The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis.

Glucose homeostasis can be improved after bariatric surgery, which alters bile flow and stimulates gut hormone secretion, particularly FGF15/19. FGFR1 expression in AGRP-expressing cells is required for bile acids' ability to improve glucose control. We show that the mouse Agrp gene has 3 promoter/enhancer regions that direct transcription of each of their own AGRP transcripts. One of these Agrp promoters/enhancers, Agrp-B, is regulated by bile acids. We generated an Agrp-B knockin FLP/knockout allele. AGRP-B-expressing cells are found in endocrine cells of the pars tuberalis and coexpress diacylglycerol lipase B - an endocannabinoid biosynthetic enzyme - distinct from pars tuberalis thyrotropes. AGRP-B expression is also found in the folliculostellate cells of the pituitary's anterior lobe. Mice without AGRP-B were protected from glucose intolerance induced by high-fat feeding but not from excess weight gain. Chemogenetic inhibition of AGRP-B cells improved glucose tolerance by enhancing glucose-stimulated insulin secretion. Inhibition of the AGRP-B cells also caused weight loss. The improved glucose tolerance and reduced body weight persisted up to 6 weeks after cessation of the DREADD-mediated inhibition, suggesting the presence of a biological switch for glucose homeostasis that is regulated by long-term stability of food availability.

A system-wide extracorporeal membrane oxygenation quality collaborative improves patient outcomes.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) use in adult patient populations has grown rapidly with wide variation in practices and outcomes. We evaluated the impact on patient outcomes, resource use, and costs of an initiative to coordinate and standardize best practices across ECMO programs within a large integrated health care system. METHODS: The ECMO Collaborative Project brought clinicians and service-line leaders from 4 programs within a single health care system together with operational subject matter experts tasked with developing and implementing standardized guidelines, order sets, and an internal database to support an automated quarterly report card. Patient outcomes, resource use, and financial measures were compared for the 16 months before (January 2017 to April 2018; "precollaborative," n = 185) versus the 14 months after (November 2018 to December 2019, "postcollaborative," n = 243) a 6-month implementation and blanking period. Subset analyses were performed for venoarterial ECMO, venovenous ECMO, and extracorporeal cardiopulmonary resuscitation. RESULTS: Survival to discharge/transfer increased significantly (in-hospital mortality hazard ratio, 0.75; 95% confidence interval [95% CI], 0.58-0.99) for the postcollaborative versus the precollaborative period (107/185, 57.8% vs 113/243, 46.5%, P = .03), predominantly due to improvement among patients receiving venoarterial ECMO (hazard ratio, 0.61; 95% CI, 0.41-0.91). The percentage of patients successfully weaned from ECMO increased from 58.9% (109/185) to 70% (170/243), P = .02. Complication rates decreased by 40% (incidence rate ratio, 0.60; 95% CI, 0.49-0.72). No significant changes were observed in ECMO duration, intensive care unit or hospital length of stay, or cost-per-case; payment-per-case and contribution-margin-per-case both decreased significantly. CONCLUSIONS: The ECMO Collaborative Project improved survival to discharge/transfer, weaning rates and complications, without additional costs, through coordination and standardization across ECMO programs within a health care system.

The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity.

BACKGROUND AND AIMS: Serotonergic and dopaminergic systems in the brain are essential for homeostatic and reward-associated regulation of food intake and systemic energy metabolism. It is largely unknown how fasting influences these systems or if such effects are altered in humans with obesity. We therefore aimed to evaluate the effects of fasting on hypothalamic/thalamic serotonin transporter (SERT) and striatal dopamine transporter (DAT) availability in lean subjects and subjects with obesity. METHODS: In this randomized controlled cross-over trial, we assessed the effects of 12 vs 24 h of fasting on SERT and DAT availability in the hypothalamus/thalamus and striatum, respectively, using SPECT imaging in 10 lean men and 10 men with obesity. RESULTS: As compared with the 12-h fast, a 24-h fast increased hypothalamic SERT availability in lean men, but not in men with obesity. We observed high inter-individual variation in the effects of fasting on thalamic SERT and striatal DAT, with no differences between lean men and those with obesity. In all subjects, fasting-induced increases in circulating free fatty acid (FFA) concentrations were associated with an increase in hypothalamic SERT availability and a decrease in striatal DAT availability. Multiple regression analysis showed that changes in plasma insulin and FFAs together accounted for 44% of the observed variation in striatal DAT availability. CONCLUSION: Lean men respond to prolonged fasting by increasing hypothalamic SERT availability, whereas this response is absent in men with obesity. Inter-individual differences in the adaptations of the cerebral serotonergic and dopaminergic systems to fasting may, in part, be explained by changes in peripheral metabolic signals of fasting, including FFAs and insulin.

Prospective empirical test suite for energy practitioners.

OBJECTIVE: To design a set of measures which were portable and cost-effective that scientists could use to determine competence of Energy Practitioners so that qualified practitioners could be employed in improving ongoing research accuracy. DESIGN: This was a prospective study with sample of convenience. SUBJECTS: 213 subjects, 185 women and 28 men, were tested in this study. OUTCOME MEASURES: Empirical outcome measures included Triaxial Extra Low Frequency Magnetic Field meter, Data Logging Multimeter, RF Field Spectrum Analyzer, Acoustimeter, Broadcast Frequency counter, digital pH meter, digital TDS meter, GDV and physiology suite including heart rate variability, galvanic skin response, respiration, EMG, EKG, temperature and blood volume pulse. Additional questions on ethics and body reading were included in the test. RESULTS: Results suggest a range of tests which could be used to determine practitioner competence. Many of the energy practitioners tested consistently produced changes in the areas being measured past the error rate of the devices being used. Across the 13 measures, practitioner success ranged from 56.8% on the Acoustimeter to 100% on the Broadcast Frequency Counter measures with 95% CI. Tri Axial ELF magnetic field meter showed significance with practitioners producing oscillations of amplitude from the L hand at p< 0.01 with and effect size D of 1.5 and R hand p< 0.001 and an effect size D of 1.6. Practitioners demonstrated the ability to produce a change in pH beyond ±.1pH in 10 minutes at a Mean of 0.5 and a SD of 0.4 at a 95% CI of 0.48-0.58 and changes in TDS beyond+/-2% at a Mean of 36.7 and a SD of 35.2 at a 95% CI of 31.9-41.5. Other measures are discussed in detail. CONCLUSIONS: This test presents a possible way to demonstrate a level of practitioner competence and improve the selection of energy practitioners for use in scientific studies of energy healing in the areas of full spectrum healing, laying-on-of-hands healing, Reiki, Qi Gong and Tai Chi.

Discordant attitudes and beliefs about cancer clinical trial participation between physicians, research staff, and cancer patients.

BACKGROUND/AIMS: Essential to bringing innovative cancer treatments to patients is voluntary participation in clinical trials but approximately 8% of American cancer patients are enrolled onto a trial. We used a domain-oriented framework to assess barriers to cancer clinical trial enrollment. METHODS: Physicians (MD, DO, fellows, residents) and research staff (physician assistants, nurse practitioners, staff and research nurses, clinical assistants, and program coordinators) involved in clinical research at a comprehensive cancer center completed an online survey in 2017; adult cancer patients not currently enrolled in a trial were interviewed in 2018. To inform the construct of our physician/staff and patient surveys and to assess barriers to clinical trial enrollment, we first conducted in-depth interviews among 14 key informants representing medical, hematologic, gynecologic, neurologic, radiation oncology, as well as members of the clinical research team (one clinical research coordinator, one research nurse practitioner). Perceived structural, provider- and patient-level barriers to clinical trial enrollment were assessed. Differences in perceptions, attitudes, and beliefs toward clinical trial enrollment between (1) physicians and staff, (2) patients by ethnicity, and (3) physicians/staff and patients were examined. RESULTS: In total, 120 physicians/staff involved in clinical research (39.2% physicians, 60.8% staff; 48.0% overall response rate) and 150 cancer patients completed surveys. Nearly three-quarters of physician/staff respondents reported difficulty in keeping track of the eligibility criteria for open studies but was more often cited by physicians than staff (84.4% vs 64.3%, p = 0.02). Physicians more often reported lack of time to present clinical trial information than did staff(p < 0.001); 44.0% of staff versus 18.2% of physicians reported patient family interaction as a clinical trial enrollment barrier (p = 0.007). Hispanic patients more often stated they would join a trial, even if standard therapy was an option compared to non-Hispanic patients (47.7% vs 20.8%, p = 0.002). Comparing the beliefs and perceptions of physicians/staff to those of patients, patients more often reported negative beliefs about clinical trial enrollment (e.g. being in a trial does not help patients personally, 32.9% vs 1.8%, p < 0.001) but less often felt they had no other options when agreeing to join (38.1% vs 85.6%, p < 0.001), and less often refused clinical trial enrollment due to lack of understanding (9.1% vs 63.3%, p = 0.001) than reported by physicians/staff. CONCLUSION: Our findings indicate a wide gap between physician/staff and patient attitudes and beliefs about clinical trial enrollment and highlight the importance of focusing future initiatives to raise awareness of this incongruency. Reconciling these differences will require tailored education to reduce implicit biases and dispel misperceptions. Strategies to improve the quality of patient-provider communication and address infrastructure and resource issues are also needed to improve patient enrollment onto cancer clinical trials.

Behavioral Medicine: a retro/prospective view of the field.

The year 2017 was the 40th anniversary of the convening of the Yale Conference on Behavioral Medicine (Schwartz and Weiss, 1977). In honor of this defining moment in the history of the birthing of behavioral medicine as a formal integrative field of biobehavioral theories, research and applications, we were invited by the editors to take a retrospective and prospective look at the field. Recognizing that much has been written about this history over the years, we decided to write about the "back-channel," presenting never-before shared events associated with the birthing and evolution of the field in a way that would be fun to write and read. In the process we look back at the evolving definitions of behavioral medicine in light of contemporary advances and controversies in science. Our review includes a discussion of some of the present challenges/opportunities, and then considers the future with some "outside the box" possibilities. We outline some of the enormous advances which have taken place in technology since the 1970s and consider how such technologies can be transformative in redefining our field.

Sorafenib for Advanced and Refractory Desmoid Tumors.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity.

When obesity is caused by consumption of a high-fat diet, the tumor suppressor pRb is phosphoinactivated in the neurons of the mediobasal hypothalamus, a brain area critical for energy-balance regulation. However, the functional relevance of pRb phosphoinactivation in the mediobasal hypothalamus to diet-induced obesity remains unknown. Here, we show that inhibiting pRb phosphorylation in the mediobasal hypothalamus can prevent and treat diet-induced obesity in mice. Expressing an unphosphorylable pRb nonselectively in the mediobasal hypothalamus or conditionally in anorexigenic POMC neurons inhibits diet-induced obesity. Intracerebroventricular delivery of US Food and Drug Administration-approved (FDA-approved) cyclin-dependent kinase 4 (CDK4) inhibitor abemaciclib inhibits pRb phosphorylation in the mediobasal hypothalamus and prevents diet-induced obesity. Oral administration of abemaciclib at doses approved for human use reduces fat mass in diet-induced obese mice by increasing lipid oxidation without significantly reducing lean mass. With analysis of recent literature identifying CDK4 as the most abundantly expressed neuronal CDK in the mediobasal hypothalamus, our work uncovers CDK4 as the major kinase for hypothalamic pRb phosphoinactivation and a highly effective central antiobesity target. As three CDK4/6 inhibitors have recently received FDA approval for life-long breast cancer therapy, our study provides a preclinical basis for their expedient repurposing for obesity management.

A gut-brain axis regulating glucose metabolism mediated by bile acids and competitive fibroblast growth factor actions at the hypothalamus.

OBJECTIVE: Bile acids have been implicated as important regulators of glucose metabolism via activation of FXR and GPBAR1. We have previously shown that FGF19 can modulate glucose handling by suppressing the activity of hypothalamic AGRP/NPY neurons. As bile acids stimulate the release of FGF19/FGF15 into the circulation, we pursued the potential of bile acids to improve glucose tolerance via a gut-brain axis involving FXR and FGF15/FGF19 within enterocytes and FGF receptors on hypothalamic AGRP/NPY neurons. METHODS: A 5-day gavage of taurocholic acid, mirroring our previous protocol of a 5-day FGF19 treatment, was performed. Oral glucose tolerance tests in mice with genetic manipulations of FGF signaling and melanocortin signaling were used to define a gut-brain axis responsive to bile acids. RESULTS: The taurocholic acid gavage led to increased serum concentrations of taurocholic acid as well as increases of FGF15 mRNA in the ileum and improved oral glucose tolerance in obese (ob/ob) mice. In contrast, lithocholic acid, an FXR antagonist but a potent agonist for GPBAR1, did not improve glucose tolerance. The positive response to taurocholic acid is dependent upon an intact melanocortinergic system as obese MC4R-null mice or ob/ob mice without AGRP did not show improvements in glucose tolerance after taurocholate gavage. We also tested the FGF receptor isoform necessary for the bile acid response, using AGRP:Fgfr1-/- and AGRP:Fgfr2-/- mice. While the absence of FGFR1 in AGRP/NPY neurons did not alter glucose tolerance after taurocholate gavage, manipulations of Fgfr2 caused bidirectional changes depending upon the experimental model. We hypothesized the existence of an endogenous hypothalamic FGF, most likely FGF17, that acted as a chronic activator of AGRP/NPY neurons. We developed two short peptides based on FGF8 and FGF17 that should antagonize FGF17 action. Both of these peptides improved glucose homeostasis after a 4-day course of central and peripheral injections. Significantly, daily average blood glucose from continuous glucose monitoring was reduced in all tested animals but glucose concentrations remained in the euglycemia range. CONCLUSIONS: We have defined a gut-brain axis that regulates glucose metabolism mediated by antagonistic fibroblast growth factors. From the intestine, bile acids stimulate FGF15 secretion, leading to activation of the FGF receptors in hypothalamic AGRP/NPY neurons. FGF receptor intracellular signaling subsequently silences AGRP/NPY neurons, leading to improvements of glucose tolerance that are likely mediated by the autonomic nervous system. Finally, short peptides that antagonize homodimeric FGF receptor signaling within the hypothalamus have beneficial effects on glucose homeostasis without inducing hypoglycemia. These peptides could provide a new mode of regulating glucose metabolism.

Blood pressure response to metoprolol and chlorthalidone in European and African Americans with hypertension.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P<.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension.

Using Literature Review and Structured Hybrid Electronic/ Manual Mortality Review to Identify System-Level Improvement Opportunities to Reduce Colorectal Cancer Mortality.

BACKGROUND: Despite colorectal cancer (CRC) screening and survival rates exceeding national averages in the United States, Kaiser Permanente Southern California (KPSC) aimed to identify system-level improvement opportunities to further reduce mortality from CRC. METHODS: To examine modifiable factors contributing to CRC mortality, a structured hybrid electronic/manual mor- tality review was used to examine 50 randomly selected cases among 524 individuals aged 25-75 years diagnosed with stage II, III, or IV CRC after July 2008 who subsequently died. Physicians conducted chart reviews using a standardized data extraction tool based on evidence-based best practices. RESULTS: Eighty-six percent (43) of the 50 decedents were initially diagnosed with stage III or IV CRC; two cases of appendiceal cancer were excluded. Thirty-one percent (15) of the remaining 48 cases presented with no history of screening; 15% (7) had documented iron deficiency anemia and abdominal pain or rectal bleeding; and 6% (3) had no follow-up colonoscopy after positive screening. Eleven (52%) of the 21 patients with initial stage II-III CRC received appropriate surveillance after curative surgery; 57% (12) developed metastases. Adjuvant chemotherapy was offered to 88% (14/16) of patients with stage III (node-positive) CRC; chemotherapy initiation was delayed in 6 patients. Missed opportunities for surgical oncology evaluation occurred among 61% (11/18) of patients with liver metastases at diagnosis. Failure to report clinically significant features on pathology occurred in 2 patients; they received appropriate treatment for other reasons. CONCLUSIONS: Improvement opportunities existed at multiple stages of care, including screening, evaluation of symp toms, timeliness of care, use of adjuvant chemotherapy, and surgical oncology practices.

Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver.

The integrative physiology of inter-organ communication in lipophagy regulation is not well understood. Lipophagy and the cytosolic lipases ATGL and HSL contribute to lipid droplet (LD) mobilization; however, whether autophagy proteins engage with lipases to promote lipid utilization remains unknown. Here, we show that cold induces autophagy in proopiomelanocortin (POMC) neurons and activates lipophagy in brown adipose tissue (BAT) and liver in mice. Targeted activation of autophagy in POMC neurons via intra-hypothalamic rapamycin is sufficient to trigger lipid utilization in room temperature-housed mice. Conversely, inhibiting autophagy in POMC neurons or in peripheral tissues or denervating BAT blocks lipid utilization. Unexpectedly, the autophagosome marker LC3 is mechanistically coupled to ATGL-mediated lipolysis. ATGL exhibits LC3-interacting region (LIR) motifs, and mutating a single LIR motif on ATGL displaces ATGL from LD and disrupts lipolysis. Thus, cold-induced activation of central autophagy activates lipophagy and cytosolic lipases in a complementary manner to mediate lipolysis in peripheral tissues.

Evaluating the use of gas discharge visualization to measure massage therapy outcomes.

BACKGROUND: The purpose of this study was to evaluate the short-term effects of massage therapy using gas discharge visualization (GDV), a computerized biophysical electrophoton capture (EPC), in tandem with traditional self-report measures to evaluate the use of GDV measurement to assess the bioenergetic whole-person effects of massage therapy. METHODS: This study used a single treatment group, pre-post-repeated measures design with a sample of 23 healthy adults. This study utilized a single 50-min full-body relaxation massage with participants. GDV measurement method, an EPC, and traditional paper-based measures evaluating pain, stress, muscle tension, and well-being were used to assess intervention outcomes. RESULTS: Significant differences were found between pre- and post-measures of well-being, pain, stress, muscle tension, and GDV parameters. Pearson correlations indicate the GDV measure is correlated with pain and stress, variables that impact the whole person. CONCLUSIONS: This study demonstrates that GDV parameters may be used to indicate significant bioenergetic change from pre- to post-massage. Findings warrant further investigation with a larger diverse sample size and control group to further explore GDV as a measure of whole-person bioenergetic effects associated with massage.

Enhancement of adaptive biological effects by nanotechnology preparation methods in homeopathic medicines.

Multiple studies have demonstrated that traditional homeopathic manufacturing reagents and processes can generate remedy source and silica nanoparticles (NPs). Homeopathically-made NPs would initiate adaptive changes in an organism as a complex adaptive system (CAS) or network. Adaptive changes would emerge from several different endogenous amplification processes that respond to exogenous danger or threat signals that manufactured nanomaterials convey, including (1) stochastic resonance (SR) in sensory neural systems and (2) time-dependent sensitization (TDS)/oscillation. SR is nonlinear coherent amplification of a weak signal by the superposition of a larger magnitude white noise containing within it the same frequencies of the weak signal. TDS is progressive response magnitude amplification and oscillatory reversal in response direction to a given low dose at physiological limits with the passage of time. Hormesis is an overarching adaptive phenomenon that reflects the observed nonlinear adaptive dose-response relationship. Remedies would act as enhanced micro- and nanoscale forms of their source material via direct local ligand-receptor interactions at very low potencies and/or by triggering systemic adaptive network dynamical effects via their NP-based electromagnetic, optical, and quantum mechanical properties at higher potencies. Manufacturing parameters including dilution modify sizes, shapes, and surface charges of nanoparticles, thereby causing differences in physico-chemical properties and biological effects. Based on surface area, size, shape, and charge, nanoparticles adsorb a complex pattern of serum proteins, forming a protein corona on contact that constitutes a unique biological identity. The protein corona may capture individualized dysfunctional biological mediator information of the organism onto the surfaces of the salient, i.e., resonant, remedy nanostructures. SR would amplify this weak signal from the salient remedy NPs with protein corona adsorbed, leading to sensitized nonlinear dynamical modulation of gene expression and associated changes in biological signaling pathways. When the system reaches its physiological limits during a homeopathic aggravation or the natural disease state, the amplified remedy signal triggers a nonlinear reversal in dynamical direction back towards health.

Vitamin D in blood and risk of prostate cancer: lessons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial.

The effects of blood levels of 25-hydroxyvitamin D (25-OHD) on the risk of total, low-, and high-grade prostate cancer were examined in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Prostate Cancer Prevention Trial (PCPT). In the SELECT study, plasma 25-OHD levels were associated with a linear decrease in prostate cancer risk for high-grade cancers in African American men and an apparent "U"-shaped effect in other men. The "U-shaped" curve may reflect detection bias. In the PCPT study, in which detection bias was minimized, serum 25-OHD levels were associated with a linear decrease in the risk of high-grade prostate cancers. The results from these large prevention trials support the hypothesis that circulating levels of 25-OHD decrease the risk of clinically relevant prostate cancers.

Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study.

Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.