Scholarly Works, Virginia Tech Carilion School of Medicine (VTCSOM)

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Education Research: Entrustable Professional Activities for General Neurology Advanced Practice Providers: Results of a Modified Delphi Consensus Process
Harrison, Daniel S.; Doherty, Elyse M.; Meffert, Cassandra C.; Doughty, Christopher T.; Morgenlander, Joel C.; Entrustable Professional Activities for General Neurology APPs (EPAGNA) Study Group; Shah, Aashit (Wolters Kluwer Health, 2026-03)
BACKGROUND AND OBJECTIVES: A dedicated didactic framework, assessment strategy, and consensus expectations for advanced practice providers (APPs) entering general neurology practice for the first time have not been described. We aimed to define entrustable professional activities (EPAs) for general neurology APPs and to provide further validity evidence for the EPAs through application of the EQual rubric. METHODS: This was a modified Delphi consensus process. Panelists were leaders of neurology APP fellowship programs and other established experts in neurology APP education. The steering committee identified putative EPA topics. Panelists voted on a 5-point Likert scale how important it was that a new general neurology APP be able to perform specific activities with indirect supervision remotely available by the end of their on-the-job training. Panelists were allowed to propose modifications to putative EPAs and suggest new EPAs. After 3 rounds of voting, full EPA descriptions were drafted by the steering committee. Full EPA descriptions were sent to external experts in neurology APP education for assessment of their structure and quality. The steering committee met again to discuss feedback from the external experts and make adjustments as needed. The full EPA descriptions were sent to the Delphi panelists for a final round of voting. RESULTS: Of 35 experts invited to participate in the Delphi process, 30 agreed to serve as panelists, 16 of whom were program leaders in neurology APP fellowship programs. The steering committee proposed 13 core and 52 nested EPA topics and the panelists proposed 6 modifications and an additional 4 nested EPAs. After 3 rounds of voting, 13 core and 46 nested EPAs were retained and full EPA descriptions were authored. All EPA descriptions met the pre-specified cut score for quality and structure and were retained in a final Delphi round. Overall entrustment expectations did not differ between panelists who were fellowship program leaders and those who were not (5-point Likert median [interquartile range], 4 [4-5] vs 4 [4-5], p = 0.980, r = 0.005). DISCUSSION: These consensus EPAs may be applied for curricular development and assessment for new general neurology APPs. Entrustment expectations did not differ between those who were leaders in fellowship programs and those who were not.
Managing the Behavioral and Psychological Symptoms of Dementia
Unwin, Brian K. (2026-02-01)
Scaffold-free 3D-Cell Culture Model System for the Study of Metastatic Cell Behavior in the Brain TME
Sarkar, Pratistha; Ahuja, Shreya; Lazar, Iuliana M. (Cold Spring Harbor Laboratory, 2025-11-03)
Cancer is a complex disease involving dynamic interactions between cancer, stromal, and infiltrating immune cells, as well as between these cells and the extracellular matrix components of the tumor microenvironment. Brain metastases arise primarily from solid tumors and often result in fatal outcomes. An in-depth understanding of the complex intercellular interactions that evolve in the brain microenvironment is essential to enabling early cancer diagnostics and improving patient outcomes. The protected tumor microenvironment of the brain hinders, however, direct access, impeding the execution of mechanistic studies and limiting the ability to derive meaningful insights. Several in vitro 2D and 3D model systems have been developed to circumvent this problem, none, however, without limitations. The 2D models fail to recapitulate the 3D architecture of the in-vivo environment lacking therefore physiological relevance, while the 3D models present challenges related to the lack of control over cell positioning, lack of vascularization, contamination from non-human scaffolds, batch-to-batch reproducibility, and high production costs. To overcome some of these limitations, we developed an in vitro scaffold-free 3D tumor model system to simulate the in vivo brain metastatic niche. The model was constructed from human brain endothelial cells (HBEC-5i) and two different cancer cell lines derived from breast (MDA-MB-231/triple negative and SK-BR-3/HER2+) and aggressive ovarian (SK-OV-3) cancers. The development of the model relies on a newly identified affinity between the endothelial and cancer cells that enables them to self-assemble in 3D networked constructs, a feature facilitated by the high collagen production by endothelial cells and the secretion of key chemokines by both endothelial and cancer cells. The model mimics the attachment of metastasized cancer cells to the brain microvasculature, enabling the study of temporal changes in endothelial morphology and molecular signaling processes that sustain cancer cell migration, survival, proliferation, and angiogenic processes. Moreover, the model exhibits long-term stability, reproducibility, and effectiveness in evaluating anti-cancer agents. Altogether, the scaffold-free, simple 3D in vitro model systems provides a low cost, physiologically relevant tool for studying the dynamic molecular crosstalk between cancer and brain endothelial cells, and for investigating the fundamental biological processes that unfold in the tumor microenvironment.
Impact of maternal obesity and mode of delivery on the newborn skin and oral microbiomes
Seifert, Allison; Ingram, Kelly; Eko, Embelle Ngalame; Nunziato, Jaclyn; Ahrens, Monica; Howell, Brittany R. (Microbiology Society, 2025-04-10)
Introduction. Previous studies have shown vast differences in the skin and oral microbiomes of newborns based on delivery method [Caesarean section (C-section) vs vaginal]. Exposure to or absence of certain bacteria during delivery can impact the neonate’s future susceptibility to infections, allergies or autoimmunity by altering immune functions. Few studies have focused on the impact of maternal obesity on the variations of newborn skin and oral microbiomes. Obese pregnant women typically have a higher vaginal microbiome diversity, and their pregnancies are at higher risk for adverse outcomes and complications. Hypothesis. We hypothesized that the skin and oral microbiomes of newborns born to obese mothers would include more diverse, potentially pathogenic bacteria and that the skin and oral microbiome in C-section delivered newborns would be less diverse than vaginally delivered newborns. Aim. We aim to begin to establish maternal obesity and mode of delivery as factors contributing to increased risk for negative newborn outcomes through impacts on newborn bacterial dysbiosis. Methodology. A skin swab was collected immediately following delivery of 39 newborns from 13 healthy weight body mass index (BMI 18.50–24.99), 11 overweight (BMI 25.0–29.99) and 15 obese (BMI ≥30.00) pregnant participants. An oral swab was collected immediately following delivery for 38 of these newborns from 13 healthy weight, 10 overweight and 15 obese pregnant participants. Bacterial genera were identified via 16S rRNA amplicon sequencing. Results. The newborn skin microbiome was comprised of typical skin bacteria (i.e. Corynebacterium). Newborns of obese participants had a higher relative abundance of Peptoniphilus in their skin microbiome compared to newborns of healthy weight participants (P=0.007). Neonates born via C-section had a higher relative abundance of Ureaplasma in their oral microbiome compared to neonates delivered vaginally (P=0.046). Conclusion. We identified differences in the newborn skin and oral microbiomes based on pre-pregnancy BMI and method of delivery. These differences could be linked to an increased risk of allergies, autoimmune disease and infections. Future longitudinal studies will be crucial in determining the long-term impact of these specific genera on newborn outcomes. Understanding these connections could lead to targeted interventions that reduce the risk of adverse outcomes and improve overall health trajectory.
Expanding Access to Retinal Imaging Through Patient-Operated Optical Coherence Tomography in a Veterans Affairs Retina Clinic
Dogan, Alan B.; Barber, Katherine G.; Devine, Brigid C.; Kuo, Blanche; Drummond, Colin K.; Mehra, Ankur A.; Eleff, Eric S.; Sobol, Warren M. (MDPI, 2026-01-05)
This study evaluated the feasibility, image quality, and referral accuracy of a patient-operated optical coherence tomography (OCT) device (SightSync) compared with technician-acquired Heidelberg OCT. This study was conducted in a Veterans Affairs retina clinic (Cleveland, Ohio), resulting in a predominantly male (98%) study population representative of the local veteran demographics. One hundred patients attempted self-administered OCT imaging after brief instruction, yielding 118 successful scans (59% of eyes) with no significant association between scan success and age, visual acuity, or diagnosis. Quantitative analysis of 142 paired images showed that SightSync produced interpretable scans with comparable sharpness to Heidelberg OCT, though signal- and intensity-based metrics (signal-to-noise ratio; SNR, contrast-to-noise ratio; CNR, entropy, pixel intensity; p90) were lower, consistent with hardware differences between a compact patient-operated prototype and a clinical-grade system. Among 121 high-quality SightSync scans, referral decisions demonstrated strong agreement with Heidelberg OCT, with a sensitivity of 83.9%, specificity of 75.6%, and a negative predictive value of 93.2%, indicating reliable exclusion of clinically significant pathology. These findings demonstrate that patients can independently acquire clinically interpretable OCT images and that SightSync provides safe, conservative triage performance—supporting its potential as a scalable community-based retinal imaging solution—while a review of unsuccessful scans has identified prototype modifications expected to further improve device feasibility.
Toward Safer Diagnoses: A SEIPS-Based Narrative Review of Diagnostic Errors
Yen, Carol; Epling, John W.; Rockwell, Michelle; Vaughn-Cooke, Monifa (MDPI, 2026-01-21)
Diagnostic errors have been a critical concern in healthcare, leading to substantial financial burdens and serious threats to patient safety. The Improving Diagnosis in Health Care report by the National Academies of Sciences, Engineering, and Medicine (NASEM) defines diagnostic errors, focusing on accuracy, timeliness, and communication, which are influenced by clinical knowledge and the broader healthcare system. This review aims to integrate existing literature on diagnostic error from a systems-based perspective and examine the factors across various domains to present a comprehensive picture of the topic. A narrative literature review was structured upon the Systems Engineering Initiative for Patient Safety (SEIPS) model that focuses on six domains central to the diagnostic process: Diagnostic Team Members, Tasks, Technologies and Tools, Organization, Physical Environment, and External Environment. Studies on contributing factors for diagnostic error in these domains were identified and integrated. The findings reveal that the effectiveness of diagnostics is influenced by complex, interconnected factors spanning all six SEIPS domains. In particular, socio-behavioral factors, such as team communication, cognitive bias, and workload, and environmental pressures, stand out as significant but difficult-to-capture contributors in traditional and commonly used data resources like electronic health records (EHRs), which limits the scope of many studies on diagnostic errors. Factors associated with diagnostic errors are often interconnected across healthcare system stakeholders and organizations. Future research should address both technical and behavioral elements within the diagnostic ecosystem to reduce errors and enhance patient outcomes.
A mindfulness-based multicomponent caregiver intervention (PAACC): Objectives, study design and cohort description
Sapra, Mamta; Hagemann, Lauren; Luci, Katherine; Savla, Jyoti (Wiley, 2025-03)
INTRODUCTION: Effective interventions are needed to reduce caregiver burden and stress, particularly among family caregivers of veterans with dementia. Unique risk factors such as traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) further complicate caregiving. This study compares a four-session mindfulness-based multicomponent intervention (PAACC) with a cognitive behavioral intervention (REACH), both designed to alleviate caregiver burden, and provides a baseline evaluation of caregivers in the intervention. A two-arm, blinded, randomized controlled trial assigned 133 dementia caregivers to PAACC (n = 67) or REACH (n = 66). Baseline assessments included caregiver stress, burden, mindfulness receptivity, rumination, compassion, depressive symptoms, anxiety, and care recipient behavior. Participants averaged 67.17 years, 85% were women, and 70% were spousal caregivers. Caregivers in PAACC reported higher depressive symptoms and anxiety and lower mindfulness receptivity. This study introduces the first mindfulness-based intervention for veteran caregivers, designed to enhance cognitive flexibility, cultivate compassion, and provide practical skills to improve quality of life. METHODS: The study utilized a two-arm, blinded, prospective randomized controlled trial to compare the PAACC and REACH interventions. A total of 133 dementia caregivers experiencing moderate to severe caregiver burden were assigned to receive either the PAACC intervention (n = 67) or the REACH intervention (n = 66). Baseline evaluations included caregiver stress, burden, mindfulness receptivity, rumination, compassion, depressive symptoms, anxiety, and the memory and behavior problems of the veteran living with dementia, using widely accepted measures from caregiving literature. RESULTS: Baseline assessments were conducted on 133 family caregivers of veterans living with dementia. The average caregiver age was 67.17 years (SD = 9.8), 85% were women, and 70% were spousal caregivers. No significant demographic differences were found between the two intervention groups. However, baseline comparisons showed that caregivers in the PAACC intervention reported higher depressive symptoms and anxiety, and lower mindfulness receptivity. A detailed protocol for the mindfulness-based multicomponent caregiver intervention PAACC is described. DISCUSSION: There is a growing need for multicomponent, skill-building interventions tailored for dementia caregivers who are at high risk of stress. This study introduces the first mindfulness-based intervention specifically for caregivers of veterans, designed to enhance cognitive flexibility, cultivate compassion, and equip caregivers with practical skills to improve their quality of life. Highlights: PAACC is a mindfulness-based multicomponent intervention for dementia caregivers of veterans. No demographic differences suggest psychological differences are not due to demographics. Baseline mental health and mindfulness readiness may impact intervention effectiveness.
New focus on cardiac voltage-gated sodium channel β1 and β1B: Novel targets for treating and understanding arrhythmias?
Williams, Zachary J.; Payne, Laura Beth; Wu, Xiaobo; Gourdie, Robert G. (Elsevier, 2025-01)
Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by 2 classes of membrane-spanning subunit: an α-subunit (pore forming) and 2 β-subunits (non–pore forming). NaV1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including NaV1.6, being present. There are 4 β-subunits (β1–β4) encoded by 4 genes (SCN1B–SCN4B), each of which is expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the β-subunit extracellular amino-terminal domain facilitates adhesive interactions in intercalated discs and that its carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway, with a carboxyl-terminal peptide generated by β1 RIP trafficked to the nucleus and altering transcription of various genes, including NaV1.5. In addition to β1, the Scn1b gene encodes for an alternative splice variant, β1B, which contains an identical extracellular adhesion domain to β1 but has a unique carboxyl-terminus. Although β1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with NaV1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known of the 2 β-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate β1 and β1B may be attractive targets for novel antiarrhythmic therapeutics.
Gap junctional and ephaptic coupling in cardiac electrical propagation: homocellular and heterocellular perspectives
Wu, Xiaobo; Payne, Laura Beth; Gourdie, Robert G. (Wiley, 2025-05-31)
Electrical communication in the heart is crucial for maintaining normal cardiac function. Traditionally, gap junctional coupling between cardiomyocytes has been accepted as the primary mechanism governing electrical propagation in the heart. However, numerous studies have demonstrated that gap junctions are also present between different cell types in heterocellular structures and disruption of such gap junctional coupling can be associated with cardiac dysfunction. In addition to gap junctional coupling, ephaptic coupling has been proposed as another mechanism for electrical communication between cardiomyocytes. Reducing ephaptic coupling has been shown to have negative impacts on cardiac conduction. While the existence of ephaptic coupling between different types of cardiac cell is under investigation, a recent study suggests that ephaptic coupling at heterocellular contacts between cardiomyocytes and fibroblasts may provide a proarrhythmic substrate in cardiac disease. In this review, we examine the current literature on electrical communication in the heart, including gap junctional and ephaptic coupling in homocellular and heterocellular contexts. Further, we offer a perspective on gaps in knowledge and opportunities for further advancing our understanding of electrical coupling mechanisms in action potential propagation in the heart. (Figure presented.).
Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction
Adams, William P.; Raisch, Tristan B.; Zhao, Yajun; Davalos, Rafael V.; Barrett, Sarah; King, D. Ryan; Bain, Chandra B.; Colucci-Chang, Katrina; Blair, Grace A.; Hanlon, Alexandra L.; Lozano, Alicia; Veeraraghavan, Rengasayee; Wan, Xiaoping; Deschenes, Isabelle; Smyth, James W.; Hoeker, Gregory S.; Gourdie, Robert G.; Poelzing, Steven (Lippincott Williams & Wilkins, 2023-09-29)
BACKGROUND: Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces. METHODS: Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. RESULTS: CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran 70 kDa; albumin or dextran 2 MDa; dextran 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. CONCLUSIONS: Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.
PERM1 Gene Delivery via AAV Prevents Heart Failure in a Mouse Model of Pressure Overload
Sreedevi, Karthi; Montalvo, Ryan; Doku, Abbigail; Korte, Audrey; Thomas, Rebekah; Salama, Sarah; Burrows, Steven; Yan, Zhen; Zaitsev, Alexey V.; Warren, Junco S. (2025-09-30)
Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of mortality worldwide. A hallmark of HFrEF is impaired cardiomyocyte contractility accompanied by disrupted mitochondrial bioenergetics; however, no current therapy targets both pathologies simultaneously. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is downregulated in HFrEF patients. We recently demonstrated that overexpression of PERM1 via adeno-associated virus 9 (AAV9-PERM1) enhances both cardiac contractility and mitochondrial biogenesis in C57BL/6 mice. In this study, we evaluated the therapeutic potential of AAV9-PERM1 in a pressure overload-induced mouse model of HFrEF. C57BL/6 mice were treated with either AAV9-PERM1 or control AAV9-GFP (1×1012 GC/mouse), followed by transverse aortic constriction (TAC) surgery. At 4 weeks post-TAC, control mice receiving AAV-GFP exhibited reduced left ventricular ejection fraction (LVEF), whereas AAV-PERM1 preserved LVEF at baseline levels. This cardioprotective effect was sustained through 8 weeks. Notably, AAV9-PERM1 completely abrogated TAC-induced cardiac hypertrophy and fibrosis. Mitochondrial analysis revealed that AAV9-PERM1 preserved mitochondrial DNA copy number and TFAM protein levels, both of which were reduced by TAC in control hearts. AAV9-PERM1 also improved mitochondrial respiration using pyruvate and octanoylcarnitine as substrates and prevented TAC-induced impairments in oxidative capacity. While PGC-1α expression remained unchanged in control TAC hearts, it was modestly yet significantly upregulated by AAV9-PERM1 in both sham and TAC groups. In addition, AAV9-PERM1 suppressed TACinduced increases in O-GlcNAcylation, a stress-related posttranslational modification of proteins. Coimmunoprecipitation further revealed interactions of PERM1 with creatine kinase and troponin C, key proteins in ATP transduction and contractility, suggesting a functional coupling between mitochondrial energetics and contractility. In conclusion, AAV-PERM1 gene therapy effectively preserves cardiac function under pressure overload by maintaining mitochondrial biogenesis, respiration capacity and contractility. This study further suggests AAV-PERM1 as a promising therapeutic strategy for HFrEF.
A Twist in the Tale: The Unmasking of Listeria in a PMR Case
Al‐Qaysi, Ghassan; Kaja, Viswaja; Anumola, Rishitha; Bankole, Adegbenga (Wiley, 2026-01)
In general, an older patient presenting with proximal muscle pain and fatigue, with elevated inflammatory markers, would generally result in an extensive evaluation. If this is negative, it would be reasonable for a diagnosis of polymyalgia rheumatica (PMR) to be made and the patient referred to rheumatology. Our patient presented myalgia in proximal muscles and an elevated sedimentation rate. He was treated with steroids for polymyalgia rheumatica with improvement. He was subsequently admitted to the intensive care unit (ICU), where a diagnosis of Listeria monocytogenes sepsis was made and treated. With antibiotics he improved and was discharged from the hospital. This Case Report underscores the importance of considering unusual infections when entertaining a systemic autoimmune rheumatic disease (SARD) as the cause of systemic inflammatory response syndrome.
Beyond Bell’s: A Case Study of Bilateral Facial Paralysis From Lyme Neuroborreliosis
Wu, Kainuo; Peterson, Christopher; Gomez de la Espriella, Mariana; Fazili, Tasaduq (Springer, 2025-12-26)
Bilateral facial palsy is a rare neurological presentation that often reflects an underlying systemic disease that requires prompt and comprehensive diagnostic evaluation to guide appropriate management. A 50-year-old man presented with bilateral facial palsy without a recent history of vector exposure or characteristic rash. Extensive diagnostic studies included autoimmune panels, neurovascular and structural imaging, cerebrospinal fluid (CSF) analysis, infectious cultures, and various viral and bacterial serologies. The absence of a clear exposure history and variable latency period following initial exposure contributed to diagnostic uncertainty. Lyme meningitis was confirmed based on CSF findings and a markedly elevated Borrelia CSF to serum antibody index after other etiologies were excluded. The patient was treated with seven days of intravenous ceftriaxone and 14 days of oral doxycycline, achieving complete neurological recovery at three months. This case highlights the exhaustive workup required to identify the cause of bilateral facial palsy. Early specialty consultation is critical to expedite diagnostic workup. Clinicians should maintain a high index of clinical suspicion for Lyme disease despite an absent exposure history or rash. Prompt recognition of bilateral facial palsy and timely intervention are essential to ensure optimal neurological recovery.
New-Onset Atrial Fibrillation Potentially Associated With Tirzepatide: A Case Report
Purvez, Akhtar; Mirza, Mohd; Bashir, Mudhasir (Springer, 2025-12)
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is increasingly prescribed for the treatment of type 2 diabetes and obesity. Although it is generally considered cardiometabolically beneficial, rare cardiac rhythm disturbances may occur. We describe a 62-year-old woman without a prior history of cardiovascular disease who developed new-onset atrial fibrillation (AF) shortly after initiating tirzepatide. She presented with palpitations, hypotension, and rapid ventricular response requiring intensive care, rate control, anticoagulation, and electrical cardioversion. A thorough examination showed that there was no structural heart disease, electrolyte imbalance, or endocrine disorder. Following discontinuation of tirzepatide, AF did not recur during follow-up. This case highlights the importance of clinical vigilance for arrhythmias when initiating novel incretin-based therapies.
Multiplexed smFISH reveals the spatial organization of neuropil localized mRNAs is linked to abundance
Tarannum, Renesa; Mun, Grace; Quddos, Fatima; Swanger, Sharon A.; Steward, Oswald; Farris, Shannon (Society for Neuroscience, 2025-11)
RNA localization to neuronal axons and dendrites provides spatiotemporal control over gene expression to support synapse function. Neuronal messenger RNAs (mRNAs) localize as ribonucleoprotein particles (RNPs), commonly known as RNA granules, the composition of which influences when and where proteins are made. High-throughput sequencing has revealed thousands of mRNAs that localize to the hippocampal neuropil. Whether these mRNAs are spatially organized into common RNA granules or distributed as independent mRNAs for proper delivery to synapses is debated. Here, using highly multiplexed single molecule fluorescence in situ hybridization (HiPlex smFISH) and colocalization analyses, we investigate the subcellular spatial distribution of 15 synaptic neuropil localized mRNAs in the male and female rodent hippocampus. We observed that these mRNAs are present in the neuropil as heterogeneously sized fluorescent puncta with spatial colocalization patterns that generally scale by neuropil mRNA abundance. Indeed, differentially expressed mRNAs across cell types displayed colocalization patterns that scaled by abundance, as did simulations that reproduce cell-specific differences in abundance. Thus, the probability of these mRNAs colocalizing in the neuropil is best explained by stochastic interactions based on abundance, which places constraints on the mechanisms mediating efficient transport to synapses.Significance statement RNA localization establishes compartment-specific gene expression that is critical for synapse function. Thousands of mRNAs localize to the hippocampal synaptic neuropil, however, whether mRNAs are spatially organized as similar or distinctly composed ribonucleoprotein particles for delivery to synapses is unknown. Using multiplexed smFISH to assess the spatial organization of 15 neuropil localized mRNAs, we find that these mRNAs are present in variably sized puncta suggestive of heterogeneous transcript copy number states. RNA colocalization analyses in multiple hippocampal cell types suggest that the spatial relationship of these mRNAs is best described by their abundance in the neuropil. Stochastic RNA-RNA interactions based on neuropil abundance are consistent with models indicating that global principles, such as energy minimization, influence population localization strategies.
High-Frequency Irreversible Electroporation Alters Proteomic Profiles and Tropism of Small Tumor-Derived Extracellular Vesicles to Promote Immune Cell Infiltration
Murphy, Kelsey R.; Aycock, Kenneth N.; Marsh, Spencer; Yang, Liping; Hinckley, Jonathan; Selmek, Aubrie; Gourdie, Robert G.; Bracha, Shay; Davalos, Rafael V.; Rossmeisl, John H.; Dervisis, Nikolaos G. (MDPI, 2025-11-13)
High-frequency irreversible electroporation (H-FIRE) is a nonthermal tumor ablation technique that disrupts the blood–brain barrier (BBB) in a focal and reversible manner. However, the mechanisms underlying this disruption remain poorly understood, particularly the role of small tumor-derived extracellular vesicles (sTDEVs) released from ablated tumor cells. In this study, we investigate the proteomic and functional alterations of sTDEVs released from F98 glioma and LL/2 Lewis lung carcinoma cells following H-FIRE ablation. Mass spectrometry analysis revealed 108 unique proteins in sTDEVs derived from ablative doses of H-FIRE, which are capable of disrupting the BBB in an in vitro model. Proteomic analysis of TDEVs highlights key changes in pathways related to integrin signaling, Platelet-derived growth factor receptor (PDGFR) signaling, and ubiquitination, which may underline their interactions with brain endothelial cells. These “disruptive” sTDEVs exhibit enhanced tropism for cerebral endothelial cells both in vitro and in vivo, where they persist in the brain longer than sTDEVs released after non-ablative H-FIRE doses. Notably, when introduced into a healthy Fischer rat model, disruptive sTDEVs are associated with increased recruitment of Iba1+ immune cells, suggesting a potential role in modulating post-ablation immune responses. However, despite their altered protein composition, these vesicles do not directly increase BBB permeability in vivo. This study is the first to demonstrate that electroporation-based tumor ablation significantly alters the composition and functionality of tumor-derived extracellular vesicles, potentially influencing the tumor microenvironment post-ablation. These findings have important implications for developing multimodal treatment strategies that combine H-FIRE with systemic therapies to enhance efficacy while managing the peritumoral microenvironment.
Continuous non-invasive measurement of tidal volume and minute ventilation using a smart nasal cannula
Dogan, Alan B.; Patel, Neel; Gottschalk, Carter; Blankenship, Rae L.; Young, Valerie K.; Wicks, Alfred; Sofi, Umar F. (2025-11-27)
The Flow Regulated Nasal Delivery System (FRNDS) is a novel smart nasal cannula platform developed to enable noninvasive, continuous monitoring of tidal volume (VT) and detection of abnormal breathing events. Combined with peripheral capillary oxygen saturation (SpO₂) data modulation of oxygen flow can be accomplished. In a cohort of 57 adults, FRNDS-derived VT and minute ventilation were compared to reference measurements from respiratory inductance plethysmography (RIP) across a range of oxygen flow rates. While the cannula system tended to overestimate inspiratory and underestimate expiratory VT—especially at higher flow rates—these errors were substantially reduced by applying machine learning regression models trained on anatomical and physiological features, achieving strong agreement with RIP averaging a 53.5 mL error, 78.2 mL root-mean error, and is within ~ 11% of the actual value. The system also demonstrated robust performance in classifying clinically relevant breathing patterns, including apneic spells and mouth breathing, suggesting utility for real-time respiratory surveillance and sleep apnea detection. These results support FRNDS as a promising, adaptable solution for individualized respiratory monitoring in both clinical and home environments.
On-X aortic valve replacement patients treated with low-dose warfarin and low-dose aspirin
Oo, Aung Y.; Loubani, Mahmoud; Gerdisch, Marc W.; Zacharias, Joseph; Tsang, Geoffrey M.; Perchinsky, Michael J.; Hagberg, Robert Carl; Joseph, Mark; Sathyamoorthy, Mohanakrishnan (Oxford University Press, 2024-05-03)
OBJECTIVES To assess if warfarin targeted to international normalized ratio (INR) 1.8 (range 1.5-2.0) is safe for all patients with an On-X aortic mechanical valve. METHODS This prospective, observational registry follows patients receiving warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus daily aspirin (75-100 mg) after On-X aortic valve replacement. The primary end point is a composite of thromboembolism, valve thrombosis and major bleeding. Secondary end points include the individual rates of thromboembolism, valve thrombosis and major bleeding, as well as the composite in subgroups of home or clinic-monitored INR and risk categorization for thromboembolism. The control was the patient group randomized to standard-dose warfarin (INR 2.0-3.0) plus daily aspirin 81 mg from the PROACT trial. RESULTS A total of 510 patients were enroled at 23 centres in the UK, USA and Canada. Currently, the median follow-up duration is 3.4 years, and median achieved INR is 1.9. The primary composite end point rate in the low INR patients is 2.31% vs 5.39% (95% confidence interval 4.12-6.93%) per patient-year in the PROACT control group, constituting a 57% reduction. Results are consistent in subgroups of home or clinic-monitored, and high-risk patients, with reductions of 56%, 57% and 57%, respectively. Major and total bleeding are decreased by 85% and 73%, respectively, with similar rates of thromboembolic events. No valve thrombosis occurred. CONCLUSIONS Interim results suggest that warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus aspirin is safe and effective in patients with an On-X aortic mechanical valve with or without home INR monitoring.
Telerehabilitation in Physical Therapist Practice: A Clinical Practice Guideline From the American Physical Therapy Association
Lee, Alan C.; Deutsch, Judith E.; Holdsworth, Lesley; Kaplan, Sandra L.; Kosakowski, Heidi; Latz, Robert; Mcneary, Lydia Lennox; O'Neil, Jennifer; Ronzio, Oscar; Sanders, Kelly; Sigmund-Gaines, Michelle; Wiley, Michele; Russell, Trevor (Oxford University Press, 2024-05-30)
A clinical practice guideline on telerehabilitation was developed by an American Physical Therapy Association volunteer guideline development group consisting of international physical therapists and physiotherapists, a physician, and a consumer. The guideline was based on systematic reviews of current scientific literature, clinical information, and accepted approaches to telerehabilitation in physical therapist practice. Seven recommendations address the impact of, preparation for, and implementation of telerehabilitation in physical therapist practice. Research recommendations identify current gaps in knowledge. Overall, with shared decision-making between clinicians and patients to inform patients of service delivery options, direct and indirect costs, barriers, and facilitators of telerehabilitation, the evidence supports the use of telerehabilitation by physical therapists for both examination and intervention. The Spanish and Chinese versions of this clinical practice guideline, as well as the French version of the recommendations, are available as supplementary material ().
Injury-induced connexin 43 expression regulates endothelial wound healing
Sedovy, Meghan W.; Renton, Mark C.; Roberts, Kailynn; Leng, Xinyan; Dennison, Clare L.; Toler, Caroline O.; Leaf, Melissa R.; Lampe, Paul D.; Best, Angela K.; Isakson, Brant E.; Johnstone, Scott R. (American Physiological Society, 2025-10-28)
Endothelial cell (EC) injury is a major contributing factor to vascular surgical failure. As such, understanding the mechanisms of endothelial healing is essential to the development of vascular therapeutics and procedures. Gap junctions formed by connexin 43 (Cx43) are implicated in regulating skin wound healing, but their role in endothelial healing is unknown. Secondary analysis of RNA-seq data from in vivo injured mouse aortas (GEO: GSE115618) identified significant Cx43 upregulation in EC postinjury. We developed a novel in vivo model of EC injury using mouse carotid artery ligation to test the role of Cx43. We identified that EC immediately adjacent to the wound edge upregulate Cx43 protein expression, predominantly at cell-cell junctions. We show significantly delayed EC healing in a mouse model of inducible EC-specific Cx43 deletion [EC-Cx43 knockout (KO)] at 24 h post ligation. Single-cell RNA-seq analysis of 10,829 cells from 18 h injured EC-wild type (WT) and EC-Cx43 KO carotids revealed a Cx43-associated reduction in enrichment of EC pathways associated with migration, proliferation, and ERK/MAPK signaling pathways. Finally, the importance of Cx43 phosphorylation on EC healing was tested in mice with single-point alanine mutations (phospho-null) in known phosphorylation sites that alter Cx43 channel assembly and opening. Mice containing alanine mutations at ERK phosphorylated Cx43 serines (Cx43S²⁵⁵/²⁶²/²⁷⁹/²⁸²A) have reduced healing rates similar to EC-Cx43 KO mice. These data suggest that EC injury-induced Cx43 upregulation and subsequent Cx43 gap junction-mediated cell-to-cell communication are required for normal EC migration during wound healing after vascular injury.

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