Medical Specialties Commons^™

Synaptic Fidelity For Drug Development: Is It Time To Move Beyond Glutamate Release And Receptors?, Chadi G Abdallah, Amanda J F Tamman

Faculty, Staff and Students Publications

No abstract provided.

A Content Analysis Of Self-Report Child Anxiety Measures, Minjee Kook, Jane W Clinger, Eric Lee, Sophie C Schneider, Eric A Storch, Andrew G Guzick

Faculty, Staff and Students Publications

A clear understanding of the item content of psychological assessments is critical but often overlooked. This study describes the content overlap of seven commonly used and psychometrically validated measures of anxiety among children and adolescents. Symptom codes were created for all items across measures and items were sorted by these codes, which all fell into specific symptom categories. We conducted two analyses of all items: a "bottom-up" content categorization approach, which used symptom categories that were developed during this study, and a "top-down" DSM-5 categorization which mapped items onto symptoms of anxiety disorders in the DSM-5. Findings reveal a weak …

Comparison Of Open Thoracoabdominal Repair For Chronic Aortic Dissections And Aneurysms, Ian O Cook, Susan Y Green, Kimberly R Rebello, Qianzi Zhang, Veronica A Glover, Rodrigo Zea-Vera, Marc R Moon, Scott A Lemaire, Joseph S Coselli

Faculty, Staff and Students Publications

Objective: Aortic dissection is common in patients undergoing open surgical repair of thoracoabdominal aortic aneurysms (TAAAs). Most often, dissection is chronic and is associated with progressive aortic dilatation. Because contemporary outcomes in chronic dissection are not clearly understood, we compared patient characteristics and outcomes after open TAAA repair between patients with chronic dissection and those with non-dissection aneurysm.

Methods: We retrospectively analyzed data from 3470 open TAAA repairs performed in a single practice. Operations were for non-dissection aneurysm in 2351 (67.8%) and chronic dissection in 1119 (32.2%). Outcomes included operative mortality and adverse events, a composite variable comprising operative death …

Fathers In The United States Are Getting Older, Larry I Lipshultz, Blair T Stocks

Faculty, Staff and Students Publications

No abstract provided.

Glutathione Dynamics In Subcellular Compartments And Implications For Drug Development, Hanfeng Lin, Lingfei Wang, Xiqian Jiang, Jin Wang

Faculty, Staff and Students Publications

Glutathione (GSH) is a pivotal tripeptide antioxidant essential for maintaining cellular redox homeostasis and regulating diverse cellular processes. Subcellular compartmentalization of GSH underscores its multifaceted roles across various organelles including the cytosol, mitochondria, endoplasmic reticulum, and nucleus, each exhibiting distinct regulatory mechanisms. Perturbations in GSH dynamics contribute to pathophysiological conditions, emphasizing the clinical significance of understanding its intricate regulation. This review consolidates current knowledge on subcellular GSH dynamics, highlighting its implications in drug development, particularly in covalent drug design and antitumor strategies targeting intracellular GSH levels. Challenges and future directions in deciphering subcellular GSH dynamics are discussed, advocating for innovative …

Asynchronous Online Training Increased Knowledge, Confidence, And Intent To Screen And Treat Substance Use Disorders Among Primary Care Clinicians Practicing In Texas, Roger Zoorob, Sung In Kim-Vences, Jacqueline M Hirth, Kylie Schaper, Larissa Grigoryan, Sandra Gonzalez, Alicia Kowalchuk

Faculty, Staff and Students Publications

Introduction: Despite increasing prevalence of substance use disorders (SUD), few patients are diagnosed and treated in primary care settings. This study evaluated changes in knowledge, confidence, and intention to implement screening and brief intervention (SBI) and SUD treatment after clinicians participated in an asynchronous online education course.

Methods: A self-selected sample of primary care clinicians in Texas participated in online SBI and SUD education March 2021-July 2023. Baseline and post-training surveys evaluated changes in knowledge, confidence, and intent to implement SBI and SUD treatment. Changes were compared using paired t-tests. Multivariable linear regression examined factors potentially associated with confidence and …

A Rare Variant In Mrc2 Associated With Familial Supraventricular Tachycardia And Wolff-Parkinson-White Syndrome, Adam S Potter, Christina Y Miyake, Claudia Gonzaga-Jauregui, Yuriana Aguilar-Sanchez, Mohit M Hulsurkar, Satadru K Lahiri, Lucia M Moreira, Neelam Mehta, Mahshid S Azamian, James R Lupski, Svetlana Reilly, Seema R Lalani, Xander H T Wehrens

Faculty, Staff and Students Publications

Background: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model.

Methods: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, …

2023 American College Of Rheumatology (Acr)/American College Of Chest Physicians (Chest) Guideline For The Screening And Monitoring Of Interstitial Lung Disease In People With Systemic Autoimmune Rheumatic Diseases, Sindhu R Johnson, Elana J Bernstein, Marcy B Bolster, Jonathan H Chung, Sonye K Danoff, Michael D George, Dinesh Khanna, Gordon Guyatt, Reza D Mirza, Rohit Aggarwal, Aberdeen Allen, Shervin Assassi, Lenore Buckley, Hassan A Chami, Douglas S Corwin, Paul F Dellaripa, Robyn T Domsic, Tracy J Doyle, Catherine Marie Falardeau, Tracy M Frech, Fiona K Gibbons, Monique Hinchcliff, Cheilonda Johnson, Jeffrey P Kanne, John S Kim, Sian Yik Lim, Scott Matson, Zsuzsanna H Mcmahan, Samantha J Merck, Kiana Nesbitt, Mary Beth Scholand, Lee Shapiro, Christine D Sharkey, Ross Summer, John Varga, Anil Warrier, Sandeep K Agarwal, Danielle Antin-Ozerkis, Bradford Bemiss, Vaidehi Chowdhary, Jane E Dematte D'Amico, Robert Hallowell, Alicia M Hinze, Patil A Injean, Nikhil Jiwrajka, Elena K Joerns, Joyce S Lee, Ashima Makol, Gregory C Mcdermott, Jake G Natalini, Justin M Oldham, Didem Saygin, Kimberly Showalter Lakin, Namrata Singh, Joshua J Solomon, Jeffrey A Sparks, Marat Turgunbaev, Samera Vaseer, Amy Turner, Stacey Uhl, Ilya Ivlev

Faculty, Staff and Students Publications

Objective: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease.

Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and …

The Emerging Role Of Glucagon-Like Peptide-1 Receptor Agonists For The Treatment Of Metabolic Dysfunction-Associated Steatohepatitis, Layla A Abushamat, Pir Ahmad Shah, Robert H Eckel, Stephen A Harrison, Diana Barb

Faculty, Staff and Students Publications

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 in 3-4 adult individuals and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Insulin resistance plays a central role in MASLD/MASH pathophysiology with higher rates of MASLD (2 in 3) and MASH with fibrosis (1 in 5) in adults with obesity and diabetes. This review summarizes the role of glucagon-like peptide-1 receptor agonists in treating MASLD/MASH. Although not approved by the Food and Drug Administration for the treatment of MASLD, this class of medication is available to treat obesity and type 2 diabetes and has been shown to reverse steatohepatitis, reduce …

Molecular And Physiological Changes In The Spacex Inspiration4 Civilian Crew, Christopher W Jones, Eliah G Overbey, Jerome Lacombe, Adrian J Ecker, Cem Meydan, Krista Ryon, Braden Tierney, Namita Damle, Matthew Mackay, Evan E Afshin, Jonathan Foox, Jiwoon Park, Theodore M Nelson, Mir Suhail Mohamad, Syed Gufran Ahmad Byhaqui, Burhan Aslam, Ummer Akbar Tali, Liaqun Nisa, Priya V Menon, Chintan O Patel, Sharib A Khan, Doug J Ebert, Aaron Everson, Michael C Schubert, Nabila N Ali, Mallika S Sarma, Jangkeun Kim, Nadia Houerbi, Kirill Grigorev, J Sebastian Garcia Medina, Alexander J Summers, Jian Gu, John A Altin, Ali Fattahi, Mohammad I Hirzallah, Jimmy H Wu, Alexander C Stahn, Afshin Beheshti, Remi Klotz, Veronica Ortiz, Min Yu, Laura Patras, Irina Matei, David Lyden, Ari Melnick, Neil Banerjee, Sean Mullane, Ashley S Kleinman, Michael Loesche, Anil S Menon, Dorit B Donoviel, Emmanuel Urquieta, Jaime Mateus, Ashot E Sargsyan, Mark Shelhamer, Frederic Zenhausern, Eric M Bershad, Mathias Basner, Christopher E Mason

Faculty, Staff and Students Publications

Human spaceflight has historically been managed by government agencies, such as in the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first all-civilian crew to low Earth orbit, which included the youngest American astronaut (aged 29), new in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables and immune profiling), ocular alignment measurements and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular …

Trajectory Of C-Reactive Protein And Incident Heart Failure In Black Adults: The Jackson Heart Study, Arsalan Hamid, Wondwosen K Yimer, Adebamike A Oshunbade, Muhammad Shahzeb Khan, Daisuke Kamimura, Rodney K Kipchumba, Ambarish Pandey, Donald Clark, Robert J Mentz, Ervin R Fox, Jarett D Berry, R Brandon Stacey, Amil Shah, Adolfo Correa, Salim S Virani, Javed Butler, Michael E Hall

Faculty, Staff and Students Publications

Background: Increased hsCRP (high-sensitivity C-reactive protein), a marker of inflammation, is associated with incident cardiovascular events. We aim to determine whether the baseline or trajectory of hsCRP levels over time predicts incident heart failure (HF) hospitalization.

Methods: JHS (Jackson Heart Study) participants' (n=3920 Black adults) hsCRP levels were measured over 3 visits (from 2000 to 2013). We assessed the association of hsCRP at baseline (visit 1) with incident HF hospitalization using Cox proportional hazards models. Furthermore, we assessed the association of the trajectory of hsCRP over repeated measurements (visits 1-3) with incident HF using joint models. Hazard ratios are reflective …

Individual Variation In The Distribution Of Apolipoprotein B Levels Across The Spectrum Of Ldl-C Or Non-Hdl-C Levels, Ahmed Sayed, Eric D Peterson, Salim S Virani, Allan D Sniderman, Ann Marie Navar

Faculty, Staff and Students Publications

Importance: Although apolipoprotein B (apoB) is a superior marker of lipid-related risk compared with low-density lipoprotein cholesterol (LDL-C), few data exist to translate the goals and thresholds from LDL-C to their apoB equivalent. In addition, although current American College of Cardiology/American Heart Association guidelines provide a relative indication for apoB measurement among individuals with hypertriglyceridemia, whether discordance is limited to those subgroups is unknown.

Objectives: To assess the variability in apoB level across the spectrum of LDL-C or non-high-density lipoprotein cholesterol (non-HDL-C) levels and evaluate whether discordance between apoB and LDL-C or non-HDL-C is limited to specifiable subgroups.

Design, setting, …

A Lexicon For First-Trimester Us: Society Of Radiologists In Ultrasound Consensus Conference Recommendations, Shuchi K Rodgers, Mindy M Horrow, Peter M Doubilet, Mary C Frates, Anne Kennedy, Rochelle Andreotti, Kristyn Brandi, Laura Detti, Sarah K Horvath, Aya Kamaya, Atsuko Koyama, Penelope Chun Lema, Katherine E Maturen, Tara Morgan, Sarah G Običan, Kristen Olinger, Roya Sohaey, Suneeta Senapati, Lori M Strachowski

Faculty, Staff and Students Publications

The Society of Radiologists in Ultrasound convened a multisociety panel to develop a first-trimester US lexicon based on scientific evidence, societal guidelines, and expert consensus that would be appropriate for imagers, clinicians, and patients. Through a modified Delphi process with consensus of at least 80%, agreement was reached for preferred terms, synonyms, and terms to avoid. An intrauterine pregnancy (IUP) is defined as a pregnancy implanted in a normal location within the uterus. In contrast, an ectopic pregnancy (EP) is any pregnancy implanted in an abnormal location, whether extrauterine or intrauterine, thus categorizing cesarean scar implantations as EPs. The term …

Editorial Comment: Diversity And Disparities In Orthopaedic Surgery: Update 2024, Kimberly J Templeton, Melvyn A Harrington

Faculty, Staff and Students Publications

No abstract provided.

Challenges Of Insulin-Like Growth Factor-1 Testing, Rongrong Huang, Junyan Shi, Ruhan Wei, Jieli Li

Faculty, Staff and Students Publications

Insulin-like growth factor 1 (IGF-1), primarily synthesized in the liver, was initially discovered due to its capacity to replicate the metabolic effects of insulin. Subsequently, it emerged as a key regulator of the actions of growth hormone (GH), managing critical processes like cell proliferation, differentiation, and apoptosis. Notably, IGF-1 displays a longer half-life compared to GH, making it less susceptible to factors that may affect GH concentrations. Consequently, the measurement of IGF-1 proves to be more specific and sensitive when diagnosing conditions such as acromegaly or GH deficiency. The recognition of the existence of IGFBPs and their potential to interfere …

An Innovative Approach To Aligning Healthcare With What Matters Most To Patients: A Hybrid Type 1 Trial Protocol Of Patient Priorities Care For Older Adults With Multiple Chronic Conditions, Aanand D Naik, Mackenzie L Shanahan, Lilian Dindo, Marcia C Mecca, Jennifer Arney, Amber B Amspoker, Sheena Wydermyer, Jack Banks, Richard L Street, Lea Kiefer, Maria Zenoni, Tracey Rosen, Raquel D Gonzalez, Angela Catic, Terri R Fried

Faculty, Staff and Students Publications

Background: Providing healthcare for older adults with multiple chronic conditions (MCC) is challenging. Polypharmacy and complex treatment plans can lead to high treatment burden and risk for adverse events. For clinicians, managing the complexities of patients with MCC leaves little room to identify what matters and align care options with patients' health priorities. New care approaches are needed to navigate these challenges. In this clinical trial, we evaluate implementation and effectiveness outcomes of an innovative, structured, patient-centered care approach (Patient Priorities Care; PPC) for reducing treatment burden and aligning health care decisions with the health priorities of older adults with …

Validation Of Electronic Diagnostic Codes For Rapid Eye Movement Sleep Behavior Disorder, Melissa B Jones, Carlos H Schenck, Mehrnaz Azarian, Ricardo E Jorge, Amir Sharafkhaneh, Javad Razjouyan

Faculty, Staff and Students Publications

We investigated the accuracy of International Classification of Diseases (ICD) codes for the identification of veterans with rapid eye movement sleep behavior disorder. The charts of 139 randomly sampled veterans with ≥ 1 ICD-9 and ICD-10 code(s) for rapid eye movement sleep behavior disorder were reviewed for documentation of a suspected, previous, or current diagnosis; clinical symptoms; and/or empiric treatments for this disorder. Notably, 71 (51.1%) patients with rapid eye movement sleep behavior disorder electronic diagnoses had not undergone polysomnography, and 29 (20.9%) had polysomnography reports without commentary on rapid eye movement sleep without atonia. Sleep centers are therefore encouraged …

Safety And Efficacy Outcomes Of Early Cessation Of Anti-Pd1 Therapy In Patients 80 Years Or Older: A Retrospective Cohort Study, Kylie Fletcher, Alessio Cortellini, Teja Ganta, Roma Kankaria, Haocan Song, Fei Ye, Rebecca Irlmeier, Neha Debnath, Anwaar Saeed, Maluki Radford, Asrar Alahmadi, Akiva Diamond, Christopher Hoimes, Carolyn J Presley, Dwight H Owen, Sarah Abou Alaiwi, Amin H Nassar, Giuseppe Lamberti, Fabiana Perrone, Sebastiano Buti, Raffaele Giusti, Marco Filetti, Vito Vanella, Domenico Mallardo, Tamara A Sussman, Domenico Galetta, Foteini Kalofonou, Ella Daniels, Paolo A Ascierto, David J Pinato, Caroline Nebhan, Stephanie Berg, Toni K Choueiri, Thomas U Marron, Yinghong Wang, Abdul Rafeh Naqash, Douglas B Johnson

Faculty, Staff and Students Publications

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (< 12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8-97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of < 12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy.

Histone Serotonylation Regulates Ependymoma Tumorigenesis, Hsiao-Chi Chen, Peihao He, Malcolm Mcdonald, Michael R Williamson, Srinidhi Varadharajan, Brittney Lozzi, Junsung Woo, Dong-Joo Choi, Debosmita Sardar, Emmet Huang-Hobbs, Hua Sun, Siri M Ippagunta, Antrix Jain, Ganesh Rao, Thomas E Merchant, David W Ellison, Jeffrey L Noebels, Kelsey C Bertrand, Stephen C Mack, Benjamin Deneen

Faculty, Staff and Students Publications

Bidirectional communication between tumors and neurons has emerged as a key facet of the tumor microenvironment that drives malignancy1,2. Another hallmark feature of cancer is epigenomic dysregulation, where alterations in gene expression influences cell states and interactions with the tumor microenvironment3. Ependymoma (EPN) is a pediatric brain tumor that relies on epigenomic remodeling to engender malignancy4,5; how these epigenetic mechanisms intersect with extrinsic neuronal signaling during EPN tumor progression is unknown. Here we show that activity of serotonergic neurons regulates EPN tumorigenesis, while serotonin itself also serves as an activating …

Low Vitamin D Levels In Patients With Symptoms Of Gastroparesis: Relationships With Nausea And Vomiting, Gastric Emptying And Gastric Myoelectrical Activity, Kenneth L Koch, Henry P Parkman, Katherine P Yates, Mark L Van Natta, Madhusudan Grover, Gianrico Farrugia, Thomas L Abell, Richard W Mccallum, Irene Sarosiek, Braden Kuo, Robert J Shulman, Laura Miriel, James Tonascia, Pankaj J Pasricha

Faculty, Staff and Students Publications

Patients with gastroparesis (Gp) often have diets deficient in calories, electrolytes, and vitamins. Vitamin D levels have been reported to be low in some patients with Gp but has not been systematically studied.

AIMS: To determine vitamin D levels and relationships among symptoms, gastric emptying and gastric myoelectrical activity (GMA) in patients with symptoms of Gp.

METHODS: 25-hydroxy-vitamin D was measured in patients at enrollment in the Gastroparesis Clinical Consortium Registry. Gastroparesis Cardinal Symptoms Index (GCSI), gastric emptying, and GMA before and after water load satiety test (WLST) were measured. GMA, expressed as percentage distribution of activity in normal and …

Structure Of Adenylyl Cyclase 5 In Complex With Gβγ Offers Insights Into Adcy5-Related Dyskinesia, Yu-Chen Yen, Yong Li, Chun-Liang Chen, Thomas Klose, Val J Watts, Carmen W Dessauer, John J G Tesmer

Faculty, Staff and Student Publications

The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Gαs, but their response to Gβγ regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C1b) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based …

Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial, Jason L Sperry, Francis X Guyette, Bedda L Rosario-Rivera, Matthew E Kutcher, Lucy Z Kornblith, Bryan A Cotton, Chad T Wilson, Kenji Inaba, Eva V Zadorozny, Laura E Vincent, Ashley M Harner, Emily T Love, Joseph E Doherty, Joseph Cuschieri, Aaron E Kornblith, Erin E Fox, Yu Bai, Marcus K Hoffman, Catherine P Seger, Jay Hudgins, Sheila Mallett-Smith, Matthew D Neal, Christine M Leeper, Philip C Spinella, Mark H Yazer, Stephen R Wisniewski, Cold Stored Platelet For Hemorrhagic Shock (Crisp-Hs) Study Group

Faculty, Staff and Student Publications

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock.

BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury.

METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus …

Parkinson’S Disease Variant Detection And Disclosure: Pd Generation, A North American Study, Lola Cook, Jennifer Verbrugge, Tae-Hwi Schwantes-An, Jeanine Schulze, Tatiana Foroud, Anne Hall, Karen S Marder, Ignacio F Mata, Niccolò E Mencacci, Martha A Nance, Michael A Schwarzschild, Tanya Simuni, Susan Bressman, Anne-Marie Wills, Hubert H Fernandez, Irene Litvan, Kelly E Lyons, Holly A Shill, Carlos Singer, Thomas F Tropea, Nora Vanegas Arroyave, Janfreisy Carbonell, Rossy Cruz Vicioso, Linn Katus, Joseph F Quinn, Priscila D Hodges, Yan Meng, Samuel P Strom, Cornelis Blauwendraat, Katja Lohmann, Cynthia Casaceli, Shilpa C Rao, Kamalini Ghosh Galvelis, Anna Naito, James C Beck, Roy N Alcalay

Faculty, Staff and Students Publications

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's …

Fetal Malrotation With Midgut Volvulus: Prenatal Diagnosis And Planning, Jai Sidpra, Sniya Sudhakar, Asthik Biswas, Flavia Massey, Valentina Turchetti, Tracy Lau, Edward Cook, Javeria Raza Alvi, Hasnaa M Elbendary, Jerry L Jewell, Antonella Riva, Alessandro Orsini, Aglaia Vignoli, Zara Federico, Jessica Rosenblum, An-Sofie Schoonjans, Matthias De Wachter, Ignacio Delgado Alvarez, Ana Felipe-Rucián, Nourelhoda A Haridy, Shahzad Haider, Mashaya Zaman, Selina Banu, Najwa Anwaar, Fatima Rahman, Shazia Maqbool, Rashmi Yadav, Vincenzo Salpietro, Reza Maroofian, Rajan Patel, Rupa Radhakrishnan, Sanjay P Prabhu, Klaske Lichtenbelt, Helen Stewart, Yoshiko Murakami, Ulrike Löbel, Felice D'Arco, Emma Wakeling, Wendy Jones, Eleanor Hay, Sanjay Bhate, Thomas S Jacques, David M Mirsky, Matthew T Whitehead, Maha S Zaki, Tipu Sultan, Pasquale Striano, Anna C Jansen, Maarten Lequin, Linda S De Vries, Mariasavina Severino, Andrew C Edmondson, Lara Menzies, Philippe M Campeau, Henry Houlden, Amy Mctague, Stephanie Efthymiou, Kshitij Mankad

Faculty, Staff and Students Publications

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or …

A Group 3 Medulloblastoma Stem Cell Program Is Maintained By Otx2-Mediated Alternative Splicing, Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D Hendrikse, Paul Layug, Victor Gordon, Kimberly A Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M Gonzales, Gareth Palidwor, Christopher J Porter, Stéphane Richard, Tanveer Sharif, Kathleen J Millen, Brad W Doble, Michael D Taylor, Tamra E Werbowetski-Ogilvie

Faculty, Staff and Students Publications

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among …

Bigh3 Mediates Apoptosis And Gap Junction Failure In Osteocytes During Renal Cell Carcinoma Bone Metastasis Progression, Tianhong Pan, Fengshuo Liu, Xiaoxin Hao, Shubo Wang, Murtaza Wasi, Jian H Song, Valerae O Lewis, Patrick P Lin, Bryan Moon, Justin E Bird, Theocharis Panaretakis, Sue-Hwa Lin, Danielle Wu, Mary C Farach-Carson, Liyun Wang, Ningyan Zhang, Zhiqiang An, Xiang H-F Zhang, Robert L Satcher

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens …

Detection Of Soil-Transmitted Helminths And Schistosoma Spp By Nucleic Acid Amplification Test: Results Of The First 5 Years Of The Only International External Quality Assessment Scheme, Annemiek H J Schutte, Rob Koelewijn, Sitara S R Ajjampur, Bruno Levecke, James S Mccarthy, Rojelio Mejia, Steven A Williams, Jaco J Verweij, Lisette Van Lieshout, Jaap J Van Hellemond

Faculty, Staff and Students Publications

BACKGROUND: Infections with soil-transmitted helminths (STH) and schistosomiasis (SCH) result in a significant global health burden, particularly in rural communities in low and middle-income countries. While microscopy remains the primary diagnostic method for STH and SCH in resource-limited settings, nucleic acid amplification tests (NAATs) are gaining prominence as tools for evaluation of public health control programs in endemic countries, and individual diagnosis in high-income countries. Despite the high sensitivity and specificity of NAATs, previous research has highlighted inter-laboratory variations, both in technical and clinical performance, justifying the need for continuous proficiency testing.

METHODOLOGY: Results from 5 rounds over a 5-year …

Circuit-Specific Deep Brain Stimulation Provides Insights Into Movement Control., Aryn H Gittis, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Deep brain stimulation (DBS), a method in which electrical stimulation is delivered to specific areas of the brain, is an effective treatment for managing symptoms of a number of neurological and neuropsychiatric disorders. Clinical access to neural circuits during DBS provides an opportunity to study the functional link between neural circuits and behavior. This review discusses how the use of DBS in Parkinson's disease and dystonia has provided insights into the brain networks and physiological mechanisms that underlie motor control. In parallel, insights from basic science about how patterns of electrical stimulation impact plasticity and communication within neural circuits are …

Preeclampsia In The Context Of Covid-19: Mechanisms, Pathophysiology, And Clinical Outcomes, Guilherme M Nobrega, Brittany R Jones, Indira U Mysorekar, Maria Laura Costa

Center on Aging Staff Publications

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the global COVID-19 pandemic, significantly impacting the health of pregnant women. Obstetric populations, already vulnerable, face increased morbidity and mortality related to COVID-19, aggravated by preexisting comorbidities. Recent studies have shed light on the potential correlation between COVID-19 and preeclampsia (PE), a leading cause of maternal and perinatal morbidity worldwide, emphasizing the significance of exploring the relationship between these two conditions. Here, we review the pathophysiological similarities that PE shares with COVID-19, with a particular focus on severe COVID-19 cases and in PE-like syndrome cases related with …

Intestinal Crypt Apoptosis As An Orchestrator Of Necrotizing Enterocolitis: A New Mechanism?, Wei Yu, Aparna Venkatraman, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.