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1.  Walking to meet physical activity guidelines in knee osteoarthritis: Is 10,000 steps enough? 
Objective
To study if step goals (e.g. walking 10,000 steps/day) approximate meeting 2008 Physical Activity Guidelines for Americans among adults with or at high risk of knee OA.
Design
Cross-sectional observational cohort
Setting
Community
Participants
People with or at high risk of knee OA
Interventions
None
Main Outcome Measures
Objective physical activity data were collected over 7 consecutive days from people with or at high risk of knee (OA) participating in the Multicenter Osteoarthritis Study. Using activity monitor data, we determined the proportion that 1) walked ≥10,000 steps/day, 2) met the 2008 Physical Activity Guidelines, and 3) achieved both recommendations.
Results
Of 1788 subjects studied (age 67 ± 8 yrs, BMI 31 ± 6 kg/m2, 60% women), 16.7% of men and 12.6% of women walked ≥10,000 steps/day, while 6% of men and 5% of women met the 2008 Physical Activity Guidelines for Americans. Of those walking ≥10,000 steps/day, 16.7% and 26.7% of men and women also met the 2008 Physical Activity Guidelines.
Conclusions
Among this sample of older adults with or at high risk of knee OA, walking ≥10,000 steps/day did not translate into meeting public health guidelines. These findings highlight the disparity between number of steps/day believed to be needed and recommended time-intensity guidelines to achieve positive health benefits.
doi:10.1016/j.apmr.2012.11.038
PMCID: PMC3608824  PMID: 23228625
Physical Activity; knee osteoarthritis; pedometer; Public Health Guidelines; Walking
2.  PERIPATELLAR SYNOVITIS: COMPARISON BETWEEN NON-CONTRAST-ENHANCED AND CONTRAST-ENHANCED MRI AND ASSOCIATION WITH PAIN. THE MOST STUDY 
Purpose
To assess the diagnostic performance of signal changes in Hoffa's fat pad (HFP) assessed on non-contrast-enhanced (CE) MRI in detecting synovitis, and the association of pain with signal changes in Hoffa’s fat pad on non-CE MRI and peripatellar synovial thickness on CE MRI.
Methods
The Multicenter Osteoarthritis (MOST) Study is an observational study of individuals who have or are at high risk for knee OA. All subjects with available non-CE and CE MRIs were included. Signal changes in HFP were scored from 0 to 3 in 2 regions using non-CE MRI. Synovial thickness was scored from 0 to 2 on CE MRI in 5 peripatellar regions. Sensitivity, specificity and accuracy of HFP signal changes were calculated considering synovial thickness on CE MRI as the reference standard. We used logistic regression to assess the associations of HFP changes (non-CE MRI) and synovial thickness (CE MRI) with pain from walking up or down stairs, after adjusting for potential confounders.
Results
A total of 393 subjects were included. Sensitivity of infrapatellar and intercondylar signal changes in HFP was high (71% and 88%), but specificity was low (55% and 30%). No significant associations were found between HFP changes on non-CE MRI and pain. Grade 2 synovial thickness assessed on CE MRI was significantly associated with pain after adjustments for potential confounders.
Conclusion
Signal changes in HFP detected on non-CE MRI are a sensitive but non-specific surrogate for the assessment of synovitis. CE MRI identifies associations with pain better than non-CE MRI.
doi:10.1016/j.joca.2012.12.006
PMCID: PMC3578385  PMID: 23277189
Knee osteoarthritis; synovitis; magnetic resonance imaging; knee pain
3.  Association of Electrocardiographically Determined Left Ventricular Mass With Incident Diabetes, 1985–1986 to 2010–2011 
Diabetes Care  2013;36(3):645-647.
OBJECTIVE
Electrocardiographic indices reflecting left ventricular hypertrophy are associated with incident diabetes in clinical populations at risk for coronary heart disease. We tested whether electrocardiographically determined left ventricular mass was positively associated with incident diabetes in a population sample.
RESEARCH DESIGN AND METHODS
Coronary Artery Risk Development in Young Adults (CARDIA) study participants (n = 4,739) were followed from 1985–1986 to 2010–2011 for incident diabetes. Validated sex- and race-specific formulas were applied to standard electrocardiograms to determine left ventricular mass.
RESULTS
Over 25 years, 444 participants developed diabetes (9.4%). After adjustment for demographic, behavioral, and clinical covariates, participants in the highest quartile of left ventricular mass index (LVMI) were twice as likely to develop diabetes than participants in the lower three quartiles (hazard ratio 2.61 [95% CI 2.16–3.17]). Neither Cornell voltage nor Cornell voltage product was associated with incident diabetes in fully adjusted models.
CONCLUSIONS
Electrocardiographically determined LVMI may be a useful noninvasive marker for identifying adults at risk for diabetes.
doi:10.2337/dc12-1359
PMCID: PMC3579342  PMID: 23160723
4.  PRETERM BIRTH AND FUTURE MATERNAL BLOOD PRESSURE, INFLAMMATION AND INTIMAL MEDIAL THICKNESS: THE CARDIA STUDY 
Hypertension  2013;61(3):641-646.
Preterm birth (PTB, <37 weeks) may be a marker of endothelial dysfunction and a pro-inflammatory phenotype; both are risk factors for cardiovascular disease. We studied 916 women (46% Black) with 1,181 live births between enrollment in the Coronary Artery Risk Development in Young Adults (CARDIA) study (age 18-30 years) and 20 years later. C-reactive protein (CRP) was measured at years 7, 15 and 20. Interleukin-6 (IL-6) and carotid intima-media thickness (IMT) which incorporated the common carotid arteries, bifurcations, and internal carotid arteries were measured at year 20. Blood pressure, lipids, anthropometrics, and pregnancy events were assessed at all visits. Change in risk factors and differences in inflammatory markers and IMT according to PTB were evaluated. Women with PTBs (n=226) had higher mean systolic blood pressures (SBP) before pregnancy (106 vs. 105 mmHg, respectively; p=0.03). Systolic and diastolic blood pressure increased more rapidly over 20 years compared to women with term births (p<0.01 time interaction) even after removing women with self-reported hypertension in pregnancy. Women with PTB vs. term births had similar mean IMT adjusted for age, BMI, race, lifestyle and cardiovascular risk factors. CRP and IL-6 did not differ according to PTB. Women with PTB, regardless of hypertension during pregnancy, had higher blood pressure after pregnancy compared to women with term births. In the U.S. where rates of PTB are high and race disparities persist, PTB may identify women with higher blood pressure the years after pregnancy.
doi:10.1161/HYPERTENSIONAHA.111.00143
PMCID: PMC3583341  PMID: 23319540
hypertension; inflammation; intima-media thickness; pregnancy
5.  Prevalent cartilage damage and cartilage loss over time are associated with incident bone marrow lesions in the tibiofemoral compartments: the MOST Study 
Objective
To assess the association of prevalent cartilage damage and cartilage loss over time with incident bone marrow lesions (BMLs) in the same subregion of the tibiofemoral compartments as detected on magnetic resonance imaging (MRI).
Methods
The Multicenter Osteoarthritis Study is an observational study of individuals with or at risk for knee osteoarthritis (OA). Subjects whose baseline and 30-month follow-up MRIs were read for findings of OA were included. MRI was performed with a 1.0T extremity system. Tibiofemoral compartments were divided into 10 subregions. Cartilage morphology was scored from 0 to 6 and BMLs were scored from 0 to 3. Prevalent cartilage damage and cartilage loss over time were considered predictors of incident BMLs. Associations were assessed using logistic regression, with adjustments for potential confounders.
Results
Medially, incident BMLs were associated with baseline cartilage damage (adjusted odds ratio (OR) 3.9 [95% CI 3.0, 5.1]), incident cartilage loss (7.3 [95% CI 5.0, 10.7]) and progression of cartilage loss (7.6 [95% CI 5.1, 11.3]) Laterally, incident BMLs were associated with baseline cartilage damage (4.1 [95% CI 2.6, 6.3]), incident cartilage loss (6.0 [95% CI 3.1, 11.8]), and progression of cartilage loss (11.9 [95% CI 6.2, 23.0]).
Conclusion
Prevalent cartilage damage and cartilage loss over time are strongly associated with incident BMLs in the same subregion, supporting the significance of the close interrelation of the osteochondral unit in the progression of knee OA.
doi:10.1016/j.joca.2012.11.005
PMCID: PMC3556203  PMID: 23178289
Bone marrow; cartilage; knee; osteoarthritis; magnetic resonance imaging
6.  Association of early adult modifiable cardiovascular risk factors with left atrial size over a 20-year follow-up period: the CARDIA study 
BMJ Open  2014;4(1):e004001.
Objectives
We investigate how early adult and 20-year changes in modifiable cardiovascular risk factors (MRF) predict left atrial dimension (LAD) at age 43–55 years.
Methods
The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled black and white adults (1985–1986). We included 2903 participants with echocardiography and MRF assessment in follow-up years 5 and 25. At years 5 and 25, LAD was assessed by M-mode echocardiography, then indexed to body surface area (BSA) or height. Blood pressure (BP), body mass index (BMI), heart rate (HR), smoking, alcohol use, diabetes and physical activity were defined as MRF. Associations of MRF with LAD were assessed using multivariable regression adjusted for age, ethnicity, gender and year-5 left atrial (LA) size.
Results
The participants were 30±4 years; 55% white; 44% men. LAD and LAD/height were modest but significantly higher over the follow-up period, but LAD/BSA decreased slightly. Increased baseline and 20-year changes in BP were related to enlargement of LAD and indices. Higher baseline and changes in BMI were also related to higher LAD and LAD/height, but the opposite direction was found for LAD/BSA. Increase in baseline HR was related to lower LAD but not LAD indices, when only baseline covariates were included in the model. However, baseline and 20-year changes in HR were significantly associated to LA size.
Conclusions
In a biracial cohort of young adults, the most robust predictors for LA enlargement over a 20-year follow-up period were higher BP and BMI. However, an inverse direction was found for the relationship between BMI and LAD/BSA. HR showed an inverse relation to LA size.
doi:10.1136/bmjopen-2013-004001
PMCID: PMC3902509  PMID: 24384901
Cardiology; Epidemiology
7.  Do radiographic disease and pain account for why people with or at high risk of knee osteoarthritis do not meet Physical Activity Guidelines? 
Arthritis and rheumatism  2013;65(1):139-147.
OBJECTIVE
Knee Osteoarthritis (OA) and pain are assumed to be barriers for meeting physical activity guidelines, but this has not been formally evaluated. The purpose of this study was to determine the proportion of people with and without knee OA and knee pain who met recommended physical activity levels through walking.
METHODS
Cross-sectional analysis of community dwelling adults who have or who are at high risk of knee OA from The Multicenter Osteoarthritis Study. Participants wore a StepWatch activity monitor to record steps/day over 7 days. The proportion that met the recommended physical activity levels was determined as those accumulating ≥150 minutes/week at ≥100 steps/minute in bouts lasting ≥10 minutes. These proportions were also determined for those with and without knee OA, as classified by radiograph, and by severity of knee pain.
RESULTS
Of the 1788 study participants (age 67 sd 8 yrs, BMI 31 sd 6 kg/m2, 60% female), lower overall percentages of participants with radiographic knee OA and knee pain met recommended physical activity levels. However, these differences were not statistically significant between those with and without knee OA; 7.3% and 10.1% of men (p=0.34), and 6.3% and 7.8% of women (p=0.51), respectively, met recommended physical activity levels. Similarly, for those with moderate/severe pain versus no pain, 12.9% and 10.9% of men (p=0.74) and 6.7% and 11.0% (p=0.40) of women met recommended physical activity levels.
CONCLUSIONS
Disease and pain have little impact on achieving recommended physical activity levels among people with or at high risk of knee OA.
doi:10.1002/art.37748
PMCID: PMC3535507  PMID: 23124774
8.  Co-Localization of non-cartilaginous articular pathology increases risk of cartilage loss in the tibiofemoral joint - the MOST Study 
Annals of the rheumatic diseases  2012;72(6):10.1136/annrheumdis-2012-201810.
Purpose
To assess risk of cartilage loss in the tibiofemoral joint in relation to baseline damage severity, and to analyze the association of nearby pathologic findings on the risk of subsequent cartilage loss.
Methods
The Multicenter Osteoarthritis (MOST) Study is a longitudinal study of individuals with or at high risk for knee osteoarthritis. Magnetic resonance imaging (MRI) examinations were assessed according to the Whole Organ Magnetic Resonance Imaging Score (WORMS). Included were all knees with available baseline and 30 months MRIs. Ordinal logistic regression was used to estimate risk of cartilage loss in each subregion in relation to the number of associated articular features including bone marrow lesions, meniscal damage and extrusion and also in regard to baseline damage severity, respectively.
Results
13524 subregions of 1365 knees were included. 3777 (27.9%) subregions exhibited prevalent cartilage damage at baseline and 1119 (8.3%) subregions showed cartilage loss at 30-month follow-up. Risk of cartilage loss was increased for subregions with associated features (ORs 2.53, 95% confidence interval [CI] 2.03-3.15 for one, 4.32 95% CI 3.42-5.47 for two and 5.30 95% CI 3.95-7.12 for three associated features; p for trend <0.0001). Subregions with prevalent cartilage damage showed increased risk for further cartilage loss compared to subregions with intact cartilage at baseline with small superficial defects exhibiting highest risk.
Conclusion
Risk of cartilage loss is increased for subregions with associated pathology and further increased when more than one type of associated feature is present. In addition, prevalent cartilage damage increases risk for subsequent cartilage loss.
doi:10.1136/annrheumdis-2012-201810
PMCID: PMC3871211  PMID: 22956600
magnetic resonance imaging; osteoarthritis; risk factors; cartilage loss; meniscal damage; mensical extrusion; bone marrow lesions
9.  Predictive validity of within-grade scoring of longitudinal changes of MRI-based cartilage morphology and bone marrow lesion assessment in the tibio-femoral joint - the MOST Study 
Objective
In order to increase sensitivity to detect longitudinal change, recording of within-grade changes was introduced for cartilage morphology and bone marrow lesion (BML) assessment in semiquantitative magnetic resonance imaging (MRI) scoring of knee osteoarthritis. The aim of this study was to examine the validity provided by within-grade scoring.
Design
The Multicenter Osteoarthritis (MOST) Study is a longitudinal study of subjects with or at risk of knee osteoarthritis. Baseline and 30 months MRIs were read according to the modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) system including within-grade changes for cartilage and BMLs. We tested the validity of within-grade changes by whether the 30 month changes in cartilage and bone marrow lesion assessment were predicted by baseline ipsi-compartmental meniscal damage and malalignment, factors known to affect cartilage loss and bone marrow lesions, using ordinal logistic regression.
Results
1867 knees (from 1411 participants) were included. Severe medial meniscal damage predicted partial grade (aOR 4.4, 95%CI 2.2,8.7) but not ≥ full grade (aOR 1.3, 95%CI 0.8,2.2) worsening of cartilage loss and predicted both, partial grade (aOR 9.6, 95%CI 3.6,25.1) and ≥ full grade (aOR 5.1, 95%CI 3.2,8.2) worsening of BMLs. Severe, but not moderate, malalignment predicted ipsicompartmental within-grade (medial cartilage damage: aOR 5.5, 95%CI 2.6,11.6; medial worsening of BMLs: aOR 4.9, 95%CI 2.0,12.3) but not full grade worsening of BMLs and cartilage damage.
Conclusions
Within-grade changes in semiquantitative MRI assessment of cartilage and bone marrow lesions are valid and their use may increase the sensitivity of semiquantitative readings in detecting longitudinal changes in these structures.
doi:10.1016/j.joca.2012.07.012
PMCID: PMC3863692  PMID: 22846715
osteoarthritis; MRI; semiquantitative scoring; WORMS; within grade; validity
10.  Maintaining a High Physical Activity Level Over 20 Years and Weight Gain 
JAMA : the journal of the American Medical Association  2010;304(23):10.1001/jama.2010.1843.
Context
Data supporting physical activity guidelines to prevent long-term weight gain are sparse, particularly during the period when the highest risk of weight gain occurs.
Objective
To evaluate the relationship between habitual activity levels and changes in body mass index (BMI) and waist circumference over 20 years.
Design, Setting, and Participants
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective longitudinal study with 20 years of follow-up, 1985-86 to 2005-06. Habitual activity was defined as maintaining high, moderate, and low activity levels based on sex-specific tertiles of activity scores at baseline. Participants comprised a population-based multi-center cohort (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) of 3554 men and women aged 18 to 30 years at baseline.
Main Outcome Measures
Average annual changes in BMI and waist circumference
Results
Over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use, and energy intake. Men maintaining high activity gained 2.6 fewer kilograms (+ 0.15 BMI units per year; 95 % confidence interval [CI] 0.11-0.18 vs +0.20 in the lower activity group; 95% CI, 0.17-0.23) and women maintaining higher activity gained 6.1 fewer kilograms (+0.17 BMI units per year; 95 % CI, 0.12-0.21 vs. +0.30 in the lower activity group; 95 % CI, 0.25-0.34). Men maintaining high activity gained 3.1 fewer centimeters in waist circumference (+0.52 cm per year; 95 % CI, 0.43-0.61 cm vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75) and women maintaining higher activity gained 3.8 fewer centimeters (+0.49 cm per year; 95 % CI, 0.39-0.58 vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75).
Conclusion
Maintaining high activity levels through young adulthood may lessen weight gain as young adults transition to middle age, particularly in women.
doi:10.1001/jama.2010.1843
PMCID: PMC3864556  PMID: 21156948
11.  The Role of Varus and Valgus Alignment in the Initial Development of Knee Cartilage Damage by MRI: the MOST Study 
Annals of the rheumatic diseases  2012;72(2):10.1136/annrheumdis-2011-201070.
Objective
Varus and valgus alignment are associated with progression of knee osteoarthritis, but their role in incident disease is less certain. Radiographic measures of incident knee osteoarthritis may be capturing early progression rather than disease development. We tested the hypothesis: in knees with normal cartilage morphology by MRI, varus is associated with incident medial cartilage damage and valgus with incident lateral damage.
Methods
In MOST, a prospective study of persons at risk for or with knee osteoarthritis, baseline full-limb x-rays and baseline and 30-month MRIs were acquired. In knees with normal baseline cartilage morphology in all tibiofemoral subregions, we used logistic regression with GEE to examine the association between alignment and incident cartilage damage adjusting for age, gender, BMI, laxity, meniscal tear, and extrusion.
Results
Of 1881 knees, 293 from 256 persons met criteria. Varus vs. non-varus was associated with incident medial damage (adjusted OR 3.59, 95% CI: 1.59, 8.10), as was varus vs. neutral, with evidence of a dose effect (adjusted OR 1.38/1° varus, 95% CI: 1.19, 1.59). Findings held even excluding knees with medial meniscal damage. Valgus was not associated with incident lateral damage. Varus and valgus were associated with a reduced risk of incident lateral and medial damage, respectively.
Conclusion
In knees with normal cartilage morphology, varus was associated with incident cartilage damage in the medial compartment, and varus and valgus with a reduced risk of incident damage in the less loaded compartment. These results support that varus increases the risk for initial development of knee osteoarthritis.
doi:10.1136/annrheumdis-2011-201070
PMCID: PMC3845483  PMID: 22550314
12.  Correlates of heart rate recovery over 20 years in a population sample 
Medicine and science in sports and exercise  2012;44(2):10.1249/MSS.0b013e31822cb190.
Introduction
Slow heart rate recovery (HRR) from a graded exercise treadmill test (GXT) is a marker of impaired parasympathetic reactivation that is associated with elevated mortality. Our objective was to test whether demographic, behavioral or coronary heart disease (CHD) risk factors during young adulthood were associated with the development of slow HRR.
Methods
Participants from the Coronary Artery Risk Development in Young Adults study underwent symptom-limited maximal GXT using a modified Balke protocol at baseline (1985–86) and 20-year follow-up (2005–06) examinations. HRR was calculated as the difference between peak heart rate (HR) and HR two-minutes following cessation of the GXT. Slow HRR was defined as 2-minute HRR < 22 beats·min−1.
Results
In 2,730 participants who did not have slow HRR at baseline, mean HRR was 44 beats*min−1 (SD = 11) at baseline and declined to 40 beats·min−1 (SD=12) in 2005–06; slow HRR developed in 5% (n=135) of the sample by 2005–06. Female sex, black race, fewer years of education, obesity, cigarette smoking, higher depressive symptoms, higher fasting glucose, hypertension, metabolic syndrome and physical inactivity and low fitness were each associated with incident slow HRR. In a multivariable model higher BMI, larger waist, low education, fasting glucose and current smoking remained significantly associated with incident slow HRR. Increasing BMI (per SD higher) over follow-up and incident hypertension, diabetes and metabolic syndrome (in the subsets of participants who were free from those conditions at baseline), were each associated with a significantly elevated odds of incident slow HRR.
Conclusions
On average, HRR declines with aging; however, the odds of having slow HRR in early middle age is significantly associated with traditional CHD risk factors.
doi:10.1249/MSS.0b013e31822cb190
PMCID: PMC3838873  PMID: 21796053
Epidemiology; Cardiovascular Disease; Exercise; Autonomic Nervous System
13.  Relationships Between Serum and Urine Phosphorus with All-Cause and Cardiovascular Mortality: the Osteoporotic Fractures in Men (MrOS) Study 
Background
Serum phosphorus is associated with cardiovascular disease (CVD) in the general population but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus/creatinine ratio (UPi/UCr, a marker of intestinal absorption) or urine fractional excretion of phosphorus (FePi, a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain.
Study Design
Prospective observational study.
Setting and Participants
1,325 community-dwelling men aged ≥65 years.
Predictors
Serum phosphorus, UPi/UCr, and FePi.
Outcomes
All-cause and CVD death.
Results
Mean age was 74±6 years, eGFR was 75±16 ml/min/1.73m2, and serum phosphorus was 3.2±0.4 mg/dL. During 9.3 years median follow-up, there were 364 deaths (120 CVD deaths). After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), UPi/UCr, and FePi were 1.63 (95% CI 1.23-2.17), 1.22 (95% CI 0.90-1.65), and 0.88 (95% CI 0.64-1.23), respectively. Results were similar for CVD death. Results were also similar irrespective of eGFR above or below 60 ml/min/1.73m2.
Limitations
Older, all male cohort. Few had advanced CKD. Specimens were collected in the morning after an overnight fast.
Conclusions
In community-living older men, higher serum phosphorus is associated with all-cause and CVD death. In contrast, UPi/UCr and FePi were not. These findings do not support using UPi/UCr or FePi as adjuvant measures to predict risk of mortality or CVD in the general population.
doi:10.1053/j.ajkd.2012.11.033
PMCID: PMC3815620  PMID: 23261120
Phosphorus; urine phosphorus; mortality; cardiovascular disease; kidney disease; geriatrics
14.  Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study 
The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up.
The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower-than-expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues.
The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power.
Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.
doi:10.1177/1740774511432726
PMCID: PMC3790961  PMID: 22334468
15.  Health care access and weight change among young adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Public health nutrition  2012;16(10):1796-1800.
Objective
Health care access is associated with improved control of multiple chronic diseases, but the association between health care access and weight change is unclear. This study aims to test the association between health care access and weight change.
Design
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a multi-center population-based prospective study. Weight change was calculated at 3 and 13 years after CARDIA year 7 (1992–1993). Health care access was defined as no barriers or one or more barriers to access (health insurance gap, no usual source of care, not seeking care due to expense). Intermediary variables evaluated included history of dieting, and use of diet pills, meal replacements, or weight control programs.
Setting
Four cities in the United States.
Subjects
Participants were aged 18–30 years at baseline (1985–1986). Analyses include 3922 black and white men and women with relevant data from CARDIA years 7, 10, and 20 (1992–1993, 1995–1996, and 2005–2006, respectively).
Results
Mean weight change was +4.9 pounds by 3 years and +18.7 pounds by 13 years, with no differences by health care access. Being on a weight-reducing diet was not consistently associated with health care access across examinations. Use of diet pills, meal replacements or organized weight control programs was low, and did not vary by health care access.
Conclusions
Weight gain was high irrespective of health care access. Public health and clinical approaches are needed to address weight gain.
doi:10.1017/S1368980012003813
PMCID: PMC3574627  PMID: 22894769
health care accessibility; body weight change
17.  When it hurts, a positive attitude may help: The association of positive affect with daily walking in knee OA: the MOST Study 
Arthritis care & research  2012;64(9):1312-1319.
OBJECTIVE
While depressive symptoms and knee pain are independently known to impede daily walking in older adults, it is unknown whether positive affect promotes daily walking. This study investigated this association among adults with knee osteoarthritis (OA) and examined whether knee pain modified this association.
DESIGN
Cross-sectional analysis of the Multicenter Osteoarthritis Study. We included 1018 participants (mean age 63.1 ± 7.8 years, 60% female) who had radiographic knee OA and had worn a StepWatch monitor to record steps/day. High- and low- positive affect, and depressive symptoms were based on the Center for Epidemiologic Studies-Depression Scale. Knee pain was categorized as present in respondents who reported pain on most days at both a clinic visit and a telephone screen.
RESULTS
Compared to respondents with low positive affect (27% of respondents), those with high positive affect (63%) walked similar steps/day while those with depressive symptoms (10%) walked less (adjusted beta coefficients = −32.6 [−458.9, 393.8] and −579.1 [−1274.9, 116.7], respectively). There was a statistically significant interaction of positive affect by knee pain (p= 0.0045). Among respondents with knee pain (39%), those with high positive affect walked significantly more steps/day (711.0 [55.1, 1366.9]) than those with low positive affect.
CONCLUSION
High positive affect was associated with more daily walking among adults with painful knee OA. Positive affect may be an important psychological factor to consider to promote physical activity among people with painful knee OA.
doi:10.1002/acr.21694
PMCID: PMC3410957  PMID: 22504854
Physical Activity; Positive Affect; Depressive Symptoms; Knee Pain; Walking
18.  Vitamin K Deficiency Is Associated with Incident Knee Osteoarthritis 
The American journal of medicine  2013;126(3):243-248.
BACKGROUND
Osteoarthritis is the most common form of arthritis, with knee osteoarthritis being the leading cause of lower extremity disability among older adults in the US. There are no treatments available to prevent the structural pathology of osteoarthritis. Because of vitamin K’s role in regulating skeletal mineralization, it has potential to be a preventative option for osteoarthritis. We therefore examined the relation of vitamin K to new-onset radiographic knee osteoarthritis and early osteoarthritis changes on magnetic resonance imaging (MRI).
METHODS
Subjects from the Multicenter Osteoarthritis (MOST) Study had knee radiographs and MRI scans obtained at baseline and 30 months later, and plasma phylloquinone (vitamin K) measured at baseline. We examined the relationship of subclinical vitamin K deficiency to incident radiographic knee osteoarthritis and MRI-based cartilage lesions and osteophytes, respectively, using log binomial regression with generalized estimating equations, adjusting for potential confounders.
RESULTS
Among 1180 participants (62% women, mean age 62 ± 8 years, mean body mass index 30.1 ± 5.1 kg/m2), subclinical vitamin K deficiency was associated with incident radiographic knee osteoarthritis (risk ratio [RR] 1.56; 95% confidence interval [CI], 1.08–2.25) and cartilage lesions (RR 2.39; 95% CI, 1.05–5.40) compared with no deficiency, but not with osteophytes (RR 2.35; 95% CI, 0.54–10.13). Subclinically vitamin K-deficient subjects were more likely to develop osteoarthritis in one or both knees than neither knee (RR 1.33; 95% CI, 1.01–1.75 and RR 2.12; 95% CI, 1.06-4.24, respectively).
CONCLUSION
In the first such longitudinal study, subclinical vitamin K deficiency was associated with increased risk of developing radiographic knee osteoarthritis and MRI-based cartilage lesions. Further study of vitamin K is warranted given its therapeutic/prophylactic potential for osteoarthritis.
doi:10.1016/j.amjmed.2012.10.011
PMCID: PMC3641753  PMID: 23410565
Incident knee osteoarthritis; MRI cartilage abnormalities; Vitamin K
19.  Intermuscular Adipose Tissue and Metabolic Associations in HIV Infection 
Obesity (Silver Spring, Md.)  2010;19(2):283-291.
Intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities similar to those associated with visceral adipose tissue (VAT). Increased IMAT has been found in obese human immunodeficiency virus (HIV)-infected women. We hypothesized that IMAT, like VAT, would be similar or increased in HIV-infected persons compared with healthy controls, despite decreases in subcutaneous adipose tissue (SAT) found in HIV infection. In the second FRAM (Study of Fat Redistribution and Metabolic Change in HIV infection) exam, we studied 425 HIV-infected subjects and 211 controls (from the Coronary Artery Risk Development in Young Adults study) who had regional AT and skeletal muscle (SM) measured by magnetic resonance imaging (MRI). Multivariable linear regression identified factors associated with IMAT and its association with metabolites. Total IMAT was 51% lower in HIV-infected participants compared with controls (P = 0.003). The HIV effect was attenuated after multivariable adjustment (to −28%, P < 0.0001 in men and −3.6%, P = 0.70 in women). Higher quantities of leg SAT, upper-trunk SAT, and VAT were associated with higher IMAT in HIV-infected participants, with weaker associations in controls. Stavudine use was associated with lower IMAT and SAT, but showed little relationship with VAT. In multivariable analyses, regional IMAT was associated with insulin resistance and triglycerides (TGs). Contrary to expectation, IMAT is not increased in HIV infection; after controlling for demographics, lifestyle, VAT, SAT, and SM, HIV+ men have lower IMAT compared with controls, whereas values for women are similar. Stavudine exposure is associated with both decreased IMAT and SAT, suggesting that IMAT shares cellular origins with SAT.
doi:10.1038/oby.2010.115
PMCID: PMC3731045  PMID: 20539305
20.  HIV viremia and changes in kidney function 
AIDS (London, England)  2009;23(9):1089-1096.
Objective
To evaluate the effect of HIV infection on longitudinal changes in kidney function and to identify independent predictors of kidney function changes in HIV-infected individuals.
Design
A prospective cohort.
Methods
Cystatin C was measured at baseline and at the 5-year follow-up visit of the Study of Fat Redistribution and Metabolic Change in HIV infection in 554 HIV-infected participants and 230 controls. Control participants were obtained from the Coronary Artery Risk Development in Young Adults study. Glomerular filtration rate (eGFRcys) was estimated using the formula 76.7 × cysC−1.19.
Results
Compared with controls, HIV-infected participants had a greater proportion of clinical decliners (annual decrease in eGFRcys > 3 ml/min per 1.73 m2; 18 versus 13%, P=0.002) and clinical improvers (annual increase in eGFRcys > 3 ml/min per 1.73 m2; 26 versus 6%, P< 0.0001). After multivariable adjustment, HIV infection was associated with higher odds of both clinical decline (odds ratio 2.2; 95% confidence interval 1.3, 3.9, P = 0.004) and clinical improvement (odds ratio 7.3; 95% confidence interval 3.9, 13.6, P ≤ 0.0001). Among HIV-infected participants, a decrease in HIV viral load during follow-up was independently associated with clinical improvement; conversely, higher baseline and an increase in viral load during follow-up were associated with clinical decline. No individual antiretroviral drug or drug class appeared to be substantially associated with clinical decline or improvement.
Conclusion
Compared with controls, HIV-infected persons were more likely both to have clinical decline and clinical improvement in kidney function during 5 years of follow-up. The extent of viremic control had a strong association with longitudinal changes in kidney function.
doi:10.1097/QAD.0b013e32832a3f24
PMCID: PMC3725756  PMID: 19352136
cystatin C; glomerular filtration rate; HIV; kidney; viral load
21.  Calcium Plus Vitamin D Supplementation Has Limited Effects on Femur Geometric Strength in Older Postmenopausal Women: The Women’s Health Initiative 
Calcified tissue international  2011;88(3):198-208.
Purpose
Calcium plus vitamin D (CaD) supplementation has a modest but significant effect on slowing loss of femoral bone mass and reducing risk of hip fractures in adherent postmenopausal women. The goal of this study was to determine if CaD supplementation influences hip structural parameters that are associated with fracture risk.
Methods
We studied 1,970 postmenopausal women enrolled in the Women’s Health Initiative randomized controlled trial of CaD at one of three bone mineral density (BMD) clinical centers. Hip structural analysis software measured BMD and strength parameters on DXA scans at three regions: femoral narrow neck, intertrochanteric and shaft. Random effects models were used to test the average differences in hip BMD and geometry between intervention and placebo.
Results
There was greater preservation of hip BMD at the narrow neck with CaD relative to placebo across six years of intervention. CaD also altered the underlying cross-sectional geometry at the narrow neck in the direction of greater strength with small increases in cross-sectional area and section modulus, and a decrease in buckling ratio with CaD relative to placebo. While trends at both the intertrochanter and shaft regions were similar to those noted at the narrow neck, no significant intervention effects were evident. There was no significant interaction of CaD and age or baseline calcium levels for hip structural properties.
Conclusions
CaD supplementation is associated with modest beneficial effects on hip structural features at the narrow neck, which may explain some of the benefit of CaD in reducing hip fracture risk.
doi:10.1007/s00223-010-9449-x
PMCID: PMC3726200  PMID: 21253715
Calcium and Vitamin D Supplementation; Bone Strength; Postmenopausal Women; Hip Structure
22.  Association Between Insulin Resistance and Lean Mass Loss and Fat Mass Gain in Older Men without Diabetes Mellitus 
OBJECTIVES
To examine the associations between insulin resistance and changes in body composition in older men without diabetes mellitus.
DESIGN
Longitudinal cohort study of older men participating in the Osteoporotic Fractures in Men (MrOS) study.
SETTING
Six U.S. clinical centers.
PARTICIPANTS
Three thousand one hundred thirty-two ambulatory men aged 65 and older at baseline.
MEASUREMENTS
Baseline insulin resistance was calculated for men without diabetes mellitus using the homeostasis model assessment of insulin resistance (HOMA-IR). Total lean, appendicular lean, total fat, and truncal fat mass were measured using dual energy X-ray absorptiometry scans at baseline and 4.6 ± 0.3 years later in 3,132 men with HOMA-IR measurements.
RESULTS
There was greater loss of weight, total lean mass, and appendicular lean mass and less gain in total fat mass and truncal fat mass with increasing quartiles of HOMA-IR (P<.001 for trend). Insulin-resistant men in the highest quartile had higher odds of 5% or more loss of weight (odds ratio (OR) = 1.88, 95% confidence interval (CI) = 1.46–2.43), total lean mass (OR = 2.09, 95% CI = 1.60–2.73) and appendicular lean mass (OR= 1.57, 95% CI = 1.27–1.95) and lower odds of 5% or more gain in total fat mass (OR = 0.56, 95% CI = 0.45–0.68) and truncal fat mass (OR = 0.52, 95% CI = 0.42–0.64) than those in the lowest quartile. These findings remained significant after accounting for age, site, baseline weight, physical activity, and change in physical activity. These associations were also independent of other metabolic syndrome features and medications.
CONCLUSION
Greater lean mass loss and lower fat mass gain occurred in insulin-resistant men without diabetes mellitus than in insulin-sensitive men. Insulin resistance may accelerate age-related sarcopenia.
doi:10.1111/j.1532-5415.2011.03472.x
PMCID: PMC3716256  PMID: 21718263
older men; lean mass; fat mass; insulin resistance; body composition
23.  Prevalence of Electrocardiographic Abnormalities in a Middle-Aged, Biracial Population: Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Journal of electrocardiology  2010;43(5):385.e1-385.e9.
Background
Few studies to date have described the prevalence of electrocardiographic (ECG) abnormalities in a biracial middle-aged cohort.
Methods and Results
Participants underwent measurement of traditional risk factors and 12-lead ECGs coded using both Minnesota Code (MC) and Novacode (NC) criteria. Among 2585 participants, of whom 57% were women and 44% were black (mean age 45 years), the prevalence of major and minor abnormalities were significantly higher (all P<0.001) among black men and women compared to whites. These differences were primarily due to higher QRS voltage and ST/T wave abnormalities among blacks. There was also a higher prevalence of Q waves (MC 1-1, 1-2, 1-3) than described by previous studies. These racial differences remained after multivariate adjustment for traditional cardiovascular (CV) risk factors.
Conclusions
Black men and women have a significantly higher prevalence of ECG abnormalities, independent of traditional CV risk factors, than whites in a contemporary cohort middle-aged participants.
doi:10.1016/j.jelectrocard.2010.02.001
PMCID: PMC3569004  PMID: 20374967
24.  Rheumatoid Arthritis is Associated with Less Optimal Hip Structural Geometry 
The overall goal of this study was to assess the longitudinal changes in bone strength in women reporting rheumatoid arthritis (RA) (n=78) compared to non-arthritic control participants (n=4,779) of the Women's Health Initiative Bone Mineral Density sub-cohort. Hip structural analysis program was applied to archived dual energy X-ray absorptiometry scans (baseline, years 3, 6, and 9) to estimate bone mineral density (BMD) and hip structural geometry parameters in three femoral regions: narrow neck, intertrochanteric and shaft. The association between RA and hip structural geometry was tested using linear regression and random coefficient models (RCM). Compared to the non-arthritic control the RA group had a lower BMD (p=0.061) and significantly lower outer diameter (p=0.017), cross-sectional area (p=0.004), and section modulus (p=0.035) at the narrow neck region in the longitudinal models. No significant associations were seen at the intertrochanteric or shaft regions, and the association was not modified by age, ethnicity, glucocorticoid use, or time. Within the WHI-BMD, women with RA group had reduced BMD and structural geometry at baseline, and this reduction was seen at a fixed rate throughout the nine years of study.
doi:10.1016/j.jocd.2011.06.003
PMCID: PMC3221772  PMID: 21852170
Rheumatoid Arthritis; Hip Structural Geometry; Osteoporosis; Epidemiology
25.  Pre-pregnancy stress reactivity and pregnancy outcome 
Summary
Stress has been proposed as a cause of preterm birth (PTB) and small for gestational age (SGA), but stress does not have the same effects on all women. It may be that a woman’s reaction to stress relates to her pregnancy health, and previous studies indicate higher reactivity is associated with reduced birthweight and gestational age. The objective of the study was to examine the relationship between pre-pregnancy cardiovascular reactivity to stress and pregnancy outcome. The sample included 917 women in the Coronary Artery Risk Development in Young Adults (CARDIA) Study who had cardiovascular reactivity measured in 1987–1988 and at least one subsequent singleton live birth within an 18-year period. Cardiovascular reactivity was measured using a video game, star tracing, and cold pressor test. Gestational age and birthweight were based on the women’s self-report, with PTB defined as birth <37 weeks’ gestation and SGA as weight <10th percentile for gestational age. Linear and poisson regression and generalised estimating equations were used to model the relationship between reactivity to stress and birth outcomes with control for confounders. Few associations were seen between reactivity and pregnancy outcomes. Higher pre-pregnancy diastolic blood pressure (adjusted relative risk, 1.14, 95% confidence interval 0.98–1.34) and mean arterial pressure (MAP) reactivity (1.15, 0.98–1.36) were associated with risk of PTB at first pregnancy, while SGA was associated with lower SBP reactivity (0.76, 0.60–0.95). No associations were seen with other measures of reactivity. Contrary to hypothesis, the association between heart rate reactivity and preterm birth in first pregnancy was stronger in whites (aRRs 1.39, 1.03–1.88) than in blacks (1.00, 0.83–1.20; p for interaction=0.08). Similar results were found for mean arterial pressure. No strong associations were found between higher pre-pregnancy stress reactivity and SGA or PTB, and stress reactivity did not have a stronger association with birth outcomes in blacks than whites.
doi:10.1111/j.1365-3016.2010.01152.x
PMCID: PMC3506123  PMID: 20955234

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