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Background: The accuracy of gadolinium-enhanced magnetic resonance pulmonary angiography and magnetic resonance venography for diagnosing pulmonary embolism has not been determined conclusively.Objective: To investigate performance characteristics of magnetic resonance angiography, with or without magnetic resonance venography, for diagnosing pulmonary embolism.Design: Prospective, multicenter study from 10 April 2006 to 30 September 2008.Setting: 7 hospitals and their emergency services.Patients: 371 adults with diagnosed or excluded pulmonary embolism.Measurements: Sensitivity, specificity, and likelihood ratios were measured by comparing independently read magnetic resonance imaging with the reference standard for diagnosing pulmonary embolism. Reference standard diagnosis or exclusion was made by using various tests, including computed tomographic angiography and venography, ventilation-perfusion lung scan, venous ultrasonography, d-dimer assay, and clinical assessment.Results: Magnetic resonance angiography, averaged across centers, was technically inadequate in 25% of patients (92 of 371). The proportion of technically inadequate images ranged from 11% to 52% at various centers. Including patients with technically inadequate images, magnetic resonance angiography identified 57% (59 of 104) with pulmonary embolism. Technically adequate magnetic resonance angiography had a sensitivity of 78% and a specificity of 99%. Technically adequate magnetic resonance angiography and venography had a sensitivity of 92% and a specificity of 96%, but 52% of patients (194 of 370) had technically inadequate results.Limitation: A high proportion of patients with suspected embolism was not eligible or declined to participate.Conclusion: Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures. [ABSTRACT FROM AUTHOR]

Objective: Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program.Research Design and Methods: A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status.Results: CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia.Conclusions: Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously. [ABSTRACT FROM AUTHOR]

Background: The accuracy of multidetector computed tomographic angiography (CTA) for the diagnosis of acute pulmonary embolism has not been determined conclusively. Methods: The Prospective Investigation of Pulmonary Embolism Diagnosis II trial was a prospective, multicenter investigation of the accuracy of multidetector CTA alone and combined with venous-phase imaging (CTA-CTV) for the diagnosis of acute pulmonary embolism. We used a composite reference test to confirm or rule out the diagnosis of pulmonary embolism. Results: Among 824 patients with a reference diagnosis and a completed CT study, CTA was inconclusive in 51 because of poor image quality. Excluding such inconclusive studies, the sensitivity of CTA was 83 percent and the specificity was 96 percent. Positive predictive values were 96 percent with a concordantly high or low probability on clinical assessment, 92 percent with an intermediate probability on clinical assessment, and nondiagnostic if clinical probability was discordant. CTA-CTV was inconclusive in 87 of 824 patients because the image quality of either CTA or CTV was poor. The sensitivity of CTA-CTV for pulmonary embolism was 90 percent, and specificity was 95 percent. CTA-CTV was also nondiagnostic with a discordant clinical probability. Conclusions: In patients with suspected pulmonary embolism, multidetector CTA-CTV has a higher diagnostic sensitivity than does CTA alone, with similar specificity. The predictive value of either CTA or CTA-CTV is high with a concordant clinical assessment, but additional testing is necessary when the clinical probability is inconsistent with the imaging results. [ABSTRACT FROM AUTHOR]

Study Objective: To review the published experience with gadolinium-enhanced magnetic resonance angiography (MRA) for the detection of acute pulmonary embolism (PE) in order to test the hypothesis that gadolinium-enhanced MRA may be potentially sensitive and specific enough to include it among diagnostic alternatives in the evaluation of patients with suspected PE.Methods: Studies were identified by searching MEDLINE for trials that used gadolinium-enhanced MRA to diagnose acute PE based on the visualization of an intraluminal filling defect or a cutoff vessel, using pulmonary angiography as a reference standard.Results: Twenty-eight investigations were identified in which MRA was used to diagnose PE. Only three studies, however, met the criteria for inclusion in the analysis. In these three case series, the sensitivity of gadolinium-enhanced MRA ranged from 77 to 100%, and the specificity ranged from 95 to 98%.Conclusion: Gadolinium-enhanced MRA may be a useful diagnostic alternative in some patients with suspected acute PE, particularly if they have an elevated creatinine level, have an allergy to radiographic contrast material, or should, if possible, avoid exposure to ionizing radiation. [ABSTRACT FROM AUTHOR]

We obtained perspectives on increasing access to general education from high school students who provided ongoing support to their peers with moderate or severe disabilities. Focus groups were conducted with 32 high school students without disabilities representative of students who participated in a structured service-learning peer support program. Analysis of their comments resulted in four categories of student responses: (a) perceived challenges to general education participation; (b) action taken by peer supports to increase access to general education by students with disabilities; (c) recommendations for improving a peer support program; and (d) perceived benefits to participating students and teachers. Findings are discussed and recommendations are provided for (a) refining a model of peer support to promote peer interaction and access to general education and (b) informing practice. [ABSTRACT FROM AUTHOR]

Aims: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group., Methods: This long-term follow-up (median 10 years, interquartile range 9.0-10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually., Results: After 10 years' follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (-2 to -3) and diastolic (-6 to -6.5 mmHg) blood pressure, and for LDL cholesterol (-0.51 to -0.6 mmol/l) and triglycerides (-0.23 to -0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study., Conclusion: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Objective: In a recent multi-center trial of gadolinium contrast-enhanced magnetic resonance angiography (Gd-MRA) for diagnosis of acute pulmonary embolism (PE), two centers utilized a common MRI platform though at different field strengths (1.5T and 3T) and realized a signal-to-noise gain with the 3T platform. This retrospective analysis investigates this gain in signal-to-noise of pulmonary vascular targets., Methods: Thirty consecutive pulmonary MRA examinations acquired on a 1.5T system at one institution were compared to 30 consecutive pulmonary MRA examinations acquired on a 3T system at a different institution. Both systems were from the same MRI manufacturer and both used the same Gd-MRA pulse sequence, although there were some protocol adjustments made due to field strength differences. Region-of-interests were manually defined on the main pulmonary artery, 4 pulmonary veins, thoracic aorta, and background lung for objective measurement of signal-to-noise, contrast-to-noise, and bolus timing bias between centers., Results: The 3T pulmonary MRA protocol achieved higher spatial resolution yet maintained significantly higher signal-to-noise ratio (≥13%, p = 0.03) in the main pulmonary vessels relative to 1.5T. There was no evidence of operator bias in bolus timing or patient hemodynamic differences between groups., Conclusion: Relative to 1.5T, higher spatial resolution Gd-MRA can be achieved at 3T with a sustained or greater signal-to-noise ratio of enhanced vasculature.

Background: In the 2.8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term., Methods: All active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5.7 years (IQR 5.5-5.8). 910 participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group (850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00038727., Findings: During the 10.0-year (IQR 9.0-10.5) follow-up since randomisation to DPP, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years (95% CI 4.1-5.7) in the intensive lifestyle intervention group, 7.8 (6.8-8.8) in the metformin group, and 11.0 (9.8-12.3) in the placebo group. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5.9 per 100 person-years (5.1-6.8) for lifestyle, 4.9 (4.2-5.7) for metformin, and 5.6 (4.8-6.5) for placebo. Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo., Interpretation: During follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years., Funding: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

In this work, the methods of the Prospective Investigation of Pulmonary Embolism Diagnosis III (PIOPED III) are described in detail. PIOPED III is a multicenter collaborative investigation sponsored by the National Heart, Lung and Blood Institute. The purpose is to determine the accuracy of gadolinium-enhanced magnetic resonance angiography in combination with venous phase magnetic resonance venography for the diagnosis of acute pulmonary embolism (PE). A composite reference standard based on usual diagnostic methods for PE is used. All images will be read by 2 blinded and study-certified central readers. Patients with no PE according to the composite reference test will be randomized to undergo gadolinium-enhanced magnetic resonance angiography in combination with venous phase magnetic resonance venography. This procedure will reduce the proportion of patients with negative tests at no loss in evaluation of sensitivity and specificity.

Purpose: To formulate comprehensive recommendations for the diagnostic approach to patients with suspected pulmonary embolism, based on randomized trials., Methods: Diagnostic management recommendations were formulated based on results of the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) and outcome studies., Results: The PIOPED II investigators recommend stratification of all patients with suspected pulmonary embolism according to an objective clinical probability assessment. D-dimer should be measured by the quantitative rapid enzyme-linked immunosorbent assay (ELISA), and the combination of a negative D-dimer with a low or moderate clinical probability can safely exclude pulmonary embolism in many patients. If pulmonary embolism is not excluded, contrast-enhanced computed tomographic pulmonary angiography (CT angiography) in combination with venous phase imaging (CT venography), is recommended by most PIOPED II investigators, although CT angiography plus clinical assessment is an option. In pregnant women, ventilation/perfusion scans are recommended by many as the first imaging test following D-dimer and perhaps venous ultrasound. In patients with discordant findings of clinical assessment and CT angiograms or CT angiogram/CT venogram, further evaluation may be necessary., Conclusion: The sequence for diagnostic test in patients with suspected pulmonary embolism depends on the clinical circumstances.

Aims: To explore the association between obesity and major adverse coronary events (MACE) in patients with established coronary artery disease (CAD)., Methods and Results: The Prevention of Events with Angiotensin Converting Enzyme-Inhibition (PEACE) Trial randomized 8290 patients with stable CAD and left ventricular (LV) ejection fraction (EF) (LVEF) > or =0.40 to trandolapril or placebo and followed them for a median of 4.8 years. In PEACE patients who were non-diabetic at baseline (5693 men and 1171 women), we used proportional hazards models to conduct a post hoc analysis to examine whether obesity, defined as a body mass index (BMI) > or =30 kg/m(2), is an independent risk factor for the composite endpoint of MACE, defined as cardiovascular death, non-fatal myocardial infarction, coronary revascularization, or stroke. The analysis was conducted separately for men and women. The baseline prevalence of obesity was 28.5% in men and 28.9% in women. After adjusting for significant confounders, obesity was associated with MACE in men [hazard ratio (HR) = 1.28, 95% CI 1.13-1.46, P < 0.01], but not in women (HR = 0.96, 95% CI 0.70-1.31, P = 0.77). Further categorization of BMI showed a J-shaped association between BMI and MACE in the men, and no association in the women., Conclusion: In the presence of established CAD, obesity is associated with risk for MACE in men, but there is no support of an association in women. This finding requires further evaluation.

Insulin resistance and beta-cell dysfunction, two factors central to the pathogenesis of type 2 diabetes, were studied in relation to the development of diabetes in a group of participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP) at baseline and after specific interventions designed to prevent diabetes. Participants were randomly assigned to placebo (n = 1,082), metformin (850 mg twice a day) (n = 1,073), or intensive lifestyle intervention (n = 1,079). The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio = 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity) and with baseline insulin secretion (hazard rate ratio = 0.57-0.76 per SD). Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio = 0.46-0.95 per SD increase and 0.29-0.79 per SD increase, respectively). In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables. The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of beta-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and beta-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and beta-cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups. In conclusion, higher insulin secretion and sensitivity at baseline and improvements in response to treatment were associated with lower diabetes risk in the DPP. The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of beta-cell function.

The Diabetes Prevention Program (DPP) was a randomized clinical trial of prevention of type 2 diabetes in high-risk people. Troglitazone, an insulin-sensitizing agent, was used initially but was discontinued during the trial. Troglitazone therapy was compared with other DPP interventions, considering both the short-term "in-trial" results and the longer-term results after troglitazone were discontinued. From 1996 to 1998, participants were randomly assigned to treatment with metformin (n = 587), troglitazone (n = 585), double placebo (n = 582), or intensive lifestyle intervention (ILS) (n = 589). Because of concern regarding its liver toxicity, the troglitazone arm was discontinued in June 1998, after which follow-up of all participants continued. During the mean 0.9 year (range 0.5-1.5 years) of troglitazone treatment, the diabetes incidence rate was 3.0 cases/100 person-years, compared with 12.0, 6.7, and 5.1 cases/100 person-years in the placebo, metformin, and ILS participants (P < 0.001, troglitazone vs. placebo; P = 0.02, troglitazone vs. metformin; P = 0.18, troglitazone vs. ILS). This effect of troglitazone was in part due to improved insulin sensitivity with maintenance of insulin secretion. During the 3 years after troglitazone withdrawal, the diabetes incidence rate was almost identical to that of the placebo group. Troglitazone, therefore, markedly reduced the incidence of diabetes during its limited period of use, but this action did not persist. Whether other thiazolidinedione drugs used for longer periods can safely prevent diabetes remains to be determined.

Background: Angiotensin-converting-enzyme (ACE) inhibitors are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure. ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure., Methods: In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial, we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy. The trial was a double-blind, placebo-controlled study in which 8290 patients were randomly assigned to receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching placebo (4132 patients)., Results: The mean (+/-SD) age of the patients was 64+/-8 years, the mean blood pressure 133+/-17/78+/-10 mm Hg, and the mean left ventricular ejection fraction 58+/-9 percent. The patients received intensive treatment, with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs. The incidence of the primary end point--death from cardiovascular causes, myocardial infarction, or coronary revascularization--was 21.9 percent in the trandolapril group, as compared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group, 0.96; 95 percent confidence interval, 0.88 to 1.06; P=0.43) over a median follow-up period of 4.8 years., Conclusions: In patients with stable coronary heart disease and preserved left ventricular function who are receiving "current standard" therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization., (Copyright 2004 Massachusetts Medical Society.)

The authors investigated the effects of an intervention package to support five high school students with extensive support-needs to initiate and engage in recreational activities with general-education peers in their physical education classes. The intervention components were (a) assessing participants' recreational activity goals, (b) teaching self-prompting using a picture book, (c) programming common stimuli, and (d) asking participants to assess daily performance and evaluate daily goal achievement. The intervention was associated with increases in participants' initiation of and engagement in recreational activities with general-education peers, as well as increases in ratings of quality of interaction. In addition, participants typically assessed with accuracy their performance of recreational activities and whether they had achieved their recreational goals. Findings are discussed with respect to future research and practice.

Background: Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes., Methods: We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups., Results: The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin., Conclusions: Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.

The effects of using a multicomponent intervention package to support the classroom performance of 4 high school students with mental retardation enrolled in general education classes were investigated. Intervention components were (a) modification of teacher-assigned worksheets, (b) instruction in assignment completion, (c) instruction in self-monitoring of classroom performance skills, (d) including students in setting performance goals, and (e) instruction in goal-evaluation. Implementation of the intervention package was associated with improved performance on modified assignments for all participants and higher report card grades for 3 participants. Three of 4 participants also correctly and independently evaluated their performance in relation to their performance goals. Findings are discussed and recommendations made for future research and practice.

Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol, are important factors in the pathogenesis of age-related bone loss. The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on bone loss in elderly women. Four hundred eighty-nine elderly women with normal bone density for their age, aged 65-77 yr, were entered into a randomized double blind, placebo-controlled trial. Women were randomized to one of four groups: conjugated estrogens (0.625 mg, daily) to women without a uterus (estrogen replacement therapy) plus medroxyprogesterone acetate (2.5 mg, daily) to women with a uterus (hormone replacement therapy), calcitriol (0.25 microg twice daily), a combination of hormone replacement therapy/estrogen replacement therapy plus calcitriol, or placebos for 3 yr. The primary outcome was the change in bone mineral density of the femoral neck and spine. In the intent to treat analysis, hormone therapy (hormone replacement therapy/estrogen replacement therapy) produced a mean (+/-1 SD) increase in bone mineral density of 2.98% (+/-5.45%) at the femoral neck (P < 0.0001) and 4.36% (+/-6.42%) at the spine (P < 0.0001). There were parallel increases in total hip and trochanter bone mineral density. Calcitriol increased bone mineral density 0.10% (+/- 4.27%) at the femoral neck (P = 0.57) and 1.65% (+/- 4.83%) at the spine (P < 0.0124). The combination of hormone replacement therapy/estrogen replacement therapy + calcitriol increased bone mineral density 3.80% (+/-4.95%) at the femoral neck (P < 0.001), 4.91% (+/-6.0%) at the spine (P < 0.0001), and parallel changes at the total hip and trochanter. All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck, spine, total hip and trochanter. There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone on bone mineral density at any site in the intent to treat analysis. In a secondary analysis of the effect in women who were adherent to treatment, calcitriol had a more significant effect on spine (P = 0.003) and total hip (P = 0.004). The increase in bone mineral density in the adherent groups of women was always higher compared with the intent to treat groups. Combination therapy compared with hormone replacement therapy/estrogen replacement therapy alone produced a significantly greater response in trochanter (P = 0.007) and total hip bone mineral density (P = 0.0017). In summary, hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinically relevant sites in a group of elderly women, with normal bone density for their age. Calcitriol was effective in increasing spine bone mineral density. In the adherent women, combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone.

Objective: To conduct a randomized, controlled trial (RCT) to examine issues associated with therapeutic alternatives to standard hysterectomy for women with dysfunctional uterine bleeding., Study Design: Participants were to be randomly assigned to one of three treatment groups: hysterectomy, endometrial ablation and medical management. Recruitment was targeted at 375 women., Results: Despite multiple recruitment strategies, recruitment was weak, with only five women enrolled after six months. Providers and women screened for eligibility often expressed discomfort with randomization. The protocol was amended to an elective treatment cohort design with a randomization component. Recruitment improved, with 37 women enrolled after four months., Conclusion: The success of RCTs may be affected by multiple factors. Acceptance of the protocol by patients and providers is essential. The RCT may present providers with a conflict between the goals of research and of providing optimal individualized care. Thus, RCTs may not always be appropriate for studies designed to examine best treatments in clinical practice, and nonrandomized designs may provide appropriate alternatives in some cases.

Objective: To determine the comparability of a text to a mannequin format for the assessment of joint counts (JC) among patients with rheumatoid arthritis (RA) participating in a randomized clinical trial (RCT)., Methods: A subgroup of patients participating in the MIRA (Minocycline in RA) RCT completed self-administered JC and joint scores (JS), which were compared to those of a trained assessor., Results: JC and JS data were consistently higher for the patient than for the assessor. Higher correlations were obtained for JC than for JS., Conclusion: Our data suggest JC can be used in the context of clinical trials or in the clinical setting, but are not interchangeable with trained assessor JC.

There is a lack of substantial data on changes in calciotropic hormones and bone markers in elderly subjects living in North America. Parathyroid hormone (PTH), serum 25-hydroxyvitamin D (25(OH)D) and bone markers (serum osteocalcin and urine N-telopeptide), were measured in 735 Caucasian subjects (235 men and 500 women) aged 65-87 years. There was a significant increase in serum osteocalcin and urine N-telopeptide with age in men, and a significant increase in serum osteocalcin with age in women. Serum PTH and 25(OH)D showed no significant change with age in men or women. After adjusting for age, calcium intake, serum creatinine, season, and weight, mean serum PTH (p = 0.01), serum osteocalcin (p = 0.0001) and 24 h urine N-telopeptide (p = 0.0001) were higher in women than men, and mean serum 25(OH)D (p = 0.0001) and 24 h urine calcium (p = 0.0001) were higher in men than women. Serum PTH was correlated with serum osteocalcin in men and women, r = 0.24, r = 0.17, p < 0.001, but not with urine N-telopeptide. Serum PTH was inversely correlated with serum 25(OH)D (r = -0.25, r = -034,p < 0.001), and positively correlated with serum creatinine (r = 0.14, r = 0.17,p < 0.01) in men and women. The prevalence of serum 25(OH)D levels below 12 ng/ml was only 33% in females and 0.4% in men. Thus vitamin D deficiency was very uncommon in the U.S.A. compared with Europe. Although mean serum PTH was increased in the elderly, only 4-6% had PTH levels above the normal range. In summary, the increase in serum PTH in the elderly can be explained more by changes in vitamin D status than by declining renal function. These data also show significantly higher (p = 0.001) bone remodeling markers in women.

Objective: To (1) validate the Short-Form Health Survey (SF-36) as a generic functional health status measure in patients with rheumatoid arthritis (RA); and (2) assess correlations between the SF-36 and other outcome measures used in the Minocycline in Rheumatoid Arthritis (MIRA) Trial., Methods: We conducted a cross sectional analysis of the final visit outcome measures from the 48 week, multicenter, placebo controlled, double blind MIRA trial. Multitrait scaling analyses assessed convergent and discriminant validity and internal consistency reliability of the SF-36 in the study patients. Responses to comparable items on the SF-36 and modified Health Assessment Questionnaire (M-HAQ) regarding physical functioning were compared and questions from both instruments were also compared to other RA outcome measures., Results: In patients with RA, the SF-36 had high internal consistency and reliability, high discriminant and high convergent validity. Moderate correlations were observed (r = -0.46 to -0.61, p < 0.01 in each case) for comparable items on the SF-36 and M-HAQ regarding dressing, walking, and bending. Joint tenderness score correlations with items on the M-HAQ and SF-36, and joint tenderness score correlations with the SF-36 scales were higher than for joint swelling scores. Physician and patient global assessments were most highly correlated (r = 0.58 and 0.66; p < 0.01, respectively) with the SF-36 bodily pain item., Conclusion: The SF-36 is a valid instrument for this RA population. The SF-36 correlates with the M-HAQ and the physician and patient global assessments. The usefulness of the SF-36 in measuring change in RA clinical trials requires testing in longitudinal studies.

Objective: To assess radiographically determined disease progression in patients in the Minocycline in Rheumatoid Arthritis (MIRA) Trial., Methods: A double blind, randomized, multicenter, 48 week trial of oral minocycline (200 mg/day) or placebo in 6 clinical centers in the United States. Patients include 219 adults with active RA previously receiving limited treatment with disease modifying drugs. Posteroanterior films of the hands from baseline and final visits, blinded for sequence, were read for erosions and joint space narrowing by trained observers. Outcomes included rate of disease progression (change/month) and percentage of patients with progression from baseline, newly involved joints, and newly erosive disease., Results: Using intent-to-treat analyses, progression rates for erosions (0.11 +/- 0.42 minocycline, 0.17 +/- 0.41 placebo; p = 0.47) and joint space narrowing (0.16 +/- 0.55 minocycline and 0.23 +/- 0.71 placebo; p = 0.14) were similar. (Power 43% to detect a 50% difference.) Newly erosive joints occurred more frequently in the placebo group (44 vs 32%; p = 0.08), not a statistically significant difference., Conclusion: Radiographic measurement of disease progression using 4 measures failed to show a significant difference between minocycline and placebo treatment, although for all methods there was a trend toward treatment benefit, consistent with reported clinical results. A one year trial duration, high measurement variability, and slow rate of radiographic progression in this cohort may explain the low power to detect a treatment effect. The measurement that denoted "newly involved" joints was most sensitive in detecting change. In future trials longer term assessment (minimum 2 years) of radiographic changes and further comparison of measures of disease progression are warranted.

Objective: To compare 3 sets of criteria for meaningful improvement in a rheumatoid arthritis (RA) clinical trial, and to evaluate the implications of these criteria sets for RA trial design., Methods: Data were obtained from the Minocycline in Rheumatoid Arthritis (MIRA) trial (primary outcome measures: 50% improvement in joint tenderness and 50% improvement in joint swelling, based on joint scores). These MIRA data were evaluated against 1) the Paulus criteria (20% improvement in 4 of 6 measures: joint tenderness scores, joint swelling scores, physician's and patient's global assessments, erythrocyte sedimentation rate [ESR], and morning stiffness); and 2) the American College of Rheumatology (ACR) criteria (20% improvement in joint tenderness and joint swelling counts, and in 3 of 5 other measures: physician's and patient's global assessments, ESR, modified Health Assessment Questionnaire, and patient's pain assessment). The ACR criteria were modified using 3 of 4 remaining measures, since baseline pain assessment data were not available., Results: Percentages of minocycline-treated patients versus placebo-treated patients showing meaningful improvement were as follows: by MIRA criteria, for joint tenderness, 56% versus 41% (P = 0.021), and for joint swelling, 54% versus 39% (P = 0.023); by Paulus criteria, 41% versus 28% (P = 0.040); and by ACR criteria, 44% versus 26% (P = 0.004). Both the modified ACR criteria and the Paulus criteria demonstrated a reduced placebo response rate. Compared with the MIRA criteria, the ACR criteria increased, and the Paulus criteria decreased, absolute between-group differences in improvement; however, both criteria sets increased relative percentages of patients showing improvement in the minocycline group versus the placebo group. Study design considerations indicated that application of the ACR criteria would reduce the required sample size., Conclusion: Different placebo response rates and treatment group differences were found using the 3 RA improvement criteria sets. These findings support the use of the ACR criteria for defining improvement in RA clinical trials.

Objective: To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial., Methods: Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression., Results: At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope., Conclusion: HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.

This study was conducted to compare associations between urinary sodium and calcium in elderly men and women, overall and by level of calcium intake, and to examine associations between urinary sodium excretion and bone mineral density in the same population. Healthy men (n = 249) and women (n = 665) over age 65 y had measurements of 24-h urinary sodium and calcium and spine, hip, and whole-body bone mineral density. Urinary sodium and calcium excretion were significantly correlated in men (r = 0.42, P = 0.0001) and women (r = 0.26, P = 0.0001), but the regression coefficient was greater in men than in women (beta = 0.017 vs. 0.010, P = 0.007). Within each gender, associations between 24-h urinary sodium and calcium were similar and significant at intermediate and high calcium intakes but were not significant at very low intake levels. Urinary sodium was not correlated with bone mineral density. In conclusion, in healthy elderly men and women, urinary sodium and calcium excretion are linked at moderate and high dietary calcium intakes but not at low calcium intakes. For a given sodium excretion, elderly men excrete more calcium than women.

Objective: To assess the safety and efficacy of minocycline in the treatment of rheumatoid arthritis., Design: A double-blind, randomized, multicenter, 48-week trial of oral minocycline (200 mg/d) or placebo., Setting: 6 clinical centers in the United States., Patients: 219 adults with active rheumatoid arthritis who had previous limited treatment with disease-modifying drugs., Measurements: As the primary outcomes, 60 diarthrodial joints were examined for tenderness, and 58 joints were examined for swelling (hips excluded). Grip strength, evaluator's global assessment, morning stiffness, Modified Health Assessment Questionnaire, patient's global assessment, hematocrit, erythrocyte sedimentation rate, platelet count, and IgM rheumatoid factor levels were also assessed; radiographs of both hands and wrists were taken., Results: 109 and 110 patients were randomly assigned to receive minocycline and placebo, respectively. At entry, demographic, clinical, and laboratory measurements were similar in both groups. Most patients had mild to moderate disease activity and some evidence of destructive disease. At the week 48 visit, 79% of the minocycline group and 78% of the placebo group continued to receive the study medication. At 48 weeks, more patients in the minocycline group than in the placebo group showed improvement in joint swelling (54% and 39%) and joint tenderness (56% and 41%) (P < 0.023 for both comparisons). The minocycline group also showed greater improvement in hematocrit, erythrocyte sedimentation rate, platelet count, and IgM rheumatoid factor levels (all P values < 0.001), and more patients receiving minocycline had laboratory values within normal ranges at 48 weeks. For the remaining outcomes, P values ranged from 0.04 to 0.76, all greater than the critical value of 0.005 (Bonferroni adjustment for multiple comparisons). The frequency of reported side effects was similar in both groups, and no serious toxicity occurred., Conclusions: Minocycline was safe and effective for patients with mild to moderate rheumatoid arthritis. Its mechanisms of action remain to be determined.

Objective: To determine whether the quantitative and qualitative effects on lipoproteins differ between two doses of conjugated equine estrogen before and after progestin administration., Methods: We randomized 103 postmenopausal women into a control group and into two groups receiving either 0.625 mg or 1.25 mg of conjugated equine estrogen for 4 months and then the same estrogen dose plus cyclic medroxyprogesterone acetate for 8 months., Results: Both estrogen doses similarly lowered (P < .01) low-density lipoprotein (LDL) cholesterol and raised (P < .01) high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, triglyceride levels of all lipoproteins, and sex hormone-binding globulin capacity. Cyclic addition of the progestin reduced HDL cholesterol (P < .01) and apolipoprotein A-I (P < .05), but not LDL cholesterol in either estrogen group. A greater lowering of HDL cholesterol (P < .05) in response to the progestin was seen with the 0.625-mg dose of estrogen. Estrogen-induced triglyceride enrichment of HDL and LDL was not reversed by the progestin., Conclusion: The only significant quantitative difference in lipoprotein levels between the doses of conjugated equine estrogen before or after administration of medroxyprogesterone acetate was a greater decline in HDL cholesterol levels with the lower dose after 4 months of the progestin. This difference was not sustained over time. There were no differences between doses in the estrogen-induced triglyceride enrichment of lipoproteins, and these qualitative changes were not affected by the progestin.

Of 2882 women allocated to either transabdominal CVS (TA) or transcervical CVS (TC) at two large obstetric centres in Denmark, 2707 had blood samples drawn before and 30 min after CVS for maternal serum-alpha-fetoprotein (MSAFP) measurement. 2535 of these women had cytogenetically normal pregnancies and 2091 of them went on to have samples drawn at the 18-20 week follow-up. Post-procedure MSAFP values were correlated to the biopsy method used, with mean MSAFP values significantly higher after TA than TC, 33 and 15 kU/l, respectively (P < 0.001). Following TA procedures, 18 per cent of cases had feto-maternal transfusion higher than 0.1 ml; this occurred in only 5 per cent of TC cases. MSAFP levels were associated with spontaneous fetal loss in the TA group but not in the TC group. TC, however, was followed by more losses than TA. The post-CVS MSAFP value was positively correlated with the amount of villi aspirated. The difference in post-procedure elevation in MSAFP 30 min later (average 18 kU/l higher for TA than for TC) was not reflected in raised levels at the 18-20 week follow-up. Study medians at mid-trimester did not differ from reference group medians established from a group of singleton pregnancies with sonographically determined gestational age who did not experience invasive procedures and delivered normal infants. Our findings suggest that CVS does not compromise mid-trimester MSAFP for screening for neural tube defects (NTDs). Extremely high mid-trimester MSAFP values in the TC group could predict imminent loss.

The transabdominal chorionic villus sampling method was compared with the transcervical route and second trimester amniocentesis in a 3-winged randomised trial. Examination of 45 epidemiological variables showed the three procedure groups to be comparable at enrollment. In 3079 women at low genetic risk, we compared transabdominal with transcervical chorionic villus sampling and amniocentesis. The total fetal loss was 10.9%, 6.3% and 6.4% in the transcervical, transabdominal chorionic villus sampling groups and the amniocentesis group, respectively (p < 0.001). The two CVS procedures were compared in 2882 low and high genetic risk women with cytogenetically normal fetuses. Rates of unintended post-procedure loss were 3.7% and 7.7% for transabdominal CVS and transcervical CVS, respectively (p < 0.001), difference in rates 4.0%, 95% C.I. +2.3% to +5.8%. By a priori ultrasound scanning, more transcervical than transabdominal procedures (p < 0.001) were considered to be inaccessible for sampling. Our data indicate that transabdominal allows freer access to the placental site than transcervical sampling and is easier to adapt to than transcervical CVS. Women run comparable risks with transabdominal CVS and amniocentesis. Given the results of our study, transabdominal procedures remain the first choice for prenatal diagnosis and, since in our hands transcervical sampling entails an increased fetal risk, we have abandoned transcervical CVS in our two study centres.

We have compared three methods of prenatal diagnosis in two large obstetric centres in Denmark. Women were randomly assigned transabdominal (TA) chorionic villus sampling (CVS), transcervical (TC) CVS, or second-trimester amniocentesis (AC); women at high genetic risk were randomised between the two CVS groups only. Analysis of 45 epidemiological variables showed the three procedure groups to be similar at enrollment. All women were followed up until completion of pregnancy. Among 3079 women at low genetic risk total fetal loss rates were 10.9% for TC CVS, 6.3% for TA CVS, and 6.4% for AC (p < 0.001). More women had bleeding after the procedure in the CVS groups (p < 0.001), whereas more amniotic fluid leakage (p < 0.001) was reported after AC. No uterine infections occurred in any group. No case of oromandibular-limb abnormality was seen in the CVS groups, but 1 child in the AC group had aplasia of the right hand. The two CVS approaches were compared among 2882 women at low and high genetic risk who were found to have cytogenetically normal fetuses. Rates of unintentional loss after the procedure were 7.7% for TC CVS and 3.7% for TA CVS (p < 0.001; 95% Cl of difference 2.3-5.8%). At baseline ultrasound scanning after establishment of optimum sampling conditions, more TC than TA procedures (p < 0.001) were judged not to be feasible. We found that TA CVS allows better access to the placental site than TC sampling, is an easier skill to acquire, and has the potential that more villi can be aspirated when needed. The risk of fetal loss is similar after TA CVS and AC. However, losses after AC are at a later stage and are therefore more distressing. TA procedures remain the first choice for prenatal diagnosis. Since, in our hands, TC sampling carries a greater risk to the fetus, we have abandoned TC CVS in our two study centres.

Background: Chorionic-villus sampling is done in early pregnancy to obtain fetal cells for the prenatal diagnosis of genetic and chromosomal defects. Transcervical chorionic-villus sampling has been shown to be safe and effective in national trials. Recently, an alternative transabdominal technique has been suggested as potentially easier and safer., Methods: From April 1987 through September 1989, we prospectively compared transcervical and transabdominal chorionic-villus sampling in 3999 women with singleton pregnancies in whom the risk of a genetically abnormal fetus was increased. Women between 7 and 12 weeks of gestation underwent ultrasonographic evaluation of placental and uterine position. Those with active vaginal infections, active bleeding, or cervical polyps were excluded. If the obstetrician thought either sampling procedure was acceptable, the woman was asked to consent to random assignment to one of the two procedures. Both groups were followed to determine the outcome of pregnancy and the rate of spontaneous fetal loss after chorionic-villus sampling., Results: Among the 3999 women who entered the study, sampling was attempted in 3873 (97 percent), 1944 of whom had been assigned to undergo transcervical sampling and 1929 to undergo transabdominal sampling. Of these 3873 women, sampling was eventually successful in 3863. Sampling was successful after a single insertion of the sampling instrument in 94 percent of the transabdominal procedures and 90 percent of the transcervical procedures. Among the women with cytogenetically normal pregnancies who had sampling because of maternal age, the rate of spontaneous fetal loss through 28 weeks of pregnancy was 2.5 percent in the transcervical-sampling group and 2.3 percent in the transabdominal-sampling group (difference, 0.26 percent; 95 percent confidence interval, -0.5 to 1.0 percent)., Conclusions: Transabdominal and transcervical chorionic-villus sampling appear to be equally safe procedures for first-trimester diagnosis of fetal abnormalities.

Factors found to be associated with pregnancy loss after transcervical CVS were race (higher for non-white), history of spontaneous abortion, unplanned pregnancy, history of spotting or bleeding during the pregnancy prior to CVS, and placental position (higher for fundal or lateral locations). Whether the increase in loss risk is due to the factor, per se, or the factor plus the CVS cannot be determined due to the lack of appropriate control data.

Cytogenetic data from the United States NICHD collaborative study of chorionic villus sampling (CVS) were used to evaluate the clinical significance of chorionic mosaicism. The 10,754 patients with normal cytogenetic results were compared with 108 patients (1.0 per cent) with placental mosaicism and 181 patients (1.6 per cent) with pseudo-mosaicism. Of the pregnancies intended to continue, the pregnancy loss rate was significantly greater in patients with placental mosaicism than in the cytogenetically normal cohort (8.6 vs. 3.4 per cent, p less than 0.05). However, there was no difference in the frequencies of abruptio placenta, preterm labour or delivery, small-for-gestational-age newborns, pregnancy-induced hypertension, or neonates with Apgar scores less than 7.