Digital Commons Network^™

Barriers To And Facilitators Of Paediatric Medical Device Innovation: A Scoping Review Protocol, Lynn Kysh, Grzegorz Zapotoczny, Lisa Manzanete, Megan Carey, Payal Shah, Francesca Joseph, Haley Kempf, Abu Taher Sikder, Julia Finkel, Usha Thekkedath, Kara Toman, Chester J Koh, Kolaleh Eskandanian, Juan Espinoza

Faculty, Staff and Students Publications

INTRODUCTION: The development of paediatric medical devices continues to lag adult medical devices and contributes to issues of inequity, safety, quality and patient outcomes. New legislation and funding mechanisms have been introduced over the past two decades, but the gap remains. Clinical trials have been identified as a pain point, but components of effective clinical research infrastructure are poorly understood. As part of a multimodal research strategy, the Pediatric Device Consortia (PDC) will conduct a scoping review to better understand infrastructural barriers to and facilitators of paediatric medical device clinical research identified in the health sciences literature.

METHODS AND ANALYSIS: …

Sirt6 Protects Retinal Ganglion Cells And Optic Nerve From Degeneration During Aging And Glaucoma, Fan Xia, Shuizhen Shi, Erick Palacios, Wei Liu, Seth E Buscho, Joseph Li, Shixia Huang, Gianmarco Vizzeri, Xiaocheng Charlie Dong, Massoud Motamedi, Wenbo Zhang, Hua Liu

Faculty, Staff and Students Publications

Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level …

Cyp3a Mediates An Unusual C(Sp2)-C(Sp3) Bond Cleavage Via Ipso-Addition Of Oxygen In Drug Metabolism, Xuan Qin, Yong Wang, Qiuji Ye, John M Hakenjos, Jin Wang, Mingxing Teng, Lei Guo, Zhi Tan, Damian W Young, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon–carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H218O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) …

Delays To Antibiotics In The Emergency Department And Risk Of Mortality In Children With Sepsis, Roni D Lane, Troy Richardson, Halden F Scott, Raina M Paul, Fran Balamuth, Matthew A Eisenberg, Ruth Riggs, W Charles Huskins, Christopher M Horvat, Grant E Keeney, Leslie A Hueschen, Justin M Lockwood, Vishal Gunnala, Bryan P Mckee, Nikhil Patankar, Venessa Lynn Pinto, Amanda M Sebring, Matthew P Sharron, Jennifer Treseler, Jennifer J Wilkes, Jennifer K Workman

Faculty, Staff and Students Publications

IMPORTANCE: Pediatric consensus guidelines recommend antibiotic administration within 1 hour for septic shock and within 3 hours for sepsis without shock. Limited studies exist identifying a specific time past which delays in antibiotic administration are associated with worse outcomes.

OBJECTIVE: To determine a time point for antibiotic administration that is associated with increased risk of mortality among pediatric patients with sepsis.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from 51 US children's hospitals in the Improving Pediatric Sepsis Outcomes collaborative. Participants included patients aged 29 days to less than 18 years with sepsis recognized within 1 hour …

Molecular Therapy Nucleic Acids, Jasmin Morandell, Alan Monziani, Martina Lazioli, Deborah Donzel, Jessica Döring, Claudio Oss Pegorar, Angela D'Anzi, Miguel Pellegrini, Andrea Mattiello, Dalia Bortolotti, Guendalina Bergonzoni, Takshashila Tripathi, Virginia B Mattis, Marina Kovalenko, Jessica Rosati, Christoph Dieterich, Erik Dassi, Vanessa C Wheeler, Zdenka Ellederová, Jeremy E Wilusz, Gabriella Viero, Marta Biagioli

Faculty, Staff and Students Publications

Circular RNA (circRNA) molecules have critical functions during brain development and in brain-related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6), stemming from the Huntington’s disease (HD) gene locus that is most abundant in the central nervous system (CNS). We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD model systems. The mouse orthologue, circHtt(2,3,4,5,6), is expressed during embryogenesis, increases during nervous system development, and is aberrantly upregulated in the presence of the expanded CAG tract. …

Update On Cancer Predisposition Syndromes And Surveillance Guidelines For Childhood Brain Tumors, Jordan R Hansford, Anirban Das, Rose B Mcgee, Yoshiko Nakano, Jack Brzezinski, Sarah R Scollon, Surya P Rednam, Jaclyn Schienda, Orli Michaeli, Sun Young Kim, Mary-Louise C Greer, Rosanna Weksberg, Douglas R Stewart, William D Foulkes, Uri Tabori, Kristian W Pajtler, Stefan M Pfister, Garrett M Brodeur, Junne Kamihara

Faculty, Staff and Students Publications

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition …

Individuals With Jak1 Variants Are Affected By Syndromic Features Encompassing Autoimmunity, Atopy, Colitis, And Dermatitis, Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, …

Ectoine Enhances Mucin Production Via Restoring Il-13/Ifn-Γ Balance In A Murine Dry Eye Model, Na Lin, Xin Chen, Haixia Liu, Ning Gao, Zhao Liu, Jin Li, Stephen C Pflugfelder, De-Quan Li

Faculty, Staff and Students Publications

PURPOSE: This study aimed to explore protective effects and potential mechanism of ectoine, a natural osmoprotectant, on ocular surface mucin production in dry eye disease.

METHODS: A dry eye model was established in C57BL/6 mice exposed to desiccating stress (DS) with untreated (UT) mice as controls. DS mice were topically treated with 2.0% ectoine or PBS vehicle. Corneal epithelial defects were assessed by Oregon Green Dextran (OGD) fluorescent staining. Conjunctival goblet cells, ocular mucins, and T help (Th) cytokines were evaluated by immunofluorescent staining or ELISA, and RT-qPCR.

RESULTS: Compared with UT mice, corneal epithelial defects were detected as strong …

Autologous Her2-Specific Car T Cells After Lymphodepletion For Advanced Sarcoma: A Phase 1 Trial, Meenakshi Hegde, Shoba Navai, Christopher Derenzo, Sujith K Joseph, Khaled Sanber, Mengfen Wu, Ahmed Z Gad, Katherine A Janeway, Matthew Campbell, Dolores Mullikin, Zeid Nawas, Catherine Robertson, Pretty R Mathew, Huimin Zhang, Birju Mehta, Raksha R Bhat, Angela Major, Ankita Shree, Claudia Gerken, Mamta Kalra, Rikhia Chakraborty, Sachin G Thakkar, Olga Dakhova, Vita S Salsman, Bambi Grilley, Natalia Lapteva, Adrian Gee, Gianpietro Dotti, Riyue Bao, Ahmed Hamed Salem, Tao Wang, Malcolm K Brenner, Helen E Heslop, Winfried S Wels, M John Hicks, Stephen Gottschalk, Nabil Ahmed

Faculty, Staff and Students Publications

In this prospective, interventional phase I study (NCT00902044) for patients with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T-cells (HER2-CART) after lymphodepletion with cyclophosphamide (Cy) +/− fludarabine (Flu): 1×108 T-cells/m2 after Flu (cohort A) or Flu/Cy (cohort B), and 1×108 CAR-positive T-cells/m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2-CART after lymphodepletion. The determination of antitumor responses was the secondary outcome. Thirteen patients were treated in 14 enrollments with 7 receiving multiple infusions. HER2-CART expanded after 19 of 21 infusions. Nine of 12 patients in cohorts A and …

Bacillary Angiomatosis In A Patient With Hiv And Disseminated Mycobacterium Avium Complex Infection, Ibeth P Caceres, Angelique Ruml, Rubi Montejano, Omid Jalali, Theodore Rosen

Faculty, Staff and Students Publications

Bartonella is a genus of arthropod-borne bacterial pathogens that typically cause persistent infections of erythrocytes and endothelial cells in mammalian hosts. The species that primarily infect humans are Bartonella henselae and Bartonella quintana. Depending on immune status, the clinical presentation of B. henselae may differ, manifesting as cat-scratch disease in immunocompetent individuals or bacillary angiomatosis (BA) and peliosis in immunocompromised patients. The cutaneous manifestations of BA are typically characterized by occasionally painful, angiomatous papules and nodules, often with a chronic, persistent course. Herein, we present a case of biopsy-confirmed B. henselae infection in a 32-year-old HIV-positive female with acquired immunodeficiency …

Individual Disruption Of 12 Testis-Enriched Genes Via The Crispr/Cas9 System Does Not Affect The Fertility Of Male Mice, Akira Suzuki, Norikazu Yabuta, Keisuke Shimada, Daisuke Mashiko, Keizo Tokuhiro, Yuki Oyama, Haruhiko Miyata, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

More than 1200 genes have been shown in the database to be expressed predominantly in the mouse testes. Advances in genome editing technologies such as the CRISPR/Cas9 system have made it possible to create genetically engineered mice more rapidly and efficiently than with conventional methods, which can be utilized to screen genes essential for male fertility by knocking out testis-enriched genes. Finding such genes related to male fertility would not only help us understand the etiology of human infertility but also lead to the development of male contraceptives. In this study, we generated knockout mice for 12 genes (Acrv1, Adgrf3, …

Continuous Renal Replacement Therapy: Current State And Future Directions For Worldwide Practice, Katja M Gist, Dana Y Fuhrman, Akash Deep, Taiki Haga, Demet Demirkol, Michael J Bell, Ayse Akcan-Arikan

Faculty, Staff and Students Publications

No abstract provided.

Social Connectedness And Adolescent Suicide Risk, Alejandra Arango, David Brent, Jacqueline Grupp-Phelan, Bradley J Barney, Anthony Spirito, Megan M Mroczkowski, Rohit Shenoi, Melinda Mahabee-Gittens, T Charles Casper, Cheryl King

Faculty, Staff and Students Publications

Background: Despite evidence of the importance of interpersonal connectedness to our understanding of suicide risk, relatively little research has examined the protective and buffering effects of connectedness among adolescents. The aims of this study were to determine: (a) whether overall connectedness (composite of family, peer, and school) and specific domains of connectedness were related to a lower likelihood of suicide attempts, and (b) whether these factors buffer the prospective risk of suicide attempt for high-risk subgroups (i.e., recent suicidal ideation and/or lifetime history of suicide attempt, peer victimization, or sexual and gender minority status).

Methods: Participants were 2,897 adolescents (64.7% …

Generation Of A Humanized Mace2 And A Conditional Hace2 Mouse Models Permissive To Sars-Cov-2 Infection, I-Wen Song, Megan Washington, Carolina Leynes, Jason Hsu, Kempaiah Rayavara, Yangjin Bae, Nele Haelterman, Yuqing Chen, Ming-Ming Jiang, Aleksandra Drelich, Vivian Tat, Denise G Lanza, Isabel Lorenzo, Jason D Heaney, Chien-Te Kent Tseng, Brendan Lee, Ronit Marom

Faculty, Staff and Students Publications

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26hACE2). Although the mAce2F83Y,H353K mice were susceptible to …

Unveiling Microbial Diversity: Harnessing Long-Read Sequencing Technology, Daniel P Agustinho, Yilei Fu, Vipin K Menon, Ginger A Metcalf, Todd J Treangen, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Long-read sequencing has recently transformed metagenomics, enhancing strain-level pathogen characterization, enabling accurate and complete metagenome-assembled genomes, and improving microbiome taxonomic classification and profiling. These advancements are not only due to improvements in sequencing accuracy, but also happening across rapidly changing analysis methods. In this Review, we explore long-read sequencing's profound impact on metagenomics, focusing on computational pipelines for genome assembly, taxonomic characterization and variant detection, to summarize recent advancements in the field and provide an overview of available analytical methods to fully leverage long reads. We provide insights into the advantages and disadvantages of long reads over short reads and …

Preparing Patients For Oral Immunotherapy (Ppoint): International Delphi Consensus For Procedural Preparation And Consent, Douglas P Mack, Timothy E Dribin, Paul J Turner, Richard L Wasserman, Mariam A Hanna, Marcus Shaker, Mimi L K Tang, Pablo Rodríguez Del Río, Brad Sobolewski, Elissa M Abrams, Aikaterini Anagnostou, Stefania Arasi, Sakina Bajowala, Philippe Bégin, Scott B Cameron, Edmond S Chan, Sharon Chinthrajah, Andrew T Clark, Paul Detjen, George Du Toit, Motohiro Ebisawa, Arnon Elizur, Jeffrey M Factor, Justin Greiwe, Jonathan O'B Hourihane, Sarah W Hughes, Douglas H Jones, Antonella Muraro, Anna Nowak-Wegrzyn, Nandinee B Patel, Amy M Scurlock, Atul N Shah, Sayantani B Sindher, Stephen Tilles, Brian P Vickery, Julie Wang, Hugh H Windom, Matthew Greenhawt

Faculty, Staff and Students Publications

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process.

OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form.

METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was …

Atp1a3 Disease Spectrum Includes Paroxysmal Weakness And Encephalopathy Not Triggered By Fever, Chetan Immanneni, Daniel Calame, Song Jiao, Lisa T Emrick, Miguel Holmgren, Sho T Yano

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: Heterozygous pathogenic variants in ATP1A3, which encodes the catalytic alpha subunit of neuronal Na+/K+-ATPase, cause primarily neurologic disorders with widely variable features that can include episodic movement deficits. One distinctive presentation of ATP1A3-related disease is recurrent fever-triggered encephalopathy. This can occur with generalized weakness and/or ataxia and is described in the literature as relapsing encephalopathy with cerebellar ataxia. This syndrome displays genotype-phenotype correlation with variants at p.R756 causing temperature sensitivity of ATP1A3. We report clinical and in vitro functional evidence for a similar phenotype not triggered by fever but associated with protein loss-of-function.

METHODS: We …

Unswitched Memory B Cell Deficiency In Children With Sickle Cell Disease And Response To Pneumococcal Polysaccharide Vaccine, Venée N Tubman, Daniel Maysonet, Norma Estrada, Tripti Halder, Lindsey Ramos, Sameera Bhamidipati, Alexandre F Carisey, Charles G Minard, Carl E Allen

Faculty, Staff and Students Publications

Early mortality in sickle cell disease (SCD) is attributed to increased infections due to loss of splenic function. Marginal zone B cells are important for initial opsonization of pathogens and can be absent in spleen histopathology in SCD. The frequency of unswitched memory B cells (UMBC), the circulating correlate of marginal zone B cells, reflects the immunologic function of the spleen. We hypothesized that asplenia in SCD is associated with alterations in the peripheral blood lymphocyte population and explored whether UMBC deficiency was associated with a clinical phenotype. We analyzed B cell subsets and clinical history for 238 children with …

Cadherin-11 Targeted Cell-Specific Liposomes Enabled Skin Fibrosis Treatment By Inducing Apoptosis, Himanshu N Bhatt, Rimpy Diwan, Igor L Estevao, Rui Dong, Jennifer Smith, Chuan Xiao, Sandeep K Agarwal, Md Nurunnabi

Faculty, Staff and Students Publications

Continuous and aberrant activation of myofibroblasts is the hallmark of pathological fibrosis (e.g., abnormal wound healing). The deposition of excessive extracellular matrix (ECM) components alters or increases the stiffness of tissue and primarily accounts for multiple organ dysfunctions. Among various proteins, Cadherin-11 (CDH11) has been reported to be overexpressed on myofibroblasts in fibrotic tissues. Anti-apoptotic proteins such as (B cell lymphoma-2) (BCL-2) are also upregulated on myofibroblasts. Therefore, we hypothesize that CDH11 could be a targeted domain for cell-specific drug delivery and targeted inhibition of BCL-2 to ameliorate the development of fibrosis in the skin. To prove our hypothesis, we …

Convolutional Neural Networks To Study Contrast-Enhanced Magnetic Resonance Imaging-Based Skeletal Calf Muscle Perfusion In Peripheral Artery Disease, Bijen Khagi, Tatiana Belousova, Christina M Short, Addison A Taylor, Jean Bismuth, Dipan J Shah, Gerd Brunner

Faculty, Staff and Students Publications

Peripheral artery disease (PAD) is associated with impaired blood flow in the lower extremities and histopathologic changes of the skeletal calf muscles, resulting in abnormal microvascular perfusion. We studied the use of convolution neural networks (CNNs) to differentiate patients with PAD from matched controls using perfusion pattern features from contrast-enhanced magnetic resonance imaging (CE-MRI) of the skeletal calf muscles. We acquired CE-MRI based skeletal calf muscle perfusion in 56 patients (36 patients with PAD and 20 matched controls). Microvascular perfusion imaging was performed after reactive hyperemia at the midcalf level, with a temporal resolution of 409 ms. We analyzed perfusion …

Efemp1 Haploinsufficiency Causes A Marfan-Like Hereditary Connective Tissue Disorder, Irman Forghani, Steven H Lang, Matthew J Rodier, Stephanie A Bivona, Alejo A Morales, Stephan Zuchner, Guney Bademci, Mustafa Tekin

Faculty, Staff and Students Publications

Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele …

Seeing Beyond Reality: Considering The Impact Of Mainstream Virtual Reality Adoption On Ocular Health And The Evolving Role Of Ophthalmologists, Venkata Soumith Jonnakuti, Benjamin Jay Frankfort

Faculty, Staff and Students Publications

No abstract provided.

Comparison Of Cefiderocol In-Vitro Susceptibility Testing Modalities, Nicholas S Teran, Linh Vuong, Kady Phe, Todd M Lasco, William R Miller, Vincent H Tam

Faculty, Staff and Students Publications

No abstract provided.

Anoctamin 4 Defines Glucose-Inhibited Neurons In The Ventromedial Hypothalamus, Longlong Tu, Yanlin He, Yong Xu

Faculty, Staff and Students Publications

No abstract provided.

Neighborhood-Level Disadvantage And Delayed Adjuvant Therapy In Head And Neck Cancer, Evan M Graboyes, Joshua Lee Cagle, Salma Ramadan, Kavita Prasad, Flora Yan, John Pearce, Angela L Mazul, Jean-Sebastien Anoma, Elizabeth G Hill, Bhisham S Chera, Sidharth V Puram, Ryan Jackson, Vlad C Sandulache, Samantha Tam, Michael C Topf, Russel Kahmke, Nosayaba Osazuwa-Peters, Brian Nussenbaum, Anthony J Alberg, Katherine R Sterba, Chanita Hughes Halbert

Faculty, Staff and Students Publications

Importance: For patients with head and neck squamous cell carcinoma (HNSCC), initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery is recommended by the National Comprehensive Cancer Network Guidelines and the Commission on Cancer. Although individual-level measures of socioeconomic status are associated with receipt of timely, guideline-adherent PORT, the role of neighborhood-level disadvantage has not been examined.

Objective: To characterize the association of neighborhood-level disadvantage with delays in receiving PORT.

Design, setting, and participants: This retrospective cohort study included 681 adult patients with HNSCC undergoing curative-intent surgery and PORT from 2018 to 2020 at 4 US academic medical …

Serum Extracellular Vesicle Protein Profiling For Prediction Of Corneal Transplant Rejection, Hyun Ju Lee, Eun-Hye Bae, Jong Min Choi, Hyemee Kim, Hyeon Ji Kim, Heather Barreda, Sung Yun Jung, Joo Youn Oh, Ryang Hwa Lee

Faculty, Staff and Students Publications

Background: Corneal transplantation is the most common transplant procedure worldwide. Despite immune and angiogenic privilege of the cornea, 50% to 70% of corneal transplants fail in high-risk recipients, primarily because of immune rejection. Therefore, it is crucial to identify predictive biomarkers of rejection to improve transplant survival.

Methods: In search for predictive biomarkers, we performed proteomics analysis of serum extracellular vesicles (EVs) in a fully major histocompatibility complex-mismatched (C57BL/6-to-BALB/c) murine corneal transplantation model, wherein 50% of transplants undergo rejection by day 28 following transplantation.

Results: Our time course study revealed a decrease in the number of serum EVs on day …

Expanding The Phenotype Of Ppp1r21-Related Neurodevelopmental Disorder, Mohammed Almannai, Dana Marafi, Maha S Zaki, Reza Maroofian, Stephanie Efthymiou, Nebal Waill Saadi, Bilal Filimban, Hormos Salimi Dafsari, Fatima Rahman, Shazia Maqbool, Eissa Faqeih, Fuad Al Mutairi, Hind Alsharhan, Omar Abdelaty, Saadoun Bin-Hasan, Ruizhi Duan, Mahmoud M Noureldeen, Alaa Alqattan, Henry Houlden, Jill V Hunter, Jennifer E Posey, James R Lupski, Ayman W El-Hattab

Faculty, Staff and Students Publications

PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of …

Grafting The Alfa Tag For Structural Studies Of Aquaporin Z, Lauren Stover, Hanieh Bahramimoghaddam, Lie Wang, Samantha Schrecke, Gaya P Yadav, Ming Zhou, Arthur Laganowsky

Faculty, Staff and Students Publications

Aquaporin Z (AqpZ), a bacterial water channel, forms a tetrameric complex and, like many other membrane proteins, activity is regulated by lipids. Various methods have been developed to facilitate structure determination of membrane proteins, such as the use of antibodies. Here, we graft onto AqpZ the ALFA tag (AqpZ-ALFA), an alpha helical epitope, to make use of the high-affinity anti-ALFA nanobody (nB). Native mass spectrometry reveals the AqpZ-ALFA fusion forms a stable, 1:1 complex with nB. Single-particle cryogenic electron microscopy studies reveal the octameric (AqpZ-ALFA)

Associations Of Testosterone And Related Hormones With All-Cause And Cardiovascular Mortality And Incident Cardiovascular Disease In Men : Individual Participant Data Meta-Analyses, Bu B Yeap, Ross J Marriott, Girish Dwivedi, Robert J Adams, Leen Antonio, Christie M Ballantyne, Douglas C Bauer, Shalender Bhasin, Mary L Biggs, Peggy M Cawthon, David J Couper, Adrian S Dobs, Leon Flicker, David J Handelsman, Graeme J Hankey, Anke Hannemann, Robin Haring, Benjumin Hsu, Sean A Martin, Alvin M Matsumoto, Dan Mellström, Claes Ohlsson, Terence W O'Neill, Eric S Orwoll, Matteo Quartagno, Molly M Shores, Antje Steveling, Åsa Tivesten, Thomas G Travison, Dirk Vanderschueren, Gary A Wittert, Frederick C W Wu, Kevin Murray

Faculty, Staff and Students Publications

Background: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial.

Purpose: To clarify associations of sex hormones with these outcomes.

Data sources: Systematic literature review to July 2019, with bridge searches to March 2024.

Study selection: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up.

Data extraction: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, …

High Lipoprotein(A): Actionable Strategies For Risk Assessment And Mitigation, Gissette Reyes-Soffer, Calvin Yeang, Erin D Michos, Wess Boatwright, Christie M Ballantyne

Faculty, Staff and Students Publications

High levels of lipoprotein(a) [Lp(a)] are causal for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is the most prevalent inherited dyslipidemia and strongest genetic ASCVD risk factor. This risk persists in the presence of at target, guideline-recommended, LDL-C levels and adherence to lifestyle modifications. Epidemiological and genetic evidence supporting its causal role in ASCVD and calcific aortic stenosis continues to accumulate, although various facets regarding Lp(a) biology (genetics, pathophysiology, and expression across race/ethnic groups) are not yet fully understood. The evolving nature of clinical guidelines and consensus statements recommending universal measurements of Lp(a) and the scientific data supporting its role in multiple …