per patient were used to assess the influence of demographics, calendar time, comorbidities, disease characteristics [disease duration, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), joint counts, radiographic changes, nodules, RA complications], and therapy characteristics (DMARD use, singly or in combination, glucocorticoid use, first or subsequent regimen, effect of previous therapy) on time from DMARD initiation to discontinuation., Results: The study population comprised 345 DMARD-treated patients (73% female) with mean age of 53.1 years and mean followup 15.4 years. Median time taking any DMARD was 16.0 months for the first, and 17.9 months for all regimens. Methotrexate (MTX) had the longest time to discontinuation, with a median of 30.3 months without folate, and 61.7 months with folate supplementation. Among the various disease characteristics examined, only higher ESR at DMARD initiation was significantly associated with a shorter time taking DMARD [hazard ratio (HR) 1.05 per 10 mm/h increase, 95% CI 1.02, 1.08]. In multivariable Andersen-Gill models considering all DMARD regimens, hydroxychloroquine use (HR 0.77, 95% CI 0.64, 0.92) and MTX use (HR with folate 0.39, 95% CI 0.30, 0.51; HR without folate 0.51, 95% CI 0.39, 0.67) were significantly associated with longer time to DMARD discontinuation, whereas prior MTX use (HR 1.96, 95% CI 1.57, 2.45) was associated with shorter time to DMARD discontinuation, after adjusting for age, sex, calendar year, Charlson comorbidity index, disease duration, and ESR at DMARD initiation. Disease duration was negatively associated with time to DMARD discontinuation; each 10 year increase in disease duration corresponded to a 14% decrease in the risk of discontinuation (HR 0.86, 95% CI 0.75, 0.98)., Conclusion: Longer RA disease duration does not appear to increase the risk of DMARD discontinuation. However, high disease activity (as assessed by ESR) is associated with a higher likelihood of discontinuing DMARD. MTX failure may identify a subgroup of patients who are less likely to respond to other DMARD and therefore could be considered as candidates for biological therapies.

Objective: To compare the proportion of the risk for the development of heart failure (HF) that is attributable to traditional cardiovascular (CV) risk factors, ischemic heart disease (IHD), and alcohol abuse between subjects with and subjects without rheumatoid arthritis (RA)., Methods: A population-based inception cohort of RA patients was assembled along with a similar cohort of subjects without RA. All individuals were followed up through their complete medical records, until HF incidence, death, migration, or January 1, 2001. The attributable risk of HF was estimated as the difference between the observed cumulative incidence of HF in each cohort (estimated from multivariable Cox models and adjusted for the competing risk of death) and the predicted cumulative incidence of HF in the absence of risk factors, with results expressed as a percentage of the observed cumulative incidence., Results: A total of 575 RA subjects and 583 non-RA subjects (mean age 57 years, 73% women) without HF at incidence/index date had a mean followup of 15.1 and 17.0 years, respectively. During that period, 165 RA and 115 non-RA subjects had a first episode of HF, with a cumulative incidence of 36.3% and 20.4%, respectively, at age 80 years. Among non-RA subjects, 77% of the HF at age 80 years was attributable to CV risk factors, IHD, and alcohol abuse combined, whereas among RA subjects, only 54% of the HF at age 80 years was attributable to these factors (P < 0.01)., Conclusion: The excess risk of HF among RA patients is not explained by an increased frequency or effect of CV risk factors and IHD.

Background: The determinants of interatrial septal (IAS) thickening ("lipomatous hypertrophy"), a common echocardiographic finding in the elderly, are poorly defined. The objective of this study was to determine the clinical, laboratory, and transesophageal echocardiographic correlates of IAS thickening in the general population., Methods: The thickness of the IAS was measured by transesophageal echocardiography in 384 patients (median age: 66 years; range: 51-101 years; 53% men) participating in a population-based study (Stroke Prevention: Assessment of Risk in a Community). The associations between atherosclerosis risk factors, clinical cardiovascular disease, aortic atherosclerotic plaques, and IAS thickness were examined., Results: Age and body surface area (BSA) were significantly associated with IAS thickness (median: 6 mm; range: 2-17 mm). IAS thickness increased by 12.6% per 10 years of age (95% confidence interval: 9.0-16.4%) adjusting for sex and BSA, and increased by 7.0% per 0.1 m 2 BSA (confidence interval: 5.0-9.2%) adjusting for age and sex. Overall, age, sex, and BSA accounted for 22.5% of the variability in IAS thickness. Current smoking (20.4% increase in IAS thickness in current smokers) and hypertension treatment (8.5% increase in treated patients) were associated with increased IAS thickness, adjusting for age, sex, and BSA ( P < .05), but these two risk factor variables jointly explained only an additional 2.3% of the variability in IAS thickness beyond the variability explained by age, sex, and BSA. Clinical coronary artery and cerebrovascular disease, atrial arrhythmias, and aortic atherosclerotic plaques were not associated with IAS thickness, adjusting for age, sex, and BSA ( P > .3)., Conclusions: IAS thickening is an age-associated process. Atherosclerosis risk factors are weakly associated with IAS thickening, whereas atherosclerotic vascular disease is not.

Objective: The aims of this study were to provide estimates of 1) the risk of mortality for individuals with both diabetes and peripheral arterial disease (PAD) relative to that for individuals with either condition alone and 2) the association between PAD progression and mortality for individuals with diabetes, PAD, and both conditions., Research Design and Methods: This longitudinal cohort study was conducted in Rochester, Minnesota. Local residents age 50-70 years with a prior diagnosis of PAD and/or diabetes were identified from the Mayo Clinic diagnostic registry and invited to a baseline examination (1977-1978). Those who met inclusion criteria were assessed for PAD progression at 2 and 4 years and followed for vital status through 31 December 1999., Results: The numbers who met criteria for PAD, diabetes, and both conditions at baseline were 149, 238, and 186, respectively. Within each group, observed survival was less than expected (P <0.001). The adjusted risk of death for both conditions was 2.2 times that for PAD alone. Among the 449 who returned at 4 years, the risk of subsequent death was greater for those whose PAD had progressed; among individuals with diabetes alone at baseline, 100% (17 of 17) who met criteria for PAD progression were dead by 31 December 1999 compared with 62% (111 of 178) of those who had not met criteria (adjusted relative hazard 2.29 [95% CI 1.30-4.02], P=0.004). The increased mortality associated with PAD progression was significant only for individuals with diabetes (alone or with PAD)., Conclusions: Diabetes is a risk factor for both PAD and PAD-associated mortality, emphasizing the critical need to detect and monitor PAD in diabetic patients.

Objective: To examine trends in therapeutic strategies and to identify the determinants of starting disease modifying antirheumatic drug (DMARD) therapy over a 40-year period in a population based inception cohort of patients with rheumatoid arthritis (RA)., Methods: A population based inception cohort was assembled from among all Rochester, Minnesota, residents aged > or = 18 years who were first diagnosed with RA (1987 American College of Rheumatology criteria) between January 1, 1955, and January 1, 1995. All subjects were followed longitudinally through their complete medical records until death, migration from Olmsted County, or date of abstraction (January 1, 2001, to January 1, 2003). Drug exposure data were collected on all DMARD and corticosteroid regimens. Time to DMARD initiation was examined using the Kaplan-Meier method. The influence of calendar time and disease characteristics on time from incidence to first DMARD therapy and the number of DMARD regimens were analyzed using Cox regression and proportional odds models, respectively., Results: The study population comprised 603 patients (73% female) with a mean age of 58 years and a mean followup of 15 years. At 2 years after RA onset, 26% of patients in the 1955-74 cohort, 40% in the 1975-84 cohort, and 70% in the 1985-94 cohort had received a DMARD (log-rank p < 0.001). Age, rheumatoid factor (RF) positivity, erythrocyte sedimentation rate, large joint swelling, rheumatoid nodules, and destructive changes on radiographs were significantly associated with time to first DMARD regimen after adjustment for calendar time and sex. Patients who were older and RF positive and who did not receive CS were more likely to have received more DMARD regimens., Conclusion: Time to initiation of DMARD therapy has shortened markedly over the past 3-4 decades. These changes in management of early RA provide evidence for the translation of scientific evidence into clinical practice in rheumatology. Age and various disease characteristics are significantly associated with initiation and the number of DMARD regimens used. These should be considered as confounders when examining the effect of early DMARD treatment on disease progression and mortality.

Background and Purpose: Following publication of concerns about the results of the National Institute of Neurological Disorders and Stroke (NINDS) intravenous tissue plasminogen activator (t-PA) in acute stroke treatment trial, NINDS commissioned an independent committee "to address whether there is concern that eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials and, whether the subgroup imbalance (in baseline stroke severity) invalidates the entire trial.", Methods: The original NINDS trial data were reanalyzed to assess the t-PA treatment effect, the effect of the baseline imbalance in stroke severity between the treatment groups on the t-PA treatment effect, and whether subgroups of patients did not benefit from receiving t-PA., Results: A clinically important and statistically significant benefit of t-PA therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-PA treated patients. The adjusted t-PA to placebo odds ratio (OR) of a favorable outcome was 2.1 (95% CI, 1.5 to 2.9). Although these exploratory analyses found no statistical evidence that the t-PA treatment effect differed among patient subgroups, the study was not powered to detect subgroup treatment differences., Conclusions: These findings support the use of t-PA to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-PA trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-PA in acute ischemic stroke patients.

Background: An association between systemic inflammatory markers and the presence and severity of atherosclerotic plaques has not been demonstrated in a nonselected population. The purpose of this study was to examine the association of inflammatory markers with aortic atherosclerotic plaques in a sample of the general population and in a subgroup free of clinical vascular disease., Methods: Transesophageal echocardiography was performed in 386 subjects (median age, 66 years; 53% men). We examined the association between systemic inflammatory markers and aortic atherosclerotic plaques., Results: Aortic plaques were present in 267 subjects (69%). Plaques at least 4 and 6 mm thick and mobile debris were present in 114, 41, and 20 subjects, respectively. High-sensitivity C-reactive protein (hs-CRP) level was associated with the presence of aortic plaques, adjusting for age, sex, smoking status, and additional atherosclerosis risk factors. Among subjects with plaques, hs-CRP level was independently associated with plaques at least 6 mm thick; similar trends were observed for the associations of hs-CRP level with plaques at least 4 mm thick and mobile debris. In subjects with aortic plaques who were free of clinically apparent coronary artery or cerebrovascular disease, hs-CRP level was independently associated with plaques at least 6 mm thick., Conclusions: Level of hs-CRP is independently associated with the presence and severity of aortic atherosclerotic plaques. These observations establish the association of systemic inflammation with anatomically defined atherosclerosis in the general population.

Objective: We examined whether widespread use of laparoscopy was accompanied by increased diagnosis of asymptomatic endometriosis, inflated rates of diagnosis, or changes in the clinical spectrum of disease., Design: Population-based cohort., Setting: Olmsted County, Minnesota., Patient(s): All participants were women residents, aged > or =15 years., Intervention(s): None., Main Outcome Measure(s): We estimated the likelihood that women with a surgical procedure during which endometriosis could be visualized would receive a surgical diagnosis, as well as the proportions of all diagnoses, regardless of setting, that were [1] assigned without surgery, [2] refuted by surgery, [3] surgically confirmed, and [4] asymptomatic. The incidence of diagnosed endometriosis for 1987 to 1999 was compared with published rates for 1970 to 1979., Result(s): Of 8,229 women aged > or =15 years with > or =1 surgery during which endometriosis could be visualized, 11.5% received a surgical diagnosis of endometriosis. The incidence of diagnosed endometriosis, regardless of setting, was 1.9 per 1,000 person-years (10% were without relevant surgery, 6% had surgery but no surgical evidence, 85% had surgical evidence); 85% of surgically confirmed diagnoses had presenting symptoms. Using definitions comparable with those in the 1970 to 1979 study, the 1987 to 1999 incidence was 2.46 per 1,000 versus 2.49 per 1,000 for 1970 to 1979; 88% of symptomatic incident diagnoses were surgically confirmed versus 65% for 1970 to 1979., Conclusion(s): Widespread use of laparoscopy does not appear to have contributed to dramatically increased rates of endometriosis diagnoses but rather to a smaller proportion of diagnoses being assigned without surgical confirmation.

Atherosclerosis-related mechanisms, including inflammation and possibly infection, are likely to be involved in the pathogenesis of calcific aortic valve disease. The purpose of this study was to examine whether systemic inflammatory markers and Chlamydia pneumoniae seropositivity are associated with aortic valve sclerosis (AVS) in a sample of the general population. Transesophageal echocardiography was performed in 381 subjects (median age: 67 years, range: 51-101; 52% men), a sample of the adult population in Olmsted County, Minnesota. The associations between systemic inflammatory markers (blood counts, including white blood cells differential counts, fibrinogen, and high-sensitivity C-reactive protein [hs-CRP]), C. pneumoniae immunoglobulin G (IgG) antibody titers, and AVS were examined. AVS was present in 140 subjects (37% of the population). After adjustment for age, sex, and smoking status: (1). hs-CRP was associated with AVS (odds ratio: 1.20 per two-fold increase in hs-CRP; 95% confidence interval: 1.01-1.43; P = 0.04) but this association was not significant after adjustment for additional risk factors for AVS, including body mass index (P = 0.52). (2). Blood counts and fibrinogen were not associated with AVS (P-values >0.30). (3). C. pneumoniae IgG antibody titers (low [1:16-1:32], intermediate [1:64-1:128], or high [>or=1:256] titers, compared with titers <1:16) were not associated with AVS (P = 0.21). In conclusion, hs-CRP is weakly associated with AVS, an association that is not independent of other AVS risk factors. Blood counts, fibrinogen, and C. pneumoniae seropositivity are not associated with AVS. These findings suggest that other non-inflammatory non-infectious mechanisms are likely to have a role in the pathogenesis of calcific aortic valve disease.

Objective: To investigate time trends in the incidence and survival of giant cell arteritis (GCA) over a 50-year period in Olmsted County, Minnesota., Methods: Using the unified record system at the Mayo Clinic, we identified all incident cases of GCA first diagnosed between 1950 and 1999. Incidence rates were estimated and adjusted to the 1980 United States white population for age and sex. The annual incidence rates were graphically illustrated using a 3-year centered moving average. Survival rates were computed and compared with the expected rates in the population., Results: There were 173 incident cases of GCA during the 50-year study period. Of these, 79% were women and the mean age at diagnosis was 74.8 years. The overall age- and sex-adjusted incidence per 100,000 persons 50 years of age or older was 18.8 (95% confidence interval [95% CI] 15.9-21.6). Incidence was higher in women (24.4; 95% CI 20.3-28.6) than in men (10.3; 95% CI 6.9-13.6). Incidence rates increased significantly over the study period (P = 0.017); in particular, a progressive increase was observed from 1950 to 1979; subsequently, no substantial increases in incidence rates were observed. A cyclic pattern of annual incidence rates was apparent, with evidence of 6 peak periods. Survival among individuals with GCA was not significantly different from that expected in the population (P = 0.80)., Conclusions: The incidence of GCA increased over the first 3 decades of the study, then remained stable over the last 20 years. The previously observed cyclic pattern of annual incidence rates was still apparent over a 50-year period. Overall survival in GCA was similar to that in the population.

Objective: Epidemiologic evidence for a protective effect of exogenous female sex hormones on the development of rheumatoid arthritis (RA) is contradictory. We examined whether exposure to either oral contraceptives (OC) or postmenopausal estrogen replacement therapy (ERT) is associated with the development of RA in women., Methods: We separately examined the relationship between use of OC and ERT on the risk of RA in a population based case-control study. Case patients, including all female residents of Rochester, Minnesota, > or = 18 years of age, who first fulfilled 1987 American College of Rheumatology criteria for RA between 1955 and 1994 (n = 445), were compared with age matched female controls from the community. Multivariable conditional logistic regression models were used to determine whether OC or ERT exposure had an effect on RA development after controlling for potential confounders., Results: We observed an inverse association between ever-use of OC and the risk of RA, which persisted after adjusting for potential confounders in multivariate analyses (OR 0.56, 95% CI 0.34, 0.92). Earlier calendar-year of first exposure to OC was associated with lower OR for RA. We found no evidence of a significant association of ERT with RA risk (adjusted OR 1.11, 95% CI 0.69, 1.78)., Conclusion: Exposure to OC, but not ERT, significantly reduces the risk of development of RA. The risk of developing RA is lower when OC exposure occurred in earlier years, which suggests that the higher doses of estrogens and progestins contained in earlier OC preparations may have a stronger protective effect against developing RA. While this protective effect is strong, it only explains a small portion of the observed decrease in RA incidence over the past few decades because the proportion of Rochester women exposed to OC is quite small.

Objective: To identify prognostic markers that are predictive of progressive erosive disease in patients with early rheumatoid arthritis (RA)., Methods: The study involved an inception cohort of 111 consecutive patients with RA and a disease duration of <1 year. Patients were treated according to an algorithm designed to avoid overtreatment of mild disease and to accelerate treatment in patients who had continuous disease activity. Patients were evaluated for the presence of clinical and laboratory disease activity markers. We determined the frequency of CD4+,CD28(null) T cells by flow cytometry, HLA-DRB1 gene polymorphisms by polymerase chain reaction (PCR)/sequencing, and 26 single-nucleotide polymorphisms in 19 candidate genes by multiplex PCR and hybridization to an immobilized probe array. Data were analyzed using proportional odds models to identify prognostic markers predictive of erosive progression over 2 years on serial hand/wrist radiographs., Results: After 2 years, disease activity in 52% of the cohort was controlled by treatment with hydroxychloroquine and nonsteroidal agents. Forty-eight percent of the patients did not develop erosions. Older age, presence of erosions at baseline, presence of rheumatoid factor, rheumatoid factor titer, and HLA-DRB1*04 alleles, particularly homozygosity for HLA-DRB1*04, were univariate predictors of radiographic progression. Promising novel markers were the frequency of CD4+,CD28(null) T cells as an immunosenescence indicator, and a polymorphism in the uteroglobin gene., Conclusion: Clinical disease activity in patients with early RA can frequently be controlled with nonaggressive treatment, but this is not always sufficient to prevent new erosions. Rheumatoid factor titer, HLA-DRB1 polymorphisms, age, and immunosenescence markers are predictors of poor radiographic outcome. A polymorphism in the uteroglobin gene may identify patients who have a low risk of erosive disease.

Objective: To determine whether physicians' satisfaction in clinical encounters with ethnic immigrant patients differs from satisfaction in clinical encounters with white patients in the local community., Patients and Methods: Postvisit assessments from primary care physicians were collected for matched pairs of ethnic and control patients at the Mayo Clinic in Rochester, Minn, during a 10-week study (April 2-June 9, 2001). Ethnic patients were defined as first-generation Somalian, Cambodian, and Hispanic immigrants. Control patients were American-born white patients who were seen by the same physician and matched to the ethnic patients in age, sex, and type of visit. T tests and Hotelling T2 tests were used to analyze differences in physician responses between groups; regression analysis was used to identify the relationship between physicians' satisfaction and ethnicity in the presence of covariates., Results: Physicians were considerably less satisfied with ethnic patient visits compared with control patient visits. Larger differences in satisfaction were reported in the areas of patient efforts with disease prevention and management of chronic diseases. Smaller differences in satisfaction were reported for issues related to communication and cultural beliefs and practices. These differences persisted after controlling for patient demographics, physician, and visit characteristics., Conclusions: Patients' ethnicity affects physician satisfaction with clinical encounters, particularly in the delivery of preventive care and chronic disease management.

Objective: To evaluate the course of glucocorticoid (GC) therapy and associated adverse events in a population-based cohort of patients with giant cell arteritis (GCA)., Methods: We identified 125 Olmsted County residents with GCA diagnosed between 1950 and 1991 and obtained followup information on the 120 patients who were diagnosed antemortem and agreed to participate in this study. Clinical variables, GC doses, and GC adverse events on each patient were recorded. The relationship between GC therapy and the development of adverse events was studied by the Cox and Anderson-Gill proportional hazards models., Results: All patients were treated with GCs and responded rapidly (median initial dosage 60 mg prednisone/day). The dosage was later reduced according to the treating physicians' judgment. The median duration required to reach 7.5 mg/day was 6.5 months and the median duration required to reach 5 mg/day was 7.5 months. Relapses or recurrences occurred in 57 patients. For the 87 patients followed to discontinuation of GC therapy and permanent remission of GCA (median of 22 months), the total median dose of prednisone was 6.47 gm. Adverse events associated with GCs were recorded in 103 (86%) patients and 2 or more events occurred in 70 patients (58%). Age and higher cumulative dose of GCs were associated with the development of adverse GC side effects., Conclusion: GCs are therapeutically effective in GCA and the prednisone dosage was reduced to physiologic levels in three-fourths of the patients within 1 year. However, most patients developed serious adverse side effects related to GCs, indicating that less toxic therapeutic measures are needed.

Background and Purpose: Mortality after cerebral infarction (CI) has remained unchanged during the past 20 years, despite advances in neurologic care. Key factors affecting survival may be underrecognized. The purpose of this study was to determine the rate and cause of mortality after first CI., Methods: In this case-control, population-based study, all available medical records were reviewed for Rochester (Minnesota) residents with a first CI between 1985 and 1989 to identify morbidities and cause of death. Predictors for mortality were analyzed., Results: First CI was recorded for 444 patients. Survival was 83% at 1 month, 71% at 1 year, and 46% at 5 years. The most frequent causes of death were cardiovascular events (22%), respiratory infection (21%), and initial stroke complications (14%). Recurrent stroke and cancer accounted for 9% and 7.5% of deaths, respectively. In the first month after CI, 51% of deaths were attributed to the initial CI, 22% to respiratory infections, and 12% to cardiovascular events. During the first year, 26% of deaths resulted from respiratory infections and 28% from cardiovascular disease. Mortality was higher among patients than controls for at least 2 years after CI. Age, cardiac comorbid conditions, CI severity, stroke recurrence, seizures, and respiratory and cardiovascular morbidities were independent predictors of death., Conclusions: In the first month after CI, mortality resulted predominantly from neurologic complications. Later mortality remained high because of respiratory and cardiovascular causes. To improve long-term survival after CI, aggressive management of pulmonary and cardiac disease is as important as secondary stroke prevention.

Background: The management of unruptured intracranial aneurysms is controversial. Investigators from the International Study of Unruptured Intracranial Aneurysms aimed to assess the natural history of unruptured intracranial aneurysms and to measure the risk associated with their repair., Methods: Centres in the USA, Canada, and Europe enrolled patients for prospective assessment of unruptured aneurysms. Investigators recorded the natural history in patients who did not have surgery, and assessed morbidity and mortality associated with repair of unruptured aneurysms by either open surgery or endovascular procedures., Findings: 4060 patients were assessed-1692 did not have aneurysmal repair, 1917 had open surgery, and 451 had endovascular procedures. 5-year cumulative rupture rates for patients who did not have a history of subarachnoid haemorrhage with aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2. 6%, 14 5%, and 40% for aneurysms less than 7 mm, 7-12 mm, 13-24 mm, and 25 mm or greater, respectively, compared with rates of 2 5%, 14 5%, 18 4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms. These rates were often equalled or exceeded by the risks associated with surgical or endovascular repair of comparable lesions. Patients' age was a strong predictor of surgical outcome, and the size and location of an aneurysm predict both surgical and endovascular outcomes., Interpretation: Many factors are involved in management of patients with unruptured intracranial aneurysms. Site, size, and group specific risks of the natural history should be compared with site, size, and age-specific risks of repair for each patient.

Objectives: The objective of this study was to examine the relationship between Chlamydia pneumoniae seropositivity and aortic atherosclerotic plaques in the general population., Background: Seroepidemiologic studies suggest that C pneumoniae infection plays a role in the pathogenesis of atherosclerosis., Methods: Transesophageal echocardiography was performed in 385 subjects (median age 66 years, range 51 to 101 years; 53% men), a sample of the Olmsted County (Minnesota) population. The association between C pneumoniae immunoglobulin (Ig) G antibody titers and aortic atherosclerotic plaques was examined., Results: Chlamydia pneumoniae IgG antibodies (titers >or=1:16) were detected in 287 subjects (74.5%): low titers (1:16 to 1:32) in 58 (15.1%), intermediate titers (1:64 to 1:128) in 144 (37.4%), and high titers (>or=1:256) in 85 subjects (22.1%). Antibody titers were not associated with the presence of aortic plaques after adjustment for age, gender, and smoking status (p = 0.64). Compared with titers <1:16, the adjusted odds ratios for aortic plaques were 1.46 (95% confidence interval [CI] 0.63 to 3.42) for low titers, 1.32 (95% CI 0.68 to 2.55) for intermediate titers, and 0.94 (95% CI 0.42 to 2.07) for high titers. Among the subgroup with plaques, antibody titers were not associated with the presence of plaques >or=4 mm thick (p = 0.99), plaques >or=6 mm (p = 0.49), or mobile debris (p = 0.71), after adjustment for age and smoking., Conclusions: Chlamydia pneumoniae IgG antibody titers are not associated with the presence or severity of aortic atherosclerosis in the general population. These observations do not support a role for C pneumoniae infection in the initiation or progression of atherosclerosis.

Objective: To describe the use of orthopedic surgery, including joint replacement surgery, in a well-defined, population-based cohort of patients with rheumatoid arthritis (RA) and to identify characteristics that predict such use., Methods: A retrospective medical record review was performed of cases of RA incident in Rochester, Minnesota, during the years 1955-1995. All joint surgeries were recorded., Results: Of the total 609 RA incident cases, 242 patients underwent 1 or more (maximum of 20/patient) surgical procedures involving joints during their followup. Overall, this RA cohort had 7.4 surgeries per 100 person-years of followup; the cumulative incidence for joint surgery for RA-related joint disease at 30 years was 33.7% +/- SEM 3.8%. The risk of having a disease-related joint surgery for RA is increased in patients who are women, younger, positive for rheumatoid factor, and have rheumatoid nodules. When adjusted for duration of followup, patients with RA diagnosed after 1985 were significantly less likely to have undergone joint surgery for RA (P < 0.001). Survival of patients who underwent total joint arthroplasty was similar to those who did not., Conclusion: Reconstructive surgeries are common in RA, although patients diagnosed after 1985 are less likely to require joint surgery. These findings may reflect trends in medical disease management and have importance for health care resource utilization planning.

Objective: The objective of this study was to conduct an economic evaluation of rofecoxib and celecoxib compared with high-dose acetaminophen or ibuprofen with and without misoprostol for patients with symptomatic knee osteoarthritis (OA)., Methods: A decision analysis model was designed over 6 months using two measures of effectiveness: 1) number of upper gastrointestinal (GI) adverse events averted; and 2) number of patients who achieved perceptible pain relief. Separate analyses were conducted for all patients and for those who did not respond to acetaminophen. Outcome probabilities were obtained from a comprehensive review of randomized controlled trials and observational studies. Costs were derived from actual resource utilization of OA patients., Results: In terms of averting GI events, acetaminophen dominates the other options for an average risk patient population. For patients who did not respond to acetaminophen, rofecoxib had the lowest incremental cost-effectiveness ratio (ICER) per GI event avoided (32,000 US dollars) relative to ibuprofen. In terms of pain control, ibuprofen had an ICER of 610.77 US dollars per additional patient achieving minimal perceptible clinical improvement (MPCI) relative to acetaminophen, while rofecoxib had an ICER of 12,000 US dollars relative to ibuprofen. For patients who did not respond to acetaminophen and who are at high risk of developing an adverse GI event, rofecoxib dominates ibuprofen as the preferred alternative for both measures of effectiveness. One-way, two-way, and probabilistic sensitivity analyses established that these results were generally robust., Conclusions: Our results suggest that for average-risk knee OA patients, acetaminophen dominates the other therapies in terms of cost per GI event averted. In terms of pain relief, cost-effectiveness acceptability curves indicate that if one values pain relief below 275 US dollars per patient achieving MPCI, acetaminophen is the therapy most likely to be optimal; between 275 US dollars and 14,150 US dollars, ibuprofen is most likely to be optimal; and above 14,150 US dollars, rofecoxib is most likely to be optimal.