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1.  Effects of diet, physical activity and performance, and body weight on incident gout in ostensibly healthy, vigorously active men 
Physical activity and cardiorespiratory fitness are not currently recognized as factors related to preventing gout, nor are risk factors for gout in physically active men well understood.
The objective was to identify risk factors for gout in ostensibly healthy, vigorously active men.
Incident self-reported gout was compared with baseline diet, body mass index (BMI; in kg/m2), physical activity (in km/d run), and cardiorespiratory fitness (in m/s during 10-km footrace) prospectively in 28 990 male runners.
Men (N=228; 0.79%) self-reported incident gout during 7.74 y of follow-up. The risk of gout increased with higher alcohol intake [per 10 g/d; relative risk (RR): 1.19; 95% CI: 1.12 to 1.26; P<0.0001], meat consumption (per servings/d; RR: 1.45; 95% CI: 1.06 to 1.92; P=0.002), and BMI (RR: 1.19; 95% CI: 1.15 to 1.23; P<0.0001) and declined with greater fruit intake (per pieces/d; RR: 0.73; 95% CI: 0.62 to 0.84; P<0.0001), running distance (per km/d; RR: 0.92; 95% CI: 0.88 to 0.97; P<0.001), and fitness (per m/s; RR: 0.55; 95% CI: 0.41 to 0.75; P<0.0001). The RR per 10 g alcohol/d consumed as wine (1.27; P=0.002), beer (1.19; P<0.0001), and mixed drinks (1.13; P=0.18) was not significantly different from each other. Men who consumed >15 g alcohol/d had 93% greater risk than abstainers, and men who averaged >2 pieces fruit/d had 50% less risk than those who ate <0.5 fruit/d. Risk of gout was 16-fold greater for BMI>27.5 than <20. Compared with the least active or fit men, those who ran ≥8 km/d or >4.0 m/s had 50% and 65% lower risk of gout, respectively. Lower BMI contributed to the risk reductions associated with distance run and fitness.
These findings, based on male runners, suggest that the risk of gout is lower in men who are more physically active, maintain ideal body weight, and consume diets enriched in fruit and limited in meat and alcohol.
PMCID: PMC4090353  PMID: 18469274
2.  Prospective Study of Incident Age-Related Macular Degeneration in Relation to Vigorous Physical Activity during a 7-Year Follow-up 
To test whether the risk of age-related macular degeneration (AMD) decreases with vigorous physical activity.
This was a prospective study of self-reported clinically diagnosed macular degeneration in male (n=29,532) and female (n=12,176) runners followed prospectively for 7.7 years. Survival analyses of incident AMD versus average running distance (kilometers per day), cardiorespiratory fitness (10-km footrace performance), body mass index (BMI), cigarette use, and diet at baseline.
The 110 men and 42 women reporting incident AMD were older than those unaffected (mean ± SE: 54.81 ± 0.97 vs. 44.86 ± 0.06 years), and the men were significantly more likely to have once smoked cigarettes (50.6 vs. 41.2%, P = 0.04 when adjusted for age). Age-and sex-adjusted AMD risk was greater in the men and women who consumed more meat (3.17 ± 0.20 vs. 2.55 ± 0.02 servings/wk) and less fruit (9.41 ± 0.70 vs. 10.92 ± 0.05 pieces/wk). The men and women reporting incident AMD ran for exercise significantly less than those who remained unaffected, when adjustment was made for age and sex (4.57 ± 0.30 vs. 5.34 ± 0.02 km/d, P ≤ 0.01). When adjusted for age, sex, diet, and smoking history, the relative risk for AMD decreased 10% per km/d increment in running distance. Moreover, compared with the men and women who averaged less than 2 km/d, those averaging 2 to 4 km/d had 19% lower adjusted risk, and those averaging ≥4 km/d had 42% to 54% lower adjusted AMD risk.
Higher doses of vigorous exercise (running) are associated with lower incident AMD risk independent of weight, cardiorespiratory fitness, and cigarette use. Limitations of the analyses include the select nature of the sample and reliance on self-report of both running history and clinically diagnosed AMD.
PMCID: PMC4090325  PMID: 18566466
3.  Effects of Running and Walking on Osteoarthritis and Hip Replacement Risk 
Running and other strenuous sports activities are purported to increase osteoarthritis (OA) risk, more so than walking and less-strenuous activities. Analyses were therefore performed to test whether running, walking, and other exercise affect OA and hip replacement risk, and to assess BMI’s role in mediating these relationships.
Proportional hazards analyses of patients’ report of having physician-diagnosed OA and hip replacement vs. exercise energy expenditure (metabolic equivalents, METs).
74,752 runners reported 2004 OA and 259 hip replacements during 7.1-year follow-up, while the 14,625 walkers reported 695 OA and 114 hip replacements over 5.7 years. Compared to running <1.8 METhr/d, the risks for OA and hip replacement decreased: 1) 18.1% (P=0.01) and 35.1% (P=0.03), respectively, for 1.8 to 3.6 METhr/d run; 2) 16.1% (P=0.03) and 50.4% (P=0.002), respectively, for 3.6 to 5.4 METhr/d run; and 3) 15.6% (P=0.02) and 38.5% (P=0.01), respectively, for ≥5.4 METhr/d run, suggesting that the risk reduction mostly occurred by 1.8 METhr/d. Baseline BMI was strongly associated with both OA (5.0% increase per kg/m2, P=2x10−8) and hip replacement risks (9.8% increase per kg/m2, P=4.8x10−5), and adjustment for BMI substantially diminished the risk reduction from running ≥1.8 METhr/d for OA (from 16.5%, P=0.01 to 8.6%, P=0.21) and hip replacement (from 40.4%, P=0.005 to 28.5%, P=0.07). The reductions in OA and hip replacement risk by exceeding 1.8 METhr/d did not differ significantly between runners and walkers. Other (non-running) exercise increased the risk of OA by 2.4% (P=0.009) and hip replacement by 5.0% per METhr/d (P=0.02), independent of BMI.
Whereas other exercise increased OA and hip replacement risk, running significantly reduced their risk due, in part, to running’s association with lower BMI.
PMCID: PMC3756679  PMID: 23377837
Prevention; exercise; epidemiology; cohort study
4.  Incident hypercholesterolemia in relation to changes in vigorous physical activity 
Test whether changes in vigorous exercise affect the risk for hypercholesterolemia.
Incident physician-diagnosed hypercholesterolemia was compared in recreational runners whose weekly distances run increased > 0.5 km/day (4034 men, 1897 women), remained constant (±0.5 km/d; 4685 men, 1904 women), or decreased > 0.5 km/d (15,678 men, 6224 women) during 7.8 yr of prospective follow-up.
Relative to those whose distance was maintained or reduced, the odds ratio (OR) (95% confidence interval) for hypercholesterolemia for those whose running increased was significantly less than 1 for men {OR: 0.82 (0.72–0.93), P = 0.0006}, women {OR: 0.71 (0.54–0.92), P = 0.01}, and men and women combined adjusted for sex {OR: 0.80 (0.72–0.89), P < 0.0001}. The significance of the odds ratios was somewhat diminished when adjusted for baseline and follow-up BMI in men {OR: 0.89 (0.79–1.01), P = 0.06}, women {OR: 0.71 (0.54–0.92), P = 0.08}, and the adjusted sexes combined {OR: 0.88 (0.79–0.98), P = 0.02}. When average distance run {i.e., (baseline + follow-up) / 2} was compared with incident hypercholesterolemia in the 6589 runners whose distance remained constant, each kilometer-per-day increment in average running distance was associated with an odds ratio significantly less than 1 in men {OR: 0.90 (0.86–0.93)}, women {OR: 0.91 (0.84–0.98)}, and the adjusted sexes combined {OR: 0.90 (0.87–0.93)}, which was also attributable in part to BMI in men {OR: 0.94 (0.90–0.97), P = 0.0005}, women {OR: 0.96 (0.89–1.04), P = 0.35}, and the adjusted sexes combined {OR: 0.94 (0.91–0.97), P = 0.0003}.
The odds for hypercholesterolemia: 1) decrease in runners who increase their running mileage and 2) decline in association with the higher dose of vigorous activity even in the absence of any change in exercise. These effects are associated in part to the runners’ BMI.
PMCID: PMC4073642  PMID: 19092705
high cholesterol; prevention; running; epidemiology
5.  Greater Weight Loss from Running than Walking during 6.2-yr Prospective Follow-up 
Test whether equivalent changes in moderate (walking) and vigorous exercise (running) produce equivalent weight loss under free-living, non-experimental conditions.
Regression analyses of changes (Δ) in BMI vs. exercise energy expenditure (ΔMETh/d, 1 metabolic equivalent or MET=3.5 ml O2•kg−1•min−1) from survey questionnaires completed at baseline and 6.2 years thereafter in 15,237 walkers and 32,216 runners.
At baseline, walkers spent less energy walking than runners spent running (mean±SD males: 2.22±1.65 vs. 5.31±3.12, females: 2.15±1.63 vs. 4.76±3.03 METh/d) and walkers were significantly heavier than runners (males: 26.63±4.04 vs. 24.09±2.58, females: 25.44±5.14 vs. 21.61±2.49 kg/m2). During follow-up, energy expenditure declined less for walking in walkers than for running in runners (males: −0.19±1.92 vs. −1.27±2.87, females: −0.30±1.93 vs. −1.28±2.85 METh/d). ΔBMI was inversely related to both ΔMETh/d run and ΔMETh/d walked, but more strongly to ΔMETh/d run than walked in men, and in heavier women. Specifically, the regression coefficient for ΔBMI vs. ΔMETh/d was significantly more negative for running than walking in men in the 1st quartile (differences in slope±SE: −0.06±0.03, P=0.01), 2nd quartile (−0.10±0.03, P=0.001), 3rd quartile (−0.17±0.03, P<10−8) and 4th quartile of BMI (−0.14±0.03, P<10−4) and in the 4th BMI quartile of women (−0.32±0.04 kg/m2 per METh/d, P<10−17). This represented 90% greater weight loss per METh/d run than walked in the 4th BMI quartile for both sexes. Age-related weight gain was attenuated by running in both sexes (P<10−6), and by walking in women (P=0.005).
Although ΔBMI was significantly associated with both ΔMETh/d run and walked, the ΔBMI was significantly greater for Δrunning than Δwalking.
PMCID: PMC4067491  PMID: 23190592
Obesity; prevention; epidemiology; overweight
6.  Walking vs running for hypertension, cholesterol, & diabetes risk reduction 
To test whether equivalent energy expenditure by moderate-intensity (e.g., walking) and vigorous-intensity exercise (e.g., running) provides equivalent health benefits.
Methods and Results
We used the National Runners’ (n=33,060) and Walkers’ (n=15,945) Health Study cohorts to examine the effect of differences in exercise mode and thereby exercise intensity on coronary heart disease (CHD) risk factors. Baseline expenditure (METhr/d) was compared to self-reported, physician-diagnosed incident hypertension, hypercholesterolemia, diabetes and CHD during 6.2 years follow-up. Running significantly decreased the risks for incident hypertension by 4.2% (P<10-7), hypercholesterolemia by 4.3% (P<10-14), diabetes by 12.1% (P<10-5), and CHD by 4.5% per METh/d run (P=0.05). The corresponding reductions for walking were 7.2% (P<10-6), 7.0% (P<10-8), 12.3% (P<10-4), and 9.3% (P=0.01). Relative to <1.8 METh/d, the risk reductions for 1.8 to 3.6, 3.6 to 5.4, 5.4 to 7.2, and ≥ 7.2 METh/d were: 1) 10.1%, 17.7%, 25.1% and 34.9% from running and 14.0%, 23.8%, 21.8% and 38.3% from walking for hypercholesterolemia; 2) 19.7%, 19.4%, 26.8% and 39.8% from running and 14.7%, 19.1%, 23.6% and 13.3% from walking for hypertension; 3) 43.5%, 44.1%, 47.7% and 68.2% from running and 34.1%, 44.2%, and 23.6% from walking for diabetes (too few cases for diabetes for walking >5.4 METh/d). The risk reductions were not significantly greater for running than walking for diabetes (P=0.94) or CHD (P=0.26), and only marginally greater for walking than running for hypertension (P=0.06) and hypercholesterolemia (P=0.04).
Equivalent energy expenditures by moderate (walking) and vigorous (running) exercise produced similar risk reductions for hypertension, hypercholesterolemia, diabetes, and CHD, but there is limited statistical power to evaluate CHD conclusively.
PMCID: PMC4067492  PMID: 23559628
7.  Walking and running are associated with similar reductions in cataract risk 
Habitual running has been associated with reduced risk of cataract development in one prospective study. The purpose of the current analyses is to provide further evidence of this potentially important benefit of vigorous exercise, and to test whether moderate exercise (e.g., walking) provides a significant and equivalent reduction in cataract risk as vigorous exercise (e.g. running).
Cox proportional hazard analyses of self-reported, physician-diagnosed incident cataracts vs. baseline energy expenditure (metabolic equivalents or METs) in 32,610 runners and 14,917 walkers during 6.2-year follow-up. Results are reported as hazard ratios (HR), percent risk reductions (100*(HR-1)), and 95% confidence intervals (95%CI).
Runners and walkers reported 733 and 1,074 incident cataracts during follow-up, respectively. When adjusted for sex, race, age, education, smoking, and intakes of meat, fruit and alcohol, lower cataract risk was significantly associated with both running (HR=0.960 per METh/d, 95%CI 0.935 to 0.986) and walking (HR=0.918 per METh/d, 95%CI: 0.881 to 0.956,), with no significant difference in the per METh/d risk reduction between running and walking, or between men and women. Compared to running or walking at or below guideline levels (≤1.8 METh/d), incident cataract risk was significantly lower for running or walking 1.8 to 3.6 (16.4% lower, 95%CI: 6.4% to 25.3%), 3.6 to 5.4 (19.0% lower, 95%CI: 5.6% to 30.4%), 5.4 to 7.2 (26.2% lower, 95%CI: 11.2% to 38.7%), 7.2 to 9.0 (34.1% lower, 95%CI: 10.0% to 51.2%), and ≥9 METh/d (41.6% lower, 95%CI: 19.8% to 57.4%).
Moderate (walking) and vigorous (running) exercise were both significantly associated with lower cataract risk, and their effects similar. Cataract risk appears to decrease linearly with increasing exercise energy expenditure through 9 METh/d.
PMCID: PMC3757559  PMID: 23274600
Vision; prevention; epidemiology; exercise
8.  Concentrated fish oil (Lovaza®) extends lifespan and attenuates kidney disease in lupus-prone short-lived (NZBxNZW)F1 mice 
A growing number of reports indicate that anti-inflammatory actions of fish oil (FO) are beneficial against systemic lupus erythematosus (SLE). However, the majority of pre-clinical studies were performed using 5–20% FO, which is higher than the clinically relevant dose for lupus patients. The present study was performed in order to determine the effective low dose of FDA-approved concentrated FO (Lovaza®) compared to the commonly used FO-18/12 (18-Eicosapentaenoic acid [EPA]/12-Docosahexaenoic acid [DHA]). We examined the dose-dependent response of Lovaza® (1% and 4%) on an SLE mouse strain (NZB×NZW)F1 and compared the same with 1% and 4% placebo, as well as 4% FO-18/12, maintaining standard chow as the control. Results show for the first time that 1% Lovaza® extends maximal lifespan (517 d) and 4% Lovaza® significantly extends both the median (502 d) and maximal (600 d) life span of (NZB×NZW)F1 mice. In contrast, FO-18/12 extends only median lifespan (410 d) compared to standard chow diet (301 d). Additionally, 4% Lovaza® significantly decreased anti-dsDNA antibodies, reduced glomerulonephritis and attenuated lipopolysaccharide-induced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in splenocytes compared to placebo. 4% Lovaza® was also shown to reduce the expression of inflammatory cytokines, including IL-1β, IL-6 and TNF-α, while increasing renal anti-oxidant enzymes in comparison to placebo. Notably, NFκB activation and p65 nuclear translocation were lowered by 4% Lovaza® compared to placebo. These data indicate that 1% Lovaza® is beneficial, but 4% Lovaza® is more effective in suppressing glomerulonephritis and extending life span of SLE-prone short-lived mice, possibly via reducing inflammation signaling and modulating oxidative stress.
PMCID: PMC3970264  PMID: 23918873
Fish oil; inflammation; kidney disease; lifespan; lupus; survival
9.  Anticipated and experienced discrimination amongst people with schizophrenia, bipolar disorder and major depressive disorder: a cross sectional study 
BMC Psychiatry  2014;14:157.
The unfair treatment of individuals with severe mental illness has been linked to poorer physical and mental health outcomes. Additionally, anticipation of discrimination may lead some individuals to avoid participation in particular life areas, leading to greater isolation and social marginalisation. This study aimed to establish the levels and clinical and socio-demographic associations of anticipated and experienced discrimination amongst those diagnosed with a schizophrenia and comparator severe mental illnesses (bipolar and major depressive disorders).
This study was a cross-sectional analysis of anticipated and experienced discrimination from 202 individuals in South London (47% with schizophrenia, 32% with depression and 20% with bipolar disorder).
93% of the sample anticipated discrimination and 87% of participants had experienced discrimination in at least one area of life in the previous year. There was a significant association between the anticipation and the experience of discrimination. Higher levels of experienced discrimination were reported by those of a mixed ethnicity, and those with higher levels of education. Women anticipated more discrimination than men. Neither diagnosis nor levels of functioning were associated with the extent of discrimination. Clinical symptoms of anxiety, depression and suspiciousness were associated with more experienced and anticipated discrimination respectively.
The unfair treatment of individuals with severe mental illnesses remains unacceptably common. Population level interventions are needed to reduce levels of discrimination and to safeguard individuals. Interventions are also required to assist those with severe mental illness to reduce internalised stigma and social avoidance.
PMCID: PMC4045950  PMID: 24885144
Schizophrenia; Depression; Bipolar; Discrimination; Gender; Ethnicity; Stigma
10.  The challenge of change in acute mental health services: measuring staff perceptions of barriers to change and their relationship to job status and satisfaction using a new measure (VOCALISE) 
Health services are subject to frequent changes, yet there has been insufficient research to address how staff working within these services perceive the climate for implementation. Staff perceptions, particularly of barriers to change, may affect successful implementation and the resultant quality of care. This study measures staff perceptions of barriers to change in acute mental healthcare. We identify whether occupational status and job satisfaction are related to these perceptions, as this might indicate a target for intervention that could aid successful implementation. As there were no available instruments capturing staff perceptions of barriers to change, we created a new measure (VOCALISE) to assess this construct.
All nursing staff from acute in-patient settings in one large London mental health trust were eligible. Using a participatory method, a nurse researcher interviewed 32 staff to explore perceptions of barriers to change. This generated a measure through thematic analyses and staff feedback (N = 6). Psychometric testing was undertaken according to standard guidelines for measure development (N = 40, 42, 275). Random effects models were used to explore the associations between VOCALISE, occupational status, and job satisfaction (N = 125).
VOCALISE was easy to understand and complete, and showed acceptable reliability and validity. The factor analysis revealed three underlying constructs: ‘confidence,’ ‘de-motivation’ and ‘powerlessness.’ Staff with negative perceptions of barriers to change held more junior positions, and had poorer job satisfaction. Qualitatively, nursing assistants expressed a greater sense of organisational unfairness in response to change.
VOCALISE can be used to explore staff perceptions of implementation climate and to assess how staff attitudes shape the successful outcomes of planned changes. Negative perceptions were linked with poor job satisfaction and to those occupying more junior roles, indicating a negative climate for implementation in those groups. Staff from these groups may therefore need special attention prior to implementing changes in mental health settings.
PMCID: PMC4016533  PMID: 24555496
Perception; Measures; Organisational change; Mental health; Nursing
11.  Low HDL3 reduces the odds of men surviving to age 85 during 53-year follow-up 
To identify high-density lipoprotein (HDL) subfractions associated with longevity in men.
Fifty-three-year prospective follow-up of Gofman’s Livermore Cohort between 1954 and 2008.
Lawrence Livermore National Laboratory.
One thousand one hundred forty-four men who consented to the study, had analytic ultracentrifuge measurements of lipoprotein subfractions at baseline, and were old enough at baseline to have survived to age 85 during follow-up.
Survival was determined according to participant contact, Social Security Death Index, and National Death Index.
Three hundred ninety men survived to 85 years old (34.1%). Survivors were less likely than nonsurvivors to be in the lowest HDL3 (% (standard error) 18.5% (2.0%) vs 27.3% (1.6%), P < .001) and HDL2 (22.1% (2.1%) vs 27.7% (1.6%), P = 0.04) quartiles. Logistic regression analyses showed that the lowest HDL3 quartile significantly predicted shorter longevity (P = 0.002), whereas the linear increases per mg/dL of HDL3 did not (P = 0.38), suggesting a risk threshold proximal to the 25th percentile. Men who were above the 25th HDL3 percentile had 70% greater odds of surviving until age 85 than those below this level, which persisted when adjusted for HDL2, very low-density lipoprotein (LDL), and standard risk factors. Proportional hazard analyses of survival before age 85 showed that being in the lowest HDL3 quartile increased age-adjusted cancer risk by 39% (P = 0.05) and noncancer risk by 23% (P = 0.04) when adjusted for other risk factors. Survivors also smoked less (mean ± SD 0.31 ± 0.48 vs 0.57 ± 0.56 packs/d, P < .001), had lower systolic (118.36 ± 11.08 vs 122.81 ± 13.55 mmHg, P < .001) and diastolic (70.61 ± 8.59 vs 73.14 ± 9.22 mmHg, P < .001) blood pressures and lower LDL mass (359.55 ± 80.42 vs 374.37 ± 86.10 mg/dL, P = 0.009) and total cholesterol concentrations (229.51 ± 43.21 vs 235.89 ± 45.40 mg/dL, P = 0.04) than nonsurvivors.
Low HDL3 reduces the odds of extended survival in men, independent of HDL2, other lipoproteins, and standard risk factors.
PMCID: PMC3926864  PMID: 22329432
12.  The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis*  
The Journal of Biological Chemistry  2013;289(7):4244-4261.
Background: Sar1 mediates the onward transport of ER cargo.
Results: Sar1B promotes VLDL secretion, whereas Sar1A antagonizes this activity, and a deficit of both reduces cholesterol biosynthesis.
Conclusion: Sar1B independently of and through its lipoprotein secretion function promotes the expression of genes regulating cholesterol biosynthesis.
Significance: Sar1B-mediated transport activities contribute to both the functional integrity of the ER membrane and blood cholesterol levels.
Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy storage depot and, where vascular systems exist, as a means of energy transport. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other or with the activity of the COPII machinery, which transports endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition. Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions.
PMCID: PMC3924288  PMID: 24338480
Apolipoproteins; Cholesterol Regulation; Endoplasmic Reticulum (ER); Lipoprotein Secretion; Transcriptomics
13.  Breast Cancer Mortality vs. Exercise and Breast Size in Runners and Walkers 
PLoS ONE  2013;8(12):e80616.
Identify predictors of breast cancer mortality in women who exercised below (<7.5 metabolic equivalent hours/week, MET-hours/wk), at (7.5 to 12.5 MET-hours/wk), or above (≥12.5 MET-hours/wk) recommended levels.
Cox proportional hazard analyses of baseline pre-diagnosis MET-hours/wk vs. breast cancer mortality adjusted for follow-up age, race, baseline menopause, and estrogen and oral contraceptive use in 79,124 women (32,872 walkers, 46,252 runners) from the National Walkers' and Runners' Health Studies.
One-hundred eleven women (57 walkers, 54 runners) died from breast cancer during the 11-year follow-up. The decline in mortality in women who exercised ≥7.5 MET-hours/wk was not different for walking and running (P = 0.34), so running and walking energy expenditures were combined. The risk for breast cancer mortality was 41.5% lower for ≥7.5 vs. <7.5 MET-hours/wk (HR: 0.585, 95%CI: 0.382 to 0.924, P = 0.02), which persisted when adjusted for BMI (HR: 0.584, 95%CI: 0.368 to 0.956, P = 0.03). Other than age and menopause, baseline bra cup size was the strongest predictor of breast cancer mortality, i.e., 57.9% risk increase per cup size when adjusted for MET-hours/wk and the other covariates (HR: 1.579, 95%CI: 1.268 to 1.966, P<0.0001), and 70.4% greater when further adjusted for BMI (HR: 1.704, 95%CI: 1.344 to 2.156, P = 10−5). Breast cancer mortality was 4.0-fold greater (HR: 3.980, 95%CI: 1.894 to 9.412, P = 0.0001) for C-cup, and 4.7-fold greater (HR: 4.668, 95%CI: 1.963 to 11.980, P = 0.0004) for ≥D-cup vs. A-cup when adjusted for BMI and other covariates. Adjustment for cup size and BMI did not eliminate the association between breast cancer mortality and ≥7.5 MET-hour/wk walked or run (HR: 0.615, 95%CI: 0.389 to 1.004, P = 0.05).
Breast cancer mortality decreased in association with both meeting the exercise recommendations and smaller breast volume.
PMCID: PMC3857169  PMID: 24349006
14.  Inadequate Exercise as a Risk Factor for Sepsis Mortality 
PLoS ONE  2013;8(12):e79344.
Test whether inadequate exercise is related to sepsis mortality.
Research Design and Methods
Mortality surveillance of an epidemiological cohort of 155,484 National Walkers' and Runners' Health Study participants residing in the United States. Deaths were monitored for an average of 11.6-years using the National Death index through December 31, 2008. Cox proportional hazard analyses were used to compare sepsis mortality (ICD-10 A40-41) to inadequate exercise (<1.07 METh/d run or walked) as measured on their baseline questionnaires. Deaths occurring within one year of the baseline survey were excluded.
Sepsis was the underlying cause in 54 deaths (sepsisunderlying) and a contributing cause in 184 deaths (sepsiscontributing), or 238 total sepsis-related deaths (sepsistotal). Inadequate exercise was associated with 2.24-fold increased risk for sepsisunderlying (95%CI: 1.21 to 4.07-fold, P = 0.01), 2.11-fold increased risk for sepsiscontributing (95%CI: 1.51- to 2.92-fold, P<10−4), and 2.13-fold increased risk for sepsistotal (95%CI: 1.59- to 2.84-fold, P<10−6) when adjusted for age, sex, race, and cohort. The risk increase did not differ significantly between runners and walkers, by sex, or by age. Sepsistotal risk was greater in diabetics (P = 10−5), cancer survivors (P = 0.0001), and heart attack survivors (P = 0.003) and increased with waist circumference (P = 0.0004). The sepsistotal risk associated with inadequate exercise persisted when further adjusted for diabetes, prior cancer, prior heart attack and waist circumference, and when excluding deaths with cancer, or cardiovascular, respiratory, or genitourinary disease as the underlying cause. Inadequate exercise also increased sepsistotal risk in 2163 baseline diabetics (4.78-fold, 95%CI: 2.1- to 13.8-fold, P = 0.0001) when adjusted, which was significantly greater (P = 0.03) than the adjusted risk increase in non-diabetics (1.80-fold, 95%CI: 1.30- to 2.46-fold, P = 0.0006).
Inadequate exercise is a risk factor for sepsis mortality, particular in diabetics.
PMCID: PMC3850902  PMID: 24324580
15.  The Childhood Asthma Management Program (CAMP): Contributions to the Understanding of Therapy and the Natural History of Childhood Asthma 
Current respiratory care reports  2012;1(4):243-250.
The Childhood Asthma Management Program (CAMP) has been in continuous existence for almost two decades, which makes it the largest randomized, placebo-controlled clinical trial with extended follow-up for children with mild to moderate asthma. As such, its cumulative data from baseline, active treatment, and post-treatment have proved to be an invaluable resource for not only assessing the efficacy and safety of long-term inhaled corticosteroid therapy in childhood, but for discovery of many other aspects of childhood asthma, including genetics and biomarkers.
PMCID: PMC3546823  PMID: 23336093
Asthma; childhood; spirometry; airway hyperresponsiveness; inhaled corticosteroids; bronchodilators; bronchodilator response; allergy; pharmacogenomics; bone mineral density; vitamin D; linear growth; cataracts; hypothalamic–pituitary–adrenal axis; remission; progression; exacerbation; oral corticosteroids; nedocromil; forced expiratory volume in one second (FEV1); forced vital capacity (FVC); symptoms; health care utilization; phenotype; genetic polymorphism; eosinophils
16.  Dose-Response Relationship of Physical Activity to Premature and Total All-Cause and Cardiovascular Disease Mortality in Walkers 
PLoS ONE  2013;8(11):e78777.
To assess the dose-response relationships between cause-specific mortality and exercise energy expenditure in a prospective epidemiological cohort of walkers.
The sample consisted of the 8,436 male and 33,586 female participants of the National Walkers' Health Study. Walking energy expenditure was calculated in metabolic equivalents (METs, 1 MET = 3.5 ml O2/kg/min), which were used to divide the cohort into four exercise categories: category 1 (≤1.07 MET-hours/d), category 2 (1.07 to 1.8 MET-hours/d), category 3 (1.8 to 3.6 MET-hours/d), and category 4 (≥3.6 MET-hours/d). Competing risk regression analyses were use to calculate the risk of mortality for categories 2, 3 and 4 relative to category 1.
22.9% of the subjects were in category 1, 16.1% in category 2, 33.3% in category 3, and 27.7% in category 4. There were 2,448 deaths during the 9.6 average years of follow-up. Total mortality was 11.2% lower in category 2 (P = 0.04), 32.4% lower in category 3 (P<10−12) and 32.9% lower in category 4 (P = 10−11) than in category 1. For underlying causes of death, the respective risk reductions for categories 2, 3 and 4 were 23.6% (P = 0.008), 35.2% (P<10−5), and 34.9% (P = 0.0001) for cardiovascular disease mortality; 27.8% (P = 0.18), 20.6% (P = 0.07), and 31.4% (P = 0.009) for ischemic heart disease mortality; and 39.4% (P = 0.18), 63.8% (P = 0.005), and 90.6% (P = 0.002) for diabetes mortality when compared to category 1. For all related mortality (i.e., underlying and contributing causes of death combined), the respective risk reductions for categories 2, 3 and 4 were 18.7% (P = 0.22), 42.5% (P = 0.001), and 57.5% (P = 0.0001) for heart failure; 9.4% (P = 0.56), 44.3% (P = 0.0004), and 33.5% (P = 0.02) for hypertensive diseases; 11.5% (P = 0.38), 41.0% (P<10−4), and 35.5% (P = 0.001) for dysrhythmias: and 23.2% (P = 0.13), 45.8% (P = 0.0002), and 41.1% (P = 0.005) for cerebrovascular diseases when compared to category 1.
There are substantial health benefits to exceeding the current exercise guidelines.
PMCID: PMC3843666  PMID: 24312170
17.  The Relationship of Walking Intensity to Total and Cause-Specific Mortality. Results from the National Walkers’ Health Study 
PLoS ONE  2013;8(11):e81098.
Test whether: 1) walking intensity predicts mortality when adjusted for walking energy expenditure, and 2) slow walking pace (≥24-minute mile) identifies subjects at substantially elevated risk for mortality.
Hazard ratios from Cox proportional survival analyses of all-cause and cause-specific mortality vs. usual walking pace (min/mile) in 7,374 male and 31,607 female recreational walkers. Survival times were left censored for age at entry into the study. Other causes of death were treated as a competing risk for the analyses of cause-specific mortality. All analyses were adjusted for sex, education, baseline smoking, prior heart attack, aspirin use, diet, BMI, and walking energy expenditure. Deaths within one year of baseline were excluded.
The National Death Index identified 1968 deaths during the average 9.4-year mortality surveillance. Each additional minute per mile in walking pace was associated with an increased risk of mortality due to all causes (1.8% increase, P=10-5), cardiovascular diseases (2.4% increase, P=0.001, 637 deaths), ischemic heart disease (2.8% increase, P=0.003, 336 deaths), heart failure (6.5% increase, P=0.001, 36 deaths), hypertensive heart disease (6.2% increase, P=0.01, 31 deaths), diabetes (6.3% increase, P=0.004, 32 deaths), and dementia (6.6% increase, P=0.0004, 44 deaths). Those reporting a pace slower than a 24-minute mile were at increased risk for mortality due to all-causes (44.3% increased risk, P=0.0001), cardiovascular diseases (43.9% increased risk, P=0.03), and dementia (5.0-fold increased risk, P=0.0002) even though they satisfied the current exercise recommendations by walking ≥7.5 metabolic equivalent (MET)-hours per week.
The risk for mortality: 1) decreases in association with walking intensity, and 2) increases substantially in association for walking pace ≥24 minute mile (equivalent to <400m during a six-minute walk test) even among subjects who exercise regularly.
PMCID: PMC3834211  PMID: 24260542
18.  Attenuated inheritance of body weight by running in monozygotic twins 
Medicine and science in sports and exercise  2012;44(1):10.1249/MSS.0b013e31822676e8.
Genetic factors account for 40%–70% of the population variation in body mass index (BMI), suggesting that genetic predisposition is a major risk factor for excess weight. The purpose of this study was to test whether exercise attenuates the inherited risk for excess body weight.
Survey questionnaires of exercise (usual running distance) and BMI were obtained from a national sample of 582 female and 344 male self-identified monozygotic (MZ) twins. Regression analyses were used to test whether running disparity diminished the inheritance of BMI when adjusted for age, education, cigarette use, and selected dietary variables.
The active twins ran between 0 and 10.7 km/d more than their less active twins if female (mean±SD:1.61±1.50 km/d) and between 0 and 13.7 km/d more if male (1.88 ± 1.78 km/d). Average BMIs of the less active twins were 22.38±3.56 and 24.59±3.08 kg/m2 in females and males, respectively. Within-twin correlations were significant (P <0.0001) for usual distance run (females: r = 0.64; males: r = 0.61) and BMI (females: r = 0.67; males: r = 0.71). Greater running differences (∆km/d) attenuated the effect of the less active twins’ BMIs on their active MZ twins’ BMI (females: −14.3% per Δkm/d, P<10−7; males: −7.4% per Δkm/d, P=0.004), such that by 4 Δkm/d, the inherited risk was reduced by 58.8% in females and 29.6% in males.
These results are consistent with the attenuation of the inherited risk of excess body weight by running, which is remarkable because BMI regulation is assumed to be multifactorial, its genetic inheritance is polygenic, and no single genetic polymorphism currently explains >1% of the BMI variance.
PMCID: PMC3817205  PMID: 21659905
19.  Combinatorial discovery of polymers resistant to bacterial attachment 
Nature biotechnology  2012;30(9):868-875.
Bacterial attachment and subsequent biofilm formation pose key challenges to the optimal performance of medical devices. In this study, we determined the attachment of selected bacterial species to hundreds of polymeric materials in a high-throughput microarray format. Using this method, we identified a group of structurally related materials comprising ester and cyclic hydrocarbon moieties that substantially reduced the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). Coating silicone with these ‘hit’ materials achieved up to a 30-fold (96.7%) reduction in the surface area covered by bacteria compared with a commercial silver hydrogel coating in vitro, and the same material coatings were effective at reducing bacterial attachment in vivo in a mouse implant infection model. These polymers represent a class of materials that reduce the attachment of bacteria that could not have been predicted to have this property from the current understanding of bacteria-surface interactions.
PMCID: PMC3796337  PMID: 22885723
20.  Detecting Depression in Patients with Coronary Heart Disease: a Diagnostic Evaluation of the PHQ-9 and HADS-D in Primary Care, Findings From the UPBEAT-UK Study 
PLoS ONE  2013;8(10):e78493.
People with coronary heart disease (CHD) are at heightened risk of depression, and this co-occurrence of conditions is associated with poorer outcomes including raised mortality. This study compares the diagnostic accuracy of two depression case finding instruments in CHD patients relative to a diagnostic standard, the revised Clinical Interview Schedule (CIS-R).
The Patient Health Questionnaire (PHQ-9), the Hospital Anxiety and Depression Scale depression subscale (HADS-D) and the CIS-R depression module were administered to 803 patients identified from the CHD registers of GP practices in Greater London.
Of 730 recruited patients without previously identified depression, 32 (4.4%) met ICD-10 depressive episode criteria according to the CIS-R. For the PHQ-9 and HADS-D lower cut-points than those routinely recommended were associated with improved case identifying properties. The PHQ-9 appeared the superior instrument using a cut-point of ≥8 (sensitivity=94%; specificity=84%). Using categorical scoring the PHQ-9 was 59% sensitive and 95% specific. For the HADS-D using cut-point ≥5, sensitivity was 81% and specificity was 77%.
Areas under the curves (AUC) (standard error) were 0.95 (0.01) and 0.88 (0.02) for the PHQ-9 and HADS-D, and 0.91 (0.02) for PHQ-9 using the categorical algorithm. Statistically significant differences between AUCs of the PHQ-9 and the HADS-D favoured the former. Severity ratings compared across measures indicated inconsistency between recommended bandings: the PHQ-9 categorised a larger proportion of participants with mild and moderate depression.
This is the first large-scale investigation of the accuracy of these commonly used measures within a primary care CHD population. Our results suggest that although both scales have acceptable abilities and can be used as case identification instruments for depression in patients with CHD, the PHQ-9 appeared diagnostically superior. Importantly, optimal cut-off points for depression identification in this population appear to differ from standard values, and severity ratings differ between these measures.
PMCID: PMC3795055  PMID: 24130903
21.  Prospective study of coronary heart disease vs HDL2, HDL3, and other lipoproteins in Gofman’s Livermore Cohort 
Atherosclerosis  2010;214(1):196-202.
To assess the relationship of lipoprotein subfractions to coronary heart disease (CHD).
Prospective 29.1 year follow-up of 1905 men measured for lipoprotein mass concentrations by analytic ultracentrifugation between 1954 and 1957. Vital status was determined for 97.2% of the cohort. Blinded physician medical record and death certificate review confirmed 179 CHD deaths. Follow-up questionnaires identified 182 nonfatal myocardial infarctions and 93 revascularization procedures from 1,346 (98.3%) of the surviving cohort and from the next-of-kin of 153 men who died.
When adjusted for age, total incident CHD was inversely related to HDL2-mass (P=0.0001) and HDL3-mass (P=0.02), and concordantly related to LDL-mass (P<10−11), IDL-mass (P<10−7), and small (P<10−7) and large VLDL-mass concentrations (P=0.003). The hazard reduction per mg/dl of HDL was greater for HDL2-mass than HDL3-mass (P=0.04). The lowest quartiles of both HDL2-mass (P=0.007) and HDL3-mass (P=0.001) independently predicted total incident CHD when adjusted for traditional risk factors. Risk for premature CHD (≤ 65 years old) was significantly greater in men within the lowest HDL2 (P=0.03) and HDL3 quartiles (P=0.04) and having higher LDL-mass concentrations (P=0.001). Serum cholesterol’s relationship to incident CHD (P<10−8) was accounted for by adjustment for LDL-mass concentrations (adjusted P=0.90).
Lipoprotein subfractions differ in their relationship to CHD.
PMCID: PMC3786414  PMID: 21109246
Lipoprotein; high-density lipoproteins; risk factors; prevention
22.  Renewable hydrogen and carbon nanotubes from biodiesel waste glycerol 
Scientific Reports  2013;3:2742.
In this report, we introduce a novel and commercially viable method to recover renewable hydrogen and carbon nanotubes from waste glycerol produced in the biodiesel process. Gas-phase catalytic reforming converts glycerol to clean hydrogen fuel and by replacing the problematical coke formed on the catalyst with high value carbon nanotubes, added value can be realised. Additional benefits of around 2.8 kg CNTs from the reforming of 1 tonne of glycerol and the production of 500 Nm3 H2 could have a considerable impact on the economics of glycerol utilization. Thereby, the contribution of this research will be a significant step forward in solving a current major technical and economic challenge faced by the biofuels industry.
PMCID: PMC3783054  PMID: 24067754
23.  Advantage of distance- versus time-based estimates of walking in predicting adiposity 
Physical activity recommendations are defined in terms of time spent being physically active (e.g., 30 minutes brisk walking, five days a week). However, walking volume may be more naturally assessed by distance than time. Analyses were therefore performed to test whether time or distance provide the best metric for relating walking volume to estimated total and regional adiposity.
Linear and logistic regression analyses were used to relate exercise dose to body mass index (BMI), body circumferences, and obesity in a cross-sectional sample of 12,384 female and 3,434 male walkers who reported both usual distance walked and time spent walking per week on survey questionnaires. Metabolic equivalent hours per day (METhr/d, 1 MET=3.5 ml O2•kg−1•min−1) were calculated from the time and pace, or distance and pace, using published compendium values. Results: Average METhr/d walked was 37% greater when calculated from time spent walking vs. usual distance in women, and 31% greater in men. Per METhr/d, declines in BMI and circumferences (slope±SE) were nearly twice as great, or greater, for distance- vs. time-derived estimates for kg/m2 of BMI (females: −0.58±0.03 vs. −0.31±0.02; males: −0.35±0.04 vs. −0.15±0.02), cm of waist circumference (females: −1.42±0.07 vs. −0.72±0.04; males: −0.96±0.10 vs. −0.45±0.07), and reductions in the odds for total obesity (odds ratio, females: 0.72 vs. 0.84; males: 0.84 vs. 0.92), and abdominal obesity (females: 0.74 vs. 0.85; males: 0.79 vs. 0.91, all comparisons significant).
Distance walked may provide a better metric of walking volume for epidemiologic obesity research, and better public health targets for weight control, than walking duration. Additional research is required to determine whether these results, derived in a sample that regularly walks for exercise, apply more generally.
PMCID: PMC3780575  PMID: 22525767
obesity; energy; physical activity; exercise volume; guidelines
24.  Optimal body weight for the prevention of coronary heart disease in normal-weight physically active men 
Obesity (Silver Spring, Md.)  2009;17(7):1428-1434.
Although 36% of US men are normal weight (BMI <25 kg/m2), the health benefits of greater leanness in normal-weight individuals are seldom acknowledged. To assess the optimal body weight with respect to minimizing coronary heart disease (CHD) risk, we applied Cox proportional hazard analyses of 20,525 nonsmoking, nondiabetic, normal-weight men followed prospectively for 7.7 years, including 20,301 who provided follow-up questionnaires. Two-hundred and forty two men reported coronary artery bypass graph (CABG) or percutaneous transluminal coronary angioplasty (PTCA) and 82 reported physician-diagnosed incident myocardial infarction (267 total). The National Death Index identified 40 additional ischemic heart disease deaths. In these normal-weight men, each kg/m2 decrement in baseline BMI was associated with 11.2% lower risk for total CHD (P = 0.005), 13.2% lower risk for nonfatal CHD (P = 0.002), 19.0% lower risk for nonfatal myocardial infarction (P = 0.01), and 12.2% lower risk for PTCA or CABG (P = 0.007). Compared to men with BMI between 22.5 and 25 kg/m2, those <22.5 kg/m2 had 24.1% lower total CHD risk (P = 0.01), 27.9% lower nonfatal CHD risk (P = 0.01), 37.8% lower nonfatal myocardial infarction risk (P = 0.05), and 27.8% lower PTCA or CABG risk (P = 0.02). In nonabdominally obese men (waist circumference <102 cm), CHD risk declined linearly with declining waist circumference. CHD risk was unrelated to change in waist circumference between 18 years old and baseline except as it contributed to baseline circumference. These results suggest that the optimal BMI for minimizing CHD risk lies somewhere <22.5 kg/m2, as suggested from our previous analyses of incident diabetes, hypertension, and hypercholesterolemia in these men.
PMCID: PMC3778502  PMID: 19553927
25.  Reductions in incident coronary heart disease risk above guideline physical activity levels in men 
Atherosclerosis  2009;209(2):524-527.
One-half of Americans currently meet guideline physical activity levels. For these individuals, exceeding guideline levels may provide additional health benefits.
Incident physician-diagnosed myocardial infarction and angina, revascularization procedures (CABG, PTCA), and ischemic heart disease deaths during 7.7-year follow-up were compared to baseline usual distance run in 35,402 male runners.
Men reported 467 incident CHD and the National Death Index identified an additional 54 ischemic heart disease deaths. Per km/day run, the men’s risks declined 5% for fatal and nonfatal CHD (P = 0.001), nonfatal CHD (P = 0.0008), and revascularization procedures (P = 0.002). Their risks for nonfatal myocardial infarctions and angina declined 7% (P = 0.02) and 10% (P = 0.003), respectively. Compared to <3 km/day run (upper limit guideline level), >9 km/day run produced risks 65% lower for angina (P = 0.008), 29% lower for nonfatal CHD (P = 0.04), and 26% lower for fatal and nonfatal CHD (P = 0.06).
Exceeding guideline physical activity levels produce important CHD-risk reductions.
PMCID: PMC3776591  PMID: 19815208
Epidemiology; physical activity; prevention; cardiovascular disease

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