69 results on '"Doty T"'
Search Results
2. Association of Donor Age and Plasma Donor-Derived Cell-Free DNA Levels with CAV Development after Heart Transplant: SHORE Preliminary Data
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Raval, N., primary, Ravichandran, A., additional, Ghosh, S., additional, Wolf-Doty, T., additional, Ross, D., additional, Hall, S., additional, and Uriel, N., additional
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- 2021
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3. The Impact of Grade 1R Endomyocardial Biopsies on Donor-Derived Cell-Free DNA, Higher-Grade Rejection and Development of Donor Specific Antibodies
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Kao, A., primary, Baran, D., additional, Ghosh, S., additional, Wolf-Doty, T., additional, Dhingra, R., additional, and Kim, P.J., additional
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- 2021
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4. (996) Relationship Between Absolute Quantification of Donor-Derived Cell-Free DNA and Donor-Derived Cell-Free DNA Fraction for Detection of Allograft Rejection in Heart Transplant Patients
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Patel, S., Uriel, N., Nguyen, A., Silvia, B., Wolf-Doty, T., Tian, W., Qu, K., and Pinney, S.
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- 2023
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- View/download PDF
5. (542) Path to Eliminating Surveillance Endomyocardial Biopsies in Heart Transplant: Early Use of Donor Derived Cell-Free DNA - One Year Follow Up
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Miklin, D., Ravi, K., Wolf-Doty, T., Shekhtman, G., Kobulnik, J., Salimbangon, A., Cartus, R., Cochran, A., Berg, A., Ackerman, M., Wolfson, A., Vaidya, A., Nattiv, J., and DePasquale, E.
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- 2023
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6. 0034 When Should You Sleep to Maximize Alertness?
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Vital-Lopez, F, primary, Doty, T J, primary, Balkin, T J, primary, and Reifman, J, primary
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- 2020
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7. 0290 Caffeine Efficacy Varies as a Function of Individual Vulnerability to Sleep Restriction
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Demiral, S B, primary, Doty, T J, primary, Ratcliffe, R H, primary, Hughes, J D, primary, Balkin, T J, primary, and Capaldi, V F, primary
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- 2020
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8. 1028 Sleep and Enteric Disease: Sleep Now for Less Diarrhea Later
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Mantua, J, primary, Gutierrez, R L, primary, Isidean, S D, primary, Alaca, A N, primary, Testa, K J, primary, Talaat, K, primary, Doty, T J, primary, Capaldi, V F, primary, and Porter, C, primary
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- 2020
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9. Psychiatric Diagnoses and Medications in Wolfram Syndrome
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Reiersen Angela M., Noel Jacob S., Doty Tasha, Sinkre Richa A., Narayanan Anagha, and Hershey Tamara
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wolfram syndrome ,psychiatry ,anxiety ,obsessive compulsive disorder ,medication ,er stress ,Psychiatry ,RC435-571 ,Psychology ,BF1-990 - Abstract
Wolfram Syndrome is a rare genetic disorder usually resulting from pathogenic variation in the WFS1 gene, which leads to an exaggerated endoplasmic reticulum (ER) stress response. The disorder is typically characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, hearing loss, and neurodegenerative features. Existing literature suggests it may also have psychiatric manifestations.
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- 2022
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10. 0114 Effects of Sleep Extension and Deprivation on Performance Using a Cognitively Demanding Emotional Task
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Alger, S E, primary, Prindle, N, additional, Brager, A J, additional, Doty, T J, additional, Ratcliffe, R H, additional, Ephrem, D, additional, Yarnell, A M, additional, Balkin, T J, additional, Capaldi, V F, additional, and Simonelli, G, additional
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- 2018
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11. Gene Expression Profiling for Cardiac Transplant Recipients: Results from the Outcomes AlloMap® Registry
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Hall, S.A., primary, Ewald, G., additional, Berman, P., additional, Sulemanjee, N., additional, Kao, A., additional, Wolf-Doty, T., additional, Sninsky, J., additional, Yee, J., additional, and Kobashigawa, J., additional
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- 2018
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12. 0236 Changes in State Anxiety over 62 hours of Sleep Deprivation and Subsequent Recovery
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Bessey, A F, primary, Prindle, N E, additional, Powers Armstrong, M, additional, Burke, T, additional, Capaldi, V F, additional, Balkin, T J, additional, and Doty, T J, additional
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- 2018
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13. 0313 2B-Alert App: A Tool to Predict Individual Trait-like Responses to Sleep Loss in Real Time
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Ramakrishnan, S, primary, Doty, T J, additional, Balkin, T J, additional, and Reifman, J, additional
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- 2018
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14. 0238 Subjective Stress During 62 Hours of Total Sleep Deprivation and Recovery
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Prindle, N E, primary, Bessey, A F, additional, Powers Armstrong, M, additional, Burke, T, additional, Capaldi, V F, additional, Balkin, T J, additional, and Doty, T J, additional
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- 2018
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15. 0140 Examining The Effects Of Moderate Blast Exposure On Sleep: Observations From Specialized Military Training Exercises
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Pattinson, C L, primary, Gill, J M, additional, Doty, T J, additional, and Carr, W S, additional
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- 2018
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16. 0231 The Impact of At-Home Actigraphy on Performance and Sleepiness in the Lab over 62 Hours of Total Sleep Deprivation
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Carlsson, K E, primary, Bessey, A F, additional, Skeiky, L, additional, Prindle, N E, additional, Powers Armstrong, M, additional, Devine, J, additional, Capaldi, V F, additional, Balkin, T J, additional, and Doty, T J, additional
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- 2018
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17. 0170 Shifting to Earlier Sleep Times during Sleep Extension: The Impact on Total Sleep Time and Self-Reported Fatigue and Stress
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Skeiky, L, primary, Chownowski, J, additional, St Pierre, M, additional, Carlsson, K E, additional, Mantua, J, additional, Burke, T, additional, Alger, S, additional, Prindle, N E, additional, Ratcliffe, R, additional, Balkin, T, additional, Capaldi, V F, additional, Simonelli, G, additional, and Doty, T J, additional
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- 2018
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18. 0215 Caffeine Dosage Strategies that Efficiently Enhance Alertness during Sleep Loss
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Vital-Lopez, F, primary, Ramakrishnan, S, additional, Doty, T J, additional, Balkin, T J, additional, and Reifman, J, additional
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- 2018
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19. (845) - Gene Expression Profiling for Cardiac Transplant Recipients: Results from the Outcomes AlloMap® Registry
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Hall, S.A., Ewald, G., Berman, P., Sulemanjee, N., Kao, A., Wolf-Doty, T., Sninsky, J., Yee, J., and Kobashigawa, J.
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- 2018
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20. Selective Attention and Audiovisual Integration: Is Attending to Both Modalities a Prerequisite for Early Integration?
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Talsma, D., primary, Doty, T. J., additional, and Woldorff, M. G., additional
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- 2006
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21. LAPAROSCOPIC EVALUATION OF MASSES IN END STAGE LIVER DISEASE PATIENTS
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Thomas, M J., primary, Buell, J F., additional, Schneider, C, additional, Weber, F, additional, Gupta, M, additional, Merchen, T D., additional, Bass, M, additional, Flannary, D, additional, Doty, T, additional, Hanaway, M J., additional, Rudich, S M., additional, and Woodle, E S., additional
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- 2004
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22. Path to Eliminating Surveillance Endomyocardial Biopsies in Heart Transplant: Early Use of Donor Derived Cell-Free DNA - One Year Follow Up.
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Miklin, D., Ravi, K., Wolf-Doty, T., Shekhtman, G., Kobulnik, J., Salimbangon, A., Cartus, R., Cochran, A., Berg, A., Ackerman, M., Wolfson, A., Vaidya, A., Nattiv, J., and DePasquale, E.
- Subjects
- *
CELL-free DNA , *HEART transplantation , *CIRCULATING tumor DNA , *BIOPSY , *ECHOCARDIOGRAPHY , *THANATOLOGY - Abstract
Novel non-invasive cardiac allograft surveillance methods such as dd-cfDNA has emerged as a viable noninvasive tool for rejection surveillance, however, with limited data for early use. We sought to describe the incidence and outcomes of early dd-cfDNA use (< 14 days) for HT rejection surveillance. Consecutive adult HT recipients were identified retrospectively from a single center (n=66). Patients were included if heart-only with at least one dd-cfDNA drawn within 14-days post HT between 8/2/2019 and 10/1/2021 (n=45). Baseline donor/recipient demographics, clinical characteristics, serial echocardiographic parameters, laboratory testing, medication regimens, and clinical course were collected over a 12-month period. The composite endpoint was defined as graft dysfunction (LVEF < 40% or >=25% decline in consecutive visit) triggering EMB, rejection >= 2R, development of de-novo donor specific antibodies (DSAs), or rejection-related death. 45 HT recipients were identified. The cohort was predominantly male (71%), non-Caucasian (67%) with DM (40%) and HTN (38%), and had a mean follow up time of 642-days. Donors were male (n=33) with mean ischemic time and donor age of 2.9h and 29.5y, respectively. Mean number of biopsies performed in the first 12 months was 1.8 and mean initial dd-cfDNA (obtained <14d) was 0.3 ± 0.2% (NL <0.12). Overall, there was no difference in baseline demographics by composite endpoint. 14 patients (31%) met the composite endpoint (rejection >= 2R (n=7), de-novo DSAs (n=6), graft dysfunction (n=4)). Biopsy frequency was increased in those meeting the endpoint (2.4 vs 1.4, p<0.004). There were no rejection-related deaths during the study period. Early use of dd-cfDNA (< 14 d) for rejection surveillance is effective in lieu of protocol endomyocardial biopsy. One-year follow up demonstrates significant reduction in protocol biopsy frequency with no rejection-related death in this cohort to date. [ABSTRACT FROM AUTHOR]
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- 2023
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23. Fructose Sweetness: A New Dimension
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Doty, T. E.
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- 1976
24. CATHARINE ELIZABETH HARRIS.
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DOTY, T. K.
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- 1865
25. Relationship Between Absolute Quantification of Donor-Derived Cell-Free DNA and Donor-Derived Cell-Free DNA Fraction for Detection of Allograft Rejection in Heart Transplant Patients.
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Patel, S., Uriel, N., Nguyen, A., Silvia, B., Wolf-Doty, T., Tian, W., Qu, K., and Pinney, S.
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- *
CELL-free DNA , *GRAFT rejection , *HEART transplant recipients , *CIRCULATING tumor DNA , *BLOOD sampling , *ALLOIMMUNITY - Abstract
Percent donor-derived cell-free DNA (dd-cfDNA %) has been widely used as a validated diagnostic tool for allograft rejection. There has been interest in evaluating whether absolute copies (AbC) of dd-cfDNA could improve the assessment of rejection. We aimed to compare the value of AbC to dd-cfDNA % in heart transplant patients to discriminate allograft rejection. Blood samples were assessed within 7 days of, and prior to, endomyocardial biopsy (EMB) from a sub-set of patients in the multi-center Surveillance HeartCare Outcomes Registry (SHORE, ClinicalTrials.gov Identifier: NCT03695601) where dd-cfDNA %, AbC of dd-cfDNA and EMB were able to be obtained. Dd-cfDNA % was performed using AlloSure (CareDx, Inc) and total cfDNA was quantified using Tapestation 4200. AbC was computed from dd-cfDNA % and total cfDNA, accounting for process efficiencies. Rejections were defined as ACR (ISHLT grade ≥2R), AMR (ISHLT grade ≥pAMR1) or mixed rejection. Receiver Operator Curve (ROC) analysis was performed to compare the ability of dd-cfDNA, AbC and their combination to discriminate rejection vs non-rejection. There were 299 blood samples from 226 patients in this cohort. This included 204 no rejection and 95 rejection (46 ACR, 48 AMR, 1 mixed) cases. In a pairwise comparison, identification of allograft rejection was not significantly different in dd-cfDNA % vs AbC (p=0.44) or dd-cfDNA % vs combination (p=0.68). The AUCs for dd-cfDNA %, AbC and the combination were 0.72, 0.69 and 0.71, respectively. (Figure 1) The performance of AbC and dd-cfDNA % in discriminating rejection from no rejection was similar. AbC may not provide additional value compared to quantifying the percentage of dd-cfDNA. It is noted that the analytical accuracy of AbC has not yet been established at very low dd-cfDNA levels, therefore future efforts are needed to understand its diagnostic role. [ABSTRACT FROM AUTHOR]
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- 2023
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26. Migratory orientation by marbled salamanders (Ambystoma opacum) near a breeding area
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Doty, T
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- 1972
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27. Lack of Association Between Donor-Derived Cell-Free DNA and Cardiac Allograft Vasculopathy.
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Alharethi R, Knight S, Luikart HI, Wolf-Doty T, Bride DL, Kim DT, and Khush KK
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- Humans, Male, Female, Middle Aged, Follow-Up Studies, Prospective Studies, Prognosis, Risk Factors, Allografts, Postoperative Complications blood, Postoperative Complications diagnosis, Postoperative Complications etiology, Case-Control Studies, Graft Rejection etiology, Graft Rejection diagnosis, Graft Rejection blood, Graft Survival, Vascular Diseases etiology, Vascular Diseases blood, Adult, Heart Transplantation adverse effects, Cell-Free Nucleic Acids blood, Tissue Donors, Biomarkers blood
- Abstract
Cardiac allograft vasculopathy (CAV) is a leading cause of death after heart transplantation (HT). We evaluated donor-derived cell-free DNA (dd-cfDNA) as a noninvasive biomarker of CAV development after HT. The INSPIRE registry at the Intermountain Medical Center was queried for stored plasma samples from HT patients with and without CAV. At Stanford University, HT patients with CAV (cases) and without CAV (controls) were enrolled prospectively, and blood samples were collected. All the samples were analyzed for dd-cfDNA using the AlloSure assay (CareDx, Inc.). CAV was defined per the ISHLT 2010 standardized classification system. Univariate associations between patient demographics and clinical characteristics and their CAV grade were tested using chi-square and Wilcoxon rank sum tests. Associations between their dd-cfDNA levels and CAV grades were examined using a nonparametric Kruskal-Wallis test. A total of 69 pts were included, and 101 samples were analyzed for dd-cfDNA. The mean age at sample collection was 58.6 ± 13.7 years; 66.7% of the patients were male, and 81% were White. CAV 0, 1, 2, and 3 were present in 37.6%, 22.8%, 22.8%, and 16.8% of included samples, respectively. The median dd-cfDNA level was 0.13% (0.06, 0.33). The median dd-cfDNA level was not significantly different between CAV (-) and CAV (+): 0.09% (0.05%-0.32%) and 0.15% (0.07%-0.33%), respectively, p = 0.25 and with similar results across all CAV grades. In our study, dd-cfDNA levels did not correlate with the presence of CAV and did not differ across CAV grades. As such, dd-cfDNA does not appear to be a reliable noninvasive biomarker for CAV surveillance., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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28. Relationship between donor-derived cell-free DNA and tissue-based rejection-related transcripts in heart transplantation.
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Lee DH, Usmani A, Wu R, Wicks T, Noh CY, Burke R, Ravichandran V, Wolf-Doty T, Dumitru I, Oliveira GH, Berman P, and Mackie B
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- Retrospective Studies, Male, Humans, Middle Aged, Female, Adult, Biopsy, Myocardium pathology, Myocardium metabolism, Heart Transplantation, Graft Rejection diagnosis, Cell-Free Nucleic Acids blood, Tissue Donors
- Abstract
Background: Endomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs, which may provide further insight into the pathophysiology of allograft rejection and injury., Methods: This is a retrospective observational study of 156 EMB evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood before EMB (up to 9 days). Diagnostic agreement between traditional histopathology, MMDx, and dd-cfDNA (threshold of 0.20%) was compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated., Results: MMDx characterized allograft tissue as no rejection (62.8%), antibody-mediated rejection (ABMR) (26.9%), T-cell-mediated rejection (TCMR) (5.8%), and mixed ABMR/TCMR (4.5%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (76.3% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters were correlated with dd-cfDNA scores, including DSAST, GRIT, HT1, QCMAT, and S4. For individual transcripts, tissue ROBO4 was significantly correlated with dd-cfDNA in both nonrejection and rejection as assessed by MMDx., Conclusions: Collectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA and expression of ROBO4 (a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of antibody-mediated rejection, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to acute cellular rejection., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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29. Relationship between blood and tissue-based rejection-related transcripts in heart transplantation.
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Lee DH, Usmani A, Ravichandran V, Wicks T, Wu R, Wolf-Doty T, Dumitru I, Berman P, Oliveira GH, and Mackie B
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- Humans, Biopsy, Gene Expression Profiling, Antibodies, Kidney Transplantation, Heart Transplantation, Doxorubicin analogs & derivatives
- Abstract
Background: The purpose of the study is to investigate the relationship between blood and tissue-derived rejection-related transcripts from blood gene expression profiling (GEP) and molecular microscope in the setting of allograft rejection in heart transplant., Methods: All heart transplant patients from August 2021 to May 2022 with both circulating blood GEP (AlloMap) and endomyocardial biopsy with molecular microscope diagnostic system (MMDx) within 4 weeks were included (N = 173 samples). We obtained individual blood GEP-based messenger RNA transcript expression levels of the 11 target genes from CareDx. Student's t-test was performed to compare blood GEP transcript expression levels between no rejection and rejection as assessed by MMDx. A Scatter plot with Spearman correlation analysis was performed to compare the relationship between transcript expression levels from AlloMap and MMDx, with and without allograft rejection., Results: There were 52 samples (30.1%) with antibody-mediated rejection (ABMR) and 15 samples (8.7%) with T-cell-mediated rejection (TCMR), as assessed by MMDx. Expression of one of the blood ITGA4 (Integrin alpha 4) expression level was elevated in ABMR, compared to no ABMR (4,607.5 vs 4,217.5; p = 0.019). Most tissue rejection-associated transcript expression levels were elevated in ABMR, and tissue ROBO4 expression correlated with the blood ITGA4 expression with moderate or greater effect size in all samples (Spearman's R = 0.31; p < 0.001). There was also a positive correlation between blood ITGA4 and tissue ROBO4 expression in samples without ABMR (Spearman's R = 0.33; p < 0.001), but no correlation between blood ITGA4 and tissue ROBO4 expression in samples with ABMR (Spearman's R = 0.009; p = 0.513)., Conclusions: Circulating blood ITGA4 expression is elevated in antibody-mediated rejection (AMR) and correlates with myocardial expression of ROBO4. The knowledge of individual transcript expression levels in blood and in tissue may provide insights into various disease processes in heart transplant patients. Taken together, the results of our study reveal an overlap between 2 objective post-heart transplant rejection surveillance methods, identify potential novel markers for ABMR, and reveal the need for a deeper understanding of molecular mechanisms underlying allograft rejection., (Copyright © 2023. Published by Elsevier Inc.)
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- 2024
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30. Effect of Peanut Paste-based Ready-to-use School Meals With and Without Milk on Fluid Cognition in Northern Ghana: A Randomized Controlled Trial.
- Author
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Stephenson KB, Wegner DR, Hershey TG, Doty T, Davis E, Steiner-Asiedu M, Saalia FK, Shani I, and Manary MJ
- Abstract
Background: Few studies have investigated the role of school feeding in low- and middle-income countries as a means of improving childhood cognition. Peanut/milk ready-to-use food (PM-RUF) or cowpea offers an affordable, scalable option that might improve cognition., Objectives: To determine whether micronutrient-fortified PM-RUF or peanut/cowpea ready-to-use food (PC-RUF) would improve fluid cognition as assessed by 4 tests from the National Institutes of Health Toolbox Cognitive Battery when compared with a micronutrient-fortified millet porridge (FP) after a year of school feeding., Methods: An individually randomly assigned, investigator-blinded, controlled clinical trial was conducted at 6 schools in Mion District in rural northern Ghana. Eight hundred seventy-one school children aged 5-12 y were randomly assigned and allocated to receive PM-RUF (n = 282), PC-RUF (n = 292), or FP (n = 297), each providing ∼400 kcal/d. The primary outcomes were 4 fluid cognition test scores: Dimensional Change Card Sort test, Flanker Inhibitory Control and Attention test, Pattern Comparison Processing Speed test, and a modified List Sorting Working Memory test. Secondary outcomes included a composite median ranking of the 4 primary outcomes and anthropometry changes., Results: Among the 871 participants (median age, 8.8 y; 47% female), 795 (91%) completed endline cognitive testing. Median attendance rates exceeded 87% in all groups. PM-RUF group demonstrated better fluid cognition on the Dimensional Change Card Sort test [odds ratio (OR): 1.5; 95% CI: 1.1, 2.0; P = 0.016] and Pattern Comparison Processing Speed test (OR: 1.4; 95% CI: 1.0, 1.9; P = 0.026) than FP, whereas there were no significant differences on Flanker Inhibitory Control and Attention or List Sorting Working Memory tests. PC-RUF group demonstrated no improvement over FP on any cognitive tests. PM-RUF group had superior fluid cognition composite median rankings (OR: 1.5; 95% CI: 1.1, 2.0; P = 0.007)., Conclusions: Among rural Ghanaian children aged 5-12 y, PM-RUF compared with FP resulted in superior fluid cognition. This trial was registered at clinicaltrials.gov as NCT04349007., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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31. The Subcapital Femoral Neck Stress Fracture: A Novel Subtype of Compression-sided Stress Fracture-A Report of Three Cases.
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Biolzi F, Dinnen R, Jacobs B, Doty T, Barkley C, Jackson KL, and Shaw KA
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- Humans, Male, Adult, Retrospective Studies, Radiography methods, Female, Fractures, Stress classification, Fractures, Stress therapy, Femoral Neck Fractures classification, Military Personnel statistics & numerical data
- Abstract
Femoral neck stress fractures (FNSFs) are increasingly common, particularly in military training. The usual mode of classifying these injuries is based on the involvement of the compression or tension side of the femoral neck; however, this may oversimplify and fail to address factors such as the orientation of the fracture line. We present a novel subtype of a compression-sided FNSF affecting the subcapital femoral neck and report the treatment outcomes in a military trainee population. A retrospective analysis of patients with a subcapital, compression-sided FNSF was identified from a single U.S. Army basic trainee installation. Radiographic evaluation as well as treatment outcomes associated with the ability to complete military training were reported. A total of three patients with a subcapital compression-sided FNSF were identified in a military trainee population, accounting for 10% of all FNSFs that developed over a 3-month period. Of these individuals, one was treated operatively while the other two were treated non-operatively. Overall, one patient was able to return to and successfully complete military training., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
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- 2023
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32. Enhancement of taste by retronasal odors in patients with Wolfram syndrome and decreased olfactory function.
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Alfaro R, Nicanor-Carreón JG, Doty T, Lugar H, Hershey T, and Pepino MY
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- Humans, Adolescent, Smell, Odorants, Taste, Sodium Chloride, Coffee, Sucrose pharmacology, Wolfram Syndrome, Olfaction Disorders
- Abstract
Wolfram syndrome is a rare disease characterized by diabetes, neurodegeneration, loss of vision, and audition. We recently found, in a young sample of participants (mean age 15 years), that Wolfram syndrome was associated with impairment in smell identification with normal smell sensitivity and whole-mouth taste function. However, these senses were assessed separately, and it is unknown whether smell-taste interactions are altered in Wolfram syndrome, which was the focus of this study. Participants with Wolfram syndrome (n = 36; 18.2 ± 6.8 years) and sex-age-equivalent healthy controls (n = 34) were assessed with a battery of sensory tests. Using sip-and-spit methods, participants tasted solutions containing gustatory and olfactory stimuli (sucrose with strawberry extract, citric acid with lemon extract, sodium chloride in vegetable broth, and coffee) with and without nose clips, and rated perceived taste and retronasal smell intensities using the generalized Labeled Magnitude Scale. Participants also completed n-butanol detection thresholds and the University of Pennsylvania Smell Identification Test (UPSIT). Retronasal smell increased taste intensity of sucrose, sodium chloride, and coffee solutions similarly in both groups (P values <0.03). Compared with the control group, participants in the Wolfram group had lower UPSIT scores and reduced smell sensitivity, retronasal intensity, and saltiness (P values <0.03), but rated other taste intensities similarly when wearing the nose clip. Despite impairments in orthonasal smell identification, odor-induced taste enhancement was preserved in participants with Wolfram syndrome who still had some peripheral olfactory function. This finding suggests that odor-induced taste enhancement may be preserved in the presence of reduced olfactory intensity., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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33. The Weekly Calendar Planning Activity to Assess Functional Cognition in Parkinson Disease.
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Foster ER, Carson L, Jonas J, Kang E, Doty T, and Toglia J
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- Cognition, Cross-Sectional Studies, Humans, Neuropsychological Tests, Dementia, Parkinson Disease psychology
- Abstract
The Weekly Calendar Planning Activity (WCPA) may improve understanding of functional cognition in people with Parkinson disease (PwPD) without dementia. We aimed to determine if WCPA performance (a) discriminates between PwPD with and without cognitive impairment and healthy controls and (b) correlates with other indicators of cognition and daily function. This was a cross-sectional study. Parkinson disease (PD) participants without dementia were divided into normal cognition (PD-NC, n = 25) and possible mild cognitive impairment (PD-MCI, n = 21) groups. Their WCPA performance was compared with that of a normative sample ( n = 196) and correlated with neuropsychological test performance and self-reported cognition and participation. Both the PD-MCI and PD-NC groups had impaired WCPA performance. WCPA performance correlated with executive function, processing speed, and self-reported cognition and participation. The WCPA can detect functional cognitive deficits in PwPD without dementia and can inform occupational therapy interventions to support functional cognition, occupational performance, and participation in this population.
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- 2022
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34. Cognitive Correlates of Instrumental Activities of Daily Living Performance in Parkinson Disease Without Dementia.
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Foster ER and Doty T
- Abstract
Objective: To investigate cognitive correlates of instrumental activities of daily living (IADL) performance among people with Parkinson disease (PD) without dementia., Design: Cross-sectional., Setting: Academic medical center., Participants: Volunteer sample (N=161) comprising participants with PD without dementia (n=102) and healthy comparison (HC) participants (n=59)., Interventions: Not applicable., Main Outcome Measures: Performance-based assessment of cognitively-demanding IADL (meal preparation, bill paying, shopping, medication management, small home repair), neuropsychological tests (attentional control/flexibility, planning, working memory, memory, crystallized intelligence), and measures of motor function and other characteristics (eg, depressive symptoms)., Results: There were no group differences in neuropsychological test performance ( P >.06). The PD group performed more poorly than the HC group on a number of cognitive IADL tasks ( P <.04). After accounting for the effects of motor impairment and other disease-related characteristics, neuropsychological test performance accounted for a small but unique portion of the variance in performance of all cognitive IADL combined, meal preparation, shopping, and medication management in the PD group ( R
2 =4%-13%; P ≤.01)., Conclusions: The PD group had cognitive IADL performance limitations despite being unimpaired on neuropsychological tests. Within PD, neuropsychological test performance accounted for a small but significant portion of the variance in cognitive IADL performance over and above the effects of motor and other impairments. These results support the added value of using performance-based IADL assessments in functional evaluations of individuals with early and mild PD without dementia., (© 2021 The Authors.)- Published
- 2021
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35. KidneyCare Guided Immuno-Optimization in Renal Allografts: The KIRA Protocol.
- Author
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Gray JN, Wolf-Doty T, Sulejmani N, Gaber O, Axelrod D, Abdalla B, and Danovitch G
- Abstract
Immunosuppressant agents are essential in every transplant recipient's care yet walking the fine line of over- or under-immunosuppression is a constant struggle for both patients and transplant providers alike. Optimization and personalization of immunosuppression has been limited by the need for non-invasive graft surveillance methods that are specific enough to identify organ injury in real time. With this in mind, we propose a pilot study protocol utilizing both donor derived cell free DNA (dd-cfDNA, gene expression profiling (GEP), and machine learning (iBox), called KidneyCare, to assess the feasibility and safety in reducing immunosuppressant exposure without increasing the risk of clinical rejection, graft injury, or allograft loss. Patients randomized to the immunominimization arm will be enrolled in one of two protocols designed to eliminate one immunosuppressant and optimize the dose of the Calcineurin Inhibitors (CNIs) using the KidneyCare platform. All patients will be maintained on dual therapy of either steroids and a low dose CNI, or mycophenolate mofetil (MMF) and low dose CNI. Their outcomes will be compared to patients who have their immunosuppressants managed using standard clinical assessment and treatment protocols to determine the impact of immuno-optimization on graft function, complications, and patient reported outcomes.
- Published
- 2020
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36. Taste and smell function in Wolfram syndrome.
- Author
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Alfaro R, Doty T, Narayanan A, Lugar H, Hershey T, and Pepino MY
- Subjects
- Adolescent, Adult, Biomarkers, Child, Child, Preschool, Humans, Taste, Young Adult, Smell, Wolfram Syndrome
- Abstract
Background: Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Although olfactory dysfunction, a classical clinical marker of neurodegenerative processes, has been reported in Wolfram syndrome, its use as a clinical marker in Wolfram is limited due to data scarcity. In addition, it is unknown whether Wolfram syndrome affects the sense of taste., Methods: Smell and taste perception were assessed in participants with Wolfram syndrome (n = 40) who were 15.1 ± 6.0 years of age (range: 5.1-28.7 years) and two sex- and age-matched control groups: one group with type 1 diabetes mellitus (T1D; n = 25) and a healthy control group (HC; n = 29). Smell sensitivity was assessed by measuring n-butanol detection thresholds and smell identification by using the University of Pennsylvania Smell Identification Test (UPSIT). Taste function was assessed using NIH Toolbox, which includes the assessment of sucrose (sweet) taste preference, and perceived intensity of sucrose, sodium chloride (salty), and quinine hydrochloride (bitter) both in the tip of the tongue (regional test) and the whole mouth., Results: Smell sensitivity was not significantly different among groups; however, smell identification was impaired in Wolfram syndrome, as reflected by significantly lower UPSIT scores in Wolfram syndrome compared to HC and T1D (P < 0.001). Compared to participants in the control groups, participants with Wolfram syndrome had a blunted perception of sweetness and saltiness when taste stimuli were applied regionally (P < 0.05), but differences in perceived intensity were no longer significant among groups when taste stimuli were tasted with the whole mouth. Groups preferred similar sucrose concentrations., Conclusion: Wolfram syndrome was associated with olfactory dysfunction. However, the olfactory dysfunction was qualitative (related to smell identification) and not secondary to olfactory insensitivity or diabetes, suggesting is arising from dysfunction in central olfactory brain regions. In contrast to olfaction, and despite decreased perception of taste intensity in the anterior tongue, the sense of taste was overall well-conserved in individuals with Wolfram syndrome. Future longitudinal studies of taste and smell perception in Wolfram syndrome will be important to determine the use of the chemical senses as clinical markers of disease progression.
- Published
- 2020
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37. Understanding activity participation among individuals with Wolfram Syndrome.
- Author
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Bumpus E, Hershey T, Doty T, Ranck S, Gronski M, Urano F, and Foster ER
- Abstract
Introduction: Wolfram Syndrome (WFS) is a rare genetic disease associated with a variety of progressive metabolic and neurologic impairments. Previous research has focused on WFS-related impairments and biomarkers for disease progression; however, information about how WFS impacts participation in daily activities is lacking., Methods: WFS (n=45; 20 children, 25 adults) participants completed an online questionnaire about activity participation. Thirty-six non-WFS comparison participants (11 children; 25 adults) completed a portion of the questionnaire. Symptom data from a subset of WFS participants (n=20) were also examined in relation to participation data., Results: WFS children and adults had lower participation than non-WFS children and adults in almost all activity domains, and social and exercise-related activities were the most problematic. In the subset of WFS adults with symptom data, poorer vision, balance, gait, hearing, and overall symptom severity related to lower participation., Conclusions: WFS appears to negatively impact participation in a variety of activities, and this effect may increase as people age and/or WFS progresses. The most functionally-pertinent WFS symptoms are those associated with neurodegeneration especially vision loss and walking and balance problems. This study revealed symptoms and activity domains that are most relevant for people with WFS and, thus, can inform current practice and treatment development research., Competing Interests: Declaration of conflicting interest: The Authors declare that there is no conflict of interest.
- Published
- 2018
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38. A longitudinal investigation of cognitive function in children and adolescents with type 1 diabetes mellitus.
- Author
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Kirchhoff BA, Jundt DK, Doty T, and Hershey T
- Subjects
- Adolescent, Age of Onset, Case-Control Studies, Child, Humans, Longitudinal Studies, Cognition physiology, Diabetes Mellitus, Type 1 psychology, Hyperglycemia psychology
- Abstract
Objective: Cross-sectional studies find altered cognition in youth with type 1 diabetes mellitus (T1DM). However, few longitudinal studies have examined the trajectories of their cognitive performance over time. The aims of this study were to explore longitudinal change in cognitive function in youth with T1DM as compared with nondiabetic sibling controls, and how glycemic control and age of onset influence cognitive performance over time., Methods: We assessed crystallized intelligence, visual-spatial ability, delayed memory, and processing speed at 3 time points using the same cognitive tasks in youth with T1DM and sibling controls. Hierarchical linear modeling examined relationships between diabetes, hyperglycemia (HbA1c values), age of onset, and cognition over 5.5 y., Results: Youth with diabetes performed worse than controls on visual-spatial ability and memory tasks over time, and did not improve as much in processing speed. Greater hyperglycemia was associated with lower crystallized intelligence and slower processing speed but better memory across all time points. There was a stronger negative relationship between hyperglycemia and visual-spatial ability for youth with earlier compared with later onset diabetes. Importantly, within-person decreases in hyperglycemia between time points were associated with improved visual-spatial ability and faster processing speed., Conclusions: On average, differences in cognitive function between youth with T1DM and nondiabetic relatives are maintained or increase during childhood and adolescence. Hyperglycemia and age of onset can have negative effects on the developmental trajectories of cognitive processes in youth with T1DM. However, treatments that lower hyperglycemia may lead to improved cognitive function in youth with T1DM., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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39. The effects of disease-related symptoms on daily function in Wolfram Syndrome.
- Author
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Doty T, Foster ER, Marshall B, Ranck S, and Hershey T
- Abstract
Objective: To investigate daily function among individuals with Wolfram Syndrome (WFS) and examine whether any limitations are related to disease-related symptoms., Methods: WFS ( n = 31), Type 1 diabetic (T1DM; n = 25), and healthy control (HC; n = 29) participants completed the Pediatric Quality of Life Questionnaire (PEDSQL) Self and Parent Report. PEDSQL domain scores were compared among these groups and between WFS patients with and without specific disease-related symptoms. Relationships between PEDSQL scores and symptom severity as assessed by the Wolfram Unified Rating Scale (WURS) Physical Scale were also examined., Results: Across most domains, the WFS group had lower PEDSQL Self and Parent Report scores than the T1DM and HC groups. WFS participants with urinary, sleep, and temperature regulation problems had lower PEDSQL scores than those without. The WURS Physical Scale correlated with Self and Parent Report PEDSQL domains. WFS group Self and Parent Reports correlated with each other., Conclusions: The WFS group reported lower daily function compared to T1DM and HC groups. Within WFS, worse symptom severity and the specific symptoms of sleep, temperature regulation, and urinary problems were associated with poorer daily function. These findings provide rationale for an increased emphasis on identifying, treating and understanding these less well-known symptoms of WFS., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.
- Published
- 2017
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40. Self-management program participation and social support in Parkinson's disease: Mixed methods evaluation.
- Author
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Pappa K, Doty T, Taff SD, Kniepmann K, and Foster ER
- Abstract
Aims: To explore the potential influence of the Stanford Chronic Disease Self-Management Program (CDSMP) on social support in Parkinson disease (PD)., Methods: This was a quasi-experimental mixed methods design. Volunteers with PD (n=27) and care partners (n=6) completed the CDSMP, questionnaires of social support and self-management outcomes, and an interview about social support in relation to CDSMP participation. PD participants (n=19) who did not participate in the CDSMP completed the questionnaires for quantitative comparison purposes., Results: Regarding the quantitative data, there were no significant effects of CDSMP participation on social support questionnaire scores; however, there were some positive correlations between changes in social support and changes in self-management outcomes from pre- to post-CDSMP participation. Three qualitative themes emerged from the interviews: lack of perceived change in amount and quality of social support, positive impact on existing social networks, and benefit from participating in a supportive PD community., Conclusions: Although participants did not acknowledge major changes in social support, there were some social support-related benefits of CDSMP participation for PD participants and care partners. These findings provide a starting point for more in-depth studies of social support and self-management in this population., Competing Interests: Declaration of Interest The authors report no financial conflicts of interest.
- Published
- 2017
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41. Clinical presentation and memory function in youth with type 1 diabetes.
- Author
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Semenkovich K, Bischoff A, Doty T, Nelson S, Siller AF, Hershey T, and Arbeláez AM
- Subjects
- Adolescent, Case-Control Studies, Child, Diabetes Mellitus, Type 1 complications, Diabetic Ketoacidosis psychology, Female, Glycated Hemoglobin analysis, Humans, Hyperglycemia complications, Hyperglycemia psychology, Intelligence Tests, Male, Neuropsychological Tests, Siblings, Cognition physiology, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 psychology, Memory physiology
- Abstract
Objective: While cerebral edema and diabetic ketoacidosis (DKA) in type 1 diabetes (T1DM) have well-described acute effects on cognition, little is known about the impact of clinical presentation on longer term cognitive outcomes. We hypothesized that clinical factors (degree of hyperglycemia exposure and DKA) at the time of diagnosis would relate to cognition within 3.5 months later in children with T1DM., Methods: Cognitive testing was performed on children 7-17 years old with T1DM (n = 66) within 3.5 months of diagnosis and siblings without T1DM (n = 33). Overall intelligence, processing speed, and memory (including a sensitive long-delay spatial memory test; spatial delayed response or SDR) were assessed. Medical records were reviewed for hemoglobin A1c (HbA1c), DKA status, and other clinical factors at diagnosis., Results: Within the group with T1DM, 17 children presented in DKA and 49 did not. After adjusting for age, gender, and socioeconomic status, the subgroup with T1DM and DKA at diagnosis performed worse on the long-delay SDR task compared to sibling controls (p = 0.006). In addition, within the group with T1DM, higher HbA1c at diagnosis was associated with worse performance on the long-delay SDR task (p = 0.027). Performance on the other cognitive tasks was not different across groups or subgroups., Conclusions: DKA and degree of hyperglycemia exposure at diagnosis have implications for long-delay spatial memory function within 3.5 months of diagnosis. These findings suggest that early detection of T1DM, which decreases risk for prolonged exposure to hyperglycemia and DKA, may avoid negative effects on memory function., Competing Interests: Duality of Interest. None of the authors in the manuscript have any financial conflicts of interest to report., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
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42. Prenatal DHA supplementation and infant attention.
- Author
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Colombo J, Gustafson KM, Gajewski BJ, Shaddy DJ, Kerling EH, Thodosoff JM, Doty T, Brez CC, and Carlson SE
- Subjects
- Adult, Female, Follow-Up Studies, Heart Rate, Humans, Infant, Infant, Newborn, Male, Pregnancy, Pregnancy Trimester, Second, Pregnancy Trimester, Third, Time Factors, Treatment Outcome, Attention drug effects, Cognition drug effects, Dietary Supplements, Docosahexaenoic Acids administration & dosage, Maternal Nutritional Physiological Phenomena
- Abstract
Background: Results of randomized trials on the effects of prenatal docosahexaenoic acid (DHA) on infant cognition are mixed, but most trials have used global standardized outcomes, which may not be sensitive to effects of DHA on specific cognitive domains., Methods: Women were randomized to 600 mg/d DHA or a placebo for the last two trimesters of pregnancy. Infants of these mothers were then followed on tests of visual habituation at 4, 6, and 9 mo of age., Results: DHA supplementation did not affect look duration or habituation parameters but infants of supplemented mothers maintained high levels of sustained attention (SA) across the first year; SA declined for the placebo group. The supplemented group also showed significantly reduced attrition on habituation tasks, especially at 6 and 9 mo., Conclusion: The findings support with the suggestion that prenatal DHA may positively affect infants' attention and regulation of state., Competing Interests: None of the authors declare a potential conflict of interest.
- Published
- 2016
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43. Selective cognitive and psychiatric manifestations in Wolfram Syndrome.
- Author
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Bischoff AN, Reiersen AM, Buttlaire A, Al-Lozi A, Doty T, Marshall BA, and Hershey T
- Subjects
- Adolescent, Adult, Child, Diabetes Mellitus, Type 1 physiopathology, Diabetes Mellitus, Type 1 psychology, Female, Humans, Intelligence physiology, Male, Memory physiology, Smell physiology, Wolfram Syndrome pathology, Young Adult, Cognition physiology, Wolfram Syndrome physiopathology, Wolfram Syndrome psychology
- Abstract
Background: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures., Methods: Individuals with genetically-confirmed WFS (n = 19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group., Results: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence., Conclusions: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well., Trial Registration: Current Clinicaltrials.gov Trial NCT02455414 .
- Published
- 2015
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44. Metabolic engineering of Aspergillus oryzae NRRL 3488 for increased production of L-malic acid.
- Author
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Brown SH, Bashkirova L, Berka R, Chandler T, Doty T, McCall K, McCulloch M, McFarland S, Thompson S, Yaver D, and Berry A
- Subjects
- Glucose metabolism, Pyruvic Acid metabolism, Aspergillus oryzae genetics, Aspergillus oryzae metabolism, Malates metabolism, Metabolic Engineering
- Abstract
Malic acid, a petroleum-derived C4-dicarboxylic acid that is used in the food and beverage industries, is also produced by a number of microorganisms that follow a variety of metabolic routes. Several members of the genus Aspergillus utilize a two-step cytosolic pathway from pyruvate to malate known as the reductive tricarboxylic acid (rTCA) pathway. This simple and efficient pathway has a maximum theoretical yield of 2 mol malate/mol glucose when the starting pyruvate originates from glycolysis. Production of malic acid by Aspergillus oryzae NRRL 3488 was first improved by overexpression of a native C4-dicarboxylate transporter, leading to a greater than twofold increase in the rate of malate production. Overexpression of the native cytosolic alleles of pyruvate carboxylase and malate dehydrogenase, comprising the rTCA pathway, in conjunction with the transporter resulted in an additional 27 % increase in malate production rate. A strain overexpressing all three genes achieved a malate titer of 154 g/L in 164 h, corresponding to a production rate of 0.94 g/L/h, with an associated yield on glucose of 1.38 mol/mol (69 % of the theoretical maximum). This rate of malate production is the highest reported for any microbial system.
- Published
- 2013
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45. Long-chain polyunsaturated fatty acid supplementation in infancy reduces heart rate and positively affects distribution of attention.
- Author
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Colombo J, Carlson SE, Cheatham CL, Fitzgerald-Gustafson KM, Kepler A, and Doty T
- Subjects
- Animals, Double-Blind Method, Humans, Infant, Infant Formula chemistry, Neuropsychological Tests, Prospective Studies, Attention drug effects, Dietary Supplements, Docosahexaenoic Acids administration & dosage, Fatty Acids, Unsaturated administration & dosage, Heart Rate drug effects
- Abstract
A double-blind, randomized, controlled, parallel-group prospective trial was conducted to determine whether a dose-response existed for four different levels of docosahexaenoic acid (DHA) supplementation on the cognitive performance of infants. A total of 122 term infants were fed one of four different formulas varying in their DHA composition (0.00, 0.32, 0.64, and 0.96% of total fatty acids as DHA) from birth to 12 mo. The three DHA-supplemented formulas also contained 0.64% of total fatty acids as arachidonic acid (ARA, 20:4n-6). Infants were tested at 4, 6, and 9 mo of age on a visual habituation protocol that yielded both behavioral and psychophysiological indices of attention. Infants in all DHA+ARA-supplemented conditions had lower heart rates than those in the unsupplemented condition; there was no dose-response for this effect. The distribution of time that infants spent in different phases of attention (a cognitive index derived from the convergence of behavioral and cardiac responses) varied as a function of dosage. Infants supplemented at the two lower DHA doses spent proportionately more time engaged in active stimulus processing than infants fed the unsupplemented formula, whereas infants fed the highest dose were intermediate and did not differ from any other group.
- Published
- 2011
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46. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA.
- Author
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Liu J, Doty T, Gibson B, and Heyer WD
- Subjects
- Apoptosis Regulatory Proteins, BRCA2 Protein chemistry, BRCA2 Protein isolation & purification, Chromatography, Affinity, DNA Repair physiology, DNA, Circular metabolism, Humans, Models, Biological, Proteasome Endopeptidase Complex physiology, Protein Binding, Protein Interaction Mapping, Rad51 Recombinase chemistry, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins isolation & purification, Recombinant Fusion Proteins physiology, Recombination, Genetic physiology, Replication Protein A, BRCA2 Protein physiology, DNA, Single-Stranded metabolism, Rad51 Recombinase physiology
- Abstract
BRCA2 is a tumor suppressor that functions in homologous recombination, a key genomic integrity pathway. BRCA2 interacts with RAD51, the central protein of recombination, which forms filaments on single-stranded DNA (ssDNA) to perform homology search and DNA strand invasion. We report the purification of full-length human BRCA2 and show that it binds to ~6 RAD51 molecules and promotes RAD51 binding to ssDNA coated by replication protein A (RPA), in a manner that is stimulated by DSS1.
- Published
- 2010
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47. Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase.
- Author
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Ehses JA, Casilla VR, Doty T, Pospisilik JA, Winter KD, Demuth HU, Pederson RA, and McIntosh CH
- Subjects
- Animals, Caspase 3, Caspases metabolism, Cell Line, Cell Survival drug effects, Mitogen-Activated Protein Kinases physiology, Phosphorylation, Receptors, Gastrointestinal Hormone metabolism, Receptors, Gastrointestinal Hormone physiology, p38 Mitogen-Activated Protein Kinases, Caspase Inhibitors, Cyclic AMP physiology, Gastric Inhibitory Polypeptide pharmacology, Islets of Langerhans physiology, Mitogen-Activated Protein Kinases metabolism
- Abstract
The incretin glucose-dependent insulinotropic polypeptide (GIP) is a major regulator of postprandial insulin secretion in mammals. Recent studies in our laboratory, and others have suggested that GIP is a potent stimulus for protein kinase activation, including the MAPK (ERK1/2) module. Based on these studies, we hypothesized that GIP could regulate cell fate and sought to examine the underlying mechanisms involved in GIP stimulation of cell survival. GIP potentiated glucose-induced beta-(INS-1)-cell growth to levels comparable with GH and GLP-1 while promoting cell survival in the face of serum and glucose-deprivation or treatment with wortmannin or streptozotocin. In the absence of GIP, 50% of cells died after 48 h of serum and glucose withdrawal, whereas 91 +/- 10% of cells remained viable in the presence of GIP [n = 3, P < 0.05; EC50 of 1.24 +/- 0.48 nm GIP (n = 4)]. Effects of GIP on cell survival and inhibition of caspase-3 were mimicked by forskolin, but pharmacological experiments excluded roles for MAPK kinase (Mek)1/2, phosphatidylinositol 3-kinase, protein kinase A, Epac, and Rap 1. Survival effects of GIP were ablated by the inhibitor SB202190, indicating a role for p38 MAPK. Furthermore, caspase-3 activity was also regulated by p38 MAPK, with a lesser role for Mek1/2, based on RNA interference studies. We propose that GIP is able to reverse caspase-3 activation via inhibition of long-term p38 MAPK phosphorylation in response to glucose deprivation (+/-wortmannin). Intriguingly, these findings contrasted with short-term phosphorylation of MKK3/6-->p38 MAPK-->ATF-2 by GIP. Thus, these data suggest that GIP is able to regulate INS-1 cell survival by dynamic control of p38 MAPK phosphorylation via cAMP signaling and lend further support to the notion that GIP regulation of MAPK signaling is critical for its regulation of cell fate.
- Published
- 2003
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48. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats.
- Author
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Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, Piteau S, Demuth HU, McIntosh CH, and Pederson RA
- Subjects
- Animals, Blood Glucose analysis, Cell Count, Cell Differentiation drug effects, Cell Division drug effects, Diabetes Mellitus, Experimental pathology, Diabetes Mellitus, Experimental physiopathology, Eating drug effects, Gastric Inhibitory Polypeptide administration & dosage, Glucagon administration & dosage, Glucagon blood, Glucagon-Like Peptide 1, Glucagon-Like Peptides, Glucose Tolerance Test, Immunohistochemistry, Insulin analysis, Insulin blood, Insulin metabolism, Insulin Secretion, Islets of Langerhans chemistry, Islets of Langerhans metabolism, Lipids blood, Liver enzymology, Male, Peptide Fragments administration & dosage, Peptide Fragments blood, Phosphoenolpyruvate Carboxykinase (GTP) analysis, Protein Precursors administration & dosage, Protein Precursors blood, Rats, Rats, Wistar, Weight Gain drug effects, Cell Survival drug effects, Diabetes Mellitus, Experimental drug therapy, Dipeptidyl Peptidase 4 blood, Islets of Langerhans pathology, Protease Inhibitors therapeutic use
- Abstract
Recent studies into the physiology of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have added stimulation of beta-cell growth, differentiation, and cell survival to well-documented, potent insulinotropic effects. Unfortunately, the therapeutic potential of these hormones is limited by their rapid enzymatic inactivation in vivo by dipeptidyl peptidase IV (DP IV). Inhibition of DP IV, so as to enhance circulating incretin levels, has proved effective in the treatment of type 2 diabetes both in humans and in animal models, stimulating improvements in glucose tolerance, insulin sensitivity, and beta-cell function. We hypothesized that enhancement of the cytoprotective and beta-cell regenerative effects of GIP and GLP-1 might extend the therapeutic potential of DP IV inhibitors to include type 1 diabetes. For testing this hypothesis, male Wistar rats, exposed to a single dose of streptozotocin (STZ; 50 mg/kg), were treated twice daily with the DP IV inhibitor P32/98 for 7 weeks. Relative to STZ-injected controls, P32/98-treated animals displayed increased weight gain (230%) and nutrient intake, decreased fed blood glucose ( approximately 26 vs. approximately 20 mmol/l, respectively), and a return of plasma insulin values toward normal (0.07 vs. 0.12 nmol/l, respectively). Marked improvements in oral glucose tolerance, suggesting enhanced insulin secretory capacity, were corroborated by pancreas perfusion and insulin content measurements that revealed two- to eightfold increases in both secretory function and insulin content after 7 weeks of treatment. Immunohistochemical analyses of pancreatic sections showed marked increases in the number of small islets (+35%) and total beta-cells (+120%) and in the islet beta-cell fraction (12% control vs. 24% treated) in the treated animals, suggesting that DP IV inhibitor treatment enhanced islet neogenesis, beta-cell survival, and insulin biosynthesis. In vitro studies using a beta-(INS-1) cell line showed a dose-dependent prevention of STZ-induced apoptotic cell-death by both GIP and GLP-1, supporting a role for the incretins in eliciting the in vivo results. These novel findings provide evidence to support the potential utility of DP IV inhibitors in the treatment of type 1 and possibly late-stage type 2 diabetes.
- Published
- 2003
- Full Text
- View/download PDF
49. Dipeptidyl peptidase IV inhibition in animal models of diabetes.
- Author
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Pospisilik JA, Ehses JA, Doty T, McIntosh CH, Demuth HU, and Pederson RA
- Subjects
- Animals, Blood Glucose metabolism, Disease Models, Animal, Insulin metabolism, Insulin Secretion, Islets of Langerhans metabolism, Models, Biological, Rats, Rats, Inbred BB, Diabetes Mellitus, Experimental drug therapy, Dipeptidyl Peptidase 4 metabolism, Protease Inhibitors therapeutic use
- Published
- 2003
- Full Text
- View/download PDF
50. Cancer survivorship and agency model: implications for patient choice, decision making, and influence.
- Author
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O'Hair D, Villagran MM, Wittenberg E, Brown K, Ferguson M, Hall HT, and Doty T
- Subjects
- Humans, Models, Organizational, Patient Advocacy, Quality of Life, Uncertainty, United States, Communication, Decision Making, Neoplasms psychology, Patient Participation, Physician-Patient Relations, Survivors psychology
- Abstract
Relative to other types of health communication research (acute care physician patient communication, communication campaigns, compliance episodes, etc.), investigations of patient communication following the diagnosis of cancer are infrequent. Theoretically driven, empirical research is desperately needed in such postdiagnostic communication processes as survivorship, quality of life, palliative and hospice care, and loss, bereavement, and grief for those millions of people who have been diagnosed with the second leading cause of death in our nation. An organizational model of patient communication is needed that identifies and describes salient issues and processes involved when cancer patients attempt to negotiate the difficult courses of action following the diagnosis of cancer. The cancer survivorship and agency model (CSAM) proposes both general and specific strategies that serve as options for patients seeking to take greater control of the decision-making process related to their treatment and care of cancer. Although seemingly practical in its offering, CSAM is intended to serve as a heuristic springboard for theoretically based, applied communication research focusing exclusively on post diagnostic cancer processes.
- Published
- 2003
- Full Text
- View/download PDF
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