Child Abuse and Neglect and Subclinical Cardiovascular Disease Among Midlife Women.

OBJECTIVE: A childhood history of abuse or neglect may be associated with elevated adult cardiovascular disease (CVD) risk. No studies have examined associations between child abuse/neglect and subclinical CVD using a validated measure of abuse and neglect. We hypothesized that midlife women with a history of childhood abuse or neglect would have increased subclinical CVD beyond standard CVD risk factors. We tested moderation of associations by sleep, hot flashes, and race/ethnicity. METHODS: Two hundred ninety-five midlife women completed the Child Trauma Questionnaire, physiologic hot flash and actigraphic sleep monitoring, blood draw, and carotid ultrasound (intima media thickness [IMT]; plaque). Relations between abuse/neglect and outcomes were tested in linear regression models adjusting for demographic, psychosocial, and CVD risk factors. Interactions with sleep, hot flashes, and race/ethnicity were tested. RESULTS: Forty-five percent of women reported a history of child abuse or neglect. Women with any child abuse or neglect had higher IMT [b(SE) = .039 (.011), p = .001] and carotid plaque [odds ratio (95% [CI] = 1.95 [1.15-3.33]); p = .014] than nonabused/neglected women. Furthermore, physical abuse, emotional abuse, and emotional neglect were associated with higher subclinical CVD. Sexual abuse was associated with higher IMT among nonwhite women. Interactions with sleep time and sleep hot flashes (p values < .05) indicated that higher subclinical CVD with an abuse/neglect history was observed primarily among women sleeping less than 6 hours/night or with sleep hot flashes. CONCLUSIONS: A history of child abuse or neglect is associated with higher subclinical CVD in women, particularly when paired with short sleep or hot flashes. Findings underscore the importance of childhood adversity in midlife women's CVD risk.

Menopausal Hot Flashes and Carotid Intima Media Thickness Among Midlife Women.

BACKGROUND AND PURPOSE: There has been a longstanding interest in the role of menopause and its correlates in the development of cardiovascular disease (CVD) in women. Menopausal hot flashes are experienced by most midlife women; emerging data link hot flashes to CVD risk indicators. We tested whether hot flashes, measured via state-of-the-art physiologic methods, were associated with greater subclinical atherosclerosis as assessed by carotid ultrasound. We considered the role of CVD risk factors and estradiol concentrations in these associations. METHODS: A total of 295 nonsmoking women free of clinical CVD underwent ambulatory physiologic hot flash assessments; a blood draw; and carotid ultrasound measurement of intima media thickness and plaque. Associations between hot flashes and subclinical atherosclerosis were tested in regression models controlling for CVD risk factors and estradiol. RESULTS: More frequent physiologic hot flashes were associated with higher carotid intima media thickness (for each additional hot flash: ß [SE]=0.004 [0.001]; P=0.0001; reported hot flash: ß [SE]=0.008 [0.002]; P=0.002, multivariable) and plaque (eg, for each additional hot flash, odds ratio [95% confidence interval] plaque index ≥2=1.07 [1.003-1.14]; P=0.04, relative to no plaque, multivariable] among women reporting daily hot flashes; associations were not accounted for by CVD risk factors or by estradiol. Among women reporting hot flashes, hot flashes accounted for more variance in intima media thickness than most CVD risk factors. CONCLUSIONS: Among women reporting daily hot flashes, frequent hot flashes may provide information about a woman's vascular status beyond standard CVD risk factors and estradiol. Frequent hot flashes may mark a vulnerable vascular phenotype among midlife women.

Novel methodology to evaluate renal cysts in polycystic kidney disease.

AIM: To develop and assess a semiautomated method for segmenting and counting individual renal cysts from mid-slice MR images in patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS: A semiautomated method was developed to segment and count individual renal cysts from mid-slice MR images in 241 subjects with ADPKD from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. For each subject, a mid-slice MR image was selected from each set of coronal T2-weighted MR images covering the entire kidney. The selected mid-slice image was processed with the semiautomated method to segment and count individual renal cysts. The number of cysts from the mid-slice image of each kidney was also measured by manual counting. The level of agreement between the semiautomated and manual cyst counts was compared using intraclass correlation (ICC) and a Bland-Altman plot. RESULTS: Individual renal cysts were successfully segmented using the semiautomated method in all 241 cases. The number of cysts in each kidney measured with the semiautomated and manual counting methods correlated well (ICC = 0.96 for the right or left kidney), with a small average difference (-0.52, with higher semiautomated counts, for the right kidney, and 0.13, with higher manual counts, for the left kidney) in the semiautomated method. However, there was substantial variation in a small number of subjects; 6 of 241 participants (2.5%) had a difference in the total cyst count of more than 15. CONCLUSION: We have developed a semiautomated method to segment individual renal cysts from mid-slice MR images in ADPKD kidneys as a quantitative indicator of characterization and disease progression of ADPKD.

Nanoanesthesia: a novel, intravenous approach to ankle block in the rat by magnet-directed concentration of ropivacaine-associated nanoparticles.

BACKGROUND: As an alternative to current methods of local nerve block, we studied the feasibility of producing ankle block in the rat with IV injection of magnetic nanoparticles (MNPs) associated with ropivacaine and application of a magnet at the ankle. METHODS: The anesthetic effect of magnet-directed ropivacaine-associated MNPs (MNP/Ropiv) was tested in the rat using paw withdrawal latencies from thermal stimuli applied to the hindpaw. The MNP/Ropiv complexes consisted of 0.7% w/v ropivacaine and 0.8% w/v MNPs containing 12% w/w magnetite (F3O4). The effect of IV injection of MNP/Ropiv with 15, 30, and 60-minute magnet application to the right ankle was compared with the effect without magnet application on the left hindpaw, to conventional ankle block with 0.1% or 0.2% ropivacaine, and to IV injection of MNPs alone with 30-minute magnet application to the right ankle. In addition, the pharmacokinetics of the MNP/Ropiv complexes were determined. RESULTS: IV injection of MNP/Ropiv with magnet application at the ankle significantly increased paw withdrawal latencies from thermal stimuli compared with pretreatment baselines in the same paw (P < 0.0001) and compared with the contralateral paw without magnet application (P < 0.0001). IV injection of MNPs alone had no significant effect on paw withdrawal latency. Absolute ropivacaine concentrations in ankle tissue, and ankle tissue-to-plasma concentration ratios were higher in the MNP/Ropiv group with 30-minute magnet application compared with MNP/Ropiv group without magnet application (mean ± SEM, 150 ± 10 ng/g vs 105 ± 15 ng/g, respectively, and 6.1 ± 0.8 vs 4.2 ± 0.7, respectively). CONCLUSIONS: The current study establishes proof of principle that it is possible to produce ankle block in the rat by IV injection of MNP/Ropiv complexes and magnet application at the ankle. The results indicate that further study of this approach is warranted.

Novel approach to estimate kidney and cyst volumes using mid-slice magnetic resonance images in polycystic kidney disease.

OBJECTIVE: To evaluate whether kidney and cyst volumes can be accurately estimated based on limited area measurements from magnetic resonance (MR) images of patients with autosomal dominant polycystic kidney disease (ADPKD). MATERIALS AND METHODS: MR coronal images of 178 ADPKD participants from the Consortium for Radiologic Imaging Studies of ADPKD (CRISP) were analyzed. For each MR image slice, we measured kidney and renal cyst areas using stereology and region-based thresholding methods, respectively. The kidney and cyst 'observed' volumes were calculated by summing up the area measurements of all the slices covering the kidney. To estimate the volume, we selected a coronal mid-slice in each kidney and multiplied its area by the total number of slices ('PANK2' for kidney and 'PANC2' for cyst). We then compared the kidney and cyst volumes predicted from PANK2 and PANC2, respectively, to the corresponding observed volumes, using a linear regression analysis. RESULTS: The kidney volume predicted from PANK2 correlated extremely well with the observed kidney volume (R(2) = 0.994 for the right kidney and 0.991 for the left kidney). The linear regression coefficient multiplier to PANK2 that best fit the kidney volume was 0.637 (95% CI: 0.629-0.644) for the right kidney and 0.624 (95% CI: 0.616-0.633) for the left kidney. The correlation between the cyst volume predicted from PANC2 and the observed cyst volume was also very high (R(2) = 0.984 for the right kidney and 0.967 for the left kidney). The least squares linear regression coefficient for PANC2 was 0.637 (95% CI: 0.624-0.649) for the right kidney and 0.608 (95% CI: 0.591-0.625) for the left kidney. CONCLUSION: Kidney and cyst volumes can be closely approximated by multiplying the product of the mid-slice area measurement and the total number of slices in the coronal MR images of ADPKD kidneys by 0.61-0.64. This information will help save processing time needed to estimate total kidney and cyst volumes of ADPKD kidneys.

A Social Media Website (Supporting Our Valued Adolescents) to Support Treatment Uptake for Adolescents With Depression or Anxiety: Pilot Randomized Controlled Trial.

BACKGROUND: Adolescents with depression or anxiety initiate mental health treatment in low numbers. Supporting Our Valued Adolescents (SOVA) is a peer support website intervention for adolescents seen in primary care settings and their parents with the goal of increasing treatment uptake through changing negative health beliefs, enhancing knowledge, offering peer emotional support, and increasing parent-adolescent communication about mental health. OBJECTIVE: This pilot study aimed to refine recruitment and retention strategies, refine document intervention fidelity, and explore changes in study outcomes (the primary outcome being treatment uptake). METHODS: We conducted a 2-group, single-blind, pilot randomized controlled trial in a single adolescent medicine clinic. Participants were aged 12 to 19 years with clinician-identified symptoms of depression or anxiety for which a health care provider recommended treatment. The patient and parent, if interested, were randomized to receive the SOVA websites and enhanced usual care (EUC) compared with EUC alone. Baseline, 6-week, and 3-month measures were collected using a web-based self-report survey and blinded electronic health record review. The main pilot outcomes assessed were the feasibility of recruitment and retention strategies. Implementation outcomes, intervention fidelity, missingness, and adequacy of safety protocols were documented. Descriptive statistics were used to summarize mental health service use and target measures with 2-sample t tests to compare differences between arms. RESULTS: Less than half of the adolescents who were offered patient education material (195/461, 42.2%) were referred by their clinician to the study. Of 146 adolescents meeting the inclusion criteria, 38 completed the baseline survey, qualifying them for randomization, and 25 (66%, 95% CI 51%-81%) completed the 6-week measures. There was limited engagement in the treatment arm, with 45% (5/11) of adolescents who completed 6-week measures reporting accessing SOVA, and most of those who did not access cited forgetting as the reason. Changes were found in target factors at 6 weeks but not in per-protocol analyses. At 12 weeks, 83% (15/18) of adolescents randomized to SOVA received mental health treatment as compared with 50% (10/20) of adolescents randomized to EUC (P=.03). CONCLUSIONS: In this pilot trial of a peer support website intervention for adolescents with depression or anxiety, we found lower-than-expected study enrollment after recruitment. Although generalizability may be enhanced by not requiring parental permission for adolescent participation in the trials of mental health interventions, this may limit study recruitment and retention. We found that implementing education introducing the study into provider workflow was feasible and acceptable, resulting in almost 500 study referrals. Finally, although not the primary outcome, we found a signal for greater uptake of mental health treatment in the arm using the SOVA intervention than in the usual care arm. TRIAL REGISTRATION: ClinicalTrials.gov NCT03318666; https://clinicaltrials.gov/ct2/show/NCT03318666. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/12117.

From Model Organisms to Humans, the Opportunity for More Rigor in Methodologic and Statistical Analysis, Design, and Interpretation of Aging and Senescence Research.

This review identifies frequent design and analysis errors in aging and senescence research and discusses best practices in study design, statistical methods, analyses, and interpretation. Recommendations are offered for how to avoid these problems. The following issues are addressed: (a) errors in randomization, (b) errors related to testing within-group instead of between-group differences, (c) failing to account for clustering, (d) failing to consider interference effects, (e) standardizing metrics of effect size, (f) maximum life-span testing, (g) testing for effects beyond the mean, (h) tests for power and sample size, (i) compression of morbidity versus survival curve squaring, and (j) other hot topics, including modeling high-dimensional data and complex relationships and assessing model assumptions and biases. We hope that bringing increased awareness of these topics to the scientific community will emphasize the importance of employing sound statistical practices in all aspects of aging and senescence research.

Randomization, design and analysis for interdependency in aging research: no person or mouse is an island.

Investigators traditionally use randomized designs and corresponding analysis procedures to make causal inferences about the effects of interventions, assuming independence between an individual's outcome and treatment assignment and the outcomes of other individuals in the study. Often, such independence may not hold. We provide examples of interdependency in model organism studies and human trials and group effects in aging research and then discuss methodologic issues and solutions. We group methodologic issues as they pertain to (1) single-stage individually randomized trials; (2) cluster-randomized controlled trials; (3) pseudo-cluster-randomized trials; (4) individually randomized group treatment; and (5) two-stage randomized designs. Although we present possible strategies for design and analysis to improve the rigor, accuracy and reproducibility of the science, we also acknowledge real-world constraints. Consequences of nonadherence, differential attrition or missing data, unintended exposure to multiple treatments and other practical realities can be reduced with careful planning, proper study designs and best practices.

Stakeholder impact on the implementation of integrated care: Opportunities to consider for patient-centered outcomes research.

Nearly half of Americans live with chronic disease. Many have multiple chronic conditions that often present as a combination of physical and mental health conditions. Aligning stakeholder-driven, patient-centered outcomes research with population health strategies such as innovative ways to deliver care management can reduce the burden of multiple chronic conditions. In addition, successfully creating meaningful, inclusive research requires actively engaging stakeholders throughout the lifecycle of a study. This study integrates stakeholder engagement, using a large health plan in western Pennsylvania, to conduct a randomized controlled trial. Three care management strategies, High-Touch, High-Tech, and Usual Care, are compared for effectiveness among members with multiple chronic conditions. Care strategies are delivered via the Community Team, a multidisciplinary community-based team, offering in-person (High-Touch) and digital (High-Tech) care management in 14 counties across Pennsylvania. Participants are followed for 12months, with repeated measurements of self-reported health status and activation in care, while tracking administrative measurements of primary and specialty health service utilization. Quality of life, care satisfaction, engagement in care, and service utilization will be compared using generalized mixed models. Additionally, semi-structured interviews are conducted for both participants and care managers over the course of the study to evaluate feasibility. This manuscript presents implementation strategies, while noting that the implementation of patient-centered outcomes research in a real-world setting requires rapid evaluation, redesign of workflow, and tailored approaches for success.

THRIVE Conceptual Framework and Study Protocol: A Community-Partnered Longitudinal Multi-Cohort Study to Promote Child and Youth Thriving, Health Equity, and Community Strength.

BACKGROUND: Given the profound inequities in maternal and child health along racial, ethnic, and socioeconomic lines, strength-based, community-partnered research is required to foster thriving children, families, and communities, where thriving is defined as optimal development across physical, mental, cognitive, and social domains. The Pittsburgh Study (TPS) is a community-partnered, multi-cohort study designed to understand and promote child and youth thriving, build health equity, and strengthen communities by integrating community partners in study design, implementation, and dissemination. TPS launched the Tracking Health, Relationships, Identity, EnVironment, and Equity (THRIVE) Study to evaluate children's developmental stages and contexts from birth through completion of high school and to inform a child health data hub accessible to advocates, community members, educators, health professionals, and policymakers. METHODS AND ANALYSIS: TPS is rooted in community-partnered participatory research (CPPR), health equity, antiracism, and developmental science. Using our community-informed conceptual framework of child thriving, the THRIVE Study will assess cross-cutting measures of place, environment, health service use, and other social determinants of health to provide longitudinal associations with developmentally appropriate child and youth thriving outcomes across participants in six cohorts spanning from pregnancy through adolescence (child ages 0-18 years). Data from electronic health records, school records, and health and human services use are integrated to assess biological and social influences of thriving. We will examine changes over time using paired t-tests and adjusted linear regression models for continuous thriving scores and McNemar tests and adjusted logistic regression models for categorical outcomes (thriving/not thriving). Data analyses will include mixed models with a random intercept (in combination with the previously-specified types of regression models) to account for within-subject correlation. DISCUSSION: By enhancing assessment of child and youth well-being, TPS will fill critical gaps in our understanding of the development of child and youth thriving over time and test strategies to support thriving in diverse communities and populations. Through CPPR and co-design, the study aims to improve child health inequities across multiple socioecological levels and developmental domains.

Racial/Ethnic Differences in Those Accompanying Medicare Patients to the Doctor: Insights from the 2013 Medicare Current Beneficiary's Survey.

Surprisingly little current, population-level detail exists regarding companion accompaniment for health care among Medicare beneficiaries, particularly by race/ethnicity. For respondents in the 2013 Medicare Current Beneficiary's Survey Access to Care public use data (N = 12,253), multivariable models predicted accompaniment to the doctor by race/ethnicity, adjusting for confounders. Chi square analyses compared, by race/ethnicity, who was accompanying and why. Overall, 37.5% of beneficiaries had accompaniment. In multivariable analyses, non-Hispanic blacks (OR 1.18; 95% CI 1.03-1.36) and Hispanics (OR 1.47; 95% CI 1.25-1.74) were significantly more likely than non-Hispanic whites to have accompaniment. Over 35% of all three groups had someone to "take notes," "ask questions," and/or "explain things," which did not vary by race/ethnicity; significant differences were seen for "explain instructions," "translate," and "moral support." Hispanics had the highest percentages for all three. Many Medicare beneficiaries have accompaniment to doctors' appointments, particularly in minority racial/ethnic groups, which should be considered in policy and practice.

Physiologically assessed hot flashes and endothelial function among midlife women.

OBJECTIVE: Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations. METHODS: Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol. RESULTS: In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol. CONCLUSIONS: Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.

Access to medications for medicare enrollees related to race/ethnicity: Results from the 2013 Medicare Current Beneficiary Survey.

BACKGROUND: Prescription medications are taken by millions of Americans to manage chronic conditions and treat acute conditions. These medications, however, are not equally accessible to all. OBJECTIVE: To examine medication access by race/ethnicity among Medicare beneficiaries. METHODS: Using the 2013 Medicare Current Beneficiary Survey (n = 10.515), this study examined access to medications related to race/ethnicity, comparing non-Hispanic blacks and Hispanics to whites. Multivariable logistic regression models were estimated, controlling for age, gender, income, education, chronic conditions, and type of drug coverage. RESULTS: Non-Hispanic blacks were less satisfied than whites with amount paid for prescriptions [OR = 0.69,95%CI(0.55,0.86)], the list of drugs covered by their plan [OR = 0.69,95%CI(0.56,0.85)], and finding a pharmacy that accepts their drug coverage [OR = 0.59,95%CI(0.48,0.72)], after adjustment. Low-income individuals were more likely to report not filling a prescription and taking less medication than prescribed. Compared to beneficiaries with excellent health, those with poor, fair, or good health were less satisfied with access. Access was also diminished for patients with depression, diabetes, and chronic obstructive pulmonary disease, emphysema or asthma. CONCLUSION: Possible interventions for non-Hispanic blacks might include assisting them in finding the best drug plan to meeting their needs, connecting them to medication assistance programs, and discussing convenience of pharmacy with patients.

Examining Factors Associated With Nonadherence And Identifying Providers Caring For Nonadherent Subgroups.

OBJECTIVES: To examine racial/ethnic and regional differences in medication adherence in patients with diabetes taking oral anti-diabetic, anti-hypertensive, and cholesterol lowering medications and to identify the pharmacies and prescribers who serve these communities. METHODS: Administrative claims data was analyzed for members enrolled in a large health plan in Hawaii (2008-2010) with diabetes mellitus who were taking three types of medications: 1) oral anti-diabetic medications; 2) anti-hypertensive medications; 3) cholesterol lowering medications (n=5136). The primary outcome was medication adherence based on medication possession ratios. Multivariable logistic regression models were estimated to examine the association between race/ethnicity and region to adherence to each drug class separately, followed by non-adherence to all three. Covariates included age, gender, education level, chronic conditions, copayment level, and number of prescribers and pharmacies from which the patients received their medications. KEY FINDINGS: After adjustment for other factors, Filipinos [OR=0.58, 95%CI(0.45,0.74)], Native Hawaiians [OR=0.74, 95%CI(0.56,0.98)], and people of other race [OR=0.67, 95%CI(0.55,0.82)] were significantly less adherent to anti-diabetic and anti-hypertensive medications than Japanese. For cholesterol-lowering medications, all racial and ethnic groups were significantly less adherent than Japanese, except mixed race. We also found that different racial/ethnic groups tended to use different pharmacies and prescribers, particularly in rural areas. CONCLUSION: Adherence differed by race/ethnicity as well as age and region. Qualitative research involving subgroups (e.g. Filipinos, Native Hawaiians, people under age 50) is needed to identify how to adapt and enhance the effects of interventions shown to be efficacious in prior studies.

Anti-Neu5Gc and anti-non-Neu5Gc antibodies in healthy humans.

Our group previously investigated the levels of anti-Gal and anti-nonGal IgM and IgG in a cohort of 75 healthy humans of various backgrounds, and found some significant differences related to factors such as age, gender, ABO blood group, diet, vaccination history, and geographic location during childhood. We have now expanded our cohort (n = 84) to investigate the levels of anti-Neu5Gc and anti-nonGal/nonNeu5Gc antibodies in healthy humans. Anti-nonGal and anti-nonGal/nonNeu5Gc human IgM and IgG binding to pRBCs and pAECs from GTKO/CD46 and GTKO/CD46/Neu5GcKO pigs were measured by flow cytometry. Anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. In summary, (i) the great majority (almost 100%) of humans had anti-Neu5Gc IgM and IgG antibodies that bound to pAECs and approximately 50% had anti-Neu5Gc antibodies that bound to pRBCs, (ii) there was significantly less human antibody binding to pig cells that did not express either Gal or Neu5Gc compared with those that did not express Gal alone, (iii) the levels of both IgM and IgG binding to GTKO/CD46/Neu5GcKO pRBCs and pAECs were low, (iv) the level of anti-Neu5Gc IgG was higher in men than women, (v) the level did not change with age or diet, and there was some variability associated with (vi) previous vaccination history and (vii) the geographic region in which the individual spent his or her childhood. Our study confirms that human antibody binding to RBCs and AECs from GTKO/CD46/Neu5GcKO pigs is greatly reduced compared to binding to GTKO/CD46 cells. However, all humans appear to have a low level of antibody that binds to pAECs that is not directed to either Gal or Neu5Gc. Our findings require consideration in planning clinical trials of xenotransplantation.

Physiologically assessed hot flashes and endothelial function among midlife women.

OBJECTIVE: Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations. METHODS: Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol. RESULTS: In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol. CONCLUSIONS: Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.

Biomonitoring of exposure in farmworker studies.

Although biomonitoring has been used in many occupational and environmental health and exposure studies, we are only beginning to understand the complexities and uncertainties involved with the biomonitoring process--from study design, to sample collection, to chemical analysis--and with interpreting the resulting data. We present an overview of concepts that should be considered when using biomonitoring or biomonitoring data, assess the current status of biomonitoring, and detail potential advancements in the field that may improve our ability to both collect and interpret biomonitoring data. We discuss issues such as the appropriateness of biomonitoring for a given study, the sampling time frame, temporal variability in biological measurements to nonpersistent chemicals, and the complex issues surrounding data interpretation. In addition, we provide recommendations to improve the utility of biomonitoring in farmworker studies.

A survey of laboratory and statistical issues related to farmworker exposure studies.

Developing internally valid, and perhaps generalizable, farmworker exposure studies is a complex process that involves many statistical and laboratory considerations. Statistics are an integral component of each study beginning with the design stage and continuing to the final data analysis and interpretation. Similarly, data quality plays a significant role in the overall value of the study. Data quality can be derived from several experimental parameters including statistical design of the study and quality of environmental and biological analytical measurements. We discuss statistical and analytic issues that should be addressed in every farmworker study. These issues include study design and sample size determination, analytical methods and quality control and assurance, treatment of missing data or data below the method's limits of detection, and post-hoc analyses of data from multiple studies. Key words: analytical methodology, biomarkers, laboratory, limit of detection, omics, quality control, sample size, statistics.

The yin and yang of 15-lipoxygenase-1 and delta-desaturases: dietary omega-6 linoleic acid metabolic pathway in prostate.

One of the major components in high-fat diets (Western diet) is the omega (omega, n)-6 polyunsaturated fatty acid (PUFA) called linoleic acid (LA). Linoleic acid is the precursor for arachidonic acid (AA). These fatty acids are metabolized to an array of eicosanoids and prostaglandins depending upon the enzymes in the pathway. Aberrant expression of the catabolic enzymes such as cyclooxygenases (COX-1 and/or -2) or lipoxygenases (5-LO, 12-LO, 15-LO-1, and 15-LO-2) that convert PUFA either AA and/or LA to bioactive lipid metabolites appear to significantly contribute to the development of PCa. However, PUFA and its cellular interactions in PCa are poorly understood. We therefore examined the mRNA levels of key enzymes involved in the LA and AA pathways in 18 human donor (normal) prostates compared to 60 prostate tumors using the Affymetrix U95Av2 chips. This comparative (normal donor versus prostate cancer) study showed that: 1) the level of 15-LO-1 expression (the key enzyme in the LA pathway) is low (P < 0.001), whereas the levels of delta-5 desaturase (P < 0.001, the key enzyme in the AA pathway), delta-6 desaturase (P = 0.001), elongase (P = 0.16) and 15-lipoxygenase-2 (15-LO-2, P = 0.74) are higher in donor (normal) prostates, and 2) Contrary to the observation in the normal tissues, significantly high levels of only 15-LO-1; whereas low levels of delta-6 desaturase, elongase, delta-5 desaturase and 15-LO-2 respectively, were observed in PCa tissues. Although the cyclooxygenase (COX)-1 and COX-2 mRNA levels were high in PCa, no significant differences were observed when compared in donor tissues. Our study underscores the importance of promising dietary intervention agents such as the omega-3 fatty acids as substrate competitors of LA/AA, aimed primarily at high 15-LO-1 and COX-2 as the molecular targets in PCa initiation and/or progression.