Diabetes, metformin use and risk of non-Hodgkin's lymphoma in postmenopausal women: A prospective cohort analysis in the Women's Health Initiative.

Epidemiologic evidence is limited about associations between T2DM, metformin, and the risk of non-Hodgkin's lymphoma (NHL). We aimed to examine associations between T2DM, metformin, and the risk of NHL in the Women's Health Initiative (WHI) Study. Information on T2DM status (diabetes status/types of antidiabetic drug use/diabetes duration) from study enrollment and during follow-up were assessed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate associations of T2DM status with risks of overall NHL and its three major subtypes [diffuse large B-cell lymphoma (DLBCL, n = 476), follicular lymphoma (FL, n = 301) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, n = 136)] based on multivariable-adjusted Cox proportional hazards models. During a median follow-up of 18.86 years (range, 0.01-25.13; SD ± 6.55), a total of 1637 women developed NHL among 147 885 postmenopausal women. Women with T2DM and with self-reported oral medication use had 38% and 55% higher risk of DLBCL, respectively [multivariable-adjusted model HR = 1.38, 95% CI (1.06-1.81) and HR = 1.55, 95% CI (1.16-2.06)] compared to the reference group (nondiabetics/untreated diabetes). Risks of NHL and DLBCL [multivariable-adjusted model: HR = 1.28, 95% CI (1.06-1.54) and HR = 1.56, 95% CI (1.13-2.14), respectively] were significantly higher in associations with relatively short duration (≤7 years) of diabetes, compared to reference group. Additionally, an increased risk of DLBCL [HR = 1.76, 95% CI (1.13-2.75)] was found in metformin users compared to the reference group. Postmenopausal women who had T2DM, who were oral antidiabetic drug users, especially metformin, and who had a shorter diabetes duration may have higher risks of DLBCL. Further well-designed research is needed to confirm our findings.

Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative.

BACKGROUND: Insulin resistance is associated with higher all-cause and cancer-specific mortality in postmenopausal women. However, to the authors' knowledge, information regarding insulin resistance and breast cancer mortality risk is limited. Therefore, the authors examined associations between insulin resistance and breast cancer incidence and mortality in a subsample of Women's Health Initiative participants. METHODS: A total of 22,837 postmenopausal women with fasting baseline glucose and insulin levels were followed for incident breast cancer and breast cancer mortality. Breast cancers were verified by medical record review and serial National Death Index linkage-enhanced mortality findings. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR). Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) with 95% confidence intervals (95% CIs) for quartile comparisons. Outcomes included breast cancer incidence, deaths from breast cancer, and deaths after breast cancer (breast cancer followed by death from any cause). RESULTS: During a median of 19.8 years of follow-up of 1328 breast cancer cases, there were 512 deaths reported, 151 of which were from breast cancer. Breast cancer incidence was higher in women in the highest HOMA-IR quartile (HR, 1.34; 95% CI, 1.12-1.61 [P for trend = .003]). Although HOMA-IR was not found to be associated with risk of death from breast cancer (HR, 1.04; 95% CI, 0.60-1.79), women in the highest versus those in the lowest HOMA-IR quartile were at a higher risk of death after breast cancer (HR, 1.78; 95% CI, 1.32-2.39 [P for trend <.001]). CONCLUSIONS: Higher levels of insulin resistance in postmenopausal women are associated with higher breast cancer incidence and higher all-cause mortality after breast cancer.

Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

Metabolic syndrome and risk of endometrial cancer in postmenopausal women: a prospective study.

BACKGROUND: Obesity is a strong risk factor for endometrial cancer, but it is unclear whether metabolic syndrome (MetS) contributes to endometrial cancer risk over and above the contribution of obesity. METHODS: We examined the association of MetS and its components with risk of endometrial cancer in a sub-cohort of 24,210 women enrolled in the Women's Health Initiative cohort study. Two variants of the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS were used: one including and one excluding waist circumference (WC). Cox proportional hazards models were used to estimate the association of the study exposures with disease risk. RESULTS: When WC was included in the definition, MetS showed an approximately two-fold increase in endometrial cancer risk (HR 2.20; 95% CI 1.61-3.02); however, when WC was excluded, MetS was no longer associated with risk. We also observed that women with hyperglycemia, dyslipidemia and hypertension, in combination, had almost a twofold increased risk of endometrial cancer, independent of WC (HR 1.94; 95% CI 1.09, 3.46). Glucose, and, in particular, WC and body mass index were also positively associated with risk. CONCLUSIONS: Our findings suggest that MetS may predict risk of endometrial cancer independent of obesity among women with the remaining four Mets components.

Metabolic obesity phenotypes and risk of colorectal cancer in postmenopausal women.

Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes and homeostasis model-insulin resistance (HOMA-IR-a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0 and ≥30.0 kg/m2 ) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis.

Cardiometabolic risk factors and survival after breast cancer in the Women's Health Initiative.

BACKGROUND: Few studies have examined the relationship between cardiometabolic risk factors linked to metabolic syndrome and mortality among women with breast cancer. METHODS: We used the Women's Health Initiative to evaluate the relationship between cardiometabolic risk factors, including waist circumference (WC), blood pressure, cholesterol level, and presence of type 2 diabetes, and their relation with death from breast cancer, cardiovascular disease (CVD), and other causes among 8641 women with local or regional stage invasive breast cancer. Cox proportional hazards models were used to estimate hazard ratios, and 95% confidence intervals, adjusted for important predictors of survival. RESULTS: After a median of 11.3 years, there were 2181 total deaths, 619 (28.4%) of which were due to breast cancer. Most participants (55.7%) had at least 2 cardiometabolic risk factors, and 4.9% had 3 or 4. Having a larger number of risk factors was associated with higher risk of CVD and other-cause mortality (P trend < .001 for both), but not with breast cancer mortality (P trend = .86). Increased WC was associated with a higher risk of CVD (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57) and other-cause mortality (HR, 1.32; 95% CI, 1.16-1.49) and only with a small and nonsignificant higher risk of breast cancer mortality (HR, 1.19; 95% CI, 0.93-1.52). The results did not differ in analyses stratified by race, hormone receptor status, or after an analysis of cases diagnosed within 5 years after baseline. CONCLUSIONS: Among women with early stage breast cancer, cardiometabolic risk factors are significantly associated with cardiovascular and other-cause mortality, but not breast cancer mortality. Cancer 2018;124:1798-807. © 2018 American Cancer Society.

C-reactive protein concentration and risk of selected obesity-related cancers in the Women's Health Initiative.

BACKGROUND: Obesity is a chronic inflammatory condition strongly associated with the risk of numerous cancers. We examined the association between circulating high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammation and strong correlate of obesity, and the risk of three understudied obesity-related cancers in postmenopausal women: ovarian cancer, kidney cancer, and multiple myeloma. METHODS: Participants were 24,205 postmenopausal women who had measurements of baseline serum hsCRP (mg/L) in the Women's Health Initiative (WHI) CVD Biomarkers Cohort, a collection of four sub-studies within the WHI. Incident cancers were identified over 17.9 years of follow-up (n = 153 ovarian, n = 110 kidney, n = 137 multiple myeloma). hsCRP was categorized into study-specific quartiles. Adjusted Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of baseline hsCRP with the risk of these cancers. RESULTS: There was no clear association between baseline hsCRP concentration and the risk of ovarian cancer (quartile 4 vs. 1: HR 0.87, 95% CI 0.56-1.37), kidney cancer (HR 0.95, 95% CI 0.56-1.61), or multiple myeloma (HR 0.82, 95% CI 0.52-1.29). HRs for 1 mg/L increases in hsCRP also approximated the null value for each cancer. CONCLUSIONS: The results of this study suggest that elevated CRP is not a major risk factor for these obesity-related cancers (ovarian or kidney cancers, or multiple myeloma) among postmenopausal women. Given the importance of elucidating the mechanisms underlying the association of obesity with cancer risk, further analysis with expanded biomarkers and in larger or pooled prospective cohorts is warranted.

Methodological considerations for disentangling a risk factor's influence on disease incidence versus postdiagnosis survival: The example of obesity and breast and colorectal cancer mortality in the Women's Health Initiative.

Often, studies modeling an exposure's influence on time to disease-specific death from study enrollment are incorrectly interpreted as if based on time to death from disease diagnosis. We studied 151,996 postmenopausal women without breast or colorectal cancer in the Women's Health Initiative with weight and height measured at enrollment (1993-1998). Using Cox regression models, we contrast hazard ratios (HR) from two time-scales and corresponding study subpopulations: time to cancer death after enrollment among all women and time to cancer death after diagnosis among only cancer survivors. Median follow-up from enrollment to diagnosis/censoring was 13 years for both breast (7,633 cases) and colorectal cancer (2,290 cases). Median follow-up from diagnosis to death/censoring was 7 years for breast and 5 years for colorectal cancer. In analyses of time from enrollment to death, body mass index (BMI) ≥ 35 kg/m2 versus 18.5-<25 kg/m2 was associated with higher rates of cancer mortality: HR = 1.99; 95% CI: 1.54, 2.56 for breast cancer (p trend <0.001) and HR = 1.40; 95% CI: 1.04, 1.88 for colorectal cancer (p trend = 0.05). However, in analyses of time from diagnosis to cancer death, trends indicated no significant association (for BMI ≥ 35 kg/m2 , HR = 1.25; 95% CI: 0.94, 1.67 for breast [p trend = 0.33] and HR = 1.18; 95% CI: 0.84, 1.86 for colorectal cancer [p trend = 0.39]). We conclude that a risk factor that increases disease incidence will increase disease-specific mortality. Yet, its influence on postdiagnosis survival can vary, and requires consideration of additional design and analysis issues such as selection bias. Quantitative tools allow joint modeling to compare an exposure's influence on time from enrollment to disease incidence and time from diagnosis to death.

Changes in the Inflammatory Potential of Diet Over Time and Risk of Colorectal Cancer in Postmenopausal Women.

We examined the associations between changes in dietary inflammatory potential and risk of colorectal cancer (CRC) in 87,042 postmenopausal women recruited from 1993-1998 by the Women's Health Initiative, conducted in the United States. Food frequency questionnaire data were used to compute patterns of change in dietary inflammatory index (DII) scores and cumulative average DII scores over 3 years. Cox regression models were used to estimate hazard ratios for CRC risk. After a median of 16.2 years of follow-up, 1,038 CRC cases were diagnosed. DII changes were not substantially associated with overall CRC, but proximal colon cancer risk was higher in the proinflammatory-change DII group than in the antiinflammatory-stable DII group (hazard ratio = 1.32, 95% confidence interval: 1.01, 1.74). Among nonusers of nonsteroidal antiinflammatory drugs (NSAIDs) (Pinteraction = 0.055), the proinflammatory-stable DII group was at increased risk of overall CRC and proximal colon cancer. Also among nonusers of NSAIDs, risks of overall CRC, colon cancer, and proximal colon cancer were higher in the highest quintile compared with the lowest cumulative average DII quintile (65%, 61%, and 91% higher risk, respectively). Dietary changes toward, or a history of, proinflammatory diets are associated with an elevated risk of colon cancer, particularly for proximal colon cancer and among nonusers of NSAIDs.

Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk.

PURPOSE: Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. METHODS: We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. RESULTS: Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata. CONCLUSIONS: Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

Serum 25-hydroxyvitamin D concentrations and lung cancer risk in never-smoking postmenopausal women.

PURPOSE: Vitamin D has been implicated in lowering lung cancer risk, but serological data on the association among never-smoking women are limited. We report results examining the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with lung cancer risk among female never smokers. We also examined whether the association was modified by vitamin D supplementation and serum vitamin A concentrations. METHODS: In the Women's Health Initiative, including the calcium/vitamin D (CaD) Trial, we selected 298 incident cases [191 non-small cell lung cancer (NSCLC) including 170 adenocarcinoma] and 298 matched controls of never smokers. Baseline serum 25(OH)D was assayed by a chemiluminescent method. Logistic regression was used to estimate odds ratios (ORs) for quartiles and predefined clinical cutoffs of serum 25(OH)D concentrations. RESULTS: Comparing quartiles 4 versus 1 of serum 25(OH)D concentrations, ORs were 1.06 [95% confidence interval (CI) 0.61-1.84] for all lung cancer, 0.94 (95% CI 0.52-1.69) for NSCLC, and 0.91 (95% CI 0.49-1.68) for adenocarcinoma. Comparing serum 25(OH)D ≥ 75 (high) versus <30 nmol/L (deficient), ORs were 0.76 (95% CI 0.31-1.84) for all lung cancer, 0.71 (95% CI 0.27-1.86) for NSCLC, and 0.81 (95% CI 0.31-2.14) for adenocarcinoma. There is suggestive evidence that CaD supplementation (1 g calcium + 400 IU D3/day) and a high level of circulating vitamin A may modify the associations of 25(OH)D with lung cancer overall and subtypes (p interaction <0.10). CONCLUSIONS: In this group of never-smoking postmenopausal women, the results did not support the hypothesis of an association between serum 25(OH)D and lung cancer risk.

The distribution of hepatitis B virus exposure and infection in a population-based sample of U.S. Hispanic adults.

UNLABELLED: Little is known regarding the prevalence and distribution of hepatitis B virus (HBV) infection in U.S. Hispanics/Latinos. We sought to determine the prevalence of HBV exposure (serum HBV core antibody; anti-HBc), active HBV infection (serum HBV surface antigen; HBsAg), and vaccine-induced HBV immunity (antibody against HBV surface antigen; anti-HBs) in U.S. Hispanics/Latinos and consider how these data inform clinical screening recommendations. Our analysis included 11,999 women and men of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based, household survey in four urban communities (Bronx, NY; Miami, FL; Chicago, IL; and San Diego, CA) of U.S. civilian, noninstitutionalized self-identifying Hispanic/Latino adults ages 18-74. Vaccine-induced immunity was defined as detection of anti-HBs, but not anti-HBc. However, if anti-HBc were present, it was considered evidence of exposure to HBV, with detection of HBsAg used to distinguish those with active HBV infection. Mean age was 45.7 years, and 7,153 were women. Vaccine-induced immunity was greatest among those ages 18-29 years (60.2% in women, 54% in men) and decreased with increasing age, regardless of country of birth. The prevalence of active HBV infection was 0.29% (95% confidence interval: 0.19-0.43), but varied by country of birth. Those born in the Dominican Republic had the highest prevalence of HBV exposure (20.3% in women, 29.7% in men) and active HBV infection (0.95%). CONCLUSIONS: The overall age-standardized prevalence of active HBV infection in Hispanic/Latino adults (0.29%) was no different from the general U.S. population estimate (0.27%) and did not exceed 2%, regardless of country of birth. These data do not support targeting HBV screening to US Hispanic/Latino adults based upon background.

Diet Quality and Colorectal Cancer Risk in the Women's Health Initiative Observational Study.

Diet quality index scores on Healthy Eating Index 2010 (HEI-2010), Alternative HEI-2010, alternative Mediterranean Diet Index, and the Dietary Approaches to Stop Hypertension (DASH) index have been inversely associated with all-cause and cancer-specific death. This study assessed the association between these scores and colorectal cancer (CRC) incidence as well as CRC-specific mortality in the Women's Health Initiative Observational Study (1993-2012), a US study of postmenopausal women. During an average of 12.4 years of follow-up, there were 938 cases of CRC and 238 CRC-specific deaths. We estimated multivariate hazard ratios and 95% confidence intervals for relationships between quintiles of diet scores (from baseline food frequency questionnaires) and outcomes. HEI-2010 score (hazard ratios were 0.81, 0.77, and 0.73 with P values of 0.04, 0.01, and <0.01 for quintiles 3-5 vs. quintile 1, respectively) and DASH score (hazard ratios were 0.72, 0.74, and 0.78 with P values of <0.01, <0.01, and 0.03 for quintiles 3-5 vs. quintile 1, respectively), but not other diet scores, were associated with a lower risk of CRC in adjusted models. No diet scores were significantly associated with CRC-specific mortality. Closer adherence to HEI-2010 and DASH dietary recommendations was inversely associated with risk of CRC in this large cohort of postmenopausal women.

Pre-existing diabetes and lung cancer prognosis.

BACKGROUND: The aims of this study are to investigate the impact of pre-existing diabetes and diabetes treatments on lung cancer prognosis. METHODS: A total of 2484 women with confirmed incident lung cancer from the Women's Health Initiative were followed for an average of 2.9 years through the date of death or 29 August 2014. RESULTS: Compared with women with lung cancer but without diabetes, women with lung cancer and diabetes had significantly increased risk of overall mortality (HR=1.27, 95% CI: 1.07-1.50). Women with diabetes receiving insulin or metformin or women who had long duration of diabetes also had increased risk of overall mortality. CONCLUSIONS: Our large prospective study provides evidence that pre-existing diabetes is associated with poor overall survival among women with lung cancer, but do not support the hypothesis that metformin use may have a protective effect in women with lung cancer and diabetes.

Metabolic Diet App Suite for inborn errors of amino acid metabolism.

BACKGROUND: An increasing number of rare inborn errors of metabolism (IEMs) are amenable to targeted metabolic nutrition therapy. Daily adherence is important to attain metabolic control and prevent organ damage. This is challenging however, given the lack of information of disorder specific nutrient content of foods, the limited availability and cost of specialty products as well as difficulties in reliable calculation and tracking of dietary intake and targets. OBJECTIVES: To develop apps for all inborn errors of amino acid metabolism for which the mainstay of treatment is a medical diet, and obtain patient and family feedback throughout the process to incorporate this into subsequent versions. METHODS & RESULTS: The Metabolic Diet App Suite was created with input from health care professionals as a free, user-friendly, online tool for both mobile devices and desktop computers (http://www.metabolicdietapp.org) for 15 different IEMs. General information is provided for each IEM with links to useful online resources. Nutrient information is based on the MetabolicPro™, a North American food database compiled by the Genetic Metabolic Dietitians International (GMDI) Technology committee. After user registration, a personalized dashboard and management plan including specific nutrient goals are created. Each Diet App has a user-friendly interface and the functions include: nutrient intake counts, adding your own foods and homemade recipes and, managing a daily food diary. Patient and family feedback was overall positive and specific suggestions were used to further improve the App Suite. DISCUSSION: The Metabolic Diet App Suite aids individuals affected by IEMs to track and plan their meals. Future research should evaluate its impact on patient adherence, metabolic control, quality of life and health-related outcomes. The Suite will be updated and expanded to Apps for other categories of IEMs. Finally, this Suite is a support tool only, and does not replace medical/metabolic nutrition professional advice.

Association between magnesium intake and risk of colorectal cancer among postmenopausal women.

PURPOSE: Data relating to magnesium intake and colorectal cancer (CRC) risk in postmenopausal women are incomplete. We investigated the association between total magnesium intake and the risk of CRC in an ethnically diverse cohort of postmenopausal women enrolled in the Women's Health Initiative. METHODS: Self-reported dietary and supplemental magnesium were combined to form total magnesium intake. Invasive incident CRC was the primary outcome. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS: During an average follow-up of 13 years (1,832,319 person-years), of the 140,601 women included for analysis, 2,381 women were diagnosed with CRC (1,982 colon cancer and 438 rectal cancer). After adjustment for potential confounding variables, an inverse association was observed in the highest quintile of total magnesium intake compared to the lowest quintile for risk of CRC (HR 0.79, 95% CI 0.67, 0.94, p trend < 0.0001) and colon cancer (HR 0.80, 95% CI 0.66, 0.97, p trend < 0.0001). A borderline significant inverse association was detected in the highest versus the lowest quintile of total magnesium intake for rectal cancer (HR 0.76, 95% CI 0.51, 1.13, p trend < 0.001). CONCLUSIONS: Findings from this study support the hypothesis that magnesium intake around 400 mg/day from both dietary and supplemental sources is associated with a lower incidence of CRC in postmenopausal women.

Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride.

We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake.

Prevalence of hepatitis C virus infection in US Hispanic/Latino adults: results from the NHANES 2007-2010 and HCHS/SOL studies.

Prevalence of hepatitis C virus (HCV) antibody has been reported in Mexican Americans, but its prevalence in other US Hispanic/Latino groups is unknown. We studied 2 populations of US Hispanic/Latino adults; 3210 from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 and 11 964 from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Age-standardized prevalence of HCV antibody was similar in NHANES 2007-2010 (1.5%) and HCHS/SOL (2.0%) but differed significantly by Hispanic/Latino background in HCHS/SOL (eg, 11.6% in Puerto Rican men vs 0.4% in South American men). These findings suggest that the HCV epidemic among US Hispanics/Latinos is heterogeneous.

Testing the proportional hazards assumption in case-cohort analysis.

BACKGROUND: Case-cohort studies have become common in epidemiological studies of rare disease, with Cox regression models the principal method used in their analysis. However, no appropriate procedures to assess the assumption of proportional hazards of case-cohort Cox models have been proposed. METHODS: We extended the correlation test based on Schoenfeld residuals, an approach used to evaluate the proportionality of hazards in standard Cox models. Specifically, pseudolikelihood functions were used to define "case-cohort Schoenfeld residuals", and then the correlation of these residuals with each of three functions of event time (i.e., the event time itself, rank order, Kaplan-Meier estimates) was determined. The performances of the proposed tests were examined using simulation studies. We then applied these methods to data from a previously published case-cohort investigation of the insulin/IGF-axis and colorectal cancer. RESULTS: Simulation studies showed that each of the three correlation tests accurately detected non-proportionality. Application of the proposed tests to the example case-cohort investigation dataset showed that the Cox proportional hazards assumption was not satisfied for certain exposure variables in that study, an issue we addressed through use of available, alternative analytical approaches. CONCLUSIONS: The proposed correlation tests provide a simple and accurate approach for testing the proportional hazards assumption of Cox models in case-cohort analysis. Evaluation of the proportional hazards assumption is essential since its violation raises questions regarding the validity of Cox model results which, if unrecognized, could result in the publication of erroneous scientific findings.

Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using 13C-glucose breath test.

Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined. Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive 13C-glucose breath test (13C-GBT). Design: A case of GSD Ib (18y; female) underwent 13C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Biochemical and clinical data were obtained from the medical records as a post-hoc chart review. Results: UCCS utilization was significantly higher in GSD Ib pre-HSCT, which reduced and stabilized 5 months post-HSCT. UCCS and Glycosade® utilizations were low and not different at 5 and 6 months post-HSCT. Blood glucose concentrations were not significantly different at any time point. Conclusions: Findings show that HSCT stabilized UCCS utilization, as reflected by lower and stable glucose oxidation. The results also illustrate the application of 13C-GBT to examine glucose metabolism in response to various carbohydrate sources after other treatment modalities like HSCT in GSD Ib.