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1.  Increasing Incidence of Type 1 Diabetes in Youth 
Diabetes Care  2013;36(6):1597-1603.
The purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000–2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes.
Diabetes cases were obtained through a retrospective population-based registry. Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004. The secondary source of validation was the School District of Philadelphia. Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period.
The overall age-adjusted incidence rate in 2000–2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025). The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort. Children aged 0–4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children. The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children.
The incidence of type 1 diabetes is rising among children in Philadelphia. The incidence rate has increased by 29% since the 1985–1989 cohort. The most marked increases were among white children ages 10–14 years and black children ages 0–4 years. The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children.
PMCID: PMC3661835  PMID: 23340888
2.  Conducting Research Using the Electronic Health Record Across Multi-Hospital Systems: Semantic Harmonization Implications for Administrators 
Administrators play a major role in choosing and managing the use of the electronic health record (EHR). The documentation policies and EHR changes enacted or approved by administrators affect the ability to use clinical data for research. This article illustrates the challenges that can be avoided through awareness of the consequences of customization, variations in documentation policies and quality, and user interface features. Solutions are posed that assist administrators in avoiding these challenges and promoting data harmonization for research and quality improvement.
PMCID: PMC3714548  PMID: 23708504
3.  Developing a Model of the Benefits and Burdens of Research Participation in Cancer Clinical Trials 
AJOB primary research  2012;3(2):10-23.
Recruiting and retaining human participants in cancer clinical trials is challenging for many investigators. Although we expect participants to identify and weigh the benefits and burdens of research participation for themselves, it is not clear what burdens adult cancer participants perceive in relation to benefits. We identify key attributes and develop an initial conceptual framework of benefit and burden based on interviews with individuals enrolled in cancer clinical research.
Semistructured interviews were conducted with a purposive sample of 32 patients enrolled in cancer clinical trials at a large northeastern cancer center. Krueger's guidelines for qualitative methodology were followed.
Respondents reported a range of benefits and burdens associated with research participation. Benefits such as access to needed medications that subjects otherwise might not be able to afford, early detection and monitoring of the disease, potential for remission or cure, and the ability to take control of their lives through actively participating in the trial were identified. Burdens included the potentiality of side effects, worry and fear of the unknown, loss of job support, and financial concerns.
Both benefit and burden influence research participation, including recruitment and retention in clinical trials. Dimensions of benefit and burden include physical, psychological, economic, familial, and social. Understanding the benefit-burden balance involved in the voluntary consent of human subjects is a fundamental tenet of research and important to ensure that subjects have made an informed decision regarding their decision to participate in clinical research.
PMCID: PMC3989990  PMID: 24748992
benefits; burdens; cancer; clinical trials; qualitative methods
4.  Immunological and Virological Analyses of Rhesus Macaques Immunized with Chimpanzee Adenoviruses Expressing the Simian Immunodeficiency Virus Gag/Tat Fusion Protein and Challenged Intrarectally with Repeated Low Doses of SIVmac 
Journal of Virology  2013;87(17):9420-9430.
Human adenovirus (AdHu)-based candidate AIDS vaccine can provide protection from simian immunodeficiency virus (SIV) transmission and disease progression. However, their potential use may be limited by widespread preexisting immunity to the vector. In contrast, preexisting immunity to chimpanzee adenoviruses (AdC) is relatively rare. In this study, we utilized two regimens of prime-boost immunizations with AdC serotype SAd-V23 (also called AdC6) and SAd-V24 (also called AdC7) expressing SIV Gag/Tat to test their immunogenicity and ability to protect rhesus macaques (RMs) from a repeated low-dose SIVmac239 challenge. Both AdC6 followed by AdC7 (AdC6/7) and AdC7 followed by AdC6 (AdC7/6) induced robust SIV Gag/Tat-specific T cell responses as measured by tetramer staining and functional assays. However, no significant protection from SIV transmission was observed in either AdC7/6- or AdC7/6-vaccinated RMs. Interestingly, in the RMs showing breakthrough infections, AdC7/6-SIV immunization was associated with a transient but significant (P = 0.035 at day 90 and P = 0.033 at day 120 postinfection) reduction in the setpoint viral load compared to unvaccinated controls. None of the measured immunological markers (i.e., number or functionality of SIV-specific CD8+ and CD4+ T cell responses and level of activated and/or CCR5+ CD4+ target cells) at the time of challenge correlated with protection from SIV transmission in the AdC-SIV-vaccinated RMs. The robust immunogenicity observed in all AdC-immunized RMs and the transient signal of protection from SIV replication exhibited by AdC7/6-vaccinated RMs even in the absence of any envelope immunogen suggest that AdC-based vectors may represent a promising platform for candidate AIDS vaccines.
PMCID: PMC3754116  PMID: 23804645
5.  Use of mobile telemedicine for cervical cancer screening 
Visual inspection of the cervix with application of 4% acetic acid (VIA) is an inexpensive alternative to cytology-based screening in areas where resources are limited, such as in many developing countries. We have examined the diagnostic agreement between off-site (remote) expert diagnosis using photographs of the cervix (photographic inspection with acetic acid, PIA) and in-person VIA. The images for remote evaluation were taken with a mobile phone and transmitted by MMS. The study population consisted of 95 HIV-positive women in Gaborone, Botswana. An expert gynaecologist made a definitive positive or negative reading on the PIA results of 64 out of the 95 women whose PIA images were also read by the nurse midwives. The remaining 31 PIA images were deemed insufficient in quality for a reading by the expert gynaecologist. The positive nurse PIA readings were concordant with the positive expert PIA readings in 82% of cases, and the negative PIA readings between the two groups were fully concordant in 89% of cases. These results suggest that mobile telemedicine may be useful to improve access of women in remote areas to cervical cancer screening utilizing the VIA `see-and-treat' method.
PMCID: PMC3746464  PMID: 21551217
6.  Determinants of Excessive Daytime Sleepiness and Fatigue in Adults with Heart Failure 
Clinical nursing research  2011;21(3):271-293.
Little is known about excessive daytime sleepiness (EDS) in heart failure (HF). The aim of this cross-sectional descriptive study was to describe the prevalence of EDS and factors associated with it in HF. A secondary purpose was to explore the correlates of fatigue. We enrolled a consecutive sample of 280 adults with a confirmed diagnosis of chronic HF from three outpatient settings in the northeastern US. Patients with major depressive illness were excluded. Clinical, sociodemographic, behavioral, and perceptual factors were explored as possible correlates of EDS. Using an Epworth Sleepiness Scale score >10, the prevalence of EDS was 23.6%. Significant determinants of EDS were worse sleep quality (p=0.048), worse functional class (p=0.004), not taking a diuretic (p=0.005), and lack of physical activity (p=0.04). Only sleep quality was associated with fatigue (p<0.001). Sleep disordered breathing was not significantly associated with EDS or with fatigue. These factors may be amenable to intervention.
PMCID: PMC3501004  PMID: 21878581
fatigue; physical activity; exercise; diuretics; functional class; excessive daytime sleepiness; heart failure
7.  Double jeopardy: the influence of excessive daytime sleepiness and impaired cognition on health-related quality of life in adults with heart failure 
European Journal of Heart Failure  2012;14(7):730-736.
To determine how excessive daytime sleepiness (EDS) and impaired cognition contribute to health-related quality of life (HRQL) in heart failure (HF).
Methods and results
Adults with chronic HF were enrolled into a prospective cohort study. Data were obtained from 280 subjects enrolled from three sites in the northeastern USA; 242 completed the 6-month study. At baseline, cohorts with and without EDS were identified using the Epworth Sleepiness Scale. Each EDS group was further subdivided into those with and without impaired cognition using a battery of five neuropsychological tests. Two disease-specific measures, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Functional Outcomes of Sleep Questionnaire (FOSQ), were used to measure HRQL. General linear modelling of square-transformed variables was used to test the hypothesis that cohort membership was a significant predictor of HRQL. At 6 months the remaining sample was 62.5 [standard deviation (SD) 12] years old, mostly male (63%), white (65%), and functionally compromised [72% New York Heart Association (NYHA) class III/IV]. The cohort with both EDS and impaired cognition had the lowest KCCQ overall summary score (60.5 ± 22.5) compared with the cohort without EDS or impaired cognition (74.6 ± 17.4, P ≤ 0.001). A similar effect was seen on the FOSQ (16.0 ± 2.8 vs. 18.5 ± 2.2, P < 0.001).
Impaired cognition alone did not explain poor HRQL, but the addition of EDS poses a significant risk for poor HRQL. Interventions designed to influence EDS may improve HRQL in this population.
PMCID: PMC3380544  PMID: 22510422
Heart failure; Quality of life; Sleep; Cognition
8.  Predictors of Objectively Measured Medication Nonadherence in Adults with Heart Failure 
Circulation. Heart Failure  2012;5(4):430-436.
Medication nonadherence rates are high. The factors predicting nonadherence in heart failure (HF) remain unclear.
Methods and Results
A sample of 202 adults with HF was enrolled from the Northeastern U.S. and followed for 6 months. Specific aims were to describe the types of objectively measured medication nonadherence (e.g. taking, timing, dosing, drug holidays) and to identify contributors to nonadherence 6 months after enrollment. Latent growth mixture modeling (GMM) was used to identify distinct trajectories of adherence. Indicators of the five World Health Organization (WHO) dimensions of adherence (socioeconomic, condition, therapy, patient, and health care system) were tested to identify contributors to nonadherence. Two distinct trajectories were identified and labeled persistent adherence (77.8%) and steep decline (22.3%). Three contributors to the steep decline in adherence were identified. Participants with lapses in attention (adjusted odds ratio (OR) = 2.65, p=0.023), those with excessive daytime sleepiness (OR = 2.51, p=0.037), and those with two or more medication dosings per day (OR = 2.59, p=0.016) were more likely to have a steep decline in adherence over time than to have persistent adherence.
Two distinct patterns of adherence were identified. Three potentially modifiable contributors to nonadherence have been identified.
PMCID: PMC3405361  PMID: 22647773
heart failure; medication adherence; patient compliance; self-care; sleep; World Health Organization
9.  Recent and Past Intimate Partner Abuse and HIV Risk Among Young Women 
To examine the associations between past intimate partner abuse experienced during adolescence (verbal and physical), recent intimate partner abuse (verbal, physical, and sexual), and HIV risk (as indicated by lack of condom use) for sexually active young adult women in relationships with male partners.
Secondary data analysis of waves II and III of the National Longitudinal Study of Adolescent Health (Add Health).
The Add Health Study is a longitudinal, in-home survey of a nationally representative sample of adolescents.
Analyses involved 2,058 sexually active young adult women.
Main Outcome Measures
HIV risk was measured by consistent condom use over the past 12 months.
Physical and verbal abuse experienced in adolescence were associated with physical/verbal abuse experienced in young adulthood. Young, sexually active women experiencing no abuse in their relationships were more likely to consistently use condoms in the past 12 months than were their abused counterparts.
A causal pathway may exist between prior abuse, current abuse, and HIV risk.
PMCID: PMC3677848  PMID: 18336447
HIV; adolescent; risk taking; intimate partner violence; dating violence; sexually transmitted diseases
10.  Parent–Adolescent Communication About Sexual Pressure, Maternal Norms About Relationship Power, and STI/HIV Protective Behaviors of Minority Urban Girls 
Racial/ethnic minority adolescent girls bear a disproportionate risk for HIV and face barriers to autonomous sexual decision making, but parental messages may help protect against sexual risk taking. The authors examined African American and Hispanic girls’ sexually transmitted infection (STI) and HIV prevention practices, parent–adolescent communication about sexual pressure, and maternal gender norms (N = 118). Teens were more likely to practice consistent STI/HIV prevention when mothers talked about partner sexual pressure (p = .017) and fathers talked about resisting partner sexual pressure (p = .034). Sexually active girls who perceived that their mothers held egalitarian beliefs about partner decision making had more consistent condom use (p = .029). Given the context of increased STI/HIV risk, it is critical that parents discuss partner dynamics with daughters. Nurses play a unique role in facilitating these conversations; they provide parents with age-appropriate resources and assist in normalizing fears, which can help increase parent–child sexual-risk communication.
PMCID: PMC3677849  PMID: 21672881
parent–adolescent communication; sexual decision making; sexual pressure; partner relationships; sexual risk; adolescent females; HIV prevention
11.  Sexual Relationship Power, Intimate Partner Violence, and Condom Use Among Minority Urban Girls 
Journal of interpersonal violence  2008;23(12):1694-1712.
This study examined the association between sexual relationship power, intimate partner violence, and condom use among African American and Hispanic urban girls. In this sample of 56 sexually active girls, 50% did not use condoms consistently and therefore were at higher risk for acquiring HIV or sexually transmitted diseases (STDs). Teens who experienced more intimate partner violence had a significantly higher likelihood of inconsistent condom use and therefore a greater risk for HIV/STDs. Girls' sense of sexual control in their relationships was not directly associated with inconsistent condom use but was inversely related to verbal and emotional abuse. Interventions aimed at reducing HIV/STD risk for adolescent girls need to address patterns of dominance and control in adolescent relationships as well as multiple forms of partner violence. This suggests the need for multilevel intervention approaches that promote girls' agency and multiple ways to keep girls safe from perpetrators of partner abuse.
PMCID: PMC3677854  PMID: 18349344
adolescents; prevention; condom use; partner abuse; relationship power; intimate partner violence
12.  The Epidemiology of Intensive Care Unit Readmissions in the United States 
Rationale: The incidence of intensive care unit (ICU) readmissions across the United States is unknown.
Objectives: To determine incidence of ICU readmissions in United States hospitals, and describe the distribution of time between ICU discharges and readmissions.
Methods: This retrospective cohort study used 196,202 patients in 156 medical and surgical ICUs in 106 community and academic hospitals participating in Project IMPACT from April 1, 2001, to December 31, 2007. We used mixed-effects logistic regression, adjusting for patient and hospital characteristics, to describe how ICU readmission rates differed across patient types, ICU models, and hospital types.
Measurements and Main Results: Measurements consisted of 48- and 120-hour ICU readmission rates and time to readmission. A total of 3,905 patients (2%) were readmitted to the ICU within 48 hours, and 7,171 (3.7%) within 120 hours. In adjusted analysis, there was no difference in ICU readmissions across patient types or ICU models. Among medical patients, those in academic hospitals had higher odds of 48- and 120-hour readmission than patients in community hospitals without residents (1.51 [95% confidence interval, 1.12–2.02] and 1.63 [95% confidence interval, 1.24–2.16]). Median time to ICU readmission was 3.07 days (interquartile range, 1.27–6.58). Closed ICUs had the longest times to readmission (3.55 d [interquartile range, 1.42–7.50]).
Conclusions: Approximately 2% and 4% of ICU patients discharged to the ward are readmitted within 48 and 120 hours, within a median time of 3 days. Medical patients in academic hospitals are more likely to be readmitted than patients in community hospitals without residents. ICU readmission rates could be useful for policy makers and investigations into their causes and consequences.
PMCID: PMC3359937  PMID: 22281829
ICU readmissions; quality indicators; hospital trends
13.  Posterior leaflet augmentation improves leaflet tethering in repair of ischemic mitral regurgitation☆,☆☆ 
Objectives: Ischemic mitral regurgitation results from annular dilatation, leaflet tethering and leaflet flattening. Undersized annuloplasty corrects annular dilatation but worsens leaflet tethering and flattening. This exacerbation of abnormal leaflet geometry may contribute to poor repair results for ischemic mitral regurgitation (IMR). Using a sheep model of IMR, we hypothesized that posterior leaflet augmentation and less-extreme annular undersizing would relieve tethering and increase leaflet curvature. Methods: Eight weeks after posterolateral infarct, 10 sheep with ≥2+ IMR underwent either a 24-mm planar ring annuloplasty (n = 5) or a 30-mm planar ring annuloplasty with concomitant posterior leaflet augmentation (n = 5). Real-time three-dimensional echocardiography allowed measurement of indices of leaflet curvature and tethering before and after annuloplasty. Results: Comparing pre- and post-repair values in the P1, P2, and P3 leaflet regions, undersized 24-mm ring annuloplasty made no significant difference to mean septolateral curvature (0.23–0.26, 0.33–0.29, and 0.27–0.37 cm−1, respectively), whereas leaflet augmentation in combination with a 30-mm ring annuloplasty increased septolateral curvature (P1 0.30–1.02, P2 0.31–1.23, and P3 0.35–0.84 cm−1, p-values ≪ 0.05). The mean tethering angle formed between the annular plane and the posterior leaflet increased in all three posterior regions for the 24-mm ring group (P1 12–23°, P2 26–31°, and P3 16–25°), but decreased in all regions for the group undergoing leaflet augmentation (P1 +5 to −6°, P2 +13 to −13°, P3 +16-15°, all p-values ≪ 0.05). Conclusions: Undersized annuloplasty exacerbates leaflet tethering. Posterior leaflet augmentation with less severe annular reduction increases leaflet curvature and decreases tethering; this technique more completely addresses the pathogenic mechanism of IMR and may improve repair durability.
PMCID: PMC3598376  PMID: 21546260
Echocardiography; Mitral regurgitation; Mitral valve repair; Myocardial infarction; Posterior leaflet
14.  Ovarian Stimulation and Low Birth Weight in Infants Conceived Through In Vitro Fertilization 
Obstetrics and gynecology  2011;118(4):863-871.
Singleton infants born after in-vitro fertilization (IVF) are at increased risk for low birth weight (LBW) and/or preterm delivery. We sought to assess if the alteration of the peri-implantation maternal environment due to ovarian stimulation may contribute to increased risk in in vitro fertilization (IVF) births.
The Society of Assisted Reproductive Technology database was used to identify IVF-conceived infants born in the United States between 2004-2006. Associations were assessed in infants born after fresh compared with frozen and thawed embryo transfer in women of similar ovarian responsiveness, in paired analysis of infants born to the same woman following both types of embryo transfer, and in infants born following oocyte donation.
Of 56,792 infants identified, 38,626 and 18,166 were conceived following transfer of fresh and frozen embryos, respectively. In singletons, there was no difference in preterm delivery. However, the odds of overall low birth weight (LBW) (10% vs.7.2%; AOR 1.35, 95% CI 1.20-1.51), LBW at term (2.5% vs. 1.2%; AOR 1.73, 95% CI 1.31-2.29), and preterm LBW (34.1% vs. 23.8%; AOR 1.49, 95% CI 1.24-1.78) were all significantly higher following fresh embryo transfer. In singletons following either fresh or frozen embryo transfer in the same patient, this association was even stronger (LBW: [11.5% vs. 5.6%; AOR 4.66, 95% CI 1.18 – 18.38,). In oocyte donor recipients who do not undergo any ovarian hormonal stimulation for either a fresh or a frozen embryo transfer, no difference in LBW was demonstrated (11.5% vs.11.3%; AOR 0.99, 95% CI 0.82 – 1.18).
The ovarian stimulation-induced maternal environment appears to represent an independent mediator contributing to the risk of LBW, but not preterm delivery, in infants conceived following IVF.
PMCID: PMC3178887  PMID: 21934450
15.  The Effect of Insurance Status on Mortality and Procedural Use in Critically Ill Patients 
Rationale: Lack of health insurance may be an independent risk factor for mortality and differential treatment in critical illness.
Objectives: To determine whether uninsured critically ill patients had differences in 30-day mortality and critical care service use compared with those with private insurance and to determine if outcome variability could be attributed to patient-level or hospital-level effects.
Methods: Retrospective cohort study using Pennsylvania hospital discharge data with detailed clinical risk adjustment, from fiscal years 2005 and 2006, consisting of 167 general acute care hospitals, with 138,720 critically ill adult patients 64 years of age or younger.
Measurements and Main Results: Measurements were 30-day mortality and receipt of five critical care procedures. Uninsured patients had an absolute 30-day mortality of 5.7%, compared with 4.6% for those with private insurance and 6.4% for those with Medicaid. Increased 30-day mortality among uninsured patients persisted after adjustment for patient characteristics (odds ratio [OR], 1.25 for uninsured vs. insured; 95% confidence interval [CI], 1.04–1.50) and hospital-level effects (OR, 1.26; 95% CI, 1.05–1.51). Compared with insured patients, uninsured patients had decreased risk-adjusted odds of receiving a central venous catheter (OR, 0.84; 95% CI, 0.72–0.97), acute hemodialysis (OR, 0.59; 95% CI, 0.39–0.91), and tracheostomy (OR, 0.43; 95% CI, 0.29–0.64).
Conclusions: Lack of health insurance is associated with increased 30-day mortality and decreased use of common procedures for the critically ill in Pennsylvania. Differences were not attributable to hospital-level effects, suggesting that the uninsured have a higher mortality and receive fewer procedures when compared with privately insured patients treated at the same hospitals.
PMCID: PMC3208649  PMID: 21700910
insurance; intensive care unit; critical care; mortality
16.  Vitamin D Deficiency is Associated with Type 2 Diabetes Mellitus in HIV Infection 
AIDS (London, England)  2011;25(4):525-529.
Metabolic complications, including type 2 diabetes mellitus (DM) and metabolic syndrome, are increasingly recognized among HIV-infected individuals. Low vitamin D levels increase the risk of type 2 DM, and vitamin D supplementation has been shown to decrease the risk of type 2 DM in patients without HIV infection.
The primary objective was to determine whether vitamin D deficiency (serum 25-hyrdoxyvitamin D<20 ng/mL) was associated with type 2 DM among HIV-infected patients. Our secondary objective was to determine whether vitamin D deficiency was associated with metabolic syndrome in HIV.
We conducted a cross-sectional study among subjects enrolled in the prospective Modena (Italy) HIV Metabolic Clinic Cohort. Clinical and laboratory data, including history of type 2 DM, fasting blood glucose, components of metabolic syndrome, and 25-hydroxyvitamin D levels, were obtained for all subjects.
After adjusting for vitamin D supplementation, sex, age, body mass index, and hepatitis C virus co-infection, vitamin D deficiency was associated with type 2 DM (adjusted OR, 1.85; 95% CI, 1.03–3.32; p=.038). The association between vitamin D deficiency and metabolic syndrome was not significant after adjusting for vitamin D supplementation, sex age and body mass index (adjusted OR 1.32; 95% CI, 1.00–1.75;p=.053).
Our study demonstrates an association between vitamin D deficiency and type 2 DM. Clinical trials are needed to better characterize the association between vitamin D deficiency and type 2 DM in HIV infection and to evaluate whether vitamin D is able to prevent or delay the onset of type 2 DM.
PMCID: PMC3366629  PMID: 21178753
vitamin D deficiency; type 2 DM; insulin resistance; metabolic syndrome
17.  Relationships Between Physical and Non-Physical Forms of Intimate Partner Violence and Depression among Urban Minority Adolescent Females 
Little is known about intimate partner violence (IPV) and depression among low income, urban African American and Hispanic adolescent females.
Interviews with 102 urban African American and Hispanic adolescent females examined physical abuse, emotional/verbal abuse, and threats, and their unique and combined associations with depression.
One-quarter of the sample experienced all three types of abuse. Non-physical forms of IPV were significantly associated with depression.
Some urban adolescent females from lower income households experience high rates of IPV. Physical and non-physical forms of IPV are important in understanding and responding to depression in this population.
PMCID: PMC3100197  PMID: 21617762
Violence; depression; adolescence
18.  Excessive Daytime Sleepiness is Associated with Poor Medication Adherence in Adults with Heart Failure 
Journal of cardiac failure  2010;17(4):340-348.
A relationship between excessive daytime sleepiness (EDS) and poor treatment adherence has been suspected but not confirmed. We hypothesized that medication adherence would be poorer in adults with heart failure (HF) and EDS and that cognitive status would be the mechanism of effect.
A sample of 280 adults with chronic HF was enrolled into a prospective cohort comparison study. We identified a cohort with EDS and a control group without EDS and further divided both groups into those with and without mild cognitive decline. Data on medication adherence was obtained at baseline, 3- and 6-months using the Basel Assessment of Adherence Scale (BAASIS). Regression analysis was used to clarify the contribution of EDS and cognition to medication adherence and to assess relationships over six months after adjusting for age, enrollment site, gender, race, functional class, depression, and premorbid intellect.
At baseline, 62% of subjects were nonadherent to their medication regime. Nonadherence was significantly more common in those with EDS, regardless of cognitive status (p=0.035). The odds of nonadherence increased by 11% for each unit increase in EDS (AOR=1.11, 95% CI=1.05–1.19, p=0.001). In longitudinal models there was a 10% increase in the odds of nonadherence for each unit increase in EDS (p=0.008). The only cognition measure significantly associated with medication adherence was attention (p=0.047).
Adults with HF and EDS are more likely to have problems adhering to their medication regimen than those without EDS, regardless of their cognitive status. Identifying and correcting factors that interfere with sleep may improve medication adherence.
PMCID: PMC3073685  PMID: 21440873
heart failure; sleep; excessive daytime sleepiness; cognition; vigilance; patient compliance; self-care
19.  Acute Anemia Elicits Cognitive Dysfunction and Evidence of Cerebral Cellular Hypoxia in Older Rats with Systemic Hypertension 
Anesthesiology  2010;113(4):845-858.
Postoperative cognitive dysfunction occurs frequently after cardiac, major vascular, and major orthopedic surgery. Aging and hypertensive cerebrovascular disease are leading risk factors for this disorder. Acute anemia, common to major surgery, has been identified as a possible contributor to postoperative cognitive dysfunction. The effect of hypoxia upon cognition and the cellular and molecular processes involved in learning and memory has been well described. Cerebrovascular changes related to chronic hypertension may expose cells to increased hypoxia with anemia.
Young to aged spontaneously hypertensive rats underwent testing for visuospatial memory and learning in the Morris water maze, measurement of cerebral tissue oxygenation via tissue oxygen probe, and measurement of hypoxia-sensitive genes and proteins, under conditions of sham and experimental isovolemic anemia.
Acute isovolemic anemia elicited evidence of aging-dependent visuospatial working memory and learning impairment. Isovolemic anemia did not result in cerebral tissue hypoxia, when measured via tissue oxygen probe. Evidence of cellular hypoxia was, however, identified in response to the anemic challenge, as hypoxia-sensitive genes and proteins were up-regulated. Importantly, cellular hypoxic gene responses were increased with anemia in an age-dependent manner in this model of aging with chronic hypertension.
In a translational model of chronic hypertension, clinically relevant levels of acute anemia were associated with an age-dependent visuospatial working memory and learning impairment that was matched by an age-dependent cellular sensitivity to anemic hypoxia. These data offer support for a possible link between anemic hypoxia and postoperative cognitive dysfunction in humans.
PMCID: PMC3233697  PMID: 20808217
20.  Shortened Sleep Duration does not Predict Obesity in Adolescents 
Journal of sleep research  2010;19(4):559-566.
Obesity continues to be a major public health issue. In adolescents, there are limited studies on the relationship between obesity and sleep duration. We hypothesied that average sleep duration of less than 6 hours in adolescents was associated with obesity. Data was from the National Longitudinal Study of Adolescent Health (ADD Health); survey of 90,000 youths, ages 12 – 18 years; surveyed in several waves. The sample population for our study was 13,568. Weighted multiple logistic regression was used to identify relationship between obesity at Wave II and sleep duration, having adjusted for skipping breakfast ≥ 2/week; race, gender, parental income, TV ≥ 2hrs/day, depression, and obesity at Wave I. At Wave I, mean age 15.96±0.11 yrs; mean sleep hours 7.91±0.04. 10.6% and 11.2% of adolescents were obese at Waves I and II, respectively. Adjusted analyses suggest that effect of shortened sleep duration in Wave I was not significantly predictive of obesity in Wave II (p<0.218).Longitudinally, depression and TV ≥ 2hrs/day at Wave I was associated with higher risk of obesity at Wave II in adjusted analyses. Depressed adolescents were almost twice as likely to be obese (OR=1.84, 95% CI=1.25–2.72); adolescents who watched TV ≥ 2hrs/day were 37% more likely to be obese (OR=1.37, 95% CI=1.09–1.72).Environmental factors including TV ≥ 2hrs/day and depression were significantly associated with obesity; shortened sleep duration was not. Future longitudinal studies in adolescents are needed to determine whether timing of television watching directly influences sleep patterns, and ultimately obesity.
PMCID: PMC2965312  PMID: 20545836
Adolescents; Obesity; Sleep; Television; Fast Food; ADD Health
21.  The Effects of Metformin and Leuprolide Acetate on Insulin Resistance and Testosterone Levels in Non-Diabetic Postmenopausal Women: A Randomized, Placebo-Controlled Trial 
Fertility and sterility  2010;94(6):2161-2166.
To determine whether insulin sensitizers lower androgen levels and whether androgen suppression improves insulin resistance in non-diabetic postmenopausal women.
Randomized, double-blind, placebo-controlled study
Clinical and Translational Research Center of a university hospital
Thirty-five postmenopausal women aged 50-79 yr with insulin resistance and higher testosterone levels
Subjects were randomized to metformin plus leuprolide placebo (LP), leuprolide plus metformin placebo (MP), or LP plus MP in a 1:1:1 fashion over a 12 week period.
Main Outcome Measures
Insulin sensitivity (M) assessed by euglycemic-hyperinsulinemic clamp and free testosterone by equilibrium dialysis.
In those randomized to metformin, free testosterone decreased by 19% (p=0.02) compared to placebo, along with an expected improvement in M. Total testosterone also decreased significantly (p=0.001) whereas sex hormone binding globulin (SHBG) did not change. In those randomized to leuprolide, the percent change in M was not different from placebo (p=0.56), despite a 48% relative decrease in free testosterone levels (p<0.001).
These data are the first to establish a causal link between insulin resistance and testosterone in postmenopausal women. They confirm that treatment of insulin resistance decreases testosterone production in this population and demonstrate that pharmacologic lowering of testosterone does not affect insulin resistance.
PMCID: PMC2891358  PMID: 20226444
Testosterone; insulin resistance; polycystic ovary syndrome; metabolic syndrome; aging; elderly; women
22.  Sex, Aging, and Preexisting Cerebral Ischemic Disease in Patients With Aortic Stenosis 
The Annals of thoracic surgery  2010;90(4):1230-1235.
Patients undergoing cardiac surgery have a high frequency of preexisting cerebral ischemic lesions, the presence of which appears to predict cognitive sequelae. Patients undergoing aortic valve replacement for aortic stenosis (AS) incur an exceptionally high risk for perioperative cerebral ischemia. The extreme risk in this subgroup may arise from the preexisting burden of cerebral ischemic disease. We tested the hypotheses that increasing age, female sex, coronary artery disease, and the severity of AS are predictive of the severity of preexisting cerebral ischemic lesions.
A total of 95 subjects were included in this study. Subjects were imaged on 1.5 Tesla magnetic resonance imaging scanners to obtain multimodal image sets which were used for the automatic segmentation of cerebral lesion volume. The dependence of lesion volume upon age, sex, coronary artery disease, and the severity of AS were tested.
The results demonstrate a strong correlation between aging, female sex, and white matter and ischemia-like lesion volume in patients with aortic stenosis.
Women and those of advanced age presenting for aortic valve replacement for AS may incur a particularly high risk for postoperative neurologic sequelae due to an exceptional preexisting burden of cerebral ischemic disease.
PMCID: PMC3019533  PMID: 20868818
23.  In Vivo Fluorometric Assessment of Cyclosporine on Mitochondrial Function During Myocardial Ischemia and Reperfusion 
The Annals of thoracic surgery  2010;89(5):1532-1537.
Cyclosporine A (CsA) limits myocardial reperfusion injury and preserves mitochondrial integrity, but its influence on mitochondrial function has not been described in vivo. Auto-fluorescence of mitochondrial nicotinamide adenine dinucleotide and flavin adenine dinucleotide correlate with mitochondrial dysfunction. We hypothesized that CsA limits mitochondrial dysfunction and that fluorometry can quantify this influence.
Seventeen rabbits were studied: untreated (UnT, n = 7), CsA preinfarction (CsAp, n = 6), and CsA on reperfusion (CsAr, n = 4). Animals underwent 30 minutes of myocardial ischemia and 3 hours reperfusion. Infarct size was determined by staining. Nicotinamide adenine dinucleotide and flavin adenine dinucleotide fluorescence was continually measured in the risk area. The redox ratio was calculated [flavin adenine dinucleotidef/(flavin adenine dinucleotidef + nicotinamide adenine dinucleotidef)]. Electron microscopy evaluated mitochondria morphology.
The infarct size by group was 39.1% ± 1.7% in CsAp, 39.1% ± 1.7% in CsAr, and 53.4% ± 1.9% in UnT (p < 0.001). During ischemia, the CsAp group demonstrated less hypoxic reduction, with the redox ratio decreasing to 75.6% ± 4.1% of baseline. The UnT and CsAr groups deceased to 67.1% ± 4.0% and 67.2% ± 3.6%, respectively (p < 0.005). During reperfusion the UnT group redox ratio increased to 1.59 ± 0.04 times baseline. This increase was blunted in the CsAp (1.17 ± 0.04, p = 0.026) and CsAr (1.35 ± 0.02, p = 0.056) groups. Electron microscopy revealed reduced mitochondrial disruption in CsAp (19.7% ± 7.6%) and CsAr (18.1% ± 7.1%) rabbits compared with UnT (53.3% ± 12.5%).
Fluorometric spectroscopy can be used in vivo to quantitatively assess the time course of CsA’s influence on the mitochondrial dysfunction associated with myocardial ischemia and reperfusion.
PMCID: PMC3021279  PMID: 20417773
24.  Neurobehavioral Effects in HIV-Positive Individuals Receiving Highly Active Antiretroviral Therapy (HAART) in Gaborone, Botswana 
PLoS ONE  2011;6(2):e17233.
To explore the prevalence and features of HIV-associated neurocognitive disorders (HANDS) in Botswana, a sub-Saharan country at the center of the HIV epidemic.
Design and Methods
A cross sectional study of 60 HIV-positive individuals, all receiving highly active antiretroviral therapy (HAART), and 80 demographically matched HIV-seronegative control subjects. We administered a comprehensive neuropsychological test battery and structured psychiatric interview. The lowest 10th percentile of results achieved by control subjects was used to define the lower limit of normal performance on cognitive measures. Subjects who scored abnormal on three or more measures were classified as cognitively impaired. To determine the clinical significance of any cognitive impairment, we assessed medication adherence, employment, and independence in activities of daily living (ADL).
HIV+ subjects were impaired for all cognitive-motor ability areas compared with matched, uninfected control subjects. Thirty seven percent of HIV+ patients met criteria for cognitive impairment.
These findings indicate that neurocognitive impairment is likely to be an important feature of HIV infection in resource-limited countries; underscoring the need to develop effective treatments for subjects with, or at risk of developing, cognitive impairment.
PMCID: PMC3041805  PMID: 21365002
25.  Hyperemic flow heterogeneity within the calf, foot, and forearm measured with continuous arterial spin labeling MRI 
Arterial spin labeling (ASL) is a noninvasive magnetic resonance imaging (MRI) technique for microvascular blood flow measurement. We used a continuous ASL scheme (CASL) to investigate the hyperemic flow difference between major muscle groups in human extremities. Twenty-four healthy subjects with no evidence of vascular disease were recruited. MRI was conducted on a 3.0 Tesla Siemens Trio whole body system with a transmit/receive knee coil. A nonmagnetic orthopedic tourniquet system was used to create a 5-min period of ischemia followed by a period of hyperemic flow (occlusion pressure = 250 mmHg). CASL imaging, lasting from 2 min before cuff inflation to 3 min after cuff deflation, was performed on the midcalf, midfoot, and midforearm in separate sessions from which blood flow was quantified with an effective temporal resolution of 16 s. When muscles in the same anatomic location were compared, hyperemic flow was found to be significantly higher in the compartments containing muscles known to have relatively higher slow-twitch type I fiber compositions, such as the soleus muscle in the calf and the extensors in the forearm. In the foot, the plantar flexors exhibited a slightly delayed hyperemic response relative to that of the dorsal compartment, but no between-group flow difference was observed. These results demonstrate that CASL is sensitive to flow heterogeneity between diverse muscle groups and that nonuniform hyperemic flow patterns following an ischemic paradigm correlate with relative fiber-type predominance.
PMCID: PMC3020668  PMID: 18310508
skeletal muscle; magnetic resonance imaging

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