Scott W. Keith

Putative contributors to the secular increase in obesity: exploring the roads less traveled

Objective:To investigate plausible contributors to the obesity epidemic beyond the two most commonly suggested factors, reduced physical activity and food marketing practices.Design:A narrative review of data and published materials that provide evidence of the role of additional putative factors in contributing to the increasing prevalence of obesity.Data:Information was drawn from ecological and epidemiological studies of humans, animal studies and studies addressing physiological mechanisms, when available.Results:For at least 10 putative additional explanations for the increased prevalence of obesity over the recent decades, we found supportive (although not conclusive) evidence that in many cases is as compelling as the evidence for more commonly discussed putative explanations.Conclusion:Undue attention has been devoted to reduced physical activity and food marketing practices as postulated causes for increases in the prevalence of obesity, leading to neglect of other plausible mechanisms and well-intentioned, but potentially ill-founded proposals for reducing obesity rates.

Ten Putative Contributors to the Obesity Epidemic

The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines in physical activity are the alleged perpetrators for the epidemic, despite a lack of solid evidence to demonstrate their causal role. While both may contribute to obesity, we call attention to their unquestioned dominance in program funding and public efforts to reduce obesity, and propose several alternative putative contributors that would benefit from equal consideration and attention. Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects as contributing factors to the obesity epidemic are reviewed herein. While the evidence is strong for some contributors such as pharmaceutical-induced weight gain, it is still emerging for other reviewed factors. Considering the role of such putative etiological factors of obesity may lead to comprehensive, cause specific, and effective strategies for prevention and treatment of this global epidemic.

Visceral adipose tissue modulates mammalian longevity.

Caloric restriction (CR) can delay many age‐related diseases and extend lifespan, while an increase in adiposity is associated with enhanced disease risk and accelerated aging. Among the various fat depots, the accrual of visceral fat (VF) is a common feature of aging, and has been shown to be the most detrimental on metabolic syndrome of aging in humans. We have previously demonstrated that surgical removal of VF in rats improves insulin action; thus, we set out to determine if VF removal affects longevity. We prospectively studied lifespan in three groups of rats: ad libitum‐fed (AL‐fed), CR (Fed 60% of AL) and a group of AL‐fed rats with selective removal of VF at 5 months of age (VF‐removed rats). We demonstrate that compared to AL‐fed rats, VF‐removed rats had a significant increase in mean (p < 0.001) and maximum lifespan (p < 0.04) and significant reduction in the incidence of severe renal disease (p < 0.01). CR rats demonstrated the greatest mean and maximum lifespan (p < 0.001) and the lowest rate of death as compared to AL‐fed rats (0.13). Taken together, these observations provide the most direct evidence to date that a reduction in fat mass, specifically VF, may be one of the possible underlying mechanisms of the anti‐aging effect of CR.

Use of self-reported height and weight biases the body mass index-mortality association

Background:Many large-scale epidemiological data sources used to evaluate the body mass index (BMI: kg/m2) mortality association have relied on BMI derived from self-reported height and weight. Although measured BMI (BMIM) and self-reported BMI (BMISR) correlate highly, self-reports are systematically biased.Objective:To rigorously examine how self-reporting bias influences the association between BMI and mortality rate.Subjects:Samples representing the US non-institutionalized civilian population.Design and Methods:National Health and Nutrition Examination Survey data (NHANES II: 1976–80; NHANES III: 1988–94) contain BMIM and BMISR. We applied Cox regression to estimate mortality hazard ratios (HRs) for BMIM and BMISR categories, respectively, and compared results. We similarly analyzed subgroups of ostensibly healthy never-smokers.Results:Misclassification by BMISR among the underweight and obesity ranged from 30–40% despite high correlations between BMIM and BMISR (r>0.9). The reporting bias was moderately correlated with BMIM (r>0.35), but not BMISR (r<0.15). Analyses using BMISR failed to detect six of eight significant mortality HRs detected by BMIM. Significantly biased HRs were detected in the NHANES II full data set (χ2=12.49; P=0.01) and healthy subgroup (χ2=9.93; P=0.04), but not in the NHANES III full data set (χ2=5.63; P=0.23) or healthy subgroup (χ2=1.52; P=0.82).Conclusions:BMISR should not be treated as interchangeable with BMIM in BMI mortality analyses. Bias and inconsistency introduced by using BMISR in place of BMIM in BMI mortality estimation and hypothesis tests may account for important discrepancies in published findings.

Waist circumference values are increasing beyond those expected from BMI increases.

Objective: The objective of this investigation was to examine the relationship between BMI and waist circumference (WC) by gender and race subgroups from U.S. population‐based data from 1959 to 2004 and to investigate the trend in WC over calendar time.

Physician Beliefs and Practices for Adjuvant and Salvage Radiation Therapy After Prostatectomy

PURPOSE Despite results of randomized trials that support adjuvant radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer with adverse pathologic features (APF), many clinicians favor selective use of salvage RT. This survey was conducted to evaluate the beliefs and practices of radiation oncologists (RO) and urologists (U) regarding RT after RP. METHODS AND MATERIALS We designed a Web-based survey of post-RP RT beliefs and policies. Survey invitations were e-mailed to a list of 926 RO and 591 U. APF were defined as extracapsular extension, seminal vesicle invasion, or positive surgical margin. Differences between U and RO in adjuvant RT recommendations were evaluated by comparative statistics. Multivariate analyses were performed to evaluate factors predictive of adjuvant RT recommendation. RESULTS Analyzable surveys were completed by 218 RO and 92 U (overallresponse rate, 20%). Adjuvant RT was recommended based on APF by 68% of respondents (78% RO, 44% U, p <0.001). U were less likely than RO to agree that adjuvant RT improves survival and/or biochemical control (p < 0.0001). PSA thresholds for salvage RT were higher among U than RO (p < 0.001). Predicted rates of erectile dysfunction due to RT were higher among U than RO (p <0.001). On multivariate analysis, respondent specialty was the only predictor of adjuvant RT recommendations. CONCLUSIONS U are less likely than RO to recommend adjuvant RT. Future research efforts should focus on defining the toxicities of post-RP RT and on identifying the subgroups of patients who will benefit from adjuvant vs. selective salvage RT.

BMI and Headache Among Women: Results From 11 Epidemiologic Datasets

Objective: To evaluate the association between BMI (kg/m2) and headaches among women.

High risk blood pressure and obesity increase the risk for left ventricular hypertrophy in African-American adolescents.

OBJECTIVE To examine the relative effects of high blood pressure (HBP) and obesity on left ventricular mass (LVM) among African-American adolescents; and if metabolic or inflammatory factors contribute to LVM. STUDY DESIGN Using a 2 × 2 design, African-American adolescents were stratified by body mass index percentile (body mass index <95th percentile = non-obese; ≥ 95th percentile = obese) and average blood pressure (BP) (normal BP <120/80 mm Hg; HBP ≥ 120/80). Glucose, insulin, insulin resistance, lipids, and inflammatory cytokines were measured. From echocardiography measures of LVM, calculated LVM index (LVMI) ≥ 95th percentile defined left ventricular hypertrophy (LVH). RESULTS Data included 301 adolescents (48% female), mean age 16.2 years, 51% obese, and 29% HBP. LVMI was highest among adolescents with both obesity and HBP. The multiplicative interaction of obesity and HBP on LVH was not significant (OR = 2.35, P = .20) but the independent additive associations of obesity and HBP with log-odds of LVH were significant; obesity OR = 3.26, P < .001; HBP OR = 2.92, P < .001. Metabolic and inflammatory risk factors were associated with obesity, but had no independent association with LVMI. Compared with those with average systolic BP (SBP) <75th percentile, adolescents with SBP from the 75th percentile to 90th percentile had higher LVMI (33.2 vs 38.7 g/m(2.7), P < .001) and greater LVH (18% vs 43%, P < .001), independent of obesity. CONCLUSIONS Prevalence of LVH is highest among African-American adolescents with average BP ≥ 120/80 mm Hg and obesity. There also is an independent association of LVMI with BP, beginning at the 75th SBP percentile.

What is the ideal radiotherapy dose to treat prostate cancer? A meta-analysis of biologically equivalent dose escalation

PURPOSE To determine if increasing the biologically equivalent dose (BED) via various radiation fractionation regimens is correlated with clinical outcomes or toxicities for prostate cancer. METHODS AND MATERIALS We performed a meta-analysis that included 12,756 prostate cancer patients from 55 studies published from 2003 to 2013 who were treated with non-dose-escalated conventionally fractionated external beam radiation therapy (non-DE-CFRT), DE-CFRT, hypofractionated RT, and high dose rate brachytherapy (HDR-BT; either mono or boost) with ⩾5-year actuarial follow-up. BEDs were calculated based on the following formula: (nd[1+d/(α/β)]), where n is the number of fractions, and d is dose per fraction; assuming an α/β of 1.5 for prostate cancer and 3.0 for late toxicities. Mixed effects meta-regression models were used to estimate weighted linear relationships between BED and the observed percentages of patients experiencing late toxicities or 5-year freedom from biochemical failure (FFBF). RESULTS Increases in 10 Gy increments in BED (at α/β of 1.5) from 140 to 200 Gy were associated with 5-unit improvements in percent FFBF. Dose escalation of BED above 200 Gy was not correlated with FFBF. Increasing BED (at α/β of 3.0) from 98 to 133 Gy was associated with increased gastrointestinal toxicity. Dose escalation above 133 Gy was not correlated with toxicity. CONCLUSIONS An increase in the BED to 200 Gy (at α/β of 1.5) was associated with increased disease control. Doses above 200 Gy did not result in additional clinical benefit.

Two hundred and eleven cases of Candida osteomyelitis: 17 case reports and a review of the literature

Candida osteomyelitis is a rare infection. We present 17 cases of Candida osteomyelitis from our institution and review 194 patients from the literature. The median age of patients was 57 ± 22 years (range, 18-90 years) with 68% male. Comorbidities associated with this infection include prior surgery (62%), broad-spectrum antibiotics (40%), central venous catheter insertion (19%), and immunosuppression (17%). The most common infecting species were Candida albicans (69%), Candida tropicalis (15%), and Candida glabrata (8%). Most initial antifungal regimens included amphotericin B (59%); however, fluconazole is increasingly being utilized for treatment of this infection (26%). Echinocandins were used infrequently (4%). Median length of treatment was 3 ± 4.5 months (mean, 4.2 months; range, 18 days to 36 months). The overall success rate of therapy was 91%, with 75% of patients cured by 6 months. The crude mortality rate was 12% with an attributable mortality rate of 6%.