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Item A framework for translating tauopathy therapeutics: Drug discovery to clinical trials(Wiley, 2024) Feldman, Howard H.; Cummings, Jeffrey L.; Boxer, Adam L.; Staffaroni, Adam M.; Knopman, David S.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Arnold, Steven E.; Ballard, Clive; Beher, Dirk; Boeve, Bradley F.; Dacks, Penny A.; Diaz, Kristophe; Ewen, Colin; Fiske, Brian; Gonzalez, M. Isabel; Harris, Glenn A.; Hoffman, Beth J.; Martinez, Terina N.; McDade, Eric; Nisenbaum, Laura K.; Palma, Jose-Alberto; Quintana, Melanie; Rabinovici, Gil D.; Rohrer, Jonathan D.; Rosen, Howard J.; Troyer, Matthew D.; Kim, Doo Yeon; Tanzi, Rudolph E.; Zetterberg, Henrik; Ziogas, Nick K.; May, Patrick C.; Rommel, Amy; Medicine, School of MedicineThe tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.Item A pilot study of the utility of a hospital-based school program for pediatric patients with cardiac diagnoses(Frontiers Media, 2024-12-11) Thibodaux, Lia K.; Orr, Ashley L.; Reisinger, Debra L.; Fodstad, Jill; Xu, Guang; Wikel, Kristin; Curtin, Michelle; Psychiatry, School of MedicineIntroduction: Pediatric patients with complex cardiac diagnoses are at increased risk for physical, cognitive, and developmental complications. Formalized school support [i.e., individualized education programs (IEPs), Section 504 Accommodation Plans (Section 504 Plans)] that addresses the needs of these patients is necessary, and hospital-based school programs (HBSPs) have the potential to bolster the acquisition of academic support. In this pilot study, we look at the impact of one such HBSP. Methods: Retrospective demographic and school support data for pediatric cardiac patients were analyzed. Results: Our sample included 29 pediatric cardiac patients spanning two academic years. These patients had 100 HBSP encounters and 82 inpatient and 12 outpatient encounters, with 68.9% of patients having multiple encounters in a single year and 44.8% of patients being seen in both years. The HBSP made recommendations for patients to receive IEPs (N = 8) and Section 504 Plans (N = 13). The patients also submitted requests for medical homebound(N = 27), obtaining releases of information (N = 39), submitting medical reports (N = 10), and completing certificates of incapacity (N = 7). Statistical analyses revealed no significant relationships with patients entering or receiving a recommendation for an IEP or Section 504 Plan in any of their encounters with the HBSP on the basis of sex, race/ethnicity, school level, or rates of encounters in this sample. Discussion: Similar to previous studies, these patients had high rates of IEPs/Section 504 Plans in place and continued to receive school recommendations through the HBSP. A high use of the HBSP was seen in the total number of encounters and communications (i.e., submitting to the school of record requests for classroom placement changes via medical homebound). Working with the HBSP provided access to information, formal support recommendations, and communication between medical and school settings in the form of changes in school status.Item Access to Knowledge in Brazil: New Research on Intellectual Property, Innovation and Development(Bloomsbury Academic, 2010) Shaver, LeaAccess to knowledge is a demand for democratic participation, for global inclusion and for economic justice. It is a reaction to the excessively restrictive international IP regime put in place over the last two decades, which seeks to reassert the public interest in a more balanced information policy. With sponsorship from the Ford Foundation, the Information Society Project at Yale Law School has embarked on a new series of access to knowledge research, in partnership with colleagues in Brazil, China, Egypt, Ethiopia, India, Russia and South Africa. The first book in this series, Access to Knowledge in Brazil, focuses on current issues in intellectual property, innovation and development policy from a Brazilian perspective. Each chapter is authored by scholars from the Fundação Getulio Vargas law schools in São Paolo and Rio de Janeiro and examines a policy area that significantly impacts access to knowledge in the country. These include: exceptions and limitations to copyright, free software and open business models, patent reform and access to medicines, and open innovation in the biotechnology sector.Item Access to Knowledge in Egypt: New Research on Intellectual Property, Innovation and Development(Bloomsbury Academic, 2010) Shaver, Lea; Rizk, NaglaThe conventional wisdom in Egypt examines the issue of intellectual property solely as a question of policing and enforcement. The high levels of protection indicated by the WTO Agreement on Trade Related Aspects of Intellectual Property Rights are unquestioningly assumed to be desirable. Policy debates - and all too often academic ones as well - focus only on the questions of how to more efficiently tighten IP protection and crack down on piracy. Yet a more critical examination is urgently needed, whereby IP law, policy, and practice are viewed from a development perspective, rather than from an enforcement perspective. This volume takes on this endeavor. It offers the first examination of IP issues in Egypt adopting a multidisciplinary bottom-up approach that aims at maximizing access and contribution to knowledge, and in turn, promoting development. Bringing rigorous empirical research to bear on unquestioned ideologies, the collaborating authors question the conventional wisdom that more IP protection is necessarily better for innovation and development.Item Advances in pediatric acute kidney injury pharmacology and nutrition: a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference(Springer, 2024) Wong Vega, Molly; Starr, Michelle C.; Brophy, Patrick D.; Devarajan, Prasad; Soranno, Danielle E.; Akcan‑Arikan, Ayse; Basu, Rajit; Goldstein, Stuart L.; Charlton, Jennifer R.; Barreto, Erin; Pediatrics, School of MedicineBackground: In the past decade, there have been substantial advances in our understanding of pediatric AKI. Despite this progress, large gaps remain in our understanding of pharmacology and nutritional therapy in pediatric AKI. Methods: During the 26th Acute Disease Quality Initiative (ADQI) Consensus Conference, a multidisciplinary group of experts reviewed the evidence and used a modified Delphi process to achieve consensus on recommendations for gaps and advances in care for pharmacologic and nutritional management of pediatric AKI. The current evidence as well as gaps and opportunities were discussed, and recommendations were summarized. Results: Two consensus statements were developed. (1) High-value, kidney-eliminated medications should be selected for a detailed characterization of their pharmacokinetics, pharmacodynamics, and pharmaco-"omics" in sick children across the developmental continuum. This will allow for the optimization of real-time modeling with the goal of improving patient care. Nephrotoxin stewardship will be identified as an organizational priority and supported with necessary resources and infrastructure. (2) Patient-centered outcomes (functional status, quality of life, and optimal growth and development) must drive targeted nutritional interventions to optimize short- and long-term nutrition. Measures of acute and chronic changes of anthropometrics, body composition, physical function, and metabolic control should be incorporated into nutritional assessments. Conclusions: Neonates and children have unique metabolic and growth parameters compared to adult patients. Strategic investments in multidisciplinary translational research efforts are required to fill the knowledge gaps in nutritional requirements and pharmacological best practices for children with or at risk for AKI.Item Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver(Wiley, 2015-08) Burgess, Kimberly S.; Philips, Santosh; Benson, Eric A.; Desta, Zeruesenay; Gaedigk, Andrea; Gaedigk, Roger; Segar, Matthew W.; Liu, Yunlong; Skaar, Todd C.; Department of Pharmacology and Toxicology, IU School of MedicineDevelopmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.Item Astrocytes Regulate the Development and Maturation of Retinal Ganglion Cells Derived from Human Pluripotent Stem Cells(Elsevier, 2019-02-12) VanderWall, Kirstin B.; Vij, Ridhima; Ohlemacher, Sarah K.; Sridhar, Akshayalakshmi; Fligor, Clarisse M.; Feder, Elyse M.; Edler, Michael C.; Baucum, Anthony J.; Cummins, Theodore R.; Meyer, Jason S.; Biology, School of ScienceRetinal ganglion cells (RGCs) form the connection between the eye and the brain, with this connectivity disrupted in numerous blinding disorders. Previous studies have demonstrated the ability to derive RGCs from human pluripotent stem cells (hPSCs); however, these cells exhibited some characteristics that indicated a limited state of maturation. Among the many factors known to influence RGC development in the retina, astrocytes are known to play a significant role in their functional maturation. Thus, efforts of the current study examined the functional maturation of hPSC-derived RGCs, including the ability of astrocytes to modulate this developmental timeline. Morphological and functional properties of RGCs were found to increase over time, with astrocytes significantly accelerating the functional maturation of hPSC-derived RGCs. The results of this study clearly demonstrate the functional and morphological maturation of RGCs in vitro, including the effects of astrocytes on the maturation of hPSC-derived RGCs.Item Binge drinking trajectories across adolescence and early adulthood: Associations with genetic influences for dual-systems impulsive personality traits, alcohol consumption, and alcohol use disorder(medRxiv, 2024-10-16) Miller, Alex P.; Spychala, Kellyn M.; Slutske, Wendy S.; Fromme, Kim; Gizer, Ian R.; Psychiatry, School of MedicineBinge drinking is a relatively common pattern of alcohol use among youth with normative frequency trajectories peaking in emerging and early adulthood. Frequent binge drinking is a critical risk factor for not only the development of alcohol use disorders (AUDs) but also increased odds of alcohol-related injury and death, and thus constitutes a significant public health concern. Changes in binge drinking across development are strongly associated with changes in impulsive personality traits (IPTs) which have been hypothesized as intermediate phenotypes associated with genetic risk for heavy alcohol use and AUD. The current study sought to examine the extent to which longitudinal changes in binge drinking and intoxication frequency across adolescence and early adulthood are associated with genetic influences underlying dual-systems IPTs (i.e., top-down [lack of self-control] and bottom-up [sensation seeking and urgency] constructs) alongside genetic risk for alcohol consumption and AUD. Associations were tested using conditional latent growth curve polygenic score (PGS) models in three independent longitudinal samples (N=10,554). Results suggested consistent significant and independent associations across all samples between sensation seeking PGSs and model intercepts (i.e., higher frequency of binge drinking at first measurement occasion) and alcohol consumption PGSs and model slopes (i.e., steeper increases toward peak binge drinking frequency). Urgency PGSs were not significantly associated with changes in binge drinking or intoxication frequency. Collectively, these findings highlight the role of unique but correlated IPT and alcohol-specific genetic factors in the emergence and escalation of binge drinking during adolescence and early adulthood.Item Build your own retina: modeling retinogenesis and disease using human pluripotent stem cells(2017) Sridhar, Akshayalakshmi; Meyer, JasonHuman pluripotent stem cells (hPSCs) allow for the unprecedented ability to recapitulate early stages of human development, which are otherwise inaccessible to investigation. This is especially true for one of the earliest events in human development, the establishment of a neuroretinal fate from an unspecified pluripotent population. To test the ability of hPSCs to serve in this capacity, hPSCs were generated using mRNA-reprogamming methods and maintained in xenogeneic-free differentiation conditions. These cells were directed to differentiate using a three-dimensional approach to analyze their ability to successfully recapitulate early events in human development in a temporal and developmentally-appropriate fashion. To do so, hPSCs were first directed to an anterior neural phenotype, which was confirmed by analysis of stage-specific neural transcription factors via immunocytochemistry and quantitative RT-PCR. Next, the cells were directed to an optic vesicle-like stage, where the presumptive retinal cells were identified by the expression of specific transcription factors. Finally, three-dimensional optic vesicle-like retinal organoids were identified, isolated, and further analyzed for the expression of markers associated with some of the differentiated cell types of the neural retina. Upon establishment of hPSC-derived retinal organoids, this system was further utilized to study the neurodegeneration in glaucoma and provide insights into the disease mechanisms. Overall, the results of this study help to demonstrate the suitability of hPSC-differentiation approaches as an effective tool to model retinal development and disease.Item Cell-Cell Communication Breakdown and Endothelial Dysfunction(Elsevier, 2020-04) Lee, Daniel D.; Schwarz, Margaret A.; Medicine, School of MedicineGuided by organ-specific signals in both development and disease response, the heterogeneous endothelial cell population is a dynamic member of the vasculature. Functioning as the gatekeeper to fluid, inflammatory cells, oxygen, and nutrients, endothelial cell communication with its local environment is critical. Impairment of endothelial cell-cell communication not only disrupts this signaling process, but also contributes to pathologic disease progression. Expanding our understanding of those processes that mediate endothelial cell-cell communication is an important step in the approach to treatment of disease processes.