General Clinical Research Centers Program Research Articles

Oxidative and Advanced Glycation End-Products Biomarkers and Their Association with the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC

Background: Type 1 diabetes confers a significant risk of cardiovascular disease (CVD), and new biomarkers of risk are needed for early detection. We have investigated the predictive value of oxidation products (OPs) and advanced glycation end-products (AGEs) for CVD events in the Diabetes Control and Complications Trial and the follow-up Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods: Using a case-control design, we measured plasma OPs including methionine sulfoxide [MetSO] and the AGE carboxyethyllysine [CEL] by LC/mass spectrometry in 459 participants (93 CVD cases and 366 controls) at three time points during DCCT, and at year 1-2 of EDIC. Cox proportional hazards models assessed the association between biomarkers as fixed or time-dependent covariates and the risk of subsequent CVD events. Prediction improvement was assessed using the C-statistic. Findings: Baseline CEL was associated with CVD (p=0·03, HR 1·15) when fully adjusted for age, HbA1c, BMI, HDL, LDL, sex, systolic and diastolic blood pressure, while MetSO at beginning of EDIC and as a time-dependent covariate, was strongly inversely associated with CVD outcomes (p < 0·001 and HR 0·58 and 0·61, respectively). MetSO also significantly increased the predictive c-statistic from 0·711 to 0·783 (p<0·001) when added to the other covariates. Interpretation: High levels of MetSO, a product of the free oxygen radical scavenger methionine, are associated with lower incidence of a primary CVD event during DCCT/EDIC· MetSO also significantly improved the predictive value over traditional risk factors, which may allow more timely institution of preventive therapies. Trial Registrations: NCT00360893, NCT00360815. Funding Statement: The DCCT/EDIC has been supported by cooperative agreement grants (1982-1993, 2012- 2017), and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (current grant numbers U01 DK094176 and U01 DK094157), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and Clinical Translational Science Center Program (2006-present), Bethesda, Maryland, USA. Declaration of Interests: None for JML and IB as noted below. PJB and Scott Howell have the following Declarations of interest: PJB is Chief Scientific Officer and Scott Howell is the Laboratory Director of PreventAGE Healthcare LLC (PHC), and PJB prepared and submitted the SBIR that funded the study in PHC’s name. PHCs goal is to develop precise biomarkers that can predict diabetic complications. Although no commercialization of the content of this manuscript has taken place, it is possible that this could occur in the future. Further detail on this relationship is contained in the enclosed ICJME form and in the “declaration of interests” section. Ethics Approval Statement: All appropriate written consents, permissions, and releases have been obtained from the participants by the DCCT/EDIC central overview committee.

322-OR: Risk Factors for Peripheral and Cardiovascular Autonomic Neuropathy in Type 1 Diabetes: Thirty Years of Follow-Up in DCCT/EDIC

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study reported that intensive glucose control as assessed by hemoglobin A1c (HbA1c) reduced the risk of diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) in type 1 diabetes (T1D), with long lasting benefits. We evaluated additional clinical parameters and risk factors that could contribute to the development of DPN and CAN in this cohort. DPN was assessed at three different times and defined as a composite of symptoms, signs, and abnormal nerve conduction studies in ≥2 nerves; CAN was assessed seven different times and defined based on R-R variation, Valsalva maneuver, and postural changes in blood pressure. Generalized estimating equation models were used to evaluate the association of DPN and CAN with individual risk factors over repeated time points spanning 30 years. Among 1,441 DCCT/EDIC participants, 32% developed DPN and 44% developed CAN. Higher mean HbA1c was the most significant risk factor for DPN (OR=1.56 per 1%, 95% CI 1.41,1.72). DPN was also associated with older age (1.43 per 5 years, 95% CI 1.31,1.55), longer duration of T1D, higher albuminuria, β-blocker use, higher mean diastolic blood pressure, and higher HbA1c at DCCT eligibility. CAN was associated (in order) with older age (1.51 per 5 years, 95% CI 1.40,1.63), longer duration of T1D (1.07 per 1 year, 95% CI 1.05,1.10), any sustained microalbuminuria (AER ≥30 mg/24 hour on two consecutive visits), higher mean HbA1c, higher mean and current pulse rate (likely as an indirect measure of CAN), higher mean systolic blood pressure, β-blocker use, any eGFR &amp;lt;60 mL/min/1.73 m2, higher HbA1c at DCCT eligibility, and current cigarette smoking. Higher mean HbA1c was the strongest risk factor for DPN, but not of CAN. These findings help identify patient phenotypes and modifiable risk factors for personalized approaches to neuropathy prevention. Disclosure B. Braffett: None. R. Gubitosi-Klug: None. J.W. Albers: Consultant; Self; Eli Lilly and Company. E.L. Feldman: None. C. Martin: None. N.H. White: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. M.F. Lopes-Virella: None. P. Raskin: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Gan &amp; Lee Pharmaceuticals, Novo Nordisk A/S. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. Funding Division of Diabetes Endocrinology &amp; Metabolic Diseases (U01DK094176, U01DK094157); National Eye Institute; National Institute of Neurologic Disorders and Stroke; General Clinical Research Centers Program; Clinical Translational Science Center

Developing Global Standards for Predicting Adult Overweight and Obesity from Childhood Body Mass Index - A Comparison of Estimates Obtained from Follow Up of a Pooled International Longitudinal Cohort to Current Standards Derived from Cross-Sectional Survey Data

Background: Historically, cut-points for childhood and adolescent overweight and obesity have been based on population-specific percentiles derived from cross-sectional data. To obtain cut-points that might better predict overweight and obesity in adulthood, we examined the association between childhood body mass index (BMI) and adult BMI status in a longitudinal cohort. Methods: Using data from the International Childhood Cardiovascular Cohort (i3C) Consortium pooled cohort we determined childhood overweight and obesity cut-points that best predict BMI status at the age of 18. Logistic regression analysis was used to assess the association between BMI in childhood and adult obesity. Area under the Receiver Operating Characteristic curve was used to assess the ability of fitted models to discriminate different BMI status groups in adulthood. The cut-points were then compared to those defined by the International Obesity Task Force (IOTF) using cross-sectional data, and tested for sensitivity and specificity in a separate, independent longitudinal sample with BMI measurements available from both childhood and adulthood. Findings: The cut-points derived from the longitudinal i3C Consortium data were lower than the IOTF cut-points. Consequently, a larger percentage of the sample was classified as overweight or obese when using the i3C cut-points in the independent sample. The i3C cut-points were better than the previously used IOTF cut-points at discriminating those who would later become overweight or obese in early adulthood from those whose BMI was normal when tested in the independent sample. Interpretation: The childhood BMI cut-points based on the i3C Consortium longitudinal data provide better predictors of future risk of adult overweight and obesity than estimates based on cross-sectional data. The result is more specific identification of the childhood population at risk of adult overweight or obesity than the currently used IOTF standards. Funding: Authors Kartiosuo, Ramakrishnan, Lemeshow, Juonala, Daniels, Sabin, Hu, Prineas and Dwyer declare no support from funding organisations for their work. Authors Woo, Jacobs, Steinberger, Urbina, Bazzano and Sinaiko declare their work was supported by the National Institutes of Health (NHLBI) grant no. i3C R01 HL121230. Dr Burns declares the acquisition and management of historic Muscatine Study data was supported by a Specialized Center of Research (SCOR) in Atherosclerosis, Lipids and Thrombosis grant from the National Heart, Lung and Blood Institute (NHLBI) HL-14230; M01-FR59 and RR-00059 from the General Clinical Research Centers Program, NCRR, NIH; and the Lipid Research Clinics Program (NIH-NHLBI-N01-HV-2-2913-L). Dr Raitakari declares The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research ; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjo Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS); European Research Council (grant 742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation. Dr Venn declares the CDAH follow-up study received grant support from the National Health and Medical Research Council (APP211316). Dr. Bazzano is also supported in part by the following grants from the National Institutes of Health: R01AG041200, R21057983, R01062309, K12HD043451, and P20GM109036. Declaration of Interest: All authors have declared no conflict of interest. Ethical Approval: The following studies used in the work were covered by ethical approval detailed as follows: The protocols for all relevant Muscatine Study data acquisition were approved by the University of Iowa Institutional Review Board. Informed consent was obtained from all parents and adult participants; assent was obtained from participants while they were children/adolescents. The Princeton and NGHS studies were approved by the IRB at Cincinnati Children’s Hospital Medical Center. The NGHS cohort all study participants or their legal guardian if <18 years, provided written informed consent according to local IRB requirements. The Young Finns Study was approved by the institutional ethics committees, and written informed consent was obtained from all the study participants. The CDAH study was approved by the Tasmanian Health and Medical Human Research Ethics Committee. Participants gave informed consent. The Bogalusa Heart Study was approved by the institutional review board at Tulane University.

Accelerometer Positioning Issues and Implications for Contemporary Analysis Methods

PURPOSE: While accelerometry is widely used to objectively measure physical activity (PA), methods are not standardized. The aim of this work was to understand how accelerometry output (vector magnitude, VM) differs between accelerometers worn on the non-dominant wrist (NDW), dominant wrist (DW), and hip, and if their relationships differ by activity type and intensity. METHODS: Forty participants (16.8 - 64.2 yr) completed sedentary and PAs in a laboratory while wearing accelerometers on the NDW, DW, and hip. 1-s VM values were compared across locations by activity type and intensity. Oxygen consumption was measured with a portable VO2 analyzer. RESULTS: The figure shows mean VM for all activities, by increasing intensity. When grouped by intensity, the DW and hip had significantly different VM for light (LPA), moderate (MPA), and vigorous (VPA) PA. The NDW and hip had significantly different VM for LPA and VPA. The DW and NDW had significantly different VM for LPA and MPA. CONCLUSION: The differing trajectories, and the differential relationships between VM from the NDW, DW, and hip indicate that accelerometer output differ based on activity type and intensity. This non-systematic error prevents scaling or comparing data collected at different wear locations, including the NDW and DW. Additionally, accelerometer data were processed using the accelerometer software. MVPA estimates from the NDW, DW, and hip differed by an average of 13.8 mins (range: 0 - 36), for the 3 hours analyzed. This indicates that substantial error is possible, and analysis methods are not interchangeable across locations. Site-specific analysis methods are needed for accurate, comparable estimates of PA. This work was funded by the University of Iowa Graduate & Professional Student Government, the National Institute of Dental and Craniofacial Research R01-DE12101 and R01-DE09551, and the General Clinical Research Centers Program from the National Center for Research Resources, M01-RR00059.Figure

Perspectives on Polycystic Ovary Syndrome: Is Polycystic Ovary Syndrome Research Underfunded?

Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic abnormality with a worldwide prevalence of 4% to 21%, depending on diagnostic criteria. The National Institutes of Health (NIH) is the largest single funding agency in the world; it invests nearly $30.0 billion annually in biomedical research. Using the NIH Research Portfolio Online Reporting tool, we searched for all grants awarded by the NIH for PCOS and three other disorders with similar degrees of morbidity and similar or lower mortality and prevalence [rheumatoid arthritis (RA), tuberculosis (TB), and systemic lupus erythematosus (SLE)]. We compared funding by the NIH for PCOS, RA, TB, and SLE research for the years 2006 to 2015, inclusive. PCOS, compared with RA, TB, and SLE, was relatively less funded (total mean 10-year funding was $215.12 million vs $454.39 million, $773.77 million, and $609.52 million, respectively). Funding for PCOS was largely provided by one NIH Institute/Center (ICs) vs at least two ICs for SLE and RA; more individual Research Project Grants were awarded for RA, SLE, and TB than for PCOS, whereas PCOS funding was more likely to be through General Clinical Research Centers Program or Specialized Centers Program awards. Our data suggest that PCOS research may be underfunded considering its prevalence, economic burden, metabolic morbidity, and negative impact on quality of life. Greater education of NIH leaders, including those at the National Heart, Lung, and Blood Institute and National Institutes of Diabetes and Digestive and Kidney Diseases; other federal and state agency leads; elected leaders; and the general public by professional societies, the scientific community, and patient advocates regarding this disorder is needed.

Eulogy for the clinical research center.

The extramural General Clinical Research Center (GCRC) program has been funded for more than 50 years, first by the National Center for Research Resources, NIH, and more recently as part of the Clinical Translational Science Award (CTSA) program through the newly formed National Center for Advancing Translation Sciences (NCATS). The GCRCs represent the federally funded laboratories that employ a highly trained cadre of research nurses, dietitians, and other support staff and in which generations of clinical investigators trained and performed groundbreaking human studies that advanced medical science and improved clinical care. Without the opportunity for adequate discussion, NCATS has now stopped funding these Research Centers. In this "eulogy," we review the origins and history of the GCRCs, their contributions to the advancement of medicine, and the recent events that have essentially defunded them. We mourn their loss.

Enhanced Infrastructure for Optimizing the Design and Execution of Clinical Trials and Longitudinal Cohort Studies in the Era of Precision Medicine

In 2006, the National Institutes of Health (NIH) launched the Clinical and Translational Science Awards (CTSA) program in order to support an accelerated pace of translational science (from bench to bedside and community, and back), both within and among academic centers. The CTSA program was also developed with an aim of training the next generation of clinical and translational scientists. The CTSA program replaced the previous General Clinical Research Centers program, for which the utilization of resources and infrastructure toward industry-sponsored trials was restrictive and had led to maintenance of both the General Clinical Research Centers and the Clinical Trial Office as dual and often redundant 1 organizations for centralized research support and review processes for NIH-funded vs industry-sponsored studies. CTSA-funded institutions have centralized both laboratory cores for research-based analytics and staff resources for regulatory (Food and Drug Administration [FDA]- and Institutional Review Board [IRB]related) expertise and process improvement. In addition, the CTSA cooperative group and colleagues have developed informatics approaches to enhance recruitment in research studies and facilitated broad adoption of a free electronic data capture system developed previously via NIH funds (REDCap). 2

Predictability of TV Viewing Throughout Childhood: Iowa Bone Development Study

PURPOSE: Tracking studies determine the stability and predictability of specific phenomena. This study examined tracking of TV viewing (TV) from middle childhood through early adolescence after adjusting for moderate and vigorous physical activity (MVPA), percentage of body fat (% BF), and maturity. METHODS: TV was measured at ages 5, 8, 11, and 13 yr (n = 434) via parental- and self-report in a population-based cohort. MVPA was measured using the Actigraph, % BF using dual-energy x-ray absorptiometry, and maturity via Mirwald predictive equations. Generalized Estimating Equations (GEE) were used to assess stability and logistic regression was used to predict children "at risk" for maintaining excessive TV (> 2 hr). Additional models examined tracking in overfat children (boys ≥ 25% BF; girls ≥ 32% BF combined). RESULTS: More than half of the sample reported more than 2 hrs of TV daily at each measurement age. The crude GEE coefficients were 0.35 (95% CI = 0.26, 0.44) for boys, 0.34 (0.26, 0.43) for girls, and 0.41 (0.23, 0.59) for overfat. The GEE, adjusted for MVPA, % BF, and maturity, were 0.35 (0.26, 0.44) for boys and 0.32 (0.23, 0.40) for girls. The GEE, adjusted for MVPA, maturity, and gender, in the overfat (boys and girls combined) was 0.45 (0.27, 0.64). Gender (being female) was significant in this model. The adjusted OR were 3.2 (2.0, 5.2) for boys, 2.9 (1.9, 4.6) for girls, and 6.2 (2.2, 17.2) for overfat. That is, boys and girls were 3 times as likely to watch excessive TV later in life if they were excessive TV watchers at age 5 yr. For those overfat at age 5 yr (especially girls), the odds were much higher (6 times as likely). CONCLUSION: TV is moderately stable throughout childhood and predictive of later viewing behavior. It appears to be entrenched in younger children, especially overfat, young girls. Adjusting for MVPA did not significantly alter results suggesting that PA and sedentarism are distinct behaviors. Since habitual patterns of excessive TV in young children tended to continue into adolescence, tailored, early intervention strategies may be warranted to prevent excessive TV before it begins. Supported by the National Institute of Dental and Craniofacial Research (R01-DE12101, R01-DE09551); General Clinical Research Centers Program (M01-RR00059); National Center for Research Resources (UL1 RR024979).

Stability and Predictability of Video Throughout Childhood: Iowa Bone Development Longitudinal Study

PURPOSE: Sedentary behaviors are generally assumed to be related to the development of obesity. Tracking studies can help determine the stability and predictability of a sedentary behavior. This information is important to the development of effective intervention strategies. The current study examined tracking of video game use (Video) from middle childhood through early adolescence. METHODS: Video was measured at ages 5, 8, 11, and 13 yr (n = 434) via parental- and self-report. In addition, we measured moderate and vigorous physical activity (MVPA) using the Actigraph, % BF using Hologic dual-energy x-ray absorptiometry, and maturity via Mirwald predictive equations. Unadjusted and adjusted Generalized Estimating Equations (GEE) were used to assess stability and logistic regression to predict children "at risk" for maintaining high Video (1 hr or more video/d) compared to children playing Video less than 1 hr/d. RESULTS: At baseline (age 5 yr) 10.7% boys and 5.3% girls spent at least 1 hr/d playing Video. Time spent in Video increased for both boys and girls over the four measurement periods. At age 13 yr, 66% boys and 18% girls spent at least one hr/d playing video games. Unadjusted GEE coefficients were 0.15 (95% CI = 0.05, 0.25) for boys, 0.24 (0.09, 0.39) for girls. GEE coefficients adjusted for MVPA, % BF, and maturity were 0.14 (0.05, 0.24) for boys and 0.24 (0.10, 0.38) for girls. The unadjusted odds ratios (OR) were 1.87 (1.1, 3.2) for boys and 3.43 (2.1, 5.8) for girls. The adjusted OR were 1.83 (1.1, 3.1) for boys and 3.46 (2.1, 5.8) for girls. CONCLUSION: Throughout childhood and into early adolescence more boys play Video than girls; however, playing Video tracks better in girls (when compared to boys). In both boys and girls, the tracking of Video is not influenced by physical activity, adiposity, or maturity. In addition, girls who play 1 hr or more of Video at age 5 are 3.5 times more likely than peers to play Video later in life. These results suggest that the effectiveness of interventions for the reduction of Video use may need to be tailored by gender. Supported by National Institute of Dental and Craniofacial Research (R01-DE12101 and R01-DE09551), General Clinical Research Centers Program (M01-RR00059[BB1]) and National Center for Research Resources (UL1 RR024979).

Family Matters: Specific Type(s) of Family Support in Adolescent Physical Activity Levels

PURPOSE: This study investigates the relationships between five types of family support and adolescent PA levels during periods of time when adolescents have more control (or agency) over the activities in which they participate, i.e., after school and weekend hours. METHODS: In a sample of 291 adolescents (144 females, 147 males), seven psychosocial variables were examined in relation to accelerometry-derived PA measured after school and during the weekend. Psychosocial variables were measured via a questionnaire based on Welk's (1999) Youth Physical Activity Promotion Model. The Actigraph 7164 was used to obtain PA measures, i.e., agency moderate-to-vigorous PA (MVPA) and agency total PA. Co-variates included % BF measured using a Hologic DXA scanner, centered age, and maturity predicted using the Mirwald equations. Spearman correlation coefficients were used to assess bi-variate associations. Stepwise linear regression analyses with forward selection were conducted to determine which combinations of the study variables (psychosocial indices, type(s) of family support, co-variates) explained the variance in Agency MVPA and Agency TA. The p-value was set at < 0.05. RESULTS: For adolescent females, % BF and maturity were significant co-variates, while centered age and % BF were significant co-variates for adolescent males. Family support demonstrated the strongest associations with female and male adolescent Agency PA variables (r = 0.27 to 0.40). Stepwise linear regressions revealed that being praised by a family member and % BF explained 13% of the variance in adolescent female Agency MVPA, while being praised and maturity explained 7% of the variance in Agency TA. For adolescent males, having a family member watch him participate combined with % BF and centered age to explain 13% of the variance in Agency MVPA, while having a family member participate with him explained 6.4% of the variance in Agency TA. CONCLUSION: Public health officials should encourage family members to provide specific type(s) of support in an effort to positively alter adolescents' PA behavior during agency times. Supported by the National Institute of Dental and Craniofacial Research (R01-DE12101; R01-DE09551); General Clinical Research Centers Program (M01-RR00059); National Center for Research Resources (UL1 RR024979)

What Can Be Done to Protect the Translational Investigator?

The Association for Patient-Oriented Research (APOR) arose from concerns expressed beginning in the late 1970s about a growing shortage of investigators interested and well trained in conducting research on human subjects. Educational debt, difficulties in securing grant funding, and greater financial rewards in clinical practice continue to discourage young practitioners from pursuing careers in clinical research. Academic medical centers have seen their margins from clinical earnings decline and have asked potential clinician-investigators to contribute to the bottom line by seeing more patients. There was also an assumption, mostly unspoken, that basic research should be the focus of support and training, and that self-evident clinical and public health applications of basic research findings would be developed without much support from government or academic institutions. But the translation of basic research knowledge to the clinic and community has proven to be challenging and complex, and the rate by which the pharmaceutical industry has been developing significant new drugs is disappointing. An especially endangered species is the clinical investigator who asks questions at the bedside, and may then pursue answers initially in the laboratory and animal models before returning to the patient with a scientifically meaningful and ethical research protocol. This bidirectional aspect has been recognized as an essential and exciting aspect of patient-oriented research for many years, as exemplified by the comments of John Oates in 1982 (Figure 1). The career development of effective investigators who are comfortable both at the bedside and in the laboratory requires many years of mentoring and experience as well as stable research funding and institutional support. Integral role of patient-oriented clinical investigation both in the discovery of new knowledge and development of new therapies (from Oates JA. Presidential address: Clinical investigation: a pathway to discovery. Trans Assoc Am Physicians. 1982; 95: lxxviii-xc). Since the 1950s, the National Institutes of Health (NIH) has provided basic infrastructure for patient-oriented research in academic medical centers through the General Clinical Research Center (GCRC) program. GCRCs were also important for training patient-oriented investigators. In the 1990s, the NIH initiated K30 grants, which supported development of curricula for clinical research education, and individual K grants for trainees (NCRR K12), young investigators (K23, K08, etc.), and mentors (K24). The NIH Roadmap proposed by former NIH Director Elias Zerhouni, MD, emphasized clinical research and culminated in the Institutional Clinical and Translational Science Awards (ICTSAs). APOR supports the ICTSA program, which aims to expand support across the broad spectrum of translational research—from bench to bedside and the community—and for training at multiple levels. Unfortunately, this comprehensive program is being implemented at a time when NIH funding is limited. There are no progress reports yet on ICTSAs, but concerns have been expressed that at some institutions infrastructure for patient-oriented research has been downsized and that support has shifted to more basic research in the translational spectrum. If so, this will impede development of patient-oriented researchers. Current plans are for fewer ICTSAs than the number of previous GCRCs, which may mean that students and junior faculty at many academic health centers will have little exposure to hypothesis-driven, investigator-initiated clinical research. Clinical research at such institutions may be visible only as clinical trials sponsored by the pharma. While partnering with pharma is a key component of the NIH Roadmap, academic centers must also provide an environment favorable to patient-oriented research that investigators pursue based on hypotheses generated at the bedside. APOR will continue to promote patient-oriented research in a rapidly changing healthcare and clinical research environment. Because patient-oriented research represents a partnership between all practitioners and patients affected by disease, APOR welcomes all who are interested in CTS research to join in this effort. APOR is partnering with other organizations with complementary goals, such as the Society for Clinical and Translational Science (SCTS) and the Association for Clinical Research Training (ACRT), in planning an annual spring meeting that will benefit members of all these organizations. APOR and SCTS are also partners in supporting CTS. APOR will continue to provide further information about its activities in future issues of this journal, as well as in our newsletter (http://www.apor.org).

Short term changes in plasma phenylalanine status and cognitive processing speed in adolescent and adult females with phenylketonuria (PKU)

Even with early and continuous diet therapy, subtle neuropsychological deficits exist in phenylketonuria (PKU). To clarify the relationship between compliance and processing speed, this study examines the relationship between short‐term changes in plasma phenylalanine (Phe) concentration and cognitive processing speed. Data were collected from twenty females with PKU (ages 12‐47 years) attending a summer camp intervention designed in part to reduce plasma Phe. Pre‐ and post‐intervention fasting plasma Phe was assessed using ion‐exchange chromatography. Pre‐ and post‐intervention processing speed was assessed in group format by Woodcock‐Johnson III timed tests of decision speed and pair cancellation. As expected, mean plasma Phe and processing speed scores significantly improved (p&lt;0.001) and pair cancellation negatively correlated with change in plasma Phe controlling for verbal ability (r=‐0.627, p=0.004). Changes in decision speed and plasma Phe, however, were unrelated. Pair cancellation may be more sensitive to improved Phe control due to the task's reliance on attention and concentration. Short‐term improved compliance may be associated with concurrent improved processing speed. Supported in part by PHS Grant M01 RR00039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources.

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health

Endocrine-Related Resources from the National Institutes of Health