Browsing by Author "Pediatrics, School of Medicine"
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Item 1,25-Dihydroxyvitamin D3 enhances glucose-stimulated insulin secretion in mouse and human islets: a role for transcriptional regulation of voltage-gated calcium channels by the vitamin D receptor(Elsevier, 2018) Kjalarsdottir, Lilja; Tersey, Sarah A.; Vishwanath, Mridula; Chuang, Jen-Chieh; Posner, Bruce A.; Mirmira, Raghavendra G.; Repa, Joyce J.; Pediatrics, School of MedicineAim Vitamin D deficiency in rodents negatively affects glucose-stimulated insulin secretion (GSIS) and human epidemiological studies connect poor vitamin D status with type 2 diabetes. Previous studies performed primarily in rat islets have shown that vitamin D can enhance GSIS. However the molecular pathways linking vitamin D and insulin secretion are currently unknown. Therefore, experiments were undertaken to elucidate the transcriptional role(s) of the vitamin D receptor (VDR) in islet function. Methods Human and mouse islets were cultured with vehicle or 1,25-dihydroxyvitamin-D3 (1,25D3) and then subjected to GSIS assays. Insulin expression, insulin content, glucose uptake and glucose-stimulated calcium influx were tested. Microarray analysis was performed. In silico analysis was used to identify VDR response elements (VDRE) within target genes and their activity was tested using reporter assays. Results Vdr mRNA is abundant in islets and Vdr expression is glucose-responsive. Preincubation of mouse and human islets with 1,25D3 enhances GSIS and increases glucose-stimulated calcium influx. Microarray analysis identified the R-type voltage-gated calcium channel (VGCC) gene, Cacna1e, which is highly upregulated by 1,25D3 in human and mouse islets and contains a conserved VDRE in intron 7. Results from GSIS assays suggest that 1,25D3 might upregulate a variant of R-type VGCC that is resistant to chemical inhibition. Conclusion These results suggest that the role of 1,25D3 in regulating calcium influx acts through the R-Type VGCC during GSIS, thereby modulating the capacity of beta cells to secrete insulin.Item 100 years of insulin: celebrating the past, present and future of diabetes therapy(Springer Nature, 2021) Sims, Emily K.; Carr, Alice L.J.; Oram, Richard A.; DiMeglio, Linda A.; Evans-Molina, Carmella; Pediatrics, School of MedicineThe year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.Item 11. Changes in Adolescent and Young Adult (AYA) Relationship Status during COVID19: Data from a 30 Country Sexual and Reproductive Health Study(Elsevier, 2022) Hensel, Devon J.; Campbell, Linda; Erausquin, Jennifer T.; Mark, Kristin P.; I-SHARE Consortium; Pediatrics, School of MedicinePurpose: Important milestones - including romantic/sexual relationship development - were impacted by COVID19 mitigation measures. We examined self-reported change in relationship status before, during and after COVID among AYA who participated in a 30-country survey. Methods: Data were drawn from the International Sexual Health And REproductive Health Survey (I-SHARE-1), a multi-country, cross-sectional, online study conducted to assess the impact of the pandemic on adult sexual health across the globe. Participants were recruited through local, regional, and national networks (e.g. listservs of professional organizations and international health organizations, social media, etc.) of each country’s research team. We drew a subsample of AYA (N=7527 18-26 years; 32.3% of the total sample; 60.1% female, 86.1% cisgender, 77.1% heterosexual). We examined 5 categories of relationship status change: 1) unpartnered pre/post; 2) unpartnered pre, new partner post; 3) same partner pre/post; 4) partnered pre, broke up, unpartnered post; 5) partnered pre, broke up, new partner post. Random intercept mixed effects multinomial regression (gllamm; Stata 17.0; all p<.05) adjusted for country-level clustering was used to understand how demographic (age, gender identity, sexual identity, employment status during COVID, mental health, distancing or isolation during COVID) and country-level predictors (income group, Oxford Stringency Index [national response to COVID], Palma Ratio [country-income inequality) and Gender Inequality Index (country-gender inequality) were associated with relationship change. Results: 15% of AYA had no partner pre/post COVID, 5% were unpartnered pre-COVID with new partner post. 63.3% had the same partner pre/post, whereas 11.3% had a partner pre-COVID, but broke up and had no new partner post-COVID. Less than 5% had a new partner post-COVID after breaking up with their pre-COVID partner. Of those who broke up with their partner, the majority ended during (44.4%) or after (26.6%) COVID-lockdowns, and one-third thought social distancing precipitated the relationship’s end. Older (RRR=0.86-0.91), female (RRR=0.32-0.63) and transgender AYA (RRR=0.10-0.37) all had a lower risk, and sexual minority AYA had a higher risk (RRR=1.35-1.51), of being in all status categories compared to being in the same relationship before-and-after COVID. Higher mental health scores were linked to lower probability of being unpartnered pre/post as compared to being partnered pre/post (RRR=0.89-0.82). Social-distancing was associated with a lower risk for pre-COVID unpartnered individuals finding new post-COVID relationships (RRR=0.76) or of partnered individuals breaking up, while ever being in isolation was associated with higher risk of being unpartnered pre/post (RRR=1.20). Higher country income was associated with being unpartered pre-COVID (RRR=0.08-0.12) and higher risk of having a pre-COVID relationship break-up (RRR=1.32). Unpartnered individuals in countries with higher lockdown stringency had a greater probability of finding a new post-COVID relationship (RRR=1.13). Conclusions: COVID measures were associated with AYA relationships both initiating and ending. Strategies for relationship development/support should be included as part of preparation for future public health emergencies.Item 11384 Medication Use Safety During Care Transitions for Children with Medical Complexity(Cambridge University Press, 2021) Abebe, Ephrem; Wiehe, Sarah; Holden, Richard J.; Pediatrics, School of MedicineABSTRACT IMPACT: This study will generate preliminary data to address a critical, care transition-related patient safety gap involving medication use among children with medical complexity. OBJECTIVES/GOALS: The objectives of this study are: (1) to understand care transition-related medication safety risks for children with medical complexity (CMC), and (2) through a participatory, human centered design (PD) approach, to develop an early prototype intervention to address identified safety risks. METHODS/STUDY POPULATION: The study population includes children with medical complexity (CMC), a medically fragile pediatric population with intensive healthcare needs. CMC rely on multiple and complex medication regimens and/or medical devices for optimal functioning. Parents of CMC report multiple unmet healthcare needs. For Aim 1, we will conduct observations and interviews with ˜15 clinicians as well as semi-structured interviews with ˜30 family caregivers during three care transition experiences: from Cardiac ICU to home, Neonatal ICU to home, and those between primary care/specialty clinic to home. For Aim 2, we will conduct participatory design sessions with up to 5 participants (separately for clinicians and family caregivers) from each of the three care transition settings to co-design a prototype intervention. RESULTS/ANTICIPATED RESULTS: The study is currently recruiting family caregivers of CMC for aim 1 research activities, with interviews planned to be completed in February/March 2021. Transcribed interviews will be used to inform development of patient journey maps. A patient journey map helps to visually depict healthcare services through the patient and family lens, and highlights important ‘touch points’ along the patient journey (e.g., decisions, encounters, constraints, emotional states, etc.) that shape the patient and family experience. The journey map will distill findings from qualitative data and generate a concise visual story focused on the medication use experience of CMC as they transition between the hospital and their home. Individual journey maps will also be combined to generate a consolidated journey map. DISCUSSION/SIGNIFICANCE OF FINDINGS: An-in-depth understanding of medication safety risks unique to the context of CMC care would be essential to develop interventions that are useful, scalable, and sustainable. This is even more important because current interventions are primarily adopted from adult care settings with mixed outcomes.Item 12-Lipoxygenase governs the innate immune pathogenesis of islet inflammation and autoimmune diabetes(The American Society for Clinical Investigation, 2021-07-22) Kulkarni, Abhishek; Pineros, Annie R.; Walsh, Melissa A.; Casimiro, Isabel; Ibrahim, Sara; Hernandez-Perez, Marimar; Orr, Kara S.; Glenn, Lindsey; Nadler, Jerry L.; Morris, Margaret A.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Anderson, Ryan M.; Pediatrics, School of MedicineMacrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.Item 12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets(Oxford University Press, 2017-08-01) Ma, Kaiwen; Xiao, An; Park, So Hyun; Glenn, Lindsey; Jackson, Laura; Barot, Tatvam; Weaver, Jessica R.; Taylor-Fishwick, David A.; Luci, Diane K.; Maloney, David J.; Mirmira, Raghavendra G.; Imai, Yumi; Nadler, Jerry L.; Pediatrics, School of MedicineContext: The 12-lipoxygenase (12-LO) pathway produces proinflammatory metabolites, and its activation is implicated in islet inflammation associated with type 1 and type 2 diabetes (T2D). Objectives: We aimed to test the efficacy of ML355, a highly selective, small molecule inhibitor of 12-LO, for the preservation of islet function. Design: Human islets from nondiabetic donors were incubated with a mixture of tumor necrosis factor α , interluekin-1β, and interferon-γ to model islet inflammation. Cytokine-treated islets and human islets from T2D donors were incubated in the presence and absence of ML355. Setting: In vitro study. Participants: Human islets from organ donors aged >20 years of both sexes and any race were used. T2D status was defined from either medical history or most recent hemoglobin A1c value >6.5%. Intervention: Glucose stimulation. Main Outcome Measures: Static and dynamic insulin secretion and oxygen consumption rate (OCR). Results: ML355 prevented the reduction of insulin secretion and OCR in cytokine-treated human islets and improved both parameters in human islets from T2D donors. Conclusions: ML355 was efficacious in improving human islet function after cytokine treatment and in T2D islets in vitro. The study suggests that the blockade of the 12-LO pathway may serve as a target for both form of diabetes and provides the basis for further study of this small molecule inhibitor in vivo.Item A 12-lipoxygenase-Gpr31 signaling axis is required for pancreatic organogenesis in the zebrafish(Wiley, 2020-11) Hernandez-Perez, Marimar; Kulkarni, Abhishek; Samala, Niharika; Sorrell, Cody; El, Kimberly; Haider, Isra; Aleem, Ansari Mukhtar; Holman, Theodore R.; Rai, Ganesha; Tersey, Sarah A.; Mirmira, Raghavendra G.; Anderson, Ryan M.; Pediatrics, School of Medicine12-Lipoxygenase (12-LOX) is a key enzyme in arachidonic acid metabolism, and alongside its major product, 12-HETE, plays a key role in promoting inflammatory signaling during diabetes pathogenesis. Although 12-LOX is a proposed therapeutic target to protect pancreatic islets in the setting of diabetes, little is known about the consequences of blocking its enzymatic activity during embryonic development. Here, we have leveraged the strengths of the zebrafish-genetic manipulation and pharmacologic inhibition-to interrogate the role of 12-LOX in pancreatic development. Lipidomics analysis during zebrafish development demonstrated that 12-LOX-generated metabolites of arachidonic acid increase sharply during organogenesis stages, and that this increase is blocked by morpholino-directed depletion of 12-LOX. Furthermore, we found that either depletion or inhibition of 12-LOX impairs both exocrine pancreas growth and unexpectedly, the generation of insulin-producing β cells. We demonstrate that morpholino-mediated knockdown of GPR31, a purported G-protein-coupled receptor for 12-HETE, largely phenocopies both the depletion and the inhibition of 12-LOX. Moreover, we show that loss of GPR31 impairs pancreatic bud fusion and pancreatic duct morphogenesis. Together, these data provide new insight into the requirement of 12-LOX in pancreatic organogenesis and islet formation, and additionally provide evidence that its effects are mediated via a signaling axis that includes the 12-HETE receptor GPR31.Item 143 Training & Sustaining: Training and learning collaborative outcomes across a statewide network for early diagnosis of children with autism(Cambridge University Press, 2024-04-03) McNally Keehn, Rebecca; Paxton, Angela; Delaney, Mary; Ciccarelli, Mary; Pediatrics, School of MedicineOBJECTIVES/GOALS: Community-based primary care autism diagnostic models are one promising solution to delays in autism diagnosis. Our objective is to describe the development and report on outcomes related to primary care professional (PCP) training and sustained engagement in a longitudinal learning collaborative across a statewide network for autism diagnosis. METHODS/STUDY POPULATION: We developed ADAPT (i.e., Accelerating the Diagnosis of Autism with Primary care Training), a training program to prepare PCPs to develop independent competency in evaluation of autism in children ages 14-48 months. ADAPT includes didactic and case-based modules and expert practice-based coaching delivered by a diagnostic specialist; following training PCPs participate in a longitudinal learning collaborative. Aligned with competency-based medical education standards, measures of autism evaluation knowledge and diagnostic competency are collected. RESULTS/ANTICIPATED RESULTS: To date, 13 PCPs have completed ADAPT didactic and practicum training reaching competency in independent autism evaluation. Clinicians demonstrated significant improvement in total autism knowledge following didactic training (p=.02). There was an overall trend toward increased scoring agreement on an autism observational assessment over case observations and practicum evaluations. Similarly, PCPs demonstrated improved evaluation competence, moving on average from Advanced Beginner to Competent Performer as rated by expert trainers. Following training, PCPs attended 57% of monthly learning collaborative sessions. DISCUSSION/SIGNIFICANCE: Training PCPs to deliver autism evaluations as part of community-based models of care is a promising solution to address access and waitlist challenges. ADAPT is an intensive, standard PCP training model which results in achievement of independent competency and sustained engagement in in autism evaluation.Item 147 Transition Across Care Boundaries: Opportunities to Improve Medication Safety for Children with Medical Complexity(Cambridge University Press, 2022) Abebe, Ephrem; Wiehe, Sarah; Holden, Richard J.; Pediatrics, School of MedicineOBJECTIVES/GOALS: Children with medical complexity (CMC) experience frequent transitions of care (e.g., hospital to home) and are at increased risk for medication-related harm. This study aimed to identify transition-related medication safety barriers experienced by family caregivers, as they shoulder most of the caregiving responsibility following discharge. METHODS/STUDY POPULATION: We conducted semi-structured qualitative research interviews of 6 family caregivers and 10 healthcare professionals with roles assisting families during hospital discharge. Interviews focused on identifying key stages of the hospital-to-home transition period as well as medication-related tasks, decisions, and contexts. Transcribed audio interviews and research meeting notes were content analyzed to develop journey maps visually depicting key phases of the families experiences managing medication at home and their decision points and unmet needs. RESULTS/ANTICIPATED RESULTS: Journey mapping identified key decision points, medication management needs, and way points navigated by family caregivers during the hospital-to-home transition. Findings were salient for each phase of the family journey: 1) initial admission/intra-unit transfer; 2) in-patient care; 3) peri-discharge planning; 4) discharge; 5) immediate post discharge period (we termed post-discharge configuration); and 6) period of ongoing tasks and needs. Illustrative examples will be presented and discussed. DISCUSSION/SIGNIFICANCE: Family caregivers of CMC have needs that evolve throughout the medication use journey, suggesting a need for interventions that account for the time variant nature of this work. Findings lay a foundation for the next step of our study which aims to develop a prototype medication safety intervention that will be evaluated with family caregivers.Item 15-Lipoxygenase worsens renal fibrosis, inflammation, and metabolism in a murine model of ureteral obstruction(American Physiological Society, 2022) Montford, John R.; Bauer, Colin; Rahkola, Jeremy; Reisz, Julie A.; Floyd, Deanna; Hopp, Katharina; Soranno, Danielle E.; Klawitter, Jelena; Weiser-Evans, Mary C. M.; Nemenoff, Raphael; Faubel, Sarah; Furgeson, Seth B.; Pediatrics, School of Medicine15-Lipoxygenase (15-LO) is a nonheme iron-containing dioxygenase that has both pro- and anti-inflammatory roles in many tissues and disease states. 15-LO is thought to influence macrophage phenotype, and silencing 15-LO reduces fibrosis after acute inflammatory triggers. The goal of the present study was to determine whether altering 15-LO expression influences inflammation and fibrogenesis in a murine model of unilateral ureteral obstruction (UUO). C57BL/6J mice, 15-LO knockout (Alox15-/-) mice, and 15-LO transgenic overexpressing (15LOTG) mice were subjected UUO, and kidneys were analyzed at 3, 10, and 14 days postinjury. Histology for fibrosis, inflammation, cytokine quantification, flow cytometry, and metabolomics were performed on injured tissues and controls. PD146176, a specific 15-LO inhibitor, was used to complement experiments involving knockout animals. Compared with wild-type animals undergoing UUO, Alox15-/- mouse kidneys had less proinflammatory, profibrotic message along with less fibrosis and macrophage infiltration. PD146176 inhibited 15-LO and resulted in reduced fibrosis and macrophage infiltration similar to Alox15-/- mice. Flow cytometry revealed that Alox15-/- UUO-injured kidneys had a dynamic change in macrophage phenotype, with an early blunting of CD11bHiLy6CHi "M1" macrophages and an increase in anti-inflammatory CD11bHiLy6CInt "M2c" macrophages and reduced expression of the fractalkine receptor chemokine (C-X3-C motif) receptor 1. Many of these findings were reversed when UUO was performed on 15LOTG mice. Metabolomics analysis revealed that wild-type kidneys developed a glycolytic shift postinjury, while Alox15-/- kidneys exhibited increased oxidative phosphorylation. In conclusion, 15-LO manipulation by genetic or pharmacological means induces dynamic changes in the inflammatory microenvironment in the UUO model and appears to be critical in the progression of UUO-induced fibrosis. NEW & NOTEWORTHY: 15-Lipoxygenase (15-LO) has both pro- and anti-inflammatory functions in leukocytes, and its role in kidney injury and repair is unexplored. Our study showed that 15-LO worsens inflammation and fibrosis in a rodent model of chronic kidney disease using genetic and pharmacological manipulation. Silencing 15-LO promotes an increase in M2c-like wound-healing macrophages in the kidney and alters kidney metabolism globally, protecting against anaerobic glycolysis after injury.