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

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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.
Pilot Study: Impact of Primary Spoken Language as a Social Determinant of Health on CPR Education and Utilization
LeNeave, Charles W.; Meier, Brian; Liffert, Heather; Perkins, John C. (California Digital Library, 2025-07-18)
Gait asymmetry persists following unilateral and bilateral total ankle arthroplasty
Carpentier, Stephanie H.; Barylak, Martin; Arena, Sara L.; Queen, Robin M. (Wiley, 2024-11-01)
Total ankle arthroplasty (TAA) improves gait symmetry in patients with unilateral end-stage ankle arthritis but has not been studied in patients undergoing bilateral TAA (B-TAA), and few studies compare TAA patients to control subjects. The purpose of this study was to compare gait symmetry in U-TAA and B-TAA patients and healthy controls. Using prospective databases, 19 unilateral and 19 bilateral ankle arthritis patients undergoing TAA were matched to 19 control subjects by age, sex, and BMI. The Normalized Symmetry Index (NSI) was determined for joint mechanics and ground reaction forces (GRF) during walking trials at a single visit for controls and preoperatively and 1 to 2 years postoperatively for TAA patients. Data was analyzed using linear mixed-effects models to determine differences among time points and cohorts at a significance of alpha = 0.05. Following surgery, B-TAA and U-TAA experienced improved peak plantarflexion moment symmetry (p = 0.017) but remained less symmetric than controls. B-TAA patients had more symmetry than U-TAA patients during peak weight acceptance GRF (p = 0.002), while U-TAA patients had greater peak dorsiflexion symmetry than B-TAA patients. TAA patients demonstrated more asymmetry compared to control subjects for all outcome measures. There was no significant impact of TAA on gait symmetry for GRF or peak ankle angles, and neither U-TAA nor B-TAA was consistently associated with higher gait symmetry. These results indicate that TAA improves symmetry during peak plantarflexion moment, and that significant gait asymmetry persists for B-TAA and U-TAA patients compared to healthy participants.
A Broken Heart: Grief-Associated Left Ventricular Rupture with Non-Occlusive Coronary Arteries
Ward, Maxwell; Wu, K.; Ayzenbart, Vira I.; Mirza, Mohd A.; Kietrsunthorn, Patrick S. (2025-09-05)
Ischemic Events Occur Early in Patients Undergoing Percutaneous Coronary Intervention and Are Reduced With Cangrelor: Findings From CHAMPION PHOENIX
Cavender, Matthew A.; Harrington, Robert A.; Stone, Gregg W.; Steg, Gabriel; Gibson, C. Michael; Hamm, Christian W.; Price, Matthew J.; Lopes, Renato D.; Leonardi, Sergio; Deliargyris, Efthymios N.; Prats, Jayne; Mahaffey, Kenneth W.; White, Harvey D.; Bhatt, Deepak L.; CHAMPION PHOENIX Investigators (Wolters Kluwer Health, 2022-01)
Background: Thrombotic events are reduced with cangrelor, an intravenous P2Y₁₂ inhibitor. We sought to characterize the timing, number, and type of early events (within 2 hours of randomization) in CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). Methods: CHAMPION PHOENIX was a double-blind, placebo-controlled trial that randomized patients undergoing percutaneous coronary intervention to cangrelor or clopidogrel. For this analysis, we evaluated the efficacy of cangrelor in the first 2 hours postrandomization with regards to the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis). Sensitivity analyses were performed evaluating a secondary, post hoc end point (death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis). Results: The majority of events (63%) that occurred in the trial occurred within 2 hours of randomization. The most common early event was myocardial infarction; next were stent thrombosis, ischemia driven revascularization, and death. In the first 2 hours after randomization, cangrelor significantly decreased the primary composite end point compared with clopidogrel (4.1% versus 5.4%; hazard ratio, 0.76 [95% CI, 0.64-0.90], P=0.002). Similar findings were seen for the composite end point of death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium stent thrombosis at 2 hours (0.9% versus 1.6%; hazard ratio, 0.57 [95% CI, 0.40-0.80], P=0.001). Between 2 and 48 hours, there was no difference in the primary composite end point (0.6% versus 0.5%; odds ratio, 1.17 [95% CI, 0.71-1.93]; P=0.53). Early (≤2 hours of randomization) GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate or severe bleeding events were infrequent, and there was no significant difference with cangrelor compared with clopidogrel (0.2% [n=10] versus 0.1% [n=4]; adjusted odds ratio, 1.41 [95% CI, 0.37-5.40]; P=0.62). Conclusions: The reductions in ischemic events and overall efficacy seen with cangrelor in CHAMPION PHOENIX occurred early and during the period of time in which patients were being actively treated with cangrelor. These findings provide evidence that supports the importance of potent platelet inhibition during percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01156571.
Delayed Thrombus on Carotid Web: Case Report With Escalation of Treatment
Kodankandath, Thomas V. (Sage, 2022-04)
Carotid artery web is an underrecognized source and is found in about 1-2% of patients with acute ischemic stroke. Although, first described four decades ago, optimal therapy for carotid web is not yet known. Carotid stenting and endarterectomy are increasingly used for carotid web treatment, given its definitive treatment and avoiding the complications associated with anticoagulation. The case reported here is of an ischemic stroke secondary to a mobile thrombus on a carotid web evident on CT angiography and successful definitive treatment with delayed carotid wall stent placement. In young patients who have a diagnosis of ischemic stroke, the carotid web should be on the differential and adequate neuroimaging with either CTA or DSA should be pursued.
Geospatial access to oral health care in Virginia: Insights from driving and public transit analysis
Sherman, Zach; Karki, Shashank; Brickhouse, Tegwyn; Vujicic, Marko; Nasseh, Kamyar; Wang, Changzhen; Kim, Hyun; Kim, Junghwan; Zhang, Mengxi (Elsevier, 2025-10-23)
Background. The authors aimed to investigate whether driving and public transit access to dental clinics differ for all dental clinics vs those participating in Medicaid, and whether sociodemographic factors are associated with driving and public transit accessibility in Virginia. Methods. Six regions in Virginia were selected for this study on the basis of the availability of transportation data. A modified two-step floating catchment area method considering vehicle ownership was applied to measure geospatial accessibility scores for the overall dental clinics and those participating in Medicaid. Inequality in accessibility among census block groups was analyzed using Gini coefficients. Spatial error models were used to estimate associations between sociodemographic variables and accessibility scores. Results. Public transit accessibility to oral health care services is lower than driving, regardless of Medicaid acceptance. Driving also provides more equitable access than public transit. Spatial error models revealed region-specific associations. Conclusions. Access to oral health care services is more challenging using public transportation than driving, especially in smaller regions of and among Medicaid beneficiaries in Virginia. The exploration of the associated factors emphasizes the need for tailored interventions according to region. Practical Implications. To improve access to oral health care in Virginia, efforts should focus on encouraging dentists to accept Medicaid, establishing new dental clinics near public transportation hubs and major roads, using ride-sharing support, and advocating for the development of robust public transportation systems.
Ultrasound-Guided Mechanical High-Intensity Focused Ultrasound (Histotripsy) Through an Acoustically Permeable Polyolefin-Based Cranioplasty Device
Ruger, Lauren; Langman, Maya; Farrell, Renata; Rossmeisl, John H. Jr.; Prada, Francesco; Vlaisavljevich, Eli (IEEE, 2024-10-01)
Histotripsy is a non-thermal focused ultrasound therapy in development for the non-invasive ablation of cancerous tumors. Intracranial histotripsy has been limited by significant pressure attenuation through the skull, requiring large, complex array transducers to overcome this effect. Objective: Recently, a biocompatible, polyolefin-based cranioplasty device was developed to allow ultrasound (US) transmission into the intracranial space with minimal distortion. In this study, we investigated the in vitro feasibility of applying US-guided histotripsy procedures across the prosthesis. Methods: Pressure waveforms and beam profiles were collected for single- and multi-element histotripsy transducers. Then, high-speed optical images of the bubble cloud with and without the prosthesis were collected in water and tissue-mimicking agarose gel phantoms. Finally, red blood cell (RBC) tissue phantom and excised brain tissue experiments were completed to test the ablative efficacy across the prosthesis. Results: Single element tests revealed increased pressure loss with increasing transducer frequency and increasing transducer-to-prosthesis angle. Array transducer measurements at 1 MHz showed average pressure losses of >50% across the prosthesis. Aberration correction recovered up to 18% of the pressure lost, and high-speed optical imaging in water, agarose gels, and RBC phantoms demonstrated that histotripsy bubble clouds could be generated across the prosthesis at pulse repetition frequencies of 50-500 Hz. Histologic analysis revealed a complete breakdown of brain tissue treated across the prosthesis. Conclusion & Significance: Overall, the results of this study demonstrate that the cranial prosthesis may be used as an acoustic window through which intracranial histotripsy can be applied under US guidance without the need for large transcranial array transducers.
Collaborative Preclinical/Clinical Efforts Aimed at Strengthening a Neurology Residency Program: Challenges, Activities and Outcomes
Nolan, Michael F.; McNamara, John P. (Springernature, 2025-02-01)
Recent trends in medical education have included efforts to better integrate traditionally preclinical content with subject matter included in the clinical years of the curriculum. The participation of clinical faculty in preclinical courses is well established; however, involvement of biomedical science faculty in resident education is less common. We describe here a project in which a basic science faculty member participated in a neurology residency program to address specific basic science knowledge weaknesses identified by the neurology department chair. We address issues and challenges associated with planning and implementation. Benefits to both the residents and the biomedical scientist are described.
Use of a Best Practice Advisory to increase the detection rate of hyperparathyroidism
Gates, Rebecca S.; McCoy, Kristin; Stewart, Jonathan; Behnke, Andrew J.; Bankole, Adegbenga; Vallia, Theresa; Nussbaum, Michael S.; Tershak, Daniel (Elsevier, 2025-09-25)
Background: Timely diagnosis and treatment of primary hyperparathyroidism requires a high index of suspicion and collaboration across specialties. The diagnosis often is overlooked. This study aimed to determine whether the introduction of a screening algorithm for primary hyperparathyroidism would increase diagnosis and treatment rates. Methods: An electronic health record Best Practice Advisory was launched in 2022, encouraging parathyroid hormone testing for patients with hypercalcemia (calcium ≥11 mg/dL). Parathyroid hormone testing, specialist referrals, and parathyroidectomy were examined pre- and postintervention. Results: There were 902 and 893 patients with hypercalcemia in the pre- and postintervention groups, respectively. Parathyroid hormone testing increased from 24.61% to 38.75% after the Best Practice Advisory was implemented (P < .01). Specialist referrals and rates of parathyroidectomy were unchanged between the pre- and postintervention groups (referrals in 41.44% vs 41.04% of those with parathyroid hormone testing, P = .93; parathyroidectomy in 27.17% vs 26.76% of those referred, P = 1.00). Parathyroid hormone testing was performed more commonly in older patients (69.63 vs 59.01 years, P < .01). Patients referred to a specialist were younger (67.59 vs 71.05 years, P = .04). Patients with primary hyperparathyroidism–associated comorbidities were more likely to undergo parathyroid hormone testing, with no differences in rates of specialist referrals (P = .11) or parathyroidectomy (P = .60). Conclusion: An electronic health record Best Practice Advisory was effective in increasing primary hyperparathyroidism screening, but did not result in a higher rate of specialist referrals or parathyroidectomies. Reflex parathyroid hormone testing as well as increased education about primary hyperparathyroidism may further improve screening, referrals, and treatment.
Exploring clinician perspectives of systems-based practice: A physician training challenge
DeWaters, Ami L.; Banerjee, Somalee; Bruce, James; Cooney, Rob; Ellison, Halle B.; Haidet, Paul; Mazotti, Lindsay; Reilly, James B.; Gonzalo, Jed D. (Wiley, 2025-02-01)
Introduction: Systems-based practice (SBP) has been a competency in US graduate medical education for over 20 years, but it is not well implemented. SBP is loosely defined as physician's responsiveness to the larger system of healthcare. The aim of this study was to describe healthcare professionals' perspectives regarding: (1) their knowledge and beliefs about SBP and (2) their beliefs regarding factors in clinical learning environments (CLE) that facilitate or hinder operationalisation and learning of SBP. Methods: Semi-structured interviews were conducted between November 2020 and April 2021 with 42 individuals from four health systems. Participants were healthcare professionals involved in graduate medical education, including physicians and interprofessional clinicians (e.g., nursing staff). Interviews were transcribed and coded using a social constructivist, codebook thematic analysis approach and themes were agreed upon through discussion amongst the research team. Results: Five themes were constructed: (1) SBP remains a challenge to define, (2) SBP may be intuitively understood, particularly when framed at the microsystem level, (3) SBP aligns with the Health Systems Science framework, (4) SBP learning must be intentionally integrated into the CLE, through training such as onboarding and (5) multidisciplinary settings and work processes are critical to engage in SBP. Workload compression is a barrier to SBP implementation. Conclusions: Healthcare professionals highlighted that current CLEs are not designed to prioritise SBP. Graduate medical education programmes may benefit from focusing systems content at the microsystem level and purposefully integrating onboarding procedures, clinical settings and rotations specifically designed to teach SBP into their residencies.
A preliminary study of the physiological and perceptual effects of GLP-1 receptor agonists during alcohol consumption in people with obesity
Quddos, Fatima; Fowler, Mary; de Lima Bovo, Ana Carolina; Elbash, Zacarya; Tegge, Allison N.; Gatchalian, Kirstin M.; Kablinger, Anita S.; DiFeliceantonio, Alexandra G.; Bickel, Warren K. (Nature Research, 2025-10-15)
Any increase in alcohol use is associated with an increase in risk of illness and mortality and consequences of chronic alcohol use include cancer, hypertension, heart and liver disease, and Alcohol Use Disorder. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective anti-glycemic and weight-loss medications with a strong safety record. There is substantial preclinical evidence and mounting retrospective and prospective randomized controlled trial evidence that GLP-1RAs could be effective for reducing alcohol consumption. However, the mechanism by which GLP-1RAs reduce alcohol intake remains unclear. While medications that reduce alcohol intake such as naltrexone and acamprosate have central nervous system action, disulfiram reduces alcohol intake through peripheral mechanisms. Here, we test whether GLP-1RAs alter alcohol’s peripheral pharmacokinetics as a potential mechanism of action for their alcohol intake suppressive effects. In this pilot study, 20 (1:1) participants with obesity in the GLP-1RA or control group consumed a challenge dose of alcohol, and we measured breath alcohol (BrAC) and the subjective effects of alcohol. We observed a delayed rise in BrAC and subjective effects in the GLP-1RA group as compared to controls, that was not explained by nausea. These data provide preliminary evidence that GLP-1RAs could act through peripheral mechanisms to suppress alcohol intake.
An EPIC Transition: Rapid Conversion of a Measurement Feedback System in Behavioral Health
Gatto, Alyssa J.; McNamara, Robert S.; Ko, Hayoung; O'Brien, Virginia C.; Jones, Sydney B.; Cooper, Lee D.; Kablinger, Anita S. (SAGE Publications, 2025-08)
Measurement-based care (MBC), while an evidence-based clinical practice, can be difficult to integrate into behavioral healthcare settings. Even when MBC has been successfully implemented in an organization, there are many challenges that create a need for rapid adaptation. As measurement feedback systems (MFSs) are increasingly hosted on dynamic digital platforms, there is always a risk of technological changes and adaptations, whether the system is prepared for them or not. This point of view is focused on managing organizational changes to continue use of MBC through a case example in adult behavioral healthcare. A hospital policy change, informed by financial considerations, led to the rapid de-implementation of the external MFS platform in favor of a system integrated into the electronic health record (EHR). Our team responsively developed a plan for maintaining MBC through this transition including written guidelines and face-to-face training to support clinical staff, while determining the best way to maintain research gains and collect data in the EHR. This manuscript discusses the challenges in switching MBC platforms and the downstream consequences of this policy change from clinical, training, and research perspectives.
Comparative Risk of Developing Interstitial Cystitis with Childhood Gastrointestinal, Urological, Autoimmune, or Psychiatric Disorders
Alipour-Vaezi, Mohammad; McNamara, Robert S.; Rukstalis, Margaret R.; Gentry, Emily C.; Rukstalis, Daniel B.; Penzien, Donald B.; Tsui, Kwok-Leung; Zhong, Huaiyang (Wiley, 2025-09-01)
Aims: Interstitial cystitis (IC) is a chronic urological condition associated with significant discomfort, posing diagnostic and therapeutic challenges. Although its etiology remains unclear, early-life conditions such as gastrointestinal (GI) disorders, urological anomalies (UA), psychiatric disorders (PD), and autoimmune diseases (AD) have been hypothesized as potential risk factors for developing IC in adulthood. This study aims to investigate these associations by conducting a retrospective cohort analysis utilizing data from the TriNetX US Collaborative Network, encompassing over 118 million patient records. Methods: The study and control groups were established across four categories of childhood disorders, with IC incidence monitored over a 14-year period. Statistical methodologies, including propensity score matching and Kaplan-Meier survival analysis, were employed to compare outcomes between cohorts. Results: Findings indicate that childhood GI and UA conditions significantly elevate the risk of IC in adulthood, with irritable bowel syndrome (IBS) and urinary tract infections (UTIs) exhibiting risk ratios of 2.9 and 3.2, respectively. Gender disparities were also noted, with females exhibiting higher incidences of diseases included, particularly UA and AD during adolescence. Additionally, individuals with these early-life conditions demonstrated a higher prevalence of comorbidities, underscoring the complex interplay of health factors contributing to IC pathogenesis. Conclusions: These findings suggest that childhood GI and UA conditions may serve as predictive markers for IC, emphasizing the need for targeted early interventions and preventative care strategies. By identifying at-risk populations, this study provides valuable insights into early detection and management approaches, potentially mitigating the long-term burden of IC on affected individuals. Trial Registration: This paper includes an observational retrospective study. No clinical trial has been conducted.
Multimodal Assessment in Clinical Simulations: A Guide for Moving Towards Precision Education
Schwengel, Deborah; Villagran, Ignacio; Miller, Geoffrey; Miranda, Constanza; Toy, Serkan (Springernature, 2025-04-01)
Technological advances and cutting-edge data analytics approaches give new prospects for using multimodal assessments in simulation-based medical education. These multimodal approaches consider the interaction of data obtained from multiple sources and can enhance our ability to assess the educational efficacy of simulations and optimize learning experiences for each individual learner. However, several challenges could jeopardize the successful implementation of this approach. We present a practical guide for integrating multimodal assessment in clinical simulation-based education, offering educators and researchers a systematic checklist to consider before undertaking these multimodal assessment initiatives.
Low-dose warfarin with a novel mechanical aortic valve: Interim registry results at 5-year follow-up
Gerdisch, Marc W.; Hagberg, Robert Carl; Perchinsky, Michael J.; Joseph, Mark; Oo, Aung Y.; Loubani, Mahmoud; Tsang, Geoffrey M.; Zacharias, Joseph; Sathyamoorthy, Mohanakrishnan (Mosby-Elsevier, 2024-12-01)
Objectives: To evaluate whether warfarin targeted at an international normalized ratio of 1.8 (range, 1.5-2.0) after On-X mechanical aortic valve implant is safe for all patients. Methods: This prospective, observational clinical registry assessed adverse event rates in adult patients receiving low-dose warfarin (target international normalized ratio, 1.8; range, 1.5-2.0) plus daily aspirin (75-100 mg) during a 5-year period after On-X aortic valve implant. The primary end point is the combined rate of major bleeding, valve thrombosis, and thromboembolism overall and in 4 subgroups. The comparator is the Prospective Randomized On-X Anticoagulation Trial control group patients on standard-dose warfarin (international normalized ratio, 2.0-3.0) plus aspirin 81 milligrams daily. Results: A total of 510 patients were recruited at 23 centers in the United States, United Kingdom, and Canada between November 2015 and January 2022. This interim analysis includes 229 patients scheduled to complete 5-year follow-up by August 16, 2023. The linearized occurrence rate (in percent per patient-year) of the primary composite end point of major bleeding, valve thrombosis, and thromboembolism is 1.83% compared with 5.39% (95% confidence interval, 4.12%-6.93%) in the comparator group. Results are consistent in clinic-monitored and home-monitored patients and in those at high risk for thromboembolism. Major bleeding and total bleeding were reduced by 87% and 71%, respectively, versus the comparator group, without an increase in thromboembolic events. Conclusions: Interim results support the continued safety of the On-X aortic mechanical valve with a target international normalized ratio of 1.8 plus low-dose aspirin through 5 years after implant, with or without home monitoring.
Mentalizing, epistemic trust and interpersonal problems in emotion regulation: A sequential path analysis across common mental health disorders and community control samples
Kumpasoglu, Guler Beril; Saunders, Rob; Campbell, Chloe; Nolte, Tobias; Montague, P. Read; Pilling, Steve; Leibowitz, Judy; Fonagy, Peter (Elsevier, 2025-03-01)
Background: Emotion regulation is a crucial function implicated in multiple mental health disorders; understanding the mechanisms by which emotion regulation has such impact is essential. Mentalizing has been posited as a prerequisite for effective emotion regulation. The current study aims to examine the roles of epistemic trust and interpersonal problems in driving the association between mentalizing and emotion regulation, contrasting clinical and non-clinical populations. Method: A total of 652 individuals (296 clinical and 356 community control) were employed. Sequential mediation analysis was used to examine the role of epistemic stances and interpersonal problems in the mentalizing-emotion regulation link, and moderated mediation analysis was conducted to identify group differences in these pathways. Results: Ineffective mentalizing was associated with emotion dysregulation and interpersonal problems. Higher levels of epistemic credulity and mistrust were associated with ineffective mentalizing, interpersonal problems, and emotion dysregulation. Sequential mediation analysis indicated that disruptions in epistemic trust (epistemic mistrust and credulity) and interpersonal problems partially mediated the relationship between inadequate mentalizing and emotion dysregulation, with these pathways being consistent across both clinical and control groups. The pathways including epistemic trust were not significant. Limitations: The study's limitations include a simplified theoretical model, a cross-sectional design preventing causal inference, and sample recruitment methods possibly limiting generalizability. Conclusions: These findings suggest a potential mechanism connecting mentalizing, disruptions in epistemic trust, interpersonal problems, and emotion regulation, to illuminate a crucial aspect of psychological functioning. These results emphasize the significance of social-communicative aspect in clinical outcomes.
CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
Raraigh, Karen S.; Paul, Kathleen C.; Goralski, Jennifer L.; Worthington, Erin N.; Faino, Anna V.; Sciortino, Stanley; Wang, Yiting; Aksit, Melis A.; Ling, Hua; Osorio, Derek L.; Onchiri, Frankline M.; Patel, Shivani U.; Merlo, Christian A.; Montemayor, Kristina; Gibson, Ronald L.; West, Natalie E.; Thakerar, Amita; Bridges, Robert J.; Sheppard, David N.; Sharma, Neeraj; Cutting, Garry R. (American Society for Clinical Investigation, 2022-03)
The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.
Comparing efficiency of patent production between US institutions using a hybrid NIH-USPTO dataset
DiSanto, Rocco M.; Van Dyke, Mark; Barker, Michael J.; Gourdie, Robert G. (Nature Portfolio, 2023-08)
A database that links patents to NIH awards enables evaluation of key milestones along the research translation pathway.
Development and characterization of the mode-of-action of inhibitory and agonist peptides targeting the voltage-gated sodium channel SCN1B beta-subunit
Williams, Zachary J.; Alvarez-Laviada, Anita; Hoagland, Daniel; Jourdan, L. Jane; Poelzing, Steven; Gorelik, Julia; Gourdie, Robert G. (Elsevier, 2024-09)
Cardiac arrhythmia treatment is a clinical challenge necessitating safer and more effective therapies. Recent studies have highlighted the role of the perinexus, an intercalated disc nanodomain enriched in voltage-gated sodium channels including both Nav1.5 and β1 subunits, adjacent to gap junctions. These findings offer insights into action potential conduction in the heart. A 19-amino acid SCN1B (β1/β1B) mimetic peptide, βadp1, disrupts VGSC beta subunit-mediated adhesion in cardiac perinexii, inducing arrhythmogenic changes. We aimed to explore βadp1's mechanism and develop novel SCN1B mimetic peptides affecting β1-mediated adhesion. Using patch clamp assays in neonatal rat cardiomyocytes and electric cell substrate impedance sensing (ECIS) in β1-expressing cells, we observed βadp1 maintained inhibitory effects for up to 5 h. A shorter peptide (LQLEED) based on the carboxyl-terminus of βadp1 mimicked this inhibitory effect, while dimeric peptides containing repeated LQLEED sequences paradoxically promoted intercellular adhesion over longer time courses. Moreover, we found a link between these peptides and β1-regulated intramembrane proteolysis (RIP) - a signaling pathway effecting gene transcription including that of VGSC subunits. βadp1 increased RIP continuously over 48 h, while dimeric agonists acutely boosted RIP for up to 6 h. In the presence of DAPT, an RIP inhibitor, βadp1's effects on ECIS-measured intercellular adhesion was reduced, suggesting a relationship between RIP and the peptide's inhibitory action. In conclusion, novel SCN1B (β1/β1B) mimetic peptides are reported with the potential to modulate intercellular VGSC β1-mediated adhesion, potentially through β1 RIP. These findings suggest a path towards the development of anti-arrhythmic drugs targeting the perinexus.

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