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High resolution tissue and cell type identification via single cell transcriptomic profiling
No full textTissue identification can be instrumental in reconstructing a crime scene but remains a challenging task in forensic investigations. Conventionally, identifying the presence of certain tissue from tissue mixture by predefined cell type markers in bulk fashion is challenging due to limitations in sensitivity and accuracy. In contrast, single-cell RNA sequencing (scRNA-Seq) is a promising technology that has the potential to enhance or even revolutionize tissue and cell type identification. In this study, we developed a high sensitive general purpose single cell annotation pipeline, scTissueID, to accurately evaluate the single cell profile quality and precisely determine the cell and tissue types based on scRNA profiles. By incorporating a crucial and unique reference cell quality differentiation phase of targeting only high confident cells as reference, scTissueID achieved better and consistent performance in determining cell and tissue types compared to 8 state-of-art single cell annotation pipelines and 6 widely adopted machine learning algorithms, as demonstrated through a large-scale and comprehensive comparison study using both forensic-relevant and Human Cell Atlas (HCA) data. We highlighted the significance of cell quality differentiation, a previously undervalued factor. Thus, this study offers a tool capable of accurately and efficiently identifying cell and tissue types, with broad applicability to forensic investigations and other biomedical research endeavors.The author(s) received no specific funding for this work
SteadFAST: Case Reports in PA Studies 1 (1)
No full textDr. Eugene A. Stead was a physician and innovator in many areas of health care and healthcare delivery. Dr. Stead is credited as the founder of the PA profession after graduating the first class of PAs in 1967. As more physicians began to specialize than remain in general practice after WW2, Dr. Stead saw the importance of increasing the number of providers for an increasing patient population. Building on the experience and training of Naval Corpsmen (advanced trained medics) who had recently left the service, he designed a program in the early 1960s to advance their medical knowledge toward physician level. Initially dubbed “assistants to physicians”, the nascent program graduated the first three physician assistants in 1967. Since that time, PAs have been on the forefront of medical care provision across nearly every specialty and in many areas of leadership. It is for the vision of Dr. Eugene Stead that we christen our case report journal SteadFAST and dedicate the knowledge from the next generation of Physician Associates.Volume 1 (1): February 19, 2025University of North Texas Health Science Center at Fort Worth Physician Assistant ProgramDedication to Dr. Eugene Stead -- Editorial Board (page i) -- Contents (page ii) -- Case Reports (page 1) -- Parvovirus B19 Infection Resulting in Fetal Hydrops / Abby Sherman, PA-C; James Herd, MD; Jamie Park, PA-C; Vic Holmes, PA-C, EdD (page 2) -- Clostridioides difficile infection in a pediatric patient with short gut syndrome / Carly Rosse, PA-S; Huong Pham, MPAS, PA-C; Lauren Dobbs, MMS, PA-C; Vic Holmes, PA-C, EdD (page 6) -- The Use of Low-Dose Aspirin to Prevent Preeclampsia in Pregnancy / Grace Buchen, PA-S; James Herd, MD; Amanda Brosnan, PA-C; Vic Holmes, PA-C, EdD (page 10) -- Liver Injury Induced by Selective Androgen Receptor Modulators Taken for Weight Loss / Tiffany Lin, PA-S; Haley Sutherland, DO; Audrey Lively, PA-C; Vic Holmes, PA-C, EdD (page 14) -- Aortic Lusoria Complicating Transradial Heart Catheterization / Sarah Khan, PA-S; Giri Munduluru, MD; Jamie Park, PA-C; Vic Holmes, PA-C, EdD (page 18) -- The Diagnosis and Treatment of New-Onset Schizophrenia / Kazlyn Roberts, PA-S; Olla Elbasheer, MD; Helene Alphonso, MD; Jamie Park, MS, MPAS, PA-C; Vic Holmes, PA-C, EdD (page 22) -- Managing PTSD Nightmares: Pharmacotherapeutic Considerations and Alternative / Sydney Clayton, PA-S; Audrey Lively, PA-C; Vic Holmes PA-C, EdD (page 26) -- A Rare Surgical Case: Gastrojejunocolic Fistula / Kellen Dunn, PA-S; Cody Starnes, MD; Jamie Park, PA-C; Vic Holmes; PA-C (page 30) -- Ovarian Torsion in a Reproductive Age Female / Abby Creighton, PA-S; Kaitlin Wagner, MD; Vic Holmes, PA-C, EdD (page 34) -- Gut Dysbiosis: An Atypical Cause of Recurrent Bacterial Vaginosis / Emily Guyton, PA-S; Ann Palagi-Pate, APRN, CNM, WHNP; Audrey Lively, PA-C; Vic Holmes, PA-C, EdD (page 38) -- The Risk of Tobacco Exposure on the Recurrence of Cervical Dysplasia / Ashley Bates, PA-S; Christopher LaFargue, MD, Vic Holmes, PA-C, EdD (page 42) -- About the PA Program (page 46
Cellular fibronectin exacerbates alpha-synuclein aggregation via integrin alpha4beta1 mediated PARP1 and SCD elevation
Get PDFMitochondrial dysfunction and lipid metabolic disturbance may promote pathologic alpha-synuclein (alpha-syn) aggregation, accelerating the progression of Parkinson's disease (PD). Whether extracellular matrices are associated with those pathological mechanisms in PD remains elusive. Here, we aimed to identify if cellular fibronectin (cFn), a component of extracellular matrices, contributes to alpha-syn abnormality via inducing mitochondrial energy depletion or disrupting lipid homeostasis. In Our study, 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-treated PD mice and human neuronal SH-SY5Y cells were used. Astrocyte-derived cFn protein delivery and AAV-mediated cFn knockdown mouse models were established to validate the functional role of cFn. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM), and the level of poly (ADP-ribose) (PAR) polymerase-1(PARP1), pathologic alpha-syn and cFn-induced lipid dysmetabolism was determined. We demonstrated that excessive cFn accumulated in the SNpc of MPTP-treated mice, and cFn rather than plasma Fn (pFn) exacerbated neuronal mitochondrial dysfunction and alpha-syn accumulation. Mechanically, cFn induced PARP1 activation via integrin alpha4beta1, which contributed to neuronal NAD + depletion and pathologic alpha-syn aggregation. Furthermore, cFn induced an increase in free fatty acids (FAs) and triglycerides (TAG) in neurons by binding to integrin alpha4beta1, which synergistically contributed to alpha-syn abnormality. We revealed that cFn induced stearoyl-CoA desaturase (SCD) activation via integrin alpha4beta1, which was interacted with SCD. Genetically depleting cFn suppressed PARP1 activation and SCD elevation, which further rescued the mitochondrial disruption and alpha-syn abnormalities in MPTP-treated mice. Overall, our findings suggest that cFn exacerbates alpha-syn aggregation via integrin alpha4beta1-mediated PARP1 and SCD elevation. cFn-targeting therapy may be a promising strategy for treating PD.This work was supported by the National Natural Science Foundation of China (NO: U24A20694, 82071414, 82471433, QW), Scientific Research Foundation of Guangzhou (NO: 202206010005, QW), Science and Technology Program of Guangdong of China (NO: 2020A0505100037, QW), Guangdong Basic and Applied Basic Research Foundation (2023A1515111058, ZFH), Natural Science Foundation of Guangdong Province (2025A1515012456, YQL), National Medical Research Council (STaR and PD LCG 000207, EKT)
Macrophage phenotypes modulate neoangiogenesis and fibroblast profiles in synovial-like organoid cultures
Get PDFOBJECTIVE: To investigate the interaction among the cells thought to be foundational to inflammation, fibrosis, and angiogenesis in the synovial membrane. METHOD: We encapsulated fibroblasts, polarized macrophages, and endothelial cells in a 3D culture system. We used this model to determine the cellular transcriptional profiles, cytokine secretion, and vascular formation associated with different macrophage phenotype conditions. RESULTS: Neo-angiogenesis reached its maximum level at approximately day 21 in the presence of pro-inflammatory macrophages conditions, but was sustained in the presence of anti-inflammatory macrophages. RNA sequencing revealed an influence of macrophage phenotype on gene expression associated with fibrosis and angiogenesis. Furthermore, by including lipopolysaccharides-coated polyethylene particles (lcPE), an inflammatory stimulus replicating wear debris from joint replacements into our system, insights into the local reaction to byproducts of different biomaterials can be ascertained. CONCLUSION: Chronic inflammation and fibrosis of the synovial membrane are often present in osteoarthritis and post-total joint arthroplasty. Our results suggest that the progression of inflammatory synovial diseases is influenced by macrophage phenotypes.This work was supported by NIH grants UG3TR002136, R01 AR063713, R01 AR073145, and the Ellenburg Chair in Surgery at Stanford University
Optimizing Recruitment and Retention in Cancer Clinical Trials in Low-Resource Settings: Barriers and Facilitators From Nigerian Provider's Perspectives
Get PDFPURPOSE: The under-representation of African countries in cancer clinical trials continues to widen the cancer health disparity. In this study, we assessed health care workers' perspectives on recruitment and retention in cancer clinical trials in Nigeria. METHODS: This study was a convergent parallel mixed-methods design, using a survey for quantitative analysis and focus group discussions (FGDs) for further qualitative investigation. The health care providers that participated in the study were drawn from the ICON-3 Practice-based Research Network across the six geopolitical zones in Nigeria. RESULTS: Of the 42 providers, 35 completed the survey and 25 participated in the FGDs. The most cited (agreed or strongly agreed) patient-related barriers were lack of understanding of cancer clinical trials (83%), cultural barriers (77%), and lack of financial compensation for study visits (77%). The most cited provider-related barriers were negative attitude of the clinical team (89%), lack of training in good clinical practice (89%), and an overwhelming clinical workload (86%). On trial-related barriers, about 71% agreed or strongly agreed that lack of trial publicity was a barrier. Over 90% of the respondents agreed or strongly agreed that several factors, including the friendliness of the study team (97%) and clarity in the presentation of trial information (97%), are important facilitators. The FGDs unveiled additional themes, including systems-related barriers such as lack of infrastructure, limited research collaboration, and prolonged ethical approval process, and capacity building and community engagement as potential facilitators. CONCLUSION: Our study provides providers' perspectives on the barriers and facilitators to the recruitment and retention of participants in cancer clinical trials in a low-resource setting and highlights the need for culturally appropriate recruitment strategies.Supported by the National Cancer Institute of the National Institutes of Health under award number P50CA098252. The National Institute of Health also supported E.E.E., B.O.O., N.I.-A., T.C.O., and I.U.I. time on this grant under award number 1UO1CA275118
A Case of Guyon’s Canal Compression Post-Surgical Intervention
No full textBackground: Ulnar nerve entrapment is a common peripheral neuropathy with compression usually occurring at the cubital tunnel and more rarely at Guyon’s Canal. Cubital tunnel is often affected by repetitive elbow flexion, trauma, or prolonged pressure at elbow. Surgical interventions such as ulnar nerve transposition are commonly used for cubital tunnel syndrome when patients fail conservative measures. This procedure relocates the ulnar nerve to reduce compression at the elbow. Guyon’s Canal is located at the wrist and serves as a passageway for the ulnar nerve and artery. Compression at this site is relatively rare; incidence and prevalence have not been accurately estimated due to a lack of studies. It is often associated with repetitive wrist activities or trauma. This case highlights delayed-onset ulnar neuropathy localized to Guyon’s canal, two years after a successful ulnar nerve transposition at the elbow. Case Presentation: A 71 year-old female presents to physiatry clinic complaining of left sided numbness and tingling involving the fourth and fifth digits of the hand with symptoms radiating distally from the left elbow. Relevant medical history includes a left ulnar nerve transposition performed 2 years ago and cervical fusion at C4/5 and C6/7 completed 6 years ago. She reported no symptoms following the ulnar nerve transposition until 3 months ago, when she began experiencing a return of numbness and tingling in her left fourth and fifth digits. She denies weakness, new neck pain, or inciting events such as repetitive activities, sports, or trauma.. Physical examination revealed positive Tinel’s sign on the left elbow and diminished sensation around the fourth and fifth digits. Tinel’s sign was negative at the left wrist. Electrodiagnostic studies show evidence of left sided ulnar neuropathy across the wrist consistent with ulnar entrapment at Guyon’s canal due to sparing of the dorsal ulnar cutaneous nerve. Conclusions: This case demonstrates delayed onset of ulnar neuropathy at Guyon’s canal, two years after ulnar nerve transposition and without exacerbating factors. Clinicians should consider distal entrapment sites like Guyon’s canal, especially in patients with prior ulnar nerve transposition. The sparing of the dorsal ulnar cutaneous nerve (DUC) in wrist compression is a helpful diagnostic clue, as the DUC branches off before the ulnar nerve enters Guyon’s canal. Its preservation suggests that compression is occurring at the wrist, rather than the elbow. Additionally, adjacent segment disease after cervical fusion can complicate diagnosis. Changes in the cervical spine following fusion can lead to nerve root compression, which may mimic or overlap with symptoms of peripheral nerve entrapment . This can affect the C8/T1 nerve roots, producing symptoms that mimic the dermatomal patterns of ulnar neuropathy. This makes it essential to evaluate both proximal (spinal) and distal (peripheral) causes. This case highlights the rare occurrence of delayed-onset Guyon’s canal compression, the diagnostic significance of DUC sparing, and the challenge of managing patients with overlapping spinal and peripheral nerve pathologies. Future research should explore diagnostic strategies and treatments for patients with complex, overlapping pathologies
Health Disparities at the Intersection of Racism, Social Determinants of Health, and Downstream Biological Pathways
Get PDFDespite overall improvements in the accessibility, quality, and outcomes of care in the U.S. health care system over the last 30 years, a large proportion of marginalized racial and ethnic minority (minoritized) groups continue to suffer from worse outcomes across most domains. Many of these health disparities are driven by inequities in access to and the scope of society's health-affirming structural resources and opportunities commonly referred to as structural drivers or social determinants of health-SDoH. Persistently health-undermining factors in the social environment and the downstream effects of these inequities on neurocognitive and biological pathways exacerbate these disparities. The consequences of these circumstances manifest as behavioral, neurohormonal, immune, and inflammatory and oxidative stress responses, as well as epigenetic changes. We propose a theoretical model of the interdependent characteristics of inequities in the SDoH driven by race-based discriminatory laws, policies, and practices that eventually culminate in poor health outcomes. This model provides a framework for developing and validating multi-level interventions designed to target root causes, thereby lessening health disparities and accelerating improved health outcomes for minoritized groups.Funding: R.J.T. is partly supported by NIH research grants U54MD000214, P30AG059298, and 5R25HL126145. M.A.B. is partly supported by NIH research grants R03AG089289 and 5R25HL126145. K.C.N is partly supported by NIH research grants UL1TR001881, P30AG021684, U2CDK129496, and P50MD017366
Imaging Findings and Management of Pulmonary Embolism in Children
No full textBackground: Pulmonary embolism (PE) is rare in children but is increasing in incidence, particularly among adolescent females due to hormonal influences of medications such as oral contraceptives. In pediatric patients, PE is often challenging to diagnose due to its nonspecific clinical presentation. This case aims to highlight the imaging findings and treatment differences that distinguish pulmonary embolism in children. Case Presentation: An adolescent girl with a family history of blood clots presented with week-long exertional dyspnea and pleuritic chest pain, later experiencing sweating, jaw pain, and dizziness. CTPA revealed large filling defects in both pulmonary arteries and signs of right heart strain, including right ventricular enlargement and straightening of the interventricular septum, confirming the diagnosis of PE. Conclusions: Imaging, particularly CT pulmonary angiography (CTPA), is crucial for accurate diagnosis and planning of treatment. In children with PE, imaging findings such as wedge-shaped parenchymal consolidation are more distinct compared to adults with PE. The presence of a vascular filling defect is a key diagnostic feature, and additional signs like right ventricular strain provide crucial information for risk stratification, which informs treatment. Therapeutic guidelines for PE in children are associated with risk stratification and contain notable difference from adult PE guidelines. This case highlights the importance of early and accurate imaging in suspected pulmonary embolism in children to lower the mortality risk and prevent long-term complications such as pulmonary hypertension and recurrent thromboembolism
Late Presentation of VEXAS Syndrome in a 77 y/o Male
No full textBackground: VEXAS syndrome is a relatively new condition (first described in 2020), having characteristics that can be classified as both a myelodysplastic syndrome and an autoinflammatory disease. VEXAS syndrome arises from a somatic mutation in the UBA1 gene which downregulates the ubiquitination process of various proteins in myeloid cell lineages. This alteration of protein degradation leads to a wide array of inflammatory conditions that typically present in late adulthood. These conditions can include fevers, polyarthritis, auricular, nasal and periorbital chondritis, unintentional weight loss, various forms of vasculitis, elevated inflammatory markers, and hematologic abnormalities. Hematologic abnormalities can include cyotopenias, progressive macrocytic anemia, vacuolization of hematopoietic precursors, and a variety of myelodysplastic manifestations have been observed. Here, we present a case in which a patient is evaluated for, and diagnosed with VEXAS syndrome and compare his presentation to those of previous case studies and reports. Case Information: In this case a 77 y/o male presents to the emergency room with sudden onset shortness of breath and severe back pain. Bilateral pleural effusion was noted on a CT scan and CBC displayed macrocytic anemia (Hbg of 6.8 with an MCV of 117) and thrombocytopenia (115k). The patient was admitted for further workup due to an unintentional 50lb weight loss, bilateral lung infiltrates, and severe anemia. Over the previous six months, the patient reported symptoms of orbital inflammation, auricular/nasal chondritis, diffuse dermatitis, and bilateral lower extremity DVT’s. Bone marrow biopsy showed findings of myelodysplastic syndrome (MDS) and a rare monoclonal B-cell lymphocytosis. A UBA1 genetic abnormality was noted which is consistent with VEXAS Syndrome in association with MDS. Conclusions: Because of the novelty of VEXAS Syndrome, this case report brings awareness to the patient presentation of the condition. Additionally, this case illustrates a unique presentation of VEXAS Syndrome including a rare monoclonal B-cell lymphocytosis on top of the myelodysplastic syndrome typically seen in this condition