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Evaluating the Efficacy of Universal Depression Screenings in the High School Setting
Full text linkPurpose/Background
Depression in adolescents is rising each year. Early detection of depression has been shown to result in better health outcomes and success in school. This scoping review aims to evaluate the implementation of universal depression screenings in the high school setting and how this detection of depression and initiation of treatment.
Methods
From August 2022 to November 2023, we used the Medline, PubMed, Elsevier, Google Scholar, and PsycINFO databases, using specific keywords related to depression in adolescents. Of the 38 articles found, 10 were chosen after extensive article critique. The publication dates ranged from 2014-2023, were full-text, and from peer-reviewed sources.
Results
One study comparing the use of the PHQ-9 and PHQ-2 showed that even though the PHQ-2 was easier and simpler to administer, the PHQ-9 proved to be superior in identifying depression. An interesting finding in another study shows that the use of the Beck Depression Inventory may be the most helpful in community settings but not with those with poor self-image or where comorbidity is high.
Implications for Nursing Practice
Results in this scoping review show that implementation of depression screenings in high school adolescents not only helps identify depression earlier but also helps patients initiate treatment. Implementation of depression screenings is needed in high schools and will only help the adolescent population receive the help they need
Interplay of Antibody Responses to Closely Related Viruses and Autoimmunity
Full text linkAntibodies produced by B cells are crucial for eliminating infectious pathogens and preventing secondary infection. However, antibodies may also bind to self-antigens and contribute to autoimmune disease. While pathogen infections have been associated with development of autoimmune diseases, the precise contributions of viral infections to autoimmunity remain elusive. The presence of autoreactive antibodies is associated with an increased risk of developing autoimmune disease. Thus, analyzing the impact of viral infection and vaccination on the development of autoreactive antibodies will provide essential insight into mechanisms that contribute to autoimmune disease
The Validity and Reliability of Ultrasound as a Tool for Assessing Skeletal Muscle Characteristics in the Pediatric Population
Full text linkAnnually, around 5 million people in the U.S. are admitted to Intensive Care Units (ICU) due to critical conditions, with pediatric patients comprising 21% of these admissions. Approximately 40% of pediatric ICU (PICU) patients require mechanical ventilation and extended stays, and about 6% result in death. Survivors often face long-term disabilities, including loss of skeletal muscle mass (SMM), a risk factor for morbidity and mortality. Abdominal computed tomography (CT) scans, often performed during PICU admissions, can assess muscle mass but pose risks of increased cost and radiation exposure. While CT and Magnetic Resonance Imaging (MRI) are gold standards for muscle quantification, alternatives like ultrasound (US) offer non-invasive, cost-effective benefits without radiation. US, commonly used by physical therapists for Rehabilitative Ultrasound Imaging (RUSI), could assess muscle structure and function, aiding therapeutic interventions. However, evidence-based research supporting US as a valid and reliable modality for measuring SMM in pediatric patients is extremely lacking in the literature, as are reliability studies comparing US measured SMM characteristics to gold standards like CT. Accurate SMM assessment is a critical clinical outcome to document as muscle loss during prolonged hospital stays can lead to long-term functional impairments, impacting overall health. Establishing US as a reliable tool for SMM assessment could revolutionize rehabilitation practices and inform Clinical Practice Guidelines for therapeutic interventions in pediatric ICU settings. This research study was comprised of a sequence of three studies which included a retrospective CT rater-reliability, a prospective US rater-reliability and a prospective modality- (US versus CT), reliability. Taken together, the purpose of the overall research project was to determine the reliability of US compared to CT and provide the preliminary evidence-based results to inform a future validation study of US as a dependable tool for evaluating muscle quality and quantity in pediatric patients. The first aim of the current study examined the inter-rater reliability of CT measured cross-sectional area (CSA) and muscle thickness, (mT) of the psoas major and rectus abdominis (RA), two key trunk stabilizing muscles, obtained by a radiologist compared to a physical therapist (PT) (Aim1a) and the intra-rater reliability of the same measurements obtained at multiple timepoints by the PT (Aim1b). The second aim examined inter-reliability of US measurements, obtained by a Registered Diagnostic Medical Sonographer (RDMS) compared to a PT, of the CSA, mT and echo intensity (EI) of the psoas major and RA muscles. The third aim examined the inter-modality reliability of US- compared to CT-obtained CSA and mT measurements of the psoas and RA muscles. The results of this study showed inter- and intra-rater reliability between a radiologist and PT, ICC: 0.951-0.994 (Aim1a) and PT intra-rater reliability ICC: 0.943-0.98 (Aim 1b). Aim 2 inter-rater reliability results between the RDMS and PT showed outstanding ICCs: 0.978-0.999, across all quantitative parameters. Aim 3 inter-modality reliability between CT and US similarly demonstrated outstanding ICCs: 0.985 to 0.999 for all muscle parameters. Additionally, exploratory analyses showed no influence of the subject populations’ demographic or anthropometric variables including sex, race, height, weight, or Body Mass Index (BMI). This study provides robust evidence supporting 1) the reliability of ultrasound as an effective modality for assessing muscle quality and quantity in pediatric patients compared to CT and 2) the proficiency of a PT compared to an RDMS in performing such ultrasound measurements as well as interpreting CT values of the afore mentioned muscle parameters compared to a radiologist. Moreover, the results of this study contribute to the significant gap in the literature on evidence-based results of muscle assessment tools applicable in the pediatric population as well as informing future physical therapy practice guidelines, particularly for the critically ill pediatric population
Anatomical and Physiological Characterization of Striatal Activation of the Cerebral Cortex
Full text linkPurpose. The striatum receives excitatory glutamatergic input from nearly all parts of the cerebral cortex, and its output is delivered by direct pathway medium spiny neurons (dMSNs) expressing D1 type dopamine (DA) receptors (D1Rs) and indirect pathway MSNs (iMSNs) expressing D2 DA receptors (D2Rs). Loss of DA results in the imbalance between the activities of dMSNs and iMSNs in Parkinson’s disease (PD), leading to ab-normal interactions between the cerebral cortex and striatum. Thus, understanding the inter-actions between the cortex and striatum is important. The monosynaptic corticostriatal cir-cuit has been extensively studied. In contrast, due to the poly-synaptic nature of the connec-tions between the striatum and the cortex, how the striatum and striatal dopaminergic activi-ty each influences or feedbacks the cerebral cortex is more difficult to study and thus poorly understood. Our study is designed to fill this knowledge gap.
Methods. Tyrosine hydroxylase knockout (TH KO) mice were used as the DA-depleted mouse model, while wild-type (WT) C57Bl/6 mice were used as the normal control mice. In TH KO mice, the TH gene is selectively deleted in DA neurons (TH is intact in epineph-rine and norepinephrine neurons), leading to a total lack of DA in the striatum, mimicking the severe DA loss in late-stage PD. TH KO and WT were crossed with D2-GFP mice to generate D2-GFP TH KO and D2-GFP WT, respectively, for identifying D1-MSNs and D2-MSNs in the striatum. Four principal methods were used as follows: First, intracranial microinjection was used to deliver drugs directly into the striatum and motor cortex. A guide cannula was implanted into the right striatum/motor cortex of each TH KO mouse, and a single microinjection of L-dopa/ D1 agonist SKF81297/ D2 agonist quinpirole/ saline into the right striatum/right motor cortex was performed 75 min before mouse perfusion. Second, c-Fos mapping was used to evaluate neuronal activity. C-Fos is an immediate-early gene with activity-dependent protein expression that can be detected by immunostaining. We observed neuronal activity in the motor cortex, striatum, motor thalamus, external seg-ment of globus pallidus (GPe), subthalamic nucleus (STN), and substantia nigra pars retic-ulata (SNr) by c-Fos immunostaining at baseline and upon activation by treatments with L-dopa and DA agonists, separately. Third, in vivo unit spike recording was used to monitor the spike firing activity of cortical neurons in freely moving mice. A micro-drivable tetrode array was implanted in the motor cortex and connected to a headstage to detect the cortical spike activity using a 16-channel spike data acquisition system. The firing activity of neu-rons was recorded for 30 minutes as baseline and 60 minutes after drug injection. Fourth, behavioral videotaping was used to record the behavioral response to the drug treatments during the spike recording sessions.
Results. The basal c-Fos expression in the striatum, motor cortex, motor thalamus, and STN was much lower in TH KO mice compared with WT mice. 10mg/kg L-dopa and 3mg/kg benserazide systemic administration significantly increased the c-Fos expression in the striatum, the entire cerebral cortex including the motor cortex, and the key brain areas in striatal-thalamocortical circuit (motor thalamus, GPe, STN, and SNr) in TH KO mice. In the neuronal spike recording, the mean firing rates of cortical pyramidal neurons (PNs) were 1.0±0.1Hz in TH KO mice and 1.8±0.2Hz in WT mice, respectively. The mean firing rates of cortical interneurons (INs) were 1.6±0.3Hz and 2.7±0.8Hz in TH KO and WT mice, separately. Both cortical PNs and INs in TH KO mice had significantly lower firing activities than those in WT mice. Moreover, with L-dopa IP injection, the firing rate of 61% PNs (N=83/135) and 66% of INs (N=25/38) was significantly increased by 80% and 150%, respectively. 24% of PNs (N=32/135) and 16% of INs (N = 6/38) had correspond-ing significant decrease of 50% and 45% in firing rates after L-dopa IP injection. L-dopa 4μg microinjection in the unilateral striatum triggered a striking increase of c-Fos expression in the injected striatum and ipsilateral wide-spreading cortex as well as ipsilat-eral STN and motor thalamus but in contralateral SNr. 92.9% of the triggered striatal c-Fos protein was expressed in D1 MSN, and the c-fos expression in the motor cortex was in all cortical layers 1-6. In addition, the firing rate of 60% PNs (N=34/57) in the motor cortex was significantly increased by 275%, and 26% PNs (N=14/57) had a 62% decrease in fir-ing rates after striatal L-dopa microinjection. However, the effect of striatal L-dopa injection to spike activity of cortical INs was detected as statistically insignificant due to the insuffi-cient number of IN recorded (N=11). Furthermore, unilateral striatal L-dopa microinjection induced consistent contralateral. Both 0.4μg SKF81297 and 0.4μg quinpirole microinjection into the right striatum triggered significantly increased c-Fos expression in the injected striatum and ipsilateral cortex, GPe, STN, and motor thalamus. But they decreased c-Fos expression in the ipsilateral SNr in TH KO mice. Striatal 0.4μg SKF81297 microinjection excited 65% PNs (N=34/52) by an in-crease of 100% and inhibited 14% PNs (N=7/52) by a decrease of 50% in the motor cor-tex. However, the cortical INs didn’t have a statistically significant response to striatal SKF81297 microinjection because of the insufficient number of IN recorded (N=14). Stria-tal 0.4μg quinpirole microinjection significantly increased the firing rate of 66% PNs (N=23/35) and 71% INs (N=17/24). Unilateral striatal SKF81297 and quinpirole mi-croinjection induced consistent contralateral rotations, respectively.
Conclusions. In Parkinson’s disease, loss of DA innervation and DA receptor activity in the striatum reduces and impairs neuronal activity in the thalamus and cerebral cortex. Stria-tal D1R activation enhances the neuronal activity in the thalamocortical circuits by activating striatal D1-MSNs; striatal D2R activation induces D2-MSN inhibition and also enhances the neuronal activity in the thalamocortical circuits in PD. Thus, striatal DA receptor activity is required for the normal circuitry operation of the cerebral cortex and brain’s motor and cognitive functions
Pan-Cancer Genomic Characterization of Human Papillomavirus Associated Tumors
Full text linkInfection with high-risk human papillomavirus (HPV) accounts for nearly all cervical cancers (CESC), a subset of other anogenital squamous cancers, and increasing rates of head and neck squamous cell carcinomas (HNSC), with each cancer type having heterogenous outcomes due to a general lack of personalized care. Large scale genomic analyses have catalogued the somatic alterations occurring frequently among squamous tumor types including HNSC and CESC, but few studies have incorporated a thorough analysis of HPV genomics. High-risk HPVs are double-stranded DNA (dsDNA) viruses capable of integrating their genomes into host chromosomes, a phenomenon known to promote HPV-associated cancer formation. HPV integration rates vary by HPV genotype and anatomic site, and some studies have suggested that viral integration, viral load, and HPV type influence HPV-associated tumor prognosis. However, methods for determining HPV status, viral load, and integration are inconsistent, hampering our ability to study viral genomic properties across cohorts. Thus, a robust analysis of viral and host genomics across a variety of tumor phenotypes is needed to improve our ability to understand and treat HPV-associated tumors in the clinic. In this dissertation, we characterized distinct molecular phenotypes of HPV-associated cancers in an integrative analysis of host and viral genome alterations across 1,334 individual tumors. First, we performed targeted paneling sequencing (TPS) of over 800 cancer related genes and whole viral genomes for HPV types 16 and 18 in a clinical cohort of 483 HNSC tumors. Integration of mutations and copy number variants (CNVs) revealed differential patterns of somatic alteration in curated driver genes and pathways that defined HPV(+) and HPV(-) tumors, with many altered genes being targets of HPV oncoproteins. We established five clinically meaningful structural classes of HPV16 based on viral genome integration, viral load, and CNVs. Decreased overall survival (OS) was observed in integrated tumors with E1/E2 oncogene CNVs and low viral load, as well as in HPV(+) or HPV(-) HNSCs with history of tobacco smoking. Episomal tumors displayed increased tobacco smoking rates, innate immunity pathway alterations, and higher viral load while tumors with integrated HPV genomes showed increased APOBEC cytidine deaminase mutagenesis, frequent viral CNVs, and lower viral load. These findings suggest HPV integration occurs because of an APOBEC-mediated innate immune response to HPV infection, and tumors with immune suppression as the result of tobacco smoking and somatic alteration have less pressure to integrate their viral genomes during HPV-associated tumorigenesis. Next, we performed a pan-cancer genomic analysis of 514 HNSC and 254 CESC tumors from The Cancer Genome Atlas (TCGA), along with 458 of the HNSC tumors previously described. We added to this cohort another 78 CESC and 30 anogenital tumors with data generated using our TPS platform. Interestingly, we noticed differences in driver alterations that are associated with anatomic site, HPV genotype, and gender. APOBEC mutagenesis signatures were highest in HPV(+) CESC and anogenital tumors, while tobacco smoking signatures were more prevalent in HNSC tumors. Across HPV(+) tumors, FGFR3 hotspot mutations were more frequent in HNSC, NFE2L2 hotspots occurred more in CESC and integrated tumors, and PTEN mutations occurred more often in females compared to males. Deletions of chromosome 11q22 frequently occurred in HPV(+) HNSC to inhibit BIRC2/3 and promote immune suppression, while antithetical amplification of 11q22 targeted YAP1 in CESC. Fewer HPV genome integrations and viral oncogene deletions occurred in HNSC tumors compared to CESC and anogenital, suggesting less genomic instability and pressure for HPV to integrate in immune suppressed HNSCs. We also reaffirm a worse prognosis in the integrated HPV(+) tumors with lowest viral load and deep deletions affecting HPV E1/E2/E5, as well as tumors bearing TP53 mutations or minor HPV types. Altogether, these findings improve our knowledge of HPV-associated tumorigenesis and establish promising methods for tumor classification and treatment
Improving Health Outcomes in Children and Adolescents with Asthma
Full text linkAsthma is among the most prevalent chronic illnesses found in the United States, affecting millions of people under the age of 18 each year. The disease burden for affected children, adolescents, their families, and the healthcare system is immense. Finding ways to mitigate its impact is critical to improving the lives of affected children, adolescents, and their families. The three chapters included in this dissertation aimed to document the asthma triggers that children and adolescents are exposed to and strategies for reducing them and to demonstrate using Imogene King’s conceptual framework to guide nursing practice to care for and nursing research focused on children and adolescents with the disease. Chapter Two describes the physical environment within public schools in the United States and other countries, how environmental triggers affect children with asthma, and the potential interventions to reduce their effects. Findings indicated that additional information is needed regarding the cost-effectiveness and efficient implementation of available interventions to mitigate asthma-trigger effects. Chapter Three presents a case study about a young child with severe and persistent asthma, hospitalized in a Pediatric Intensive Care Unit, demonstrating how his nurses unconsciously used concepts from King’s Open Systems Framework as part of their routine care practices. The chapter conclusions recommend the framework’s intentional use and the need for teaching clinicians to use theory to guide practice. Chapter Four is a secondary analysis of a multi-site data-based study exploring the interactions between personal, interpersonal, and social factors extracted from King’s framework in adolescents with asthma. The study examined adolescents’ baseline perceived self-efficacy (PSE), perceived family support (PFS), family history of asthma, the asthma healthcare provider utilized, and demographic characteristics and their relationship to the adolescents’ asthma self-management assessed using two outcomes—asthma prevention and asthma management behaviors. The study findings revealed that PSE and asthma healthcare provider type were highly associated with asthma prevention behaviors and PSE and PFS were highly associated with asthma management behaviors. Future research is warranted to explore better how adolescents can be educated and aided in self-managing their asthma, potentially reducing exacerbations and hospitalizations. Asthma in children and adolescents is a critical public health challenge requiring high-quality care guided by evidence and theory. Two of the three pediatric-related projects demonstrated the utility of King’s conceptual framework for guiding nursing practice and research, and one project presented evidence informing nursing care in this population
Taste and Learning in the Gustatory Cortex
Full text linkThis research investigates the organization of taste representations in the gustatory cortex (GC) through two experiments utilizing miniscope imaging in mice. The first experiment focuses on conditioned taste aversion (CTA) and reveals that taste representations in GC are heavily dominated by palatability, with shifts in representational space occurring as a function of learning and extinction. The second experiment explores the interrelation of aversive stimuli, the impact of novelty on taste representations, and the role of somatosensory feedback. Findings suggest that familiarity and palatability emerge as positive signals with experience, shaping taste representations in GC. The study contributes to a nuanced understanding of neural mechanisms underlying taste processing, offering insights into feeding behavior and decision-making processes. The implications extend to broader neuroscientific inquiries, expanding the understanding of the mechanisms of cortical sensory processing and behavior generation
Evaluation of Sphingolipid Biosynthetic Inhibitor L-Cycloserine to Prevent Retinal Degeneration
Full text linkRetinal degenerative diseases, affecting millions worldwide, are caused by irreversible photoreceptor cell death. These conditions lead to irreversible vision loss or blindness, presenting significant economic challenges. Retinal degenerative diseases result from a complex interplay of genetic and environmental factors, such as light exposure and oxidative stress. Effective treatments are currently limited, which underscores the urgent need for comprehensive solutions. Ceramide, a bioactive sphingolipid, has emerged as a pivotal mediator in the apoptotic cascade associated with retinal degeneration, presenting a promising target for therapeutic intervention. This research explores the therapeutic potential of L-Cycloserine, a small molecule inhibitor of de novo ceramide biosynthesis, in protecting against retinal degeneration. The first section investigates the protective effect of L-Cycloserine against oxidative stress-induced retinal cell death using a mouse photoreceptor-derived cell line, 661W. Results demonstrate that L-Cycloserine significantly protects 661W cells from oxidative stress by reducing bioactive ceramide levels, thereby mitigating cell death under oxidative stress conditions. Molecular assays further elucidate the mechanism underlying the protective action of L-Cycloserine, highlighting its modulation of antioxidant and apoptotic pathways. In the second section, the efficacy of L-Cycloserine in protecting against light-induced retinal damage is evaluated using albino BALB/c mice. Systemic administration of L-Cycloserine before light exposure significantly prevents photoreceptor cell death, preserving retinal function and morphology. Biodistribution studies confirm the presence of L-Cycloserine in target tissue, the retina, while sphingolipid analysis reveals its role as a ceramide biosynthesis inhibitor. These findings underscore the potential of L-Cycloserine as a therapeutic candidate for retinal degenerative diseases. The final section focuses on the development of in-situ hydrogels for topical ophthalmic delivery of L-Cycloserine, addressing the challenges of drug delivery to the posterior segment of the eye. Electrolyte-stimulated biopolymer-based hydrogels demonstrate sustained release of L-Cycloserine and maintain high corneal permeability, offering a promising platform for the ocular delivery of this drug. Lyophilization and stability studies highlight the feasibility of long-term storage, paving the way for further optimization and clinical translation. Collectively, this research provides comprehensive insights into the therapeutic potential of targeting ceramide biosynthesis with L-Cycloserine for the treatment of retinal degenerative diseases. This research addresses critical gaps in current therapeutic options and offers innovative solutions, including topical delivery of L-Cycloserine, to avoid systemic exposure. It lays the groundwork for developing novel therapies to combat vision loss associated with retinal degenerative diseases
Development of a Novel Drug Delivery Platform to Treat HIV-Associated Neurocognitive Disorder
Full text linkDespite the significant reduction in HIV prevalence and improvement in life expectancy achieved through the availability of widespread antiretroviral therapy (ART), there remains no definitive cure for HIV. Further, HIV infects the brain as early as eight days after initial peripheral infection leading to neuroHIV and subsequently neuronal damage and cognitive impairment. HIV can enter the brain through several mechanisms, including the migration of infected immune cells (Trojan Horse Mechanism), direct infection of endothelial cells, and cytokine-mediated disruption of the blood-brain barrier (BBB). Consequently, HIV-associated neurocognitive disorder (HAND) remains a significant challenge in the ART era, with an estimated prevalence of 42.6% among people living with HIV. The persistence of HAND is primarily due to inadequate ART penetration into the central nervous system, allowing ongoing viral replication and chronic inflammation, which contribute to cognitive decline and neuronal damage in the brain. Addressing HAND requires strategies that improve ART delivery across the blood-brain barrier and effectively target both viral replication and the resulting inflammatory responses. One of the objectives of this study was to develop a drug delivery system that enhances the penetration of ART drugs through the BBB while safely suppressing viral replication and inflammatory responses in the brain, ensuring appropriate biocompatibility. Additionally, we aimed to establish an evaluation platform for ART therapy to assess the safety and efficacy of treating HAND from in vitro to in vivo studies. Our hypothesis posits that the selected ART drug, Darunavir (DRV), will exhibit improved BBB penetration when encapsulated in nanoformulations, combined with an optimized dosing strategy, thereby enhancing DRV distribution in the EcoHIV mouse brain and alleviating HAND symptoms. In Aim 1, we investigated the distribution of DRV to the brain via intranasal (IN) and intravenous (IV) routes in mice. IN significantly enhanced brain concentrations while reducing plasma and liver levels compared to IV. These findings suggest IN delivery as a promising approach for treating HIV in brain reservoirs. In Aim 2, we developed a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART delivery system for DRV via IN to enhance metabolic stability and BBB permeability. PLGA-DRV suppressed HIV replication and inflammatory response, which was similar to that of DRV alone, in U1 macrophages without causing cytotoxicity. However, PLGA-DRV reduced oxidative stress more than DRV alone. In vitro, PLGA-DRV showed higher cellular uptake to U1 macrophages than DRV alone. Furthermore, in vivo, PLGA-DRV via the IN route increased the brain-to-plasma ratio of DRV, highlighting its potential for treating HIV-related neurological disorders. In Aim 3, to further improve nanoparticle biocompatibility, we developed an Extracellular Vesicle-Liposome Darunavir (EV-Lip-DRV) formulation through thin film hydration and extrusion. This formulation exhibited good encapsulation efficiency, appropriate particle size, and surface charge for brain drug delivery. EV-Lip-DRV demonstrated hemocompatibility, sustained 24-hour drug release, significant HIV suppression in U1 macrophages, and modulation of oxidative and neuroinflammatory responses. Furthermore, EV-Lip-DRV formulation enhanced brain delivery and improved cognitive and motor functions in EcoHIV mice compared to DRV and/or EV-Lip control alone. These findings highlight EV-Lip-DRV as a promising vehicle for brain-targeted antiretroviral therapy. In conclusion, this study demonstrates that intranasal administration of nanoparticles, especially EV-Lip-DRV, is a promising therapeutic strategy to enhance ART drug distribution to the brain, mitigate HAND, and improve overall outcomes of HIV treatment
Circulating Exosomes Alter Skeletal Muscle Gene Expression to Impair Insulin Sensitivity in Type 2 Diabetes and Mediate Adaptive Response to Exercise in Healthy Mice
Full text linkCurrent evidence from the literature suggests a role for circulating extracellular vesicles (EVs) in the pathogenesis of multiple diseases as well as a potential therapeutic role via delivery of vesicular cargo. Type 2 Diabetes is among the most prevalent and costly metabolic diseases in the world. Lifestyle intervention including exercise can cause Type 2 Diabetes to enter effective remission but remain ineffective due to poor adherence. Exercise stimulates the release of EVs from the skeletal muscle (and other tissues), and these vesicles are thought to confer a portion of the metabolic benefits of exercise. However, the direct effects of EV’s to regulate muscle metabolic disruption or how exercise-modified EVs regulate skeletal muscle gene signaling in Type 2 Diabetes is not well understood. The purpose of this project was to study EVs on skeletal muscle cells to identify the mechanisms through which circulating extracellular vesicles contribute to the phenotype of Type 2 Diabetes; and to evaluate the effects of exercise associated EVs in a mouse model of Type 2 Diabetes. We addressed this problem in part via a novel model for investigation of EVs. In our model, we utilized exosome free cell culture media to replace depleted exosomes with those from control or diabetic mice. Using this approach, we demonstrate that exosomes from diabetic mice significantly impair insulin stimulated uptake of 2-NBDG (a fluorescent glucose analog). We also report that this occurs without alteration in phosphorylation of AKT. We also observed marked deposition on neutral lipids in myotubes after exposure with no changes in expression of a subset of genes important for lipid synthesis or import. Next, we employed 3’ end RNA seq to identify differentially regulated genes in response to exosomes associated with both aerobic exercise and type 2 diabetes. We found that exosomes associated with aerobic exercise robustly downregulated the expression of MAP2K6 whereas diabetes associated exosomes upregulated the expression of PRKD1. This is important because both genes may uniquely contribute to insulin sensitivity and overall muscle health. Finally, we investigated the therapeutic utility of intravenous administration of exercise associated exosomes for diabetic mice. While the exercise exosomes improved run to fatigue time and decreased intraperitoneal glucose tolerance test area under the curve, there was no improvement in muscle mass or force production, HOMA-IR index, or hemoglobin A1C in diabetic animals. We therefore must conclude that aerobic exercise associated exosomes confer functional and metabolic benefits associated with exercise but are ineffective as a therapeutic for type 2 diabetes