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Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes
(Elsevier, 2023) Sims, Emily K.; Kulkarni, Abhishek; Hull, Audrey; Woerner, Stephanie E.; Cabrera, Susanne; Mastrandrea, Lucy D.; Hammoud, Batoul; Sarkar, Soumyadeep; Nakayasu, Ernesto S.; Mastracci, Teresa L.; Perkins, Susan M.; Ouyang, Fangqian; Webb-Robertson, Bobbie-Jo; Enriquez, Jacob R.; Tersey, Sarah A.; Evans-Molina, Carmella; Long, S. Alice; Blanchfield, Lori; Gerner, Eugene W.; Mirmira, Raghavendra G.; DiMeglio, Linda A.; Pediatrics, School of Medicine
In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing β cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with β cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during β cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m2) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve β cell function in T1D through islet cell-autonomous effects.
Preswitch Regimens Influence the Rate of Weight Gain After Switch to Tenofovir Disoproxil Fumarate, Lamivudine, and Dolutegravir (TLD): Study From an East African Cohort
(Oxford University Press, 2023-12-12) Bourgi, Kassem; Ofner, Susan; Musick, Beverly; Wools-Kaloustian, Kara; Humphrey, John M.; Diero, Lameck; Yiannoutsos, Constantin T.; Gupta, Samir K.; Medicine, School of Medicine
Background: Switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to dolutegravir (DTG) has been associated with greater weight gain.
Methods: We conducted our analysis using a longitudinal cohort of people with HIV (PWH) in Western Kenya. We evaluated changes in the rate of weight gain among treatment-experienced, virally suppressed PWH who switched from NNRTI to tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). We modeled the weights pre- and postswitch using a 2-phase model with linear trend preswitch and an inverted exponential function postswitch. We estimated an 18-month excess weight gain by comparing the projected weight with that expected using the preswitch rate.
Results: A total of 18 662 individuals were included in our analysis, with 55% switching from efavirenz (EFV) and 45% from nevirapine (NVP). Of the studied individuals, 51% were female, and the median age and body mass index (BMI) were 51 years and 22 kg/m2, respectively. For the overall population, the rate of weight gain increased from 0.47 kg/year preswitch to 0.77 kg/year, with higher increases for females (0.57 kg/year to 0.96 kg/year) than males (0.34 kg/year to 0.62 kg/year). The rate of weight gain for individuals switching from EFV-based regimens significantly increased from 0.57 kg/year preswitch to 1.11 kg/year postswitch but remained stable at 0.35 kg/year preswitch vs 0.32 kg/year postswitch for individuals switching from NVP-based regimens.
Conclusions: Switching from NNRTI-based regimens to TLD is associated with a modest increase in the rate of weight gain, with the preswitch NNRTI being the key determinant of the amount of weight gain experienced postswitch.
A Psychometric Evaluation of the NIH Toolbox Fluid Cognition Tests Adapted for Swahili and Dholuo Languages in Kenyan Children and Adolescents
(Cambridge University Press, 2023) McHenry, Megan S.; Roose, Anna; Abuonji, Emily; Nyalumbe, Mark; Ayuku, David; Ayodo, George; Tran, Tuan M.; Kaat, Aaron J.; Pediatrics, School of Medicine
Objective: Our objective was to evaluate the psychometric properties of the culturally adapted NIH Toolbox African Languages® when used in Swahili and Dholuo-speaking children in western Kenya.
Method: Swahili-speaking participants were recruited from Eldoret and Dholuo-speaking participants from Ajigo; all were <14 years of age and enrolled in primary school. Participants completed a demographics questionnaire and five fluid cognition tests of the NIH Toolbox® African Languages program, including Flanker, Dimensional Change Card Sort (DCCS), Picture Sequence Memory, Pattern Comparison, and List Sorting tests. Statistical analyses examined aspects of reliability, including internal consistency (in both languages) and test-retest reliability (in Dholuo only).
Results: Participants included 479 children (n = 239, Swahili-speaking; n = 240, Dholuo-speaking). Generally, the tests had acceptable psychometric properties for research use within Swahili- and Dholuo-speaking populations (mean age = 10.5; SD = 2.3). Issues related to shape identification and accuracy over speed limited the utility of DCCS for many participants, with approximately 25% of children unable to match based on shape. These cultural differences affected outcomes of reliability testing among the Dholuo-speaking cohort, where accuracy improved across all five tests, including speed.
Conclusions: There is preliminary evidence that the NIH Toolbox ® African Languages potentially offers a valid assessment of development and performance using tests of fluid cognition in Swahili and Dholuo among research settings. With piloting underway across other diverse settings, future research should gather additional evidence on the clinical utility and acceptability of these tests, specifically through the establishment of norming data among Kenyan regions and evaluating these psychometric properties.
Knowledge and Intention to Use Long-Acting Reversible Contraception among University Students
(Taylor & Francis, 2022-06-23) Asdell, Stephanie M.; Bennett, Rachel D.; Cordon, Sabrina A.; Zhao, Qiuhong; Peipert, Jeffrey F.; Obstetrics and Gynecology, School of Medicine
Objective: To assess the relationship between knowledge of long-acting reversible contraception (LARC) and intention to use LARC among female students.
Participants: Participants consisted of a convenience sample of 292 female undergraduate and graduate students at a large midwestern university.
Methods: We conducted a cross-sectional in-person survey and multivariate analysis of LARC knowledge and intention to use LARC.
Results: Total response rate was 84.9%. Among contraceptive users, 13.3% were using a LARC method. On average, respondents scored 4.8/10 (SD 2.5) on a 10-item LARC knowledge assessment. Higher levels of LARC knowledge were associated with the intent to use LARC in the future in our multivariate analysis (RR 1.7, 95% CI 1.14-2.54: p = .01). Common reasons for LARC hesitancy were a need for more information, safety concerns, and risk of undesirable side effects.
Conclusions: Low LARC knowledge and students' self-identified need for further LARC information represent an opportunity for campus contraceptive interventions which empower students to make informed reproductive decisions.
Obesity in CKD: A Promising Path Forward
(Wolters Kluwer, 2022) Friedman, Allon N.; Medicine, School of Medicine