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1.  A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition 
Nature medicine  2013;19(10):1331-1337.
Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis1,2. The liver possesses a rich sinusoidal capillary network with increased hypoxia and decreased gluconeogenesis in the perivenous zone3. Here, diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in normal or diabetic db/db mice, potentiating hepatic insulin signaling, decreasing gluconeogenic gene expression, increasing glycogen storage and suppressing hepatic glucose production (HGP). VEGF inhibition induced hepatic hypoxia via sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia inducible factor-2α (HIF-2α) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling via direct and indirect induction of insulin receptor substrate 2 (IRS2), an essential insulin receptor adaptor protein4–6. Further, liver IRS2 was both necessary and sufficient to mediate HIF-2α and VEGF inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between HIF-2α–mediated hypoxic signaling and hepatic insulin action via IRS2 induction, which can be co-opted by VEGF inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for HIF-1α, which promotes glycolysis7–9, versus HIF-2α, which suppresses gluconeogenesis, and suggest novel treatment approaches for type 2 diabetes mellitus.
PMCID: PMC3795838  PMID: 24037094
2.  A Source Apportionment of U.S. Fine Particulate Matter Air Pollution 
Using daily fine particulate matter (PM2.5) composition data from the 2000–2005 U.S. EPA Chemical Speciation Network (CSN) for over 200 sites, we applied multivariate methods to identify and quantify the major fine particulate matter (PM2.5) source components in the U.S. Novel aspects of this work were: (1) the application of factor analysis (FA) to multi-city daily data, drawing upon both spatial and temporal variations of chemical species; and, (2) the exclusion of secondary components (sulfates, nitrates and organic carbon) from the source identification FA to more clearly discern and apportion the PM2.5 mass to primary emission source categories. For the quantification of source-related mass, we considered two approaches based upon the FA results: 1) using single key tracers for sources identified by FA in a mass regression; and, 2) applying Absolute Principal Component Analysis (APCA). In each case, we followed a two-stage mass regression approach, in which secondary components were first apportioned among the identified sources, and then mass was apportioned to the sources and to other secondary mass not explained by the individual sources. The major U.S. PM2.5 source categories identified via FA (and their key elements) were: Metals Industry (Pb, Zn); Crustal/Soil Particles (Ca, Si); Motor Vehicle Traffic (EC, NO2); Steel Industry (Fe, Mn); Coal Combustion (As, Se); Oil Combustion (V, Ni); Salt Particles (Na, Cl) and Biomass Burning (K). Nationwide spatial plots of the source-related PM2.5 impacts were confirmatory of the factor interpretations: ubiquitous sources, such as Traffic and Soil, were found to be spread across the nation, more unique sources (such as Steel and Metals Processing) being highest in select industrialized cities, Biomass Burning was highest in the U.S. Northwest, while Residual Oil combustion was highest in cities in the Northeastern U.S. and in cities with major seaports. The sum of these source contributions and the secondary PM2.5 components agreed well with the U.S. PM2.5 observed during the study period (mean=14.3 ug/m3; R2= 0.91). Apportionment regression analyses using single-element tracers for each source category gave results consistent with the APCA estimates. Comparisons of nearby sites indicated that the PM2.5 mass and the secondary aerosols were most homogenous spatially, while traffic PM2.5 and its tracer, EC, were among the most spatially representative of the source-related components. Comparison of apportionment results to a previous analysis of the 1979–1982 IP Network revealed similar and correlated major U.S. source category factors, albeit at lower levels than in the earlier period, suggesting a consistency in the U.S. spatial patterns of these source-related exposures over time, as well. These results indicate that applying source apportionment methods to the nationwide CSN can be an informative avenue for identifying and quantifying source components for the subsequent estimation of source-specific health effects, potentially contributing to more efficient regulation of PM2.5.
PMCID: PMC3951912  PMID: 24634604
Chemical Speciation Network (CSN); Source Apportionment; fine particulate matter mass (PM2.5); Absolute Principal Component Analysis (APCA)
3.  Racial Differences in Perception of Healthy Body Weight in Mid-Life Women: Results from Do Stage Transitions Result in Detectable Effects (STRIDE) Study 
Menopause (New York, N.Y.)  2013;20(3):269-273.
Perception of a healthy body weight may influence health behaviors including physical activity level, nutritional habits, and health outcomes, and these perceptions may vary importantly by race. Midlife is a critical period for women, which typically includes weight gain. We assessed the associations between perception of healthy body weight and body mass index (BMI) and whether they vary by race.
In the Do Stage Transitions Result in Detectable Effects (STRIDE) study, body mass index (BMI) and perception of body weight (healthy, underweight, or overweight) were measured at the baseline examination. Multinomial logistic regression models examined the associations, with race (White vs. Black) as a moderator variable.
Of 729 women enrolled, 689 women (95%, N=145 Black, N=544 White) were included in these analyses. Even though the average BMI was higher for Black women compared to White women (33.1 vs. 29.2, respectively, p<.0001), Black women were less likely to report that they weighed too much (RRR (Relative Risk Ratio) [95% CI]: 0.4 [0.2, 0.9], p 0.022) and more likely to think that they did not weigh enough (RRR [95% CI]: 14.2 [1.8, 110], p 0.011).
Although Black women in general face a greater threat of morbidity from weight-related chronic diseases, they are more likely to be accepting of their weight at higher BMI’s, relative to Whites. Weight-loss interventions and counseling about healthy body size may influence healthy behavior and reduce chronic disease risk.
PMCID: PMC3593962  PMID: 23435023
Midlife; Body Image; Weight-Perception; Race; Health; Behavior
4.  Procedures of recruiting, obtaining informed consent, and compensating research participants in Qatar: findings from a qualitative investigation 
BMC Medical Ethics  2014;15:9.
Very few researchers have reported on procedures of recruiting, obtaining informed consent, and compensating participants in health research in the Arabian Gulf Region. Empirical research can inform the debate about whether to adjust these procedures for culturally diverse settings. Our objective was to delineate procedures related to recruiting, obtaining informed consent, and compensating health research participants in the extremely high-density multicultural setting of Qatar.
During a multistage mixed methods project, field observations and qualitative interviews were conducted in a general medicine clinic of a major medical center in Qatar. Participants were chosen based on gender, age, literacy, and preferred language, i.e., Arabic, English, Hindi and Urdu. Qualitative analysis identified themes about recruitment, informed consent, compensation, and other research procedures.
A total of 153 individuals were approached and 84 enrolled; the latter showed a diverse age range (18 to 75 years); varied language representation: Arabic (n = 24), English (n = 20), Hindi (n = 20), and Urdu (n = 20); and balanced gender distribution: women (n = 43) and men (n = 41). Primary reasons for 30 declinations included concern about interview length and recording. The study achieved a 74% participation rate. Qualitative analytics revealed key themes about hesitation to participate, decisions about participation with family members as well as discussions with them as “incidental research participants”, the informed consent process, privacy and gender rules of the interview environment, reactions to member checking and compensation, and motivation for participating. Vulnerability emerged as a recurring issue throughout the process among a minority of participants.
This study from Qatar is the first to provide empirical data on recruitment, informed consent, compensation and other research procedures in a general adult population in the Middle East and Arabian Gulf. This investigation illustrates how potential research participants perceive research participation. Fundamentally, Western ethical research principles were applicable, but required flexibility and culturally informed adaptations.
PMCID: PMC3937123  PMID: 24495499
Research ethics; Recruitment; Informed consent; Cultural competence; Middle East; Research participation; Vulnerability; Confidentiality; Qualitative research; Research compensation
5.  Effects of Cancer Comorbidity on Disease Management: Making the Case for Diabetes Education (A Report from the SOAR Program) 
Population Health Management  2013;16(1):53-57.
Individuals with type II diabetes have an increased risk of cancer diagnosis (relative risk [RR]=1.12–2.50) and mortality (RR=1.4) compared to normoglycemic individuals. Biologic mechanisms, including mitogenic effects of insulin, hyperglycemia, and increased oxidative stress, as well as behavioral factors (eg, difficulty managing the comorbidity) may explain the elevated risk. To investigate the effects of the comorbidity on disease management, the authors compared diabetes education utilization in individuals with diabetes-cancer co-morbidity to utilization by individuals with diabetes in the absence of cancer. The effect of diabetes education on outcomes was further assessed in the subset of individuals with diabetes–cancer comorbidity. Administrative claims data were used for this analysis. The study population included individuals >60 years of age and members of both commercial and Medicare Advantage health plans from a private national database of payer data, but excluded Medicare fee for service and Medicaid patients. Most of these individuals were eligible to receive reimbursement for diabetes education. Diabetes education utilization was identified using procedure codes. Outcomes were assessed for a 3-year time period. There was little difference in diabetes education utilization between individuals with diabetes in the absence of cancer (3.8% utilization) and those with diabetes–cancer comorbidity (3.5% utilization). Individuals who receive diabetes education are more likely to have multiple HbA1c tests per year, fewer emergency department visits, fewer hospital admissions, and lower care-associated costs (except for outpatient and pharmacy averages). When diabetes coexists with cancer, management of diabetes often lags, making diabetes education an imperative. (Population Health Management 2013;16:53–57.
PMCID: PMC3595091  PMID: 23113633
6.  Malaria Evolution in South Asia: Knowledge for Control and Elimination 
Acta tropica  2012;121(3):256-266.
The study of malaria parasites on the Indian subcontinent should help us understand unexpected disease outbreaks and unpredictable disease presentations from Plasmodium falciparum and from Plasmodium vivax infections. The Malaria Evolution in South Asia (MESA) research program is one of ten International Centers of Excellence for Malaria Research (ICEMR) sponsored by the US National Institute of Health. In this second of two reviews, we describe why population structures of Plasmodia in India will be characterized and how we will determine their consequences on disease presentation, outcome and patterns. Specific projects will determine if genetic diversity, possibly driven by parasites with higher genetic plasticity, plays a role in changing epidemiology, pathogenesis, vector competence of parasite populations, and whether innate human genetic traits protect Indians from malaria today. Deep local clinical knowledge of malaria in India will be supplemented by basic scientists who bring new research tools. Such tools will include whole genome sequencing and analysis methods; in vitro assays to measure genome plasticity, RBC cytoadhesion, invasion, and deformability; mosquito infectivity assays to evaluate changing parasite-vector compatibilities; and host genetics to understand protective traits in Indian populations. The MESA-ICEMR study sites span diagonally across India, including a mixture of very urban and rural hospitals, each with very different disease patterns and patient populations. Research partnerships include government-associated research institutes, private medical schools, city and state government hospitals, and hospitals with industry ties. Between 2012-2017, in addition to developing clinical research and basic science infrastructure at new clinical sites, our training workshops will engage new scientists and clinicians throughout South Asia in the malaria research field.
PMCID: PMC3894252  PMID: 22266213
malaria; Plasmodium falciparum; Plasmodium vivax; India; South Asia; epidemiology; drug resistance; ICEMR
7.  Progression Rates of Carotid Intima-media Thickness and Adventitial Diameter during the Menopausal Transition 
Menopause (New York, N.Y.)  2013;20(1):8-14.
The authors assessed whether the levels and progression rates of carotid intima-media thickness (IMT) and adventitial diameter (AD) vary by menopausal stage.
249 Women (42–57 years old, premenopausal (49%) or early peri-menopausal (46%)) from the Study of Women’s Health Across the Nation were included in the current analysis. Participants were followed for up to 9 years (median=3.7 years) and had up to 5 carotid scans. Linear mixed models were used for analysis.
The overall rate of change in IMT was 0.007 mm/year. Independent of age and race, progression rate of IMT increased substantially in late peri-menopausal stage (0.017 mm/year) compared to both premenopausal (0.007 mm/year) and early peri-menopausal (0.005 mm/year) stages; (P≤0.05). For AD, while the overall rate of change was negative (−0.009 mm/year), significant positive increases in the rate of change were observed in late peri-menopausal (0.024 mm/year) and postmenopausal (0.018 mm/year) stages compared to premenopausal stage (−0.032 mm/year); (P<0.05). In final models, postmenopausal stage was independently associated with higher levels of IMT and AD (P<0.05) compared to premenopausal stage.
During the menopausal transition, the carotid artery undergoes an adaptation that is reflected in adverse changes in IMT and AD. These changes may impact the vulnerability of the vessel to disease in older women.
PMCID: PMC3528819  PMID: 22990755
atherosclerosis; carotid intima-media thickness; epidemiology; menopause; risk factors
8.  RESPECT-PTSD: Re-Engineering Systems for the Primary Care Treatment of PTSD, A Randomized Controlled Trial 
Although collaborative care is effective for treating depression and other mental disorders in primary care, there have been no randomized trials of collaborative care specifically for patients with Posttraumatic stress disorder (PTSD).
To compare a collaborative approach, the Three Component Model (3CM), with usual care for treating PTSD in primary care.
The study was a two-arm, parallel randomized clinical trial. PTSD patients were recruited from five primary care clinics at four Veterans Affairs healthcare facilities and randomized to receive usual care or usual care plus 3CM. Blinded assessors collected data at baseline and 3-month and 6-month follow-up.
Participants were 195 Veterans. Their average age was 45 years, 91% were male, 58% were white, 40% served in Iraq or Afghanistan, and 42% served in Vietnam.
All participants received usual care. Participants assigned to 3CM also received telephone care management. Care managers received supervision from a psychiatrist.
PTSD symptom severity was the primary outcome. Depression, functioning, perceived quality of care, utilization, and costs were secondary outcomes.
There were no differences between 3CM and usual care in symptoms or functioning. Participants assigned to 3CM were more likely to have a mental health visit, fill an antidepressant prescription, and have adequate antidepressant refills. 3CM participants also had more mental health visits and higher outpatient pharmacy costs.
Results suggest the need for careful examination of the way that collaborative care models are implemented for treating PTSD, and for additional supports to encourage primary care providers to manage PTSD.
PMCID: PMC3539037  PMID: 22865017
posttraumatic stress disorder; integrated primary care; veterans; randomized clinical trials; treatment
9.  Marriage and motherhood are associated with lower testosterone concentrations in women 
Hormones and behavior  2012;63(1):72-79.
Testosterone has been hypothesized to modulate the trade-off between mating and parenting effort in males. Indeed, evidence from humans and other pair-bonded species suggests that fathers and men in committed relationships have lower testosterone levels than single men and men with no children. To date, only one published study has examined testosterone in relation to motherhood, finding that mothers of young children have lower testosterone than non-mothers. Here, we examine this question in 195 reproductive-age Norwegian women. Testosterone was measured in morning serum samples taken during the early follicular phase of the menstrual cycle, and marital and maternal status were assessed by questionnaire. Mothers of young children (age ≤3) had 14% lower testosterone than childless women and 19% lower testosterone than women who only had children over age 3. Among mothers, age of the youngest child strongly predicted testosterone levels. There was a trend towards lower testosterone among married women compared to unmarried women. All analyses controlled for body mass index (BMI), age, type of testosterone assay, and time of serum sample collection. This is the first study to look at testosterone concentrations in relation to marriage and motherhood in Western women, and it suggests that testosterone may differ with marital and maternal status in women, providing further corroboration of previous findings in both sexes.
PMCID: PMC3540120  PMID: 23123222
marriage; motherhood; testosterone; endocrinology
10.  The Bereaved Parent Needs Assessment: A new instrument to assess the needs of parents whose children died in the pediatric intensive care unit* 
Critical care medicine  2012;40(11):10.1097/CCM.0b013e31825fe164.
To evaluate the reliability and validity of the Bereaved Parent Needs Assessment, a new instrument to measure parents' needs and need fulfillment around the time of their child's death in the pediatric intensive care unit. We hypothesized that need fulfillment would be negatively related to complicated grief and positively related to quality of life during bereavement.
Cross-sectional survey.
Five U.S. children's hospital pediatric intensive care units.
Parents (n = 121) bereaved in a pediatric intensive care unit 6 months earlier.
Surveys included the 68-item Bereaved Parent Needs Assessment, the Inventory of Complicated Grief, and the abbreviated version of the World Health Organization Quality of Life questionnaire. each Bereaved Parent Needs Assessment item described a potential need and was rated on two scales: 1) a 5-point rating of importance (1 = not at all important, 5 = very important) and 2) a 5-point rating of fulfillment (1 = not at all met, 5 = completely met). Three composite scales were computed: 1) total importance (percentage of all needs rated ≥4 for importance), 2) total fulfillment (percentage of all needs rated ≥4 for fulfillment), and 3) percent fulfillment (percentage of important needs that were fulfilled). Internal consistency reliability was assessed by Cronbach's α and Spearman-Brown–corrected split-half reliability. Generalized estimating equations were used to test predictions between composite scales and the Inventory of Complicated Grief and World Health Organization Quality of Life questionnaire.
Measurements and Main Results
Two items had mean importance ratings <3, and 55 had mean ratings >4. reliability of composite scores ranged from 0.92 to 0.94. Total fulfillment was negatively correlated with Inventory of Complicated Grief (r = −.29; p < .01) and positively correlated with World Health Organization Quality of Life questionnaire (r = .21; p < .05). Percent fulfillment was also significantly correlated with both outcomes. Adjusting for parent's age, education, and loss of an only child, percent fulfillment remained significantly correlated with Inventory of Complicated Grief but not with World Health Organization Quality of Life questionnaire.
The Bereaved Parent Needs Assessment demonstrated reliability and validity to assess the needs of parents bereaved in the pediatric intensive care unit. Meeting parents' needs around the time of their child's death may promote adjustment to loss. (Crit Care Med 2012; 40:3050–3057)
PMCID: PMC3865522  PMID: 22890254
bereavement; death; grief; intensive care; parents; pediatrics; quality of life
11.  Body Mass Index Following Natural Menopause and Hysterectomy with and without Bilateral Oophorectomy 
The directional and temporal nature of relationships between overweight and obesity and hysterectomy with or without oophorectomy is not well understood. Overweight and obesity may be both a risk factor for the indications for these surgeries and a possible consequence of the procedure. We used prospective data to examine whether body mass index (BMI) increased more following hysterectomy with and without bilateral oophorectomy compared to natural menopause among middle-aged women.
BMI was assessed annually for up to 10 years in the Study of Women’s Health Across the Nation (SWAN (n=1962). Piecewise linear mixed growth models were used to examine changes in BMI before and after natural menopause, hysterectomy with ovarian conservation, and hysterectomy with bilateral oophorectomy. Covariates included education, race/ethnicity, menopausal status, physical activity, self-rated health, hormone therapy use, antidepressant use, and age the visit prior to the final menstrual period (FMP; for natural menopause) or surgery (for hysterectomy/oophorectomy).
By visit 10, 1780 (90.6%) women reached natural menopause, 106 (5.5%) reported hysterectomy with bilateral oophorectomy, and 76 (3.9%) reported hysterectomy with ovarian conservation. In fully adjusted models, BMI increased for all women from baseline to FMP or surgery (annual rate of change=.19 kg/m2 per year), with no significant differences in BMI change between groups. BMI also increased for all women following FMP, but increased more rapidly in women following hysterectomy with bilateral oophorectomy (annual rate of change=.21 kg/m2 per year) as compared to following natural menopause (annual rate of change=.08 kg/m2 per year, p=.03).
In this prospective examination, hysterectomy with bilateral oophorectomy was associated with greater increases in BMI in the years following surgery than following hysterectomy with ovarian conservation or natural menopause. This suggests that accelerated weight gain follows bilateral oophorectomy among women in midlife, which may increase risk for obesity-related chronic diseases.
PMCID: PMC3530639  PMID: 23007036
menopause; oophorectomy; BMI; women’s health
12.  Psychosocial Features Associated with Lifetime Comorbidity of Major Depression and Anxiety Disorders Among a Community Sample of Mid-Life Women: The SWAN Mental Health Study 
Depression and anxiety  2012;29(12):1050-1057.
In clinical samples, comorbidity between depressive and anxiety disorders is associated with greater symptom severity and elevated suicide risk. Less is known, however, regarding the long-term psychosocial impact that a lifetime history of both MDD and one or more anxiety disorders has in community samples. This report evaluates clinical, psychological, social, and stress-related characteristics associated with a lifetime history of MDD and anxiety.
Data from 915 women aged 42–52 who were recruited as part of the the Study of Women's Health Across the Nation Mental Health Study were used to examine clinical and psychosocial features across groups of women with a SCID-diagnosed lifetime history of MDD alone, anxiety alone, both MDD and anxiety, or neither MDD nor anxiety.
As compared with women with a history of either MDD or anxiety alone, women with a comorbid history were more likely to report recurrent MDD, multiple and more severe lifetime anxiety disorders, greater depressive and anxiety symptoms, diminished social support, and more past-year distressing life events. Exploratory analyses indicated that women with a comorbid history also report more childhood abuse/neglect and diminished self-esteem, as compared with women with a history of either disorder alone.
Midlife women with a comorbid history that includes both MDD and anxiety disorders report diminished social support, more symptomatic distress, and a more severe and recurrent psychiatric history. Future research is needed to clarify the biological and psychosocial risk factors associated with this comorobid profile, and to develop targeted interventions for this at-risk group.
PMCID: PMC3592574  PMID: 22930404
major depressive disorder; anxiety disorders; comorbidity; child abuse; social support; stress, psychological
13.  Prenatal Exposure to Dental Amalgam in the Seychelles Child Development Nutrition Study: Associations with Neurodevelopmental Outcomes at 9 and 30 Months 
Neurotoxicology  2012;33(6):1511-1517.
Dental amalgam is approximately 50% metallic mercury and releases mercury vapor into the oral cavity, where it is inhaled and absorbed. Maternal amalgams expose the developing fetus to mercury vapor. Mercury vapor can be toxic, but uncertainty remains whether prenatal amalgam exposure is associated with neurodevelopmental consequences in offspring.
To determine if prenatal mercury vapor exposure from maternal dental amalgam is associated with adverse effects to cognition and development in children.
We prospectively determined dental amalgam status in a cohort of 300 pregnant women recruited in 2001 in the Republic of Seychelles to study the risks and benefits of fish consumption. The primary exposure measure was maternal amalgam surfaces present during gestation. Maternal occlusal points were a secondary measure. Outcomes were the child’s mental (MDI) and psychomotor (PDI) developmental indices of the Bayley Scales of Infant Development-II (BSID-II) administered at 9 and 30 months. Complete exposure, outcome, and covariate data were available on a subset of 242 mother-child pairs.
The number of amalgam surfaces was not significantly (p>0.05) associated with either PDI or MDI scores. Similarly, secondary analysis with occlusal points showed no effect on the PDI or MDI scores for boys and girls combined. However, secondary analysis of the 9 month MDI was suggestive of an adverse association present only in girls.
We found no evidence of an association between our primary exposure metric, amalgam surfaces, and neurodevelopmental endpoints. Secondary analyses using occlusal points supported these findings, but suggested the possibility of an adverse association with the MDI for girls at 9 months. Given the continued widespread use of dental amalgam, we believe additional prospective studies to clarify this issue are a priority.
PMCID: PMC3576043  PMID: 23064204
Amalgam; mercury; methylmercury; prenatal; neurodevelopment; co-exposure
14.  Estimating Physical Splenic Filtration of Plasmodium falciparum Infected Red Blood Cells in Malaria Patients 
Cellular microbiology  2012;14(12):1880-1891.
Splenic filtration of Plasmodium falciparum infected red blood cells has been hypothesized to influence malaria pathogenesis. We have developed a minimum cylindrical diameter (MCD) filtration model which estimates physical splenic filtration during malaria infection. The key parameter in the model is the minimum cylindrical diameter (MCD), the smallest tube or cylinder that a red blood cell (RBC) can traverse without lysing. The MCD is defined by a relationship between the RBC surface area and volume. In the MCD filtration model, the MCD filtration function represents the probability of a cell becoming physically removed from circulation. This modeling approach was implemented at a field site in Blantyre, Malawi. We analyzed peripheral blood samples from 120 study participants in 4 clinically defined groups (30 subjects each): cerebral malaria, uncomplicated malaria, aparasitemic coma, and healthy controls. We found statistically significant differences in the surface area and volumes of uninfected RBCs when healthy controls were compared to malaria patients. The estimated filtration rates generated by the MCD model corresponded to previous observations in ex vivo spleen experiments and models of red blood cell loss during acute malaria anemia. There were no differences in the estimated splenic filtration rates between cerebral malaria and uncomplicated malaria patients. The MCD filtration model estimates that at time of admission, 1 ring-stage infected RBC is physically filtered by the spleen for each parasite that remains in peripheral circulation. This field study is the first to use microfluidic devices to identify rheological diversity in RBC populations associated with malaria infection and illness in well characterized groups of children living in a malaria endemic area.
PMCID: PMC3501548  PMID: 22892025
15.  The Changing Bases of Segregation in the United States 
The nature and organization of segregation shifted profoundly in the United States over the course of the twentieth century. During the first two-thirds of the century, segregation was defined by the spatial separation of whites and blacks. What changed over time was the level at which this racial separation occurred, as macro-level segregation between states and counties gave way steadily to micro-level segregation between cities and neighborhoods. During the last third of the twentieth century, the United States moved toward a new regime of residential segregation characterized by moderating racial-ethnic segregation and rising class segregation, yielding a world in which the spatial organization of cities and the location of groups and people within them will increasingly be determined by an interaction of race and class and in which segregation will stem less from overt prejudice and discrimination than from political decisions about land use, such as density zoning.
PMCID: PMC3844132  PMID: 24298193
16.  Microfluidic approaches to malaria pathogenesis 
Cellular microbiology  2008;10(10):10.1111/j.1462-5822.2008.01216.x.
Malaria is a major poverty-related human infectious disease of the world. Over a billion individuals are under threat and several million die from malaria every year. The nature of disease, especially fatal disease, has been the subject of many studies. The consensus is that parasite-induced cytoadherance of red blood cells precipitates capillary blockage and inflammatory responses in affected organs. Reduced deformability of infected erythrocytes may also contribute to disease. What is not very clear is why people with significant parasite burdens display large variations in disease outcomes. Technologies which allow a detailed description of the cytoadherance properties of infected erythrocytes in individual patients, and which allow a complete description of the flow capabilities of red blood cell populations in that patient, would be very useful. Here we review the recent introduction of microfluidic technology to study malaria pathogenesis, including the fabrication processes. The devices are cheap, versatile, portable and require very small patient samples. With greater use in research laboratories and field sites, we eventually expect microfluidic methods to play important roles in malaria diagnosis, as well as prognosis.
PMCID: PMC3818003  PMID: 18754851
17.  Additive Partial Linear Models with Measurement Errors 
Biometrika  2008;95(3):10.1093/biomet/asn024.
We consider statistical inference for additive partial linear models when the linear covariate is measured with error. We propose attenuation-to-correction and SIMEX estimators of the parameter of interest. It is shown that the first resulting estimator is asymptotically normal and requires no undersmoothing. This is an advantage of our estimator over existing backfitting-based estimators for semiparametric additive models which require undersmoothing of the nonparametric component in order for the estimator of the parametric component be root-n consistent. This feature stems from a decrease of the bias of the resulting estimator which is appropriately derived using a profile procedure. A similar characteristic in semiparametric partially linear models was obtained by Wang et al. (2005). We also discuss the asymptotics of the proposed SIMEX approach. Finite-sample performance of the proposed estimators is assessed by simulation experiments. The proposed methods are applied to a dataset from a semen study.
PMCID: PMC3816788  PMID: 24198435
Backfitting; Correction-for-attenuation; Error-prone; Local linear regression; Semen quality study; Semiparametric estimation; SIMEX; Undersmoothing
18.  Endogenous Sex Hormones Impact the Progression of Subclinical Atherosclerosis in Women during the Menopausal Transition 
Atherosclerosis  2012;225(1):180-186.
To determine whether endogenous sex hormones (estradiol (E2), testosterone (T), sex hormone binding globulin (SHBG), and follicle-stimulating hormone (FSH)) are longitudinally associated with progression of atherosclerosis among women at midlife.
249 Pre- or early peri-menopausal women (42–57 years) from the Study of Women’s Health Across the Nation (SWAN) were followed for up to 9 years (median=3.7 years) and had up to 5 repeated measures of common carotid intima-media thickness (IMT) and adventitial diameter (AD). Linear mixed models were used for statistical analysis. Final models included age at baseline, time since baseline, cycle day of blood draw, race, income, SBP, BMI, insulin resistance index, lipids, C-reactive protein and co-morbidity.
In final models for IMT, each one log unit decrease in SHBG was associated with a 0.005 mm/year increase in IMT progression (P=0.003). E2, T, and FSH were not associated with level or progression of IMT. For AD, each one log unit decrease in E2 was associated with a 0.012 mm/year increase in AD progression (P=0.04) and each one log unit increase in FSH was associated with a 0.016 mm/year increase in AD progression (P=0.003). T and SHBG were not associated with progression or level of AD.
Independent of SBP, BMI, lipids and other covariates, lower E2 and SHBG, and higher FSH were associated with increased subclinical atherosclerosis progression in women at midlife.
PMCID: PMC3478422  PMID: 22981430
subclinical atherosclerosis; sex hormones; women
Omega  2012;65(2):151-168.
Many childhood deaths in the United States occur in pediatric intensive care units (PICUs) and parents have special needs in this death context. As an interdisciplinary research team, we discuss conceptual and design issues encountered in creating a new instrument, the Bereaved Parent Needs Assessment–PICU, for assessing parents’ needs in this setting. Using a qualitative approach, our team previously explored how the culture and related ways of providing care in one urban Midwestern children’s hospital PICU affected parents’ bereavement needs and experiences. We describe using this qualitative foundation in the development of a new quantitative instrument to more widely validate and measure bereaved parents’ needs around the time of a child’s death across multiple PICUs. We highlight a series of issues that warrant consideration in designing a research instrument for this vulnerable population including setting and context, format and content, temporality, recruitment, and content expertise.
PMCID: PMC3814013  PMID: 22953511
20.  A microfluidic system to study cytoadhesion of Plasmodium falciparum infected erythrocytes to primary brain microvascularendothelial cells 
Lab on a chip  2011;11(17):10.1039/c1lc20131j.
The cellular events leading to severe and complicated malaria in some Plasmodium falciparum infections are poorly understood. Additional tools are required to better understand the pathogenesis of this disease. In this technical report, we describe a microfluidic culture system and image processing algorithms that were developed to observe cytoadhesion interactions of P. falciparum parasitized erythrocytes rolling on primary brain microvascularendothelial cells. We isolated and cultured human primary vascular endothelial cells in a closed loop microfluidic culture system where a peristaltic pump and media reservoirs were integrated onto a microscope stage insert. We developed image processing methods to enhance contrast of rolling parasitized erythrocytes on endothelial cells and to estimate the local wall shear stress. The velocity of parasitized erythrocytes rolling on primary brain microvascularendothelial cells was then measured under physiologically relevant wall shear stresses. Finally, we deployed this method successfully at a field site in Blantyre, Malawi. The method is a promising new tool for the investigation of the pathogenesis of severe malaria.
PMCID: PMC3809019  PMID: 21743938
21.  Dendritic cell-specific disruption of TGFβ receptor II leads to altered regulatory T-cell phenotype and spontaneous multi-organ autoimmunity 
In vitrodata and transgenic mouse models suggest a role for TGFβ signaling in dendritic cells (DC) to prevent autoimmunity primarily through maintenance of DCs in their immature and tolerogenic state characterized by low expression of MHCII and co-stimulatory molecules, and increased expression of indoleamine 2,3-dioxygenase (IDO), among others. To test whether a complete lack of TGFβ signaling in DCs predisposes mice to spontaneous autoimmunity, and to verify the mechanisms implicated previously in vitro, we generated conditional knock-out mice with Cre-mediated DC-specific deletion of Tgfbr2 (DC-Tgfbr2 KO). DC-Tgfbr2 KO mice die before 15 weeks of age with multi-organ autoimmune inflammation and spontaneous activation of T and B cells. Interestingly, there were no significant differences in the expression of MHCII, co-stimulatory molecules, or IDO in secondary lymphoid organ DCs, although Tgfbr2-deficient DCs were more pro-inflammatory in vitro and in vivo. DC-Tgfbr2 KO showed attenuated FoxP3 expression in regulatory T cells (Tregs) and abnormal expansion of CD25−FoxP3+ Tregs in vivo. Tgfbr2-deficient DCs secreted elevated levels of IFNγ and were not capable of directing antigen-specific Treg conversion unless in the presence of anti-IFNγ blocking antibody. Adoptive transfer of iTregs into DC-Tgfbr2 KO mice partially rescued the phenotype. Therefore, in vivo, TGFβ signaling in DCs is critical in the control of autoimmunity through both Treg dependent and independent mechanisms, but it does not affect MHCII and co-stimulatory molecule expression.
PMCID: PMC3466393  PMID: 22972928
22.  Progress in the Diagnosis of Appendicitis: A Report from Washington State’s Surgical Care and Outcomes Assessment Program (SCOAP) 
Annals of surgery  2012;256(4):586-594.
Studies suggest that CT and US can effectively diagnose and rule-out appendicitis, safely reducing negative appendectomies (NA); however, some within the surgical community remain reluctant to add imaging to clinical evaluation of patients with suspected appendicitis. The Surgical Care and Outcomes Assessment Program (SCOAP) is a physician-led quality initiative that monitors performance by benchmarking processes of care and outcomes. Since 2006, accurate diagnosis of appendicitis has been a priority for SCOAP. The objective of this study was to evaluate the association between imaging and NA in the general community.
Data were collected prospectively for consecutive appendectomy patients (age > 15) at nearly 60 hospitals. SCOAP data are obtained directly from clinical records, including radiology, operative, and pathology reports. Multivariate logistic regression models were used to examine the association between imaging and NA. Tests for trends over time were also conducted.
Among 19,327 patients (47.9% female) who underwent appendectomy, 5.4% had NA. Among patients who were imaged, frequency of NA was 4.5%, whereas among those who were not imaged, NA was 15.4% (p < 0.001). This association was consistent for males (3% vs. 10%, p < 0.001) and for reproductive-age females (6.9% vs. 24.7%, p < 0.001). In a multivariate model adjusted for age, sex, and WBC, odds of NA for patients not imaged were 3.7 times the odds for those who received imaging (95%CI 3.0 – 4.4). Among SCOAP hospitals, use of imaging increased and NA decreased significantly over time; frequency of perforation was unchanged.
Patients who were not imaged during work-up for suspected appendicitis had over three times the odds of NA as those who were imaged. Routine imaging in the evaluation of patients suspected to have appendicitis can safely reduce unnecessary operations. Programs such as SCOAP improve care through peer-led, benchmarked practice change.
PMCID: PMC3475492  PMID: 22964731
23.  Choline status and neurodevelopmental outcomes at 5 years of age in the Seychelles Child Development Nutrition Study 
The British journal of nutrition  2013;110(2):330-336.
Choline is an essential nutrient that is found in many food sources and plays a critical role in the development of the central nervous system. Animal studies have shown that choline status pre- and postnatally can have long-lasting effects on attention and memory; however, effects in human subjects have not been well studied. The aim of the present study was to examine the association between plasma concentrations of free choline and its related metabolites in children and their neurodevelopment in the Seychelles Child Development Nutrition Study, an ongoing longitudinal study assessing the development of children born to mothers with high fish consumption during pregnancy. Plasma concentrations of free choline, betaine, dimethylglycine (DMG), methionine and homocysteine and specific measures of neurodevelopment were measured in 210 children aged 5 years. The children’s plasma free choline concentration (9·17 (sd 2·09) µmol/l) was moderately, but significantly, correlated with betaine (r 0·24; P=0·0006), DMG (r 0·15; P=0·03), methionine (r 0·24; P=0·0005) and homocysteine (r 0·19; P=0·006) concentrations. Adjusted multiple linear regression revealed that betaine concentrations were positively associated with Preschool Language Scale – total language scores (β = 0·066; P=0·04), but no other associations were evident. We found no indication that free choline concentration or its metabolites, within the normal physiological range, are associated with neurodevelopmental outcomes in children at 5 years of age. As there is considerable animal evidence suggesting that choline status during development is associated with cognitive outcome, the issue deserves further study in other cohorts.
PMCID: PMC3723412  PMID: 23298754
Choline; Neurodevelopment; Children
24.  The role of a student-run clinic in providing primary care for Calgary’s homeless populations: a qualitative study 
Despite the increasing popularity of Student-Run Clinics (SRCs) in Canada, there is little existing literature exploring their role within the Canadian healthcare system. Generalizing American literature to Canadian SRCs is inappropriate, given significant differences in healthcare delivery between the two countries. Medical students at the University of Calgary started a SRC serving Calgary’s homeless population at the Calgary Drop-In and Rehabilitation Centre (CDIRC). This study explored stakeholders’ desired role for a SRC within Calgary’s primary healthcare system and potential barriers it may face.
Individual and group semi-structured interviews were undertaken with key stakeholders in the SRC project: clients (potential patients), CDIRC staff, staff from other stakeholder organizations, medical students, and faculty members. Convenience sampling was used in the recruitment of client participants. Interview transcripts were analyzed using a coding template which was derived from the literature.
Participants identified factors related to the clinic and to medical students that suggest there is an important role for a SRC in Calgary. The clinic was cited as improving access to primary healthcare for individuals experiencing homelessness. It was suggested that students may be ideally suited to provide empathetic healthcare to this population. Barriers to success were identified, including continuity of care and the exclusion of some subsets of the homeless population due to location.
SRCs possess several unique features that may make them a potentially important primary healthcare resource for the homeless. Participants identified numerous benefits of the SRC to providing primary care for homeless individuals, as well as several important limitations that need to be accounted for when designing and implementing such a program.
PMCID: PMC3718696  PMID: 23866968
Primary care; Homeless persons; Medical student; Physician shortage areas
25.  Are vasomotor symptoms associated with sleep characteristics among symptomatic midlife women? Comparisons of self-report and objective measures 
Menopause (New York, N.Y.)  2012;19(7):742-748.
Many women report vasomotor symptoms (VMS) and sleep problems during the menopausal transition. Although reported VMS are consistently related to reported sleep disturbance, findings using physiologic measures of VMS or sleep have been more mixed. Our objective was to examine whether more VMS during sleep are associated with poorer sleep among midlife women with VMS using physiologic measures of both VMS and sleep.
A subcohort of participants (N = 52) with VMS, a uterus and both ovaries, and free of medications affecting VMS from the Pittsburgh site of the Study of Women’s Health Across the Nation underwent four 24-hour periods of in-home ambulatory VMS and sleep measurement. Measures included sternal skin conductance for the measurement of VMS, actigraphy for assessing sleep, a VMS diary, and a sleep diary completed before bed and upon waking. Associations between VMS and sleep were evaluated using generalized estimating equations with covariates age, body mass index, medications affecting sleep, race, financial strain, and depressive symptoms.
More VMS recalled upon waking were associated with significantly lower actigraphy-assessed sleep efficiency, significantly higher wakefulness after sleep onset, and somewhat longer sleep latency. Conversely, physiologically measured VMS and VMS reported during the night were largely unrelated to sleep characteristics.
Associations between VMS and sleep may depend more on the awareness of and recall of VMS rather than solely on their physiologic occurrence.
PMCID: PMC3551537  PMID: 22415568
Hot flashes; Night sweats; Vasomotor symptoms; Sleep; Actigraphy; Menopause

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