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1.  MRI Investigation of the Linkage Between Respiratory Motion of the Heart and Markers on Patient’s Abdomen and Chest: Implications for Respiratory Amplitude Binning List-Mode PET and SPECT Studies 
Respiratory motion of the heart impacts the diagnostic accuracy of myocardial-perfusion emission-imaging studies. Amplitude binning has come to be the method of choice for binning list-mode based acquisitions for correction of respiratory motion in PET and SPECT. In some subjects respiratory motion exhibits hysteretic behavior similar to damped non-linear cyclic systems. The detection and correction of hysteresis between the signals from surface movement of the patient’s body used in binning and the motion of the heart within the chest remains an open area for investigation. This study reports our investigation in nine volunteers of the combined MRI tracking of the internal respiratory motion of the heart using Navigators with stereo-tracking of markers on the volunteer’s chest and abdomen by a visual-tracking system (VTS). The respiratory motion signals from the internal organs and the external markers were evaluated for hysteretic behavior analyzing the temporal correspondence of the signals. In general, a strong, positive correlation between the external marker motion (AP direction) and the internal heart motion (SI direction) during respiration was observed. The average ± standard deviation in the Spearman’s ranked correlation coefficient (ρ) over the nine volunteer studied was 0.92 ± 0.1 between the external abdomen marker and the internal heart, and 0.87 ± 0.2 between the external chest marker and the internal heart. However despite the good correlation on average for the nine volunteers, in three studies a poor correlation was observed due to hysteretic behavior between inspiration and expiration for either the chest marker and the internal motion of the heart, or the abdominal marker and the motion of the heart. In all cases we observed a good correlation of at least either the abdomen or the chest with the heart. Based on this result, we propose the use of marker motion from both the chest and abdomen regions when estimating the internal heart motion to detect and address hysteresis when binning list-mode emission data.
PMCID: PMC4013094  PMID: 24817767
Cardiac respiratory motion; emission tomography; hysteresis; MRI; signal processing
2.  Prospective Associations of Coronary Heart Disease Loci in African Americans Using the MetaboChip: The PAGE Study 
PLoS ONE  2014;9(12):e113203.
Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.
Methods and Results
Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.
Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.
PMCID: PMC4277270  PMID: 25542012
3.  Economic Return From the Women’s Health Initiative Estrogen Plus Progestin Clinical Trial 
Annals of internal medicine  2014;160(9):594-602.
The findings of the Women’s Health Initiative (WHI) estrogen plus progestin (E+P) trial led to a substantial reduction in use of combined hormone therapy (cHT) among postmenopausal women in the United States. The economic effect of this shift has not been evaluated relative to the trial’s $260 million cost (2012 U.S. dollars).
To estimate the economic return from the WHI E+P trial.
Decision model to simulate health outcomes for a “WHI scenario” with observed cHT use and a “no-WHI scenario” with cHT use extrapolated from the pretrial period.
Data Sources
Primary analyses of WHI outcomes, peer-reviewed literature, and government sources.
Target Population
Postmenopausal women in the United States, aged 50 to 79 years, who did not have a hysterectomy.
Time Horizon
2003 to 2012.
Combined hormone therapy.
Outcome Measures
Disease incidence, expenditure, quality-adjusted life-years, and net economic return.
Results of Base-Case Analysis
The WHI scenario resulted in 4.3 million fewer cHT users, 126 000 fewer breast cancer cases, 76 000 fewer cardiovascular disease cases, 263 000 more fractures, 145 000 more quality-adjusted life-years, and expenditure savings of $35.2 billion. The corresponding net economic return of the trial was $37.1 billion ($140 per dollar invested in the trial) at a willingness-to-pay level of $100 000 per quality-adjusted life-year.
Results of Sensitivity Analysis
The 95% CI for the net economic return of the trial was $23.1 to $51.2 billion.
No evaluation of indirect costs or outcomes beyond 2012.
The WHI E+P trial made high-value use of public funds with a substantial return on investment. These results can contribute to discussions about the role of public funding for large, prospective trials with high potential for public health effects.
Primary Funding Source
National Heart, Lung, and Blood Institute.
PMCID: PMC4157355  PMID: 24798522
4.  Elevated HbA1c and Fasting Plasma Glucose in Predicting Diabetes Incidence Among Older Adults 
Diabetes Care  2013;36(12):3923-3929.
To determine which measures—impaired fasting glucose (IFG), elevated HbA1c, or both—best predict incident diabetes in older adults.
From the Health, Aging, and Body Composition study, we selected individuals without diabetes, and we defined IFG (100–125 mg/dL) and elevated HbA1c (5.7–6.4%) per American Diabetes Association guidelines. Incident diabetes was based on self-report, use of antihyperglycemic medicines, or HbA1c ≥6.5% during 7 years of follow-up. Logistic regression analyses were adjusted for age, sex, race, site, BMI, smoking, blood pressure, and physical activity. Discrimination and calibration were assessed for models with IFG and with both IFG and elevated HbA1c.
Among 1,690 adults (mean age 76.5, 46% men, 32% black), 183 (10.8%) developed diabetes over 7 years. Adjusted odds ratios of diabetes were 6.2 (95% CI 4.4–8.8) in those with IFG (versus those with fasting plasma glucose [FPG] <100 mg/dL) and 11.3 (7.8–16.4) in those with elevated HbA1c (versus those with HbA1c <5.7%). When FPG and HbA1c were considered together, odds ratios were 3.5 (1.9–6.3) in those with IFG only, 8.0 (4.8–13.2) in those with elevated HbA1c only, and 26.2 (16.3–42.1) in those with both IFG and elevated HbA1c (versus those with normal FPG and HbA1c). Addition of elevated HbA1c to the model with IFG resulted in improved discrimination and calibration.
Older adults with both IFG and elevated HbA1c have a substantially increased odds of developing diabetes over 7 years. Combined screening with FPG and HbA1c may identify older adults at very high risk for diabetes.
PMCID: PMC3836095  PMID: 24135387
5.  Serum Tocopherol Levels in Very Preterm Infants After a Single Dose of Vitamin E at Birth 
Pediatrics  2013;132(6):e1626-e1633.
Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.
Ninety-three infants <27 weeks’ gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing.
Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL.
A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.
PMCID: PMC3838534  PMID: 24218460
vitamin E; preterm infants
6.  Regression Calibration in Nutritional Epidemiology: Example of Fat Density and Total Energy in Relationship to Postmenopausal Breast Cancer 
American Journal of Epidemiology  2013;178(11):1663-1672.
Regression calibration using biomarkers provides an attractive approach to strengthening nutritional epidemiology. We consider this approach to assessing the relationship of fat and total energy consumption with postmenopausal breast cancer. In analyses that included fat density data, biomarker-calibrated total energy was positively associated with postmenopausal breast cancer incidence in cohorts of the US Women's Health Initiative from 1994–2010. The estimated hazard ratio for a 20% increment in calibrated food frequency questionnaire (FFQ) energy was 1.22 (95% confidence interval (CI): 1.15, 1.30). This association was not evident without biomarker calibration, and it ceased to be apparent following control for body mass index (weight (kg)/height (m)2), suggesting that the association is mediated by body fat deposition over time. The hazard ratio for a corresponding 40% increment in FFQ fat density was 1.05 (95% CI: 1.00, 1.09). A stronger fat density association, with a hazard ratio of 1.19 (95% CI: 1.00, 1.41), emerged from analyses that used 4-day food records for dietary assessment. FFQ-based analyses were also carried out by using a second dietary assessment in place of the biomarker for calibration. This type of calibration did not correct for systematic bias in energy assessment, but may be able to accommodate the “noise” component of dietary measurement error. Implications for epidemiologic applications more generally are described.
PMCID: PMC3842904  PMID: 24064741
bias; biological markers; breast cancer; dietary assessment; dietary energy; dietary fat; postmenopausal women
7.  No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population 
Human genetics  2013;132(12):1427-1431.
Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype–phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.
PMCID: PMC3895337  PMID: 24100633
8.  Comparison of methods of acquiring attenuation maps for cardiac SPECT in the presence of respiratory motion 
We investigated the effect of the respiratory motion on attenuation-corrected (AC) SPECT images for three different SPECT systems, each using a different approach in obtaining attenuation maps: scanning-line sources (SLS) acquired simultaneous with emission; slow cone-beam CT (CBCT) acquired sequentially to emission; and fast helical CT (HCT) acquired sequentially to emission.
A torso phantom filled with 99mTc was used to model a cardiac perfusion study. Stationary baseline acquisitions were followed by the acquisitions with the phantom moving axially using a computer-controlled motion platform to simulate breathing. In addition, HCT acquisitions were made simulating breath-hold at different extents of misalignment between CT and emission. HCT images were also used to simulate the Average-CT method. Acquisitions were repeated with added breast attachments, and the heart insert in two different orientations. Visual comparison was made of AC maps, AC emission slices and polar maps. Quantitative comparisons were made of global uniformity based on the percent fractional standard deviation (%FSD) of the polar map segment values, and the ratio of the segment values in the Anterior and Inferior walls divided by that of the Lateral and Septal walls (AI/LS ratio).
The AC maps for the SLS were inferior to the CT’s, and most impacted by added large breast attachment. Motion artifacts seen on CBCT slices were minimized in the derived attenuation maps. AC maps obtained from HCT showed inconsistent organ sizes depending on the direction of respiration at the time of acquisition. Both visually and quantitatively CBCT resulted in the best uniformity (up to 3.4 % lower in %FSD) for all the stationary acquisitions, and for the motion acquisition of the female phantom with large breast attachment (up to 4.0 % lower). For the motion acquisition of the male phantoms, HCT resulted in slightly better uniformity (<0.5 % lower) than CBCT. Breath-hold at end-expiration slightly improved (up to 1.1 %) the uniformity over the HCT acquired during regular breathing. Further improvement was achieved with the Average-CT method. For all the systems, phantom respiratory motion reduced the AI/LS ratio compared to when the phantoms were stationary.
The CBCT approach resulted in the best uniformity of the AC emission images. For the female phantom with larger breast attachment, HCT and SLS were truncated at some projection angles introducing artifacts into the AC emission images. The emission image artifacts observed with HCT could be mitigated by performing breath-hold acquisition at end-expiration or Average-CT type acquisitions. (J Nucl Cardiol 2013)
PMCID: PMC3959794  PMID: 24146161
Attenuation correction; myocardial perfusion imaging; phantom; respiratory motion
9.  All-Cause, Cardiovascular, and Cancer Mortality Rates in Postmenopausal White, Black, Hispanic, and Asian Women With and Without Diabetes in the United States 
American Journal of Epidemiology  2013;178(10):1533-1541.
Using data from the Women's Health Initiative (1993–2009; n = 158,833 participants, of whom 84.1% were white, 9.2% were black, 4.1% were Hispanic, and 2.6% were Asian), we compared all-cause, cardiovascular, and cancer mortality rates in white, black, Hispanic, and Asian postmenopausal women with and without diabetes. Cox proportional hazard models were used for the comparison from which hazard ratios and 95% confidence intervals were computed. Within each racial/ethnic subgroup, women with diabetes had an approximately 2–3 times higher risk of all-cause, cardiovascular, and cancer mortality than did those without diabetes. However, the hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups. Population attributable risk percentages (PARPs) take into account both the prevalence of diabetes and hazard ratios. For all-cause mortality, whites had the lowest PARP (11.1, 95% confidence interval (CI): 10.1, 12.1), followed by Asians (12.9, 95% CI: 4.7, 20.9), blacks (19.4, 95% CI: 15.0, 23.7), and Hispanics (23.2, 95% CI: 14.8, 31.2). To our knowledge, the present study is the first to show that hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups when stratified by diabetes status. Because of the “amplifying” effect of diabetes prevalence, efforts to reduce racial/ethnic disparities in the rate of death from diabetes should focus on prevention of diabetes.
PMCID: PMC3888272  PMID: 24045960
diabetes; health disparities; menopause; mortality; obesity; women's health
10.  An evaluation of data-driven motion estimation in comparison to the usage of external-surrogates in cardiac SPECT imaging 
Physics in medicine and biology  2013;58(21):7625-7646.
Motion estimation methods in single photon emission computed tomography (SPECT) can be classified into methods which depend on just the emission data (data-driven), or those that use some other source of information such as an external surrogate. The surrogate-based methods estimate the motion exhibited externally which may not correlate exactly with the movement of organs inside the body. The accuracy of data-driven strategies on the other hand is affected by the type and timing of motion occurrence during acquisition, the source distribution, and various degrading factors such as attenuation, scatter, and system spatial resolution. The goal of this paper is to investigate the performance of two data-driven motion estimation schemes based on the rigid-body registration of projections of motion-transformed source distributions to the acquired projection data for cardiac SPECT studies. Comparison is also made of six intensity based registration metrics to an external surrogate-based method. In the data-driven schemes, a partially reconstructed heart is used as the initial source distribution. The partially-reconstructed heart has inaccuracies due to limited angle artifacts resulting from using only a part of the SPECT projections acquired while the patient maintained the same pose. The performance of different cost functions in quantifying consistency with the SPECT projection data in the data-driven schemes was compared for clinically realistic patient motion occurring as discrete pose changes, one or two times during acquisition. The six intensity-based metrics studied were mean-squared difference (MSD), mutual information (MI), normalized mutual information (NMI), pattern intensity (PI), normalized cross-correlation (NCC) and entropy of the difference (EDI). Quantitative and qualitative analysis of the performance is reported using Monte-Carlo simulations of a realistic heart phantom including degradation factors such as attenuation, scatter and system spatial resolution. Further the visual appearance of motion-corrected images using data-driven motion estimates was compared to that obtained using the external motion-tracking system in patient studies. Pattern intensity and normalized mutual information cost functions were observed to have the best performance in terms of lowest average position error and stability with degradation of image quality of the partial reconstruction in simulations. In all patients, the visual quality of PI-based estimation was either significantly better or comparable to NMI-based estimation. Best visual quality was obtained with PI-based estimation in 1 of the 5 patient studies, and with external-surrogate based correction in 3 out of 5 patients. In the remaining patient study there was little motion and all methods yielded similar visual image quality.
PMCID: PMC4152921  PMID: 24107647
Motion estimation; Data-driven; SPECT; Motion correction
11.  IFI16 Restricts HSV-1 Replication by Accumulating on the HSV-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications 
PLoS Pathogens  2014;10(11):e1004503.
Interferon-γ inducible factor 16 (IFI16) is a multifunctional nuclear protein involved in transcriptional regulation, induction of interferon-β (IFN-β), and activation of the inflammasome response. It interacts with the sugar-phosphate backbone of dsDNA and modulates viral and cellular transcription through largely undetermined mechanisms. IFI16 is a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus (HSV-1), though the mechanisms of HSV-1 restriction are not yet understood. Here, we show that IFI16 has a profound effect on HSV-1 replication in human foreskin fibroblasts, osteosarcoma cells, and breast epithelial cancer cells. IFI16 knockdown increased HSV-1 yield 6-fold and IFI16 overexpression reduced viral yield by over 5-fold. Importantly, HSV-1 gene expression, including the immediate early proteins, ICP0 and ICP4, the early proteins, ICP8 and TK, and the late proteins gB and Us11, was reduced in the presence of IFI16. Depletion of the inflammasome adaptor protein, ASC, or the IFN-inducing transcription factor, IRF-3, did not affect viral yield. ChIP studies demonstrated the presence of IFI16 bound to HSV-1 promoters in osteosarcoma (U2OS) cells and fibroblasts. Using CRISPR gene editing technology, we generated U2OS cells with permanent deletion of IFI16 protein expression. ChIP analysis of these cells and wild-type (wt) U2OS demonstrated increased association of RNA polymerase II, TATA binding protein (TBP) and Oct1 transcription factors with viral promoters in the absence of IFI16 at different times post infection. Although IFI16 did not alter the total histone occupancy at viral or cellular promoters, its absence promoted markers of active chromatin and decreased those of repressive chromatin with viral and cellular gene promoters. Collectively, these studies for the first time demonstrate that IFI16 prevents association of important transcriptional activators with wt HSV-1 promoters and suggest potential mechanisms of IFI16 restriction of wt HSV-1 replication and a direct or indirect role for IFI16 in histone modification.
Author Summary
HSV-1, a ubiquitous human pathogen that establishes a life-long infection, has evolved several mechanisms to evade host immune detection and responses. However, it is still subject to regulation by cellular factors. Recently, a host nuclear protein, IFI16, was shown to be involved in the innate defense response to HSV-1 infection. Here, we provide the first evidence that IFI16 inhibits wild-type HSV-1 replication by repressing viral gene expression independent of its roles in the immune response. We show that IFI16 binds the HSV-1 genome at the transcription start sites of several HSV-1 genes. Using a permanently IFI16-negative cell line that we generated, we demonstrate that IFI16 reduces the association of important transcription factors. IFI16 also promotes global histone modifications by increasing the markers of repressive chromatin and decreasing the markers for activating chromatin on viral and cellular genes. These insights into the role of IFI16 in HSV-1 biology suggest that stabilization of IFI16 is an attractive avenue for antiviral drug development.
PMCID: PMC4223080  PMID: 25375629
12.  Diabetes, Depressive Symptoms, and Inflammation in Older Adults: Results from the Health, Aging, and Body Composition Study 
Journal of psychosomatic research  2013;75(5):10.1016/j.jpsychores.2013.08.006.
Up-regulated levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) are common to both type 2 diabetes mellitus (T2DM) and elevated depressive symptoms, yet little attention has been given to the biological mechanisms associated with these co-morbidities. This study examined the association between inflammation and both T2DM and elevated depressive symptoms.
Baseline data were analyzed from 3,009 adults, aged 70–79, participating in the Health, Aging, and Body Composition Study. Diabetes was assessed per self-report, medication use, fasting glucose and/or glucose tolerance tests. Elevated depressive symptoms were categorized using the Center for Epidemiologic Studies Depression scale (cut-score≥20). Log-transformed IL-6, TNF-α, and CRP were analyzed using ANCOVA.
Participants with T2DM and elevated depressive symptoms (T2DM+DEP n=14) demonstrated significantly (p<.05) higher IL-6 compared to (T2DM Only n=628), (DEP Only n=49), and (No T2DM or DEP n=2,067) groups following covariate adjustment. Similarly, participants with T2DM+DEP (n=14) had significantly (p<.05) higher CRP, after covariate adjustment, compared to DEP Only (n=50) and No T2DM or DEP groups (n=2,153). No association was observed for TNF-α.
These findings provide evidence that inflammation is associated with T2DM and elevated depressive symptoms. Participants with T2DM+DEP demonstrated the highest IL-6 levels compared to all other groups. Greater CRP levels were also observed in T2DM, but not elevated depressive symptoms, which may suggest that differential associations between T2DM and depressive symptoms exist for various inflammatory markers. Further investigation into these associations could aid in understanding the biological pathways underlying both T2DM and depressive symptoms.
PMCID: PMC3817497  PMID: 24182629
Diabetes; Depressive Symptoms; Inflammation; Interleukin-6; Tumor Necrosis Factor-α; C-Reactive Protein
13.  Calcium Plus Vitamin D Supplementation and Health Outcomes Five Years After Active Intervention Ended: The Women's Health Initiative 
Journal of Women's Health  2013;22(11):915-929.
Clinical outcomes of the Women's Health Initiative (WHI) calcium plus vitamin D supplementation trial have been reported during 7.0 years of active intervention. We now report outcomes 4.9 years after the intervention stopped and cumulative findings.
Postmenopausal women (N=36,282) were randomized; postintervention follow-up continued among 29,862 (86%) of surviving participants. Primary outcomes were hip fracture and colorectal cancer. Breast cancer, all cancers, cardiovascular disease (CVD), and total mortality were predetermined major study outcomes.
Hip fracture incidence was comparable in the supplement and the placebo groups, postintervention hazard ratio (HR)=0.95, 95% confidence interval (95% CI: 0.78, 1.15) and overall HR=0.91 (95% CI: 0.79, 1.05). Overall, colorectal cancer incidence did not differ between randomization groups, HR=0.95 (95% CI: 0.80, 1.13). Throughout, there also was no difference in invasive breast cancer, CVD, and all-cause mortality between groups. In subgroup analyses, the invasive breast cancer effect varied by baseline vitamin D intake (p=0.03 for interaction). Women with vitamin D intakes >600 IU/d, had an increased risk of invasive breast cancer, HR=1.28 (95% CI; 1.03, 1.60). Over the entire study period, in post hoc analyses, the incidence of vertebral fractures, HR=0.87 (95% CI: 0.76, 0.98) and in situ breast cancers, HR=0.82 (95% CI: 0.68, 0.99) were lower among women randomized to supplementation.
After an average of 11 years, calcium and vitamin D supplementation did not decrease hip fracture or colorectal cancer incidence. Exploratory analyses found lower vertebral fracture and in situ breast cancer incidence in the supplement users. There was no effect on CVD or all-cause mortality.
PMCID: PMC3882746  PMID: 24131320
14.  Study of the effect on shelter cat intakes and euthanasia from a shelter neuter return project of 10,080 cats from March 2010 to June 2014 
PeerJ  2014;2:e646.
Cat impoundments were increasing at the municipal San Jose animal shelter in 2009, despite long-term successful low cost sterilization programs and attempts to lower the euthanasia rate of treatable-rehabilitatable impounds beginning in 2008. San Jose Animal Care and Services implemented a new strategy designed to control overall feral cat reproduction by altering and returning feral cats entering the shelter system, rather than euthanizing the cats. The purpose of this case study was to determine how the program affected the shelter cat intakes over time. In just over four years, 10,080 individual healthy adult feral cats, out of 11,423 impounded at the shelter during this time frame, were altered and returned to their site of capture. Included in the 11,423 cats were 862 cats impounded from one to four additional times for a total of 958 (9.5%) recaptures of the previously altered 10,080 cats. The remaining 385 healthy feral cats were euthanized at the shelter from March 2010 to June 2014. Four years into the program, researchers observed cat and kitten impounds decreased 29.1%; euthanasia decreased from over 70% of intakes in 2009, to 23% in 2014. Euthanasia in the shelter for Upper Respiratory Disease decreased 99%; dead cat pick up off the streets declined 20%. Dog impounds did not similarly decline over the four years. No other laws or program changes were implemented since the beginning of the program.
PMCID: PMC4217190  PMID: 25374785
Shelter; Trap; Neuter; Return; Feral cat; Population control; Cat euthanasia; Population policy
15.  Parental Support for Language Development During Joint Book Reading for Young Children With Hearing Loss 
Communication disorders quarterly  2014;35(3):167-181.
Parent and child joint book reading (JBR) characteristics and parent facilitative language techniques (FLTs) were investigated in two groups of parents and their young children; children with normal hearing (NH; n = 60) and children with hearing loss (HL; n = 45). Parent–child dyads were videotaped during JBR interactions, and parent and child behaviors were coded for specific JBR behaviors using a scale developed for this study. Children’s oral language skills were assessed using the Preschool Language Scale–4 (PLS-4). Parents of children with HL scored higher on two of the four subscales of JBR: Literacy Strategies and Teacher Techniques. Parents of children with NH utilized higher level FLTs with their children who had higher language skills. Higher level FLTs were positively related to children’s oral language abilities. Implications are discussed for professionals who work with families of very young children with HL.
PMCID: PMC4191727  PMID: 25309136
birth to 3 years; age; language; assessment; deaf/hard of hearing; exceptionalities
16.  The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases 
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
To provide a comprehensive, integrated overview of findings from the two Women’s Health Initiative (WHI) hormone therapy (HT) trials with extended post-intervention follow up.
27,347 postmenopausal women, age 50–79 years, were enrolled at 40 US centers. Interventions were conjugated equine estrogens (CEE, 0.625 mg/day) with medroxyprogesterone acetate (MPA, 2.5 mg/day) for women with an intact uterus (N = 16,608) and CEE alone for women with hysterectomy (N= 10,739), or their placebos. Intervention continued for 5.6 and 7.2 years (median), respectively, with cumulative follow-up of 13 years through September 30, 2010.
The primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and deaths. Secondary and quality-of-life outcomes were also assessed.
During the intervention phase for CEE+MPA, the hazard ratio (HR) for CHD was 1.18 (95% confidence interval [CI] 0.95–1.45) and overall risks outweighed benefits, with increases in invasive breast cancer, stroke, pulmonary embolism, and the global index. Other risks included increased dementia (in women >65 years), gallbladder disease, and urinary incontinence, while benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Post-intervention, most risks and benefits dissipated, although some elevation in breast cancer risk persisted (cumulative hazard ratio [HR] =1.28; 95% confidence interval, 1.11–1.48). During intervention for CEE alone, risks and benefits were more balanced, with a HR for CHD of 0.94 (0.78–1.14), increased stroke and venous thrombosis, decreased hip fractures and diabetes, and over cumulative follow-up, decreased breast cancer (HR=0.79 [0.65–0.97]). Neither regimen affected all-cause mortality. With CEE, younger women (50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P values for trend by age <0.05), but not for stroke and venous thrombosis. Absolute risks of adverse events (measured by the global index) per 10,000 women per year on CEE+MPA ranged from 12 excess cases for age 50–59 to 38 for age 70–79 and, for CEE, from 19 fewer cases for age 50–59 to 51 excess cases for age 70–79. Results for quality of life outcomes in both trials were mixed.
Menopausal hormone therapy has a complex pattern of risks and benefits. While appropriate for symptom management in some women, its use for chronic disease prevention is not supported by the WHI randomized trials.
clinical Identifier: NCT00000611
PMCID: PMC3963523  PMID: 24084921
17.  Diabetes, Metformin Use, and Colorectal Cancer Survival in Postmenopausal Women 
Cancer epidemiology  2013;37(5):742-749.
Observational studies have associated metformin use with lower colorectal cancer (CRC) incidence but few studies have examined metformin’s influence on CRC survival. We examined the relationships among metformin use, diabetes, and survival in postmenopausal women with CRC in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study.
2,066 postmenopausal women with CRC were followed for a median of 4.1 years, with 589 deaths after CRC diagnosis from all causes and 414 deaths directly attributed to CRC. CRC-specific survival was compared among women with diabetes with metformin use (n=84); women with diabetes with no metformin use (n=128); and women without diabetes (n=1854). Cox proportional hazard models were used to estimate associations among metformin use, diabetes and survival after CRC. Strategies to adjust for potential confounders included: multivariate adjustment with known predictors of colorectal cancer survival and construction of a propensity score for the likelihood of receiving metformin, with model stratification by propensity score quintile.
After adjusting for age and stage, CRC specific survival in women with diabetes with metformin use was not significantly different compared to that in women with diabetes with no metformin use (HR 0.75; 95% CI 0.40 –1.38, p=0.67) and to women without diabetes (HR 1.00; 95% CI 0.61 – 1.66, p=0.99). Following propensity score adjustment, the HR for CRC-specific survival in women with diabetes with metformin use compared to non-users was 0.78 (95% CI 0.38 – 1.55, p=0.47) and for overall survival was 0.86 (95% CI 0.49 – 1.52; p=0.60).
In postmenopausal women with CRC and DM, no statistically significant difference was seen in CRC specific survival in those who used metformin compared to non-users. Analyses in larger populations of colorectal cancer patients are warranted.
PMCID: PMC3769471  PMID: 23773299
Metformin; Colorectal Neoplasm; Diabetes Mellitus; Survival Rate; Treatment Outcome; Female
18.  Predictors of Adolescents’ Health- promoting Behaviors Guided by Primary Socialization Theory 
The purpose of this study was to determine the influence of parents and peers on adolescents’ health-promoting behaviors, framed by Primary Socialization Theory.
Design and Method
Longitudinal data collected annually from 1,081 rural youth (mean age = 17 ±.7; 43.5% males; 44% Hispanic) and once from their parents were analyzed using generalized linear models.
Parental monitoring and adolescent’s religious commitment significantly predicted all health-promoting behaviors (nutrition, physical activity, safety, health practices awareness, stress management). Other statistically significant predictors were parent’s responsiveness and health-promoting behaviors. Peer influence predicted safety and stress management.
Practice Implications
Nurses may facilitate adolescents’ development of health-promoting behaviors through family-focused interventions.
PMCID: PMC3801414  PMID: 24094123
Adolescence; health behaviors health promotion; parental monitoring; primary socialization; religiosity
19.  Impact of Weight Loss on Ankle-Brachial Index and Inter-Artery Blood Pressures in Overweight and Obese Adults with Diabetes 
Obesity (Silver Spring, Md.)  2014;22(4):1032-1041.
To assess whether weight loss improves markers of peripheral artery disease and vascular stenosis.
Design and Methods
The Action for Health in Diabetes randomized clinical trial compared intensive lifestyle intervention (ILI) for weight loss to a control condition of diabetes support and education (DSE) in overweight or obese adults with type 2 diabetes. Annual ankle and brachial blood pressures over four years were used compute ankle-brachial indices (ABIs) and to assess inter-artery blood pressure differences in 5018 participants.
ILI, compared to DSE, produced 7.8% (Year 1) to 3.6% (Year 4) greater weight losses. These did not affect prevalence of low (<0.90) ABI (3.60% in DSE versus 3.14% in ILI; p=0.20) or elevated (>1.40) ABI (7.52% in DSE versus 7.59% in ILI: p=0.90), but produced smaller mean (SE) maximum inter-artery systolic blood pressure differences among ankle sites [19.7 (0.2) mmHg for ILI versus 20.6 (0.2) mmHg for DSE (p<0.001)] and between arms [5.8 (0.1) mmHg for ILI versus 6.1 (0.1) mmHg for DSE (p=0.01)].
Four years of intensive behavioral weight loss intervention did not significantly alter prevalence of abnormal ABI, however it did reduce differences in systolic blood pressures among arterial sites.
PMCID: PMC3968218  PMID: 24174392
Peripheral artery disease; Weight loss; Diabetes
20.  Calcium plus vitamin D supplementation and joint symptoms in postmenopausal women in the Women's Health Initiative randomized trial 
Low vitamin D intake and levels have been associated with increased joint symptoms in some observational studies but the findings are mixed and evidence from randomized trials sparse.
To evaluate the influence of supplemental calcium and vitamin D on joint symptoms in the Women's Health Initiative randomized, placebo-controlled, clinical trial.
In post hoc analyses, the results of the WHI randomized clinical trial in which 36,282 postmenopausal women were randomized to calcium carbonate (1000 mg as elemental calcium) with vitamin D3 (400 IU) daily or placebo were examined in the 6% subgroup of 1911 participants, over-sampled for minorities, who had serial joint symptom assessment. Qualitative information on joint pain and joint swelling was collected by questionnaire before entry and 2 years after randomization. Logistic regression models were used to compare the occurrence and severity of joint symptoms across randomization groups.
At baseline, total calcium and vitamin D intakes from diet and supplements were similar in the two randomization groups. In addition, both joint pain (reported by 73%) and joint swelling (reported by 34%) were commonly reported and comparable in the supplement and placebo groups. Two years after randomization, no statistically significant differences between supplement and placebo groups were seen for joint pain frequency (74.6% compared to 75.1%, [P=0.79] for supplement and placebo groups, respectively) or joint swelling frequency (34.6% compared to 32.4%, [P=0.29], respectively) or in severity scores for either outcome. Subgroup analyses suggested study participants also using non-protocol calcium supplements at study entry may have less joint pain with supplement group randomization (interaction P-value=0.02)..
Joint symptoms are relatively common in postmenopausal women. However, daily supplementation with 1000 mg of calcium carbonate and 400 IU of vitamin D3 in a randomized, placebo-controlled clinical trial setting did not reduce the self-reported frequency or severity of joint symptoms.
PMCID: PMC4108192  PMID: 23954097
21.  Long-term Efficacy and Safety of Questionnaire-based Initiation of Urgency Urinary Incontinence Treatment 
To determine the longer-term efficacy and safety of initiating treatment for urgency-predominant urinary incontinence (UUI) in women diagnosed using a simple questionnaire rather than an extensive evaluation.
Study Design
Women completing a 12-week randomized controlled trial of fesoterodine therapy for UUI diagnosed by questionnaire were invited to participate in a 9-month open label continuation study. UUI and voiding episodes were collected using voiding diaries. Participant satisfaction was measured by questionnaire. Safety was assessed by measurement of post void residual volume and adverse event monitoring; if necessary, women underwent specialist evaluation. Longitudinal changes in UUI and voiding episodes were evaluated using linear mixed models adjusting for baseline.
Of the 567 women completing the randomized trial, 498 (87.8%) took at least one dose of medication during this open label study. Compared to the enrollment visit in the randomized trial, fesoterodine was associated with a reduction in total incontinence episodes/day and urgency incontinence episodes/day at the end of the open label study [adjusted mean (standard error (SE)) 4.6 (0.12) to 1.2 (0.13) and 3.9 (0.11) to 0.9 (0.11) respectively, p-value<.0001 for both]. Most women were satisfied with treatment (89%, 92%, and 93% at 3, 6, and 9 months). Twenty-six women experienced 28 serious adverse events, one of which was considered possibly treatment-related. Twenty-two women had specialist evaluation: 5 women’s incontinence was misclassified by the 3IQ; none experienced harm due to misclassification.
Using a simple validated questionnaire to diagnose and initiate treatment for UUI in community dwelling women is safe and effective, allowing timely treatment by primary care practitioners.
PMCID: PMC4019400  PMID: 23659987
Primary Care; Treatment; Urgency Urinary Incontinence
22.  Do weight loss and adherence cluster within behavioral treatment groups? 
Obesity (Silver Spring, Md.)  2013;22(3):638-644.
Weight loss programs are often conducted in a group format, but it is unclear whether weight losses or adherence cluster within treatment group and whether characteristics of the group (e.g. size or homogeneity) affect outcomes. We examined these questions within Look AHEAD, a multicenter study of the effects of an intensive lifestyle intervention (ILI) in overweight/obese individuals with type 2 diabetes.
Design and Methods
Weight losses and adherence (attendance, use of meal replacement products, and minutes of activity) were examined over one year of intervention in 2329 ILI participants in 209 treatment groups, which all received the same weight loss program.
Weight losses did not cluster among members of a treatment group (intra-class correlation [ICC] of .007), whereas measures of adherence had small/moderate clustering (ICCs of .05–.11). The 209 groups varied in weight losses, with a mean of 8.64 % (SD=2.35 %, interquartile range=6.82%, 10.32%), but neither size nor baseline homogeneity of members affected the outcome.
Although these findings suggest that it may not be necessary to control for clustering in behavioral weight loss studies, they also indicate that merely treating individuals in groups is not sufficient to harness social influences on weight loss.
PMCID: PMC3859866  PMID: 23804576
behavioral weight loss; clustering of outcomes; treatment groups
23.  The EARLY trials: a consortium of studies targeting weight control in young adults 
Young adulthood has been identified as a high-risk period for the development of obesity but few interventions have been tested in this population. One way to escalate our learning about effective interventions is to test a number of interventions simultaneously as a consortium of research trials. This paper describes the Early Adult Reduction of weight through LifestYle intervention (EARLY) trials. Seven research sites were funded to conduct intervention trials, agreeing to test similar primary outcomes and cooperating to use a set of common measurement tools. The EARLY consortium was able to work cooperatively using an executive committee, a steering committee, workgroups and subcommittees to help direct the common work and implement a set of common protocol and measurement tools for seven independent but coordinated weight-related intervention trials. Using a consortium of studies to help young adults reach or maintain a healthy weight will result in increased efficiency and speed in understanding the most effective intervention strategies.
PMCID: PMC4167899  PMID: 25264469
Young adults; Obesity; Intervention trials; Research consortium
24.  Post genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study 
Annals of human genetics  2013;77(5):416-425.
Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or post-menopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet<0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet=1.74E-03, I2=89.8), with a significant association in older males (P=1.39E-06) but not younger males (P=0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.
PMCID: PMC3796061  PMID: 23808484
PAGE; modifier; age; lipids; genetic association
25.  Finasteride Treatment Alters Tissue Specific Androgen Receptor Expression in Prostate Tissues 
The Prostate  2014;74(9):923-932.
Normal and pathologic growth of the prostate is dependent on the synthesis of dihydrotestosterone (DHT) from testosterone by 5α-reductase. Finasteride is a selective inhibitor of 5α-reductase 2, one isozyme of 5α-reductase found in abundance in the human prostate. The objective of this study was to investigate the effects of finasteride on androgen receptor expression and tissue morphology in human benign prostatic hyperplasia specimens.
Patients undergoing transurethral resection of the prostate and either treated or not treated with finasteride between 2004 and 2010 at the University of Wisconsin-Hospital were retrospectively identified using an institutional database. Prostate specimens from each patient were triple-stained for androgen receptor, prostate-specific antigen, and basal marker cytokeratin 5. Morphometric analysis was performed using the multispectral imaging, and results were compared between groups of finasteride treated and non-treated patients.
Epithelial androgen receptor but not stromal androgen receptor expression was significantly lower in patients treated with finasteride than in non-treated patients. Androgen receptor-regulated prostate-specific antigen was not significantly decreased in finasteride-treated patients. Significant luminal epithelial atrophy and basal cell hyperplasia were prevalent in finasteride treated patients. Epithelial androgen receptor expression was highly correlated to the level of luminal epithelial atrophy.
In this study, finasteride decreased the expression of epithelial androgen receptor in a tissue specific manner. The correlation between epithelial androgen receptor and the extent of luminal epithelial atrophy suggests that epithelial androgen receptor may be directly regulating the atrophic effects observed with finasteride treatment.
PMCID: PMC4137476  PMID: 24789081
BPH; atrophy; multispectral imaging

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