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Design of a Novel Online, Modular, Flipped-classroom Surgical Curriculum for East, Central, and Southern Africa
(Wolters Kluwer, 2022-03-02) Parker, Andrea S.; Hill, Katherine A.; Steffes, Bruce C.; Mangaoang, Deirdre; O'Flynn, Eric; Bachheta, Niraj; Bates, Maria F.; Bitta, Caesar; Carter, Nicholas H.; Davis, Richard E.; Dressler, Jeremy A.; Eisenhut, Deborah A.; Fadipe, Akinniyi E.; Kanyi, John K.; Kauffmann, Rondi M.; Kazal, Frances; Kyamanywa, Patrick; Lando, Justus O.; Many, Heath R.; Mbithi, Valentine C.; McCoy, Amanda J.; Meade, Peter C.; Ndegwa, Wairimu Y. B.; Nkusi, Emmy A.; Ooko, Philip B.; Osilli, Dixon J. S.; Parker, Madison E. D.; Rankeeti, Sinkeet; Shafer, Katherine; Smith, James D.; Snyder, David; Sylvester, Kimutai R.; Wakeley, Michelle E.; Wekesa, Marvin K.; Torbeck, Laura; White, Russell E.; Bekele, Abebe; Parker, Robert K.; Surgery, School of Medicine
Objective: We describe a structured approach to developing a standardized curriculum for surgical trainees in East, Central, and Southern Africa (ECSA). Summary background data: Surgical education is essential to closing the surgical access gap in ECSA. Given its importance for surgical education, the development of a standardized curriculum was deemed necessary. Methods: We utilized Kern's 6-step approach to curriculum development to design an online, modular, flipped-classroom surgical curriculum. Steps included global and targeted needs assessments, determination of goals and objectives, the establishment of educational strategies, implementation, and evaluation. Results: Global needs assessment identified the development of a standardized curriculum as an essential next step in the growth of surgical education programs in ECSA. Targeted needs assessment of stakeholders found medical knowledge challenges, regulatory requirements, language variance, content gaps, expense and availability of resources, faculty numbers, and content delivery method to be factors to inform curriculum design. Goals emerged to increase uniformity and consistency in training, create contextually relevant material, incorporate best educational practices, reduce faculty burden, and ease content delivery and updates. Educational strategies centered on developing an online, flipped-classroom, modular curriculum emphasizing textual simplicity, multimedia components, and incorporation of active learning strategies. The implementation process involved establishing thematic topics and subtopics, the content of which was authored by regional surgeon educators and edited by content experts. Evaluation was performed by recording participation, soliciting user feedback, and evaluating scores on a certification examination. Conclusions: We present the systematic design of a large-scale, context-relevant, data-driven surgical curriculum for the ECSA region.
Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response
(Springer Nature, 2023) Gnanaprakasam, J. N. Rashida; Kushwaha, Bhavana; Liu, Lingling; Chen, Xuyong; Kang, Siwen; Wang, Tingting; Cassel, Teresa A.; Adams, Christopher M.; Higashi, Richard M.; Scott, David A.; Xin, Gang; Li, Zihai; Yang, Jun; Lane, Andrew N.; Fan, Teresa W. M.; Zhang, Ji; Wang, Ruoning; Pediatrics, School of Medicine
Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.
Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease
(Wiley, 2023) Chang, Rui; Trushina, Eugenia; Zhu, Kuixi; Zaidi, Syed Shujaat Ali; Lau, Branden M.; Kueider-Paisley, Alexandra; Moein, Sara; He, Qianying; Alamprese, Melissa L.; Vagnerova, Barbora; Tang, Andrew; Vijayan, Ramachandran; Liu, Yanyun; Saykin, Andrew J.; Brinton, Roberta D.; Kaddurah-Daouk, Rima; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; Radiology and Imaging Sciences, School of Medicine
Introduction: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. Methods: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Results: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients. Discussion: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.
Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy
(American Medical Association, 2023) Maturi, Raj K.; Glassman, Adam R.; Josic, Kristin; Baker, Carl W.; Gerstenblith, Adam T.; Jampol, Lee M.; Meleth, Annal; Martin, Daniel F.; Melia, Michele; Punjabi, Omar S.; Rofagha, Soraya; Salehi-Had, Hani; Stockdale, Cynthia R.; Sun, Jennifer K.; DRCR Retina Network; Ophthalmology, School of Medicine
Importance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, setting, and participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main outcomes and measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME.
Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease
(Fortune Journals, 2023) Gawrieh, Samer; Karns, Rebekah; Kleiner, David E.; Olivier, Michael; Jenkins, Todd; Inge, Thomas H.; Chalasani, Naga P.; Xanthakos, Stavra; Medicine, School of Medicine
Introduction: To gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. Methods: Histological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. Results: In 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. Conclusions: There is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life.