Medical Specialties Commons^™

Mastro I: Meta-Analysis And Systematic Review Of Thrombectomy Stent Retriever Outcomes: Comparing Functional, Safety And Recanalization Outcomes Between Embotrap, Solitaire And Trevo In Acute Ischemic Stroke, Osama O Zaidat, Shelly Ikeme, Sunil A Sheth, Shinichi Yoshimura, Xin-Guang Yang, Waleed Brinjikji, David F Kallmes, Patrick Brouwer, John Pederson, Ranita Tarchand, Annie Steffenson, Kevin M Kallmes, Jillienne Touchette, Tommy Andersson

Faculty, Staff and Student Publications

Aims:

Stent-retriever (SR) thrombectomy has demonstrated superior outcomes in patients with acute ischemic stroke compared with medical management alone, but differences among SRs remain unexplored. We conducted a Systematic Review/Meta-Analysis to compare outcomes between three SRs: EmboTrap^®, Solitaire™, and Trevo^®.

Methods:

We conducted a PRISMA-compliant Systematic Review among English-language studies published after 2014 in PubMed/MEDLINE that reported SRs in ≥25 patients. Functional and safety outcomes included 90-day modified Rankin scale (mRS 0-2), mortality, symptomatic intracranial hemorrhage (sICH), and embolization to new territory (ENT). Recanalization outcomes included modified thrombolysis in cerebral infarction (mTICI) and first-pass recanalization (FPR). …

Assessment Of Heterogeneity Amongaassessment Of Heterogeneity Among Participants In The Parkinson’S Progression Markers Initiative Cohort Using Α-Synuclein Seed Amplification: A Cross-Sectional Study Participants In The Parkinson's Progression Markers Initiative Cohort Using Α-Synuclein Seed Amplification: A Cross-Sectional Study, Andrew Siderowf, Luis Concha-Marambio, David-Erick Lafontant, Carly M Farris, Yihua Ma, Paula A Urenia, Hieu Nguyen, Roy N Alcalay, Lana M Chahine, Tatiana Foroud, Douglas Galasko, Karl Kieburtz, Kalpana Merchant, Brit Mollenhauer, Kathleen L Poston, John Seibyl, Tanya Simuni, Caroline M Tanner, Daniel Weintraub, Aleksandar Videnovic, Seung Ho Choi, Ryan Kurth, Chelsea Caspell-Garcia, Christopher S Coffey, Mark Frasier, Luis M A Oliveira, Samantha J Hutten, Todd Sherer, Kenneth Marek, Claudio Soto

Faculty, Staff and Student Publications

BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups.

METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) …

Translational Studies Using The Malt1 Inhibitor (S)-Mepazine To Induce Treg Fragility And Potentiate Immune Checkpoint Therapy In Cancer, Mauro Di Pilato, Yun Gao, Yi Sun, Amina Fu, Carina Grass, Thomas Seeholzer, Regina Feederle, Irina Mazo, Samuel W Kazer, Kevin Litchfield, Ulrich H Von Andrian, Thorsten R Mempel, Russell W Jenkins, Daniel Krappmann, Peter Keller

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Introduction

Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT).

Methods

We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to …

Major Differences In Transcriptional Alterations In Dorsal Root Ganglia Between Spinal Cord Injury And Peripheral Neuropathic Pain Models, Raquel Cuevas-Diaz Duran, Yong Li, Anibal Garza Carbajal, Yanan You, Carmen W Dessauer, Jiaqian Wu, Edgar T Walters

Faculty, Staff and Student Publications

Chronic, often intractable, pain is caused by neuropathic conditions such as traumatic peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for neural regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs …

Population Pharmacokinetic And Pharmacodynamic Modeling Of Fesoterodine In Pediatric Patients With Neurogenic Detrusor Overactivity, Yamato Sano, Satoshi Shoji, Mohamed Shahin, Kevin Sweeney, Amanda Darekar, Bimal K Malhotra

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BACKGROUND AND OBJECTIVE: Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatric patients. This work aimed to characterize the population pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine) and its pharmacokinetic/pharmacodynamic relationship in pediatric patients with OAB or NDO following administration of fesoterodine.

METHODS: 5-HMT plasma concentrations from 142 participants of age ≥ 6 years were analyzed, and a nonlinear mixed-effects model was developed. Weight-based simulations of 5-HMT exposure and maximum cystometric capacity (MCC) were conducted using the final models.

RESULTS: A one-compartment model …

Bayesess: A Tool For Quantifying The Impact Of Parametric Priors In Bayesian Analysis, Jaejoon Song, Satoshi Morita, Ying-Wei Kuo, J Jack Lee

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Bayesian inference has become an attractive choice for scientists seeking to incorporate prior knowledge into their modeling framework. While the R community has been an important contributor in facilitating Bayesian statistical analyses, software to evaluate the impact of prior knowledge to such modeling framework has been lacking. In this article, we present BayesESS, a comprehensive, free, and open source R package for quantifying the impact of parametric priors in Bayesian analysis. We also introduce an accompanying web-based application for estimating and visualizing Bayesian effective sample size for purposes of conducting or planning Bayesian analyses.

Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Kyung Soo Park, Andrew Kennedy, Xingwu Zhou, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the …

Unlocking The Promise Of Systemic Sting Agonist For Cancer Immunotherapy, Xiaoqi Sun, Xingwu Zhou, Yu Leo Lei, James J Moon

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Stimulator of interferon genes (STING) pathway is the key innate immune pathway involving in cancer immunity. Emerging new molecules and drug delivery systems have made systemic STING agonist immunotherapy possible and demonstrated efficient tumor eradication in preclinical studies. In this perspective, we will discuss the potential mechanisms of STING agonism as a multifaceted anti-cancer therapy and the pharmacological challenges associated with systemic delivery of STING agonists on the level of organs, tissues, cells, and intracellular compartments. We will present and discuss drug delivery strategies to address these challenges. New advances in the field can unlock the promise of systemic STING …

Genomic And Transcriptomic Analysis Of Checkpoint Blockade Response In Advanced Non-Small Cell Lung Cancer, Arvind Ravi, Matthew D Hellmann, Monica B Arniella, Mark Holton, Samuel S Freeman, Vivek Naranbhai, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron T Griffin, Natalie I Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick M Forde, Valsamo Anagnostou, Jonathan W Riess, Don L Gibbons, Nathan A Pennell, Vamsidhar Velcheti, Subba R Digumarthy, Mari Mino-Kenudson, Andrea Califano, John V Heymach, Roy S Herbst, Julie R Brahmer, Kurt A Schalper, Victor E Velculescu, Brian S Henick, Naiyer Rizvi, Pasi A Jänne, Mark M Awad, Andrew Chow, Benjamin D Greenbaum, Marta Luksza, Alice T Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin F Gainor

Faculty, Staff and Student Publications

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of …

Redox Phospholipidomics Discovers Pro-Ferroptotic Death Signals In A375 Melanoma Cells In Vitro And In Vivo, Yulia Y Tyurina, Alexandr A Kapralov, Vladimir A Tyurin, Galina Shurin, Andrew A Amoscato, Dhivyaa Rajasundaram, Hua Tian, Yuri L Bunimovich, Yulia Nefedova, William G Herrick, Ralph E Parchment, James H Doroshow, Hulya Bayir, Apurva K Srivastava, Valerian E Kagan

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Growing cancer cells effectively evade most programs of regulated cell death, particularly apoptosis. This necessitates a search for alternative therapeutic modalities to cause cancer cell's demise, among them - ferroptosis. One of the obstacles to using pro-ferroptotic agents to treat cancer is the lack of adequate biomarkers of ferroptosis. Ferroptosis is accompanied by peroxidation of polyunsaturated species of phosphatidylethanolamine (PE) to hydroperoxy- (-OOH) derivatives, which act as death signals. We demonstrate that RSL3-induced death of A375 melanoma cells in vitro was fully preventable by ferrostatin-1, suggesting their high susceptibility to ferroptosis. Treatment of A375 cells with RSL3 caused a significant …

Prioritizing Clinical Trial Quality Assurance For Photons And Protons: A Failure Modes And Effects Analysis (Fmea) Comparison, Paige A Taylor, Elizabeth Miles, Lone Hoffmann, Sarah M Kelly, Stephen F Kry, Ditte Sloth Møller, Hugo Palmans, Kamal Akbarov, Marianne C Aznar, Enrico Clementel, Coreen Corning, Rachel Effeney, Brendan Healy, Alisha Moore, Mitsuhiro Nakamura, Samir Patel, Maddison Shaw, Markus Stock, Joerg Lehmann, Catharine H Clark

Faculty, Staff and Student Publications

Background and purpose: The Global Clinical Trials RTQA Harmonization Group (GHG) set out to evaluate and prioritize clinical trial quality assurance.

Methods: The GHG compiled a list of radiotherapy quality assurance (QA) tests performed for proton and photon therapy clinical trials. These tests were compared between modalities to assess whether there was a need for different types of assessments per modality. A failure modes and effects analysis (FMEA) was performed to assess the risk of each QA failure.

Results: The risk analysis showed that proton and photon therapy shared four out of five of their highest-risk failures (end-to-end anthropomorphic phantom …

Clinical Consensus Guideline On The Management Of Phaeochromocytoma And Paraganglioma In Patients Harbouring Germline Sdhd Pathogenic Variants, David Taïeb, George B Wanna, Maleeha Ahmad, Charlotte Lussey-Lepoutre, Nancy D Perrier, Svenja Nölting, Laurence Amar, Henri J L M Timmers, Zachary G Schwam, Anthony L Estrera, Michael Lim, Erqi Liu Pollom, Lucas Vitzthum, Isabelle Bourdeau, Ruth T Casey, Frédéric Castinetti, Roderick Clifton-Bligh, Eleonora P M Corssmit, Ronald R De Krijger, Jaydira Del Rivero, Graeme Eisenhofer, Hans K Ghayee, Anne-Paule Gimenez-Roqueplo, Ashley Grossman, Alessio Imperiale, Jeroen C Jansen, Abhishek Jha, Michiel N Kerstens, Henricus P M Kunst, James K Liu, Eamonn R Maher, Daniele Marchioni, Leilani B Mercado-Asis, Ozgur Mete, Mitsuhide Naruse, Naris Nilubol, Neeta Pandit-Taskar, Frédéric Sebag, Akiyo Tanabe, Jiri Widimsky, Leah Meuter, Jacques W M Lenders, Karel Pacak

Faculty, Staff and Student Publications

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a …

Suicidal Ideation And Psychological Dating Violence Victimization—A Short Report, Gabriel Esmailian, Qiudong Chen, Danny Ramzy, Jon A Kobashigawa, Joanna Chikwe, Fardad Esmailian

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At a time when transplantable organs are in a shortage, few cases have noted the reuse of donor hearts in a second recipient in an effort to expand the donor network. Here, we present a case in which an O Rh-positive donor heart was first transplanted into a B Rh-positive recipient and later successfully retransplanted into a second O Rh-positive recipient 10 days after the initial transplant at the same medical center. On postoperative day 1, the first recipient, a 21-year-old man with nonischemic cardiomyopathy, sustained a devastating cerebrovascular accident with progression to brain death. With preserved left ventricle and …

Vestigial-Like 1 (Vgll1): An Ancient Co-Transcriptional Activator Linking Wing, Placenta, And Tumor Development, Heather M Sonnemann, Barbara Pazdrak, Dinler A Antunes, Jason Roszik, Gregory Lizée

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Vestigial-like 1 (VGLL1) is a recently discovered driver of proliferation and invasion that is expressed in many aggressive human malignancies and is strongly associated with poor prognosis. The VGLL1 gene encodes for a co-transcriptional activator that shows intriguing structural similarity to key activators in the hippo pathway, providing important clues to its functional role. VGLL1 binds to TEAD transcription factors in an analogous fashion to YAP1 but appears to activate a distinct set of downstream gene targets. In mammals, VGLL1 expression is found almost exclusively in placental trophoblasts, cells that share many hallmarks of cancer. Due to its role as …

Does The Type Of Chronic Heart Failure Impact In-Hospital Outcomes For Aortic Valve Replacement Procedures?, Talha Mubashir, John Zaki, Sin Yeong An, Ismael A Salas De Armas, Yafen Liang, Travis Markham, Han Feng, Mehmet H Akay, Angelo Nascimbene, Bindu Akkanti, George W Williams, Fabricio Zasso, Maria Patarroyo Aponte, Igor D Gregoric, Biswajit Kar

Faculty, Staff and Student Publications

BACKGROUND: This study assessed in-hospital outcomes of patients with chronic systolic, diastolic, or mixed heart failure (HF) undergoing transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR).

METHODS: The Nationwide Inpatient Sample database was used to identify patients with aortic stenosis and chronic HF who underwent TAVR or SAVR between 2012 and 2015. Propensity score matching and multivariate logistic regression were used to determine outcome risk.

RESULTS: A cohort of 9,879 patients with systolic (27.2%), diastolic (52.2%), and mixed (20.6%) chronic HF were included. No statistically significant differences in hospital mortality were noted. Overall, patients with diastolic HF …

Interleukin-33 Facilitates Liver Regeneration Through Serotonin-Involved Gut-Liver Axis, Yankai Wen, Christoph Emontzpohl, Long Xu, Constance L Atkins, Jong-Min Jeong, Yang Yang, Kangho Kim, Chuan Wu, Shizuo Akira, Cynthia Ju

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BACKGROUND AND AIMS: Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms.

APPROACH AND RESULTS: We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be …

The Critical Role Of Mentorship In Academic Career Development: A Commentary On Proposed Initiatives By The International Society For Bipolar Disorders Early Mid-Career Committee, Arash Kamali, Sofia Milosavljevic, Anusha Gandhi, Kinsey R Lano, Parnian Shobeiri, Farzaneh Ghazi Sherbaf, Haris I Sair, Roy F Riascos, Khader M Hasan

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The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex, parahippocampal gyrus, hippocampus, hypothalamus, and thalamus. Pursuant to James Papez, Paul Yakovlev and Paul MacLean incorporated the prefrontal/orbitofrontal cortex, septum, amygdalae, and anterior temporal lobes into the limbic system. Over the past few years, diffusion-weighted tractography techniques revealed additional limbic fiber connectivity, which incorporates multiple circuits to the already known complex limbic network. In the current review, we aimed to comprehensively summarize the anatomy of the limbic system and elaborate on the anatomical connectivity …

Monte Carlo-Derived 99m Tc Uptake Quantification With Commercial Planar Mbi: Absolute Tumor Activity, Benjamin P Lopez, Srinivas Cheenu Kappadath

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BACKGROUND: Molecular breast imaging (MBI) of 99mTc-sestamibi is an emerging adjunct qualitative tool in the detection and diagnosis of breast cancer.

PURPOSE: This work outlines the development and performance evaluation of a methodology to absolutely quantify tumor 99mTc activity uptake using a commercially available dual-headed MBI system by implementing corrections for background, scatter, attenuation, and detector characteristics.

METHODS: A validated Monte Carlo application of a commercial MBI system was used to simulate over 7000 unique acquisitions of spherical and ellipsoidal tumors in breast tissue. Tumor absolute activity was calculated following background, scatter, and attenuation corrections of tumor region of interest …

Voxel-Based Dosimetry Predicting Treatment Response And Related Toxicity In Hcc Patients Treated With Resin-Based Y90 Radioembolization: A Prospective, Single-Arm Study, Nima Kokabi, Linzi Arndt-Webster, Bernard Chen, David Brandon, Ila Sethi, Amir Davarpanahfakhr, James Galt, Mohammad Elsayed, Zachary Bercu, Mircea Cristescu, S Cheenu Kappadath, David M Schuster

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BACKGROUND: There is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC).

PURPOSE: To evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization.

MATERIALS AND METHODS: This correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral …

Therapeutic Potential Of Tumor Treating Fields For Malignant Brain Tumors, Youyou Zhou, Xiaoqing Xing, Jinyun Zhou, Han Jiang, Peili Cen, Chentao Jin, Yan Zhong, Rui Zhou, Jing Wang, Mei Tian, Hong Zhang

Faculty, Staff and Student Publications

BACKGROUND: Malignant brain tumors are among the most threatening diseases of the central nervous system, and despite increasingly updated treatments, the prognosis has not been improved. Tumor treating fields (TTFields) are an emerging approach in cancer treatment using intermediate-frequency and low-intensity electric field and can lead to the development of novel therapeutic options.

RECENT FINDINGS: A series of biological processes induced by TTFields to exert anti-cancer effects have been identified. Recent studies have shown that TTFields can alter the bioelectrical state of macromolecules and organelles involved in cancer biology. Massive alterations in cancer cell proteomics and transcriptomics caused by TTFields …

Enhancing Oral Delivery Of Plant-Derived Vesicles For Colitis, Yuan Liu, Adrian Lankenau Ahumada, Emine Bayraktar, Paul Schwartz, Mamur Chowdhury, Sixiang Shi, Manu M Sebastian, Htet Khant, Natalia De Val, Nazende Nur Bayram, Guodong Zhang, Thanh Chung Vu, Zuliang Jie, Nicholas B Jennings, Cristian Rodriguez-Aguayo, Jody Swain, Elaine Stur, Lingegowda S Mangala, Yutuan Wu, Supriya Nagaraju, Brooke Ermias, Chun Li, Gabriel Lopez-Berestein, Janet Braam, Anil K Sood

Faculty, Staff and Student Publications

Plant-derived vesicles (PDVs) are attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs did not have an appreciable impact on PDV structure, number, or therapeutic effect. Additionally, packaging the lyophilized Eudragit S100-coated PDVs into capsules allowed them to pass through the …

Predictors Of Perceived Functional Status In Early Systemic Sclerosis: A Prospective Longitudinal Study Of An Early Disease Cohort, Julia Chernis, Maryam Buni, Sarah Kazzaz, Jun Ying, Marka Lyons, Shervin Assassi, Maureen Mayes

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OBJECTIVE: The modified Health Assessment Questionnaire (M-HAQ) is a well-established patient-reported outcome measure in systemic sclerosis (SSc) studies that reflects how a patient functions in several categories of activities of daily living. This study analyzed clinical, demographic, and socioeconomic factors that predict M-HAQ scores over time.

METHODS: This study included 388 patients with baseline M-HAQ scores from the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) early disease cohort with a mean disease duration of 2.5 years, mean follow-up time of 3.9 years, and median follow-up of 7.2 years. A total of 1,950 M-HAQ measurements were analyzed. Baseline disease characteristics …

Gwas And Meta-Analysis Identifies 49 Genetic Variants Underlying Critical Covid-19, Erola Pairo-Castineira, Konrad Rawlik, Andrew D Bretherick, Ting Qi, Yang Wu, Isar Nassiri, Glenn A Mcconkey, Marie Zechner, Lucija Klaric, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David Maslove, Alistair Nichol, Malcolm G Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny Mcauley, Hugh Montgomery, Peter J M Openshaw, Colin Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Genomicc Investigators, Scourge Consortium, Isaricc Investigators, 23andme Covid-19 Team, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak Abedalthagafi, Andre D Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin Fairfax, Sara Clohisey Hendry, J Kenneth Baillie

Faculty, Staff and Student Publications

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a …

Characterizing The Interplay Of Treatment Parameters And Complexity And Their Impact On Performance On An Iroc Imrt Phantom Using Machine Learning, Hunter Mehrens, Andrea Molineu, Nadia Hernandez, Laurence Court, Rebecca Howell, David Jaffray, Christine B Peterson, Julianne Pollard-Larkin, Stephen F Kry

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AIM OF THE STUDY: To elucidate the important factors and their interplay that drive performance on IMRT phantoms from the Imaging and Radiation Oncology Core (IROC).

METHODS: IROC's IMRT head and neck phantom contains two targets and an organ at risk. Point and 2D dose are measured by TLDs and film, respectively. 1,542 irradiations between 2012-2020 were retrospectively analyzed based on output parameters, complexity metrics, and treatment parameters. Univariate analysis compared parameters based on pass/fail, and random forest modeling was used to predict output parameters and determine the underlying importance of the variables.

RESULTS: The average phantom pass rate was …

Quantitative Dual-Energy Ct Image Guidance For Thermochemical Ablation: In Vivo Results In The Rabbit Vx2 Model, Emily A Thompson, Natalie W Fowlkes, Megan C Jacobsen, Rick R Layman, Erik N K Cressman

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PURPOSE: To evaluate the feasibility of using dual-energy computed tomography (CT) and theranostic cesium hydroxide (CsOH) for image guidance of thermochemical ablation (TCA) in a rabbit VX2 tumor model.

MATERIALS AND METHODS: In vivo experiments were performed on New Zealand white rabbits, where VX2 tumor fragments (0.3 mL) were inoculated into the right and left flanks (n = 16 rabbits, 32 tumors). Catheters were placed in the approximate center of 1- to 2-cm diameter tumors under ultrasound guidance. TCA was delivered in 1 of 3 treatment groups: untreated control, 5-M TCA, or 10-M TCA. The TCA base reagent was doped …

Applicability And Usage Of Dose Mapping/Accumulation In Radiotherapy, Martina Murr, Kristy K Brock, Marco Fusella, Nicholas Hardcastle, Mohammad Hussein, Michael G Jameson, Isak Wahlstedt, Johnson Yuen, Jamie R Mcclelland, Eliana Vasquez Osorio

Faculty, Staff and Student Publications

Dose mapping/accumulation (DMA) is a topic in radiotherapy (RT) for years, but has not yet found its widespread way into clinical RT routine. During the ESTRO Physics workshop 2021 on "commissioning and quality assurance of deformable image registration (DIR) for current and future RT applications", we built a working group on DMA from which we present the results of our discussions in this article. Our aim in this manuscript is to shed light on the current situation of DMA in RT and to highlight the issues that hinder consciously integrating it into clinical RT routine. As a first outcome of …

Critical Review Of Oncologic Medical Malpractice Claims Against Orthopaedic Surgeons, William Davis, Shravya Kichena, Michael D Eckhoff, Benjamin R Childs, Rajiv Rajani, Matthew E Wells, Sean P Kelly

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INTRODUCTION: The purpose of this study was to determine the most common allegations for malpractice litigation brought against orthopaedic surgeons for oncologic matters and the resulting verdicts.

METHODS: The Westlaw Legal research database was queried for malpractice cases filed against orthopaedic surgeons for oncologic matters in the United States after 1980. Plaintiff demographics, state of filing, allegations, and outcomes of lawsuits were recorded and reported accordingly.

RESULTS: A total of 36 cases met the inclusion and exclusion criteria and were subsequently included in the final analysis. The overall rate of cases filed remained consistent through the past four decades and …

Heterogeneity Of Treatment Effects Of Hydrocortisone By Risk Of Bronchopulmonary Dysplasia Or Death Among Extremely Preterm Infants In The National Institute Of Child Health And Human Development Neonatal Research Network Trial: A Secondary Analysis Of A Randomized Clinical Trial, Samuel J Gentle, Matthew A Rysavy, Lei Li, Matthew M Laughon, Ravi M Patel, Erik A Jensen, Susan Hintz, Namasivayam Ambalavanan, Waldemar A Carlo, Kristi Watterberg, National Institute Of Child Health And Human Development Neonatal Research Network

Faculty, Staff and Student Publications

IMPORTANCE: Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death.

OBJECTIVE: To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death.

DESIGN, SETTING, AND PARTICIPANTS: …

Sarcoidosis And Airway Disease After Immune Checkpoint Inhibitor Therapy: Case Study And Review Of The Literature, Felipe Soto, Luis F Torre-Sada, Frank E Mott, Sang T Kim, Roza Nurieva, Vickie R Shannon, Saadia A Faiz, Roberto F Casal, Mehmet Altan, Julie Lin, Ajay Sheshadri

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Pulmonary toxicity from immune checkpoint inhibitor therapy is typically a severe and potentially fatal complication, but these observations are driven by the most common toxicity, pneumonitis. Rarer pulmonary immune related adverse events, like airway disease and sarcoidosis, may have a more benign course. In this case report, we present a patient in whom therapy with the PD-1 inhibitor pembrolizumab resulted in severe eosinophilic asthma and sarcoidosis. This is the first case showing that anti-IL-5 inhibition may be safe in patients who develop eosinophilic asthma after ICI therapy. We further show that sarcoidosis does not necessarily require treatment cessation. This case …

Brain Engagement During A Cognitive Flexibility Task Relates To Academic Performance In English Learners, Tehila Nugiel, Mackenzie E Mitchell, Damion V Demeter, Annacarolina Garza, Paul T Cirino, Arturo E Hernandez, Jenifer Juranek, Jessica A Church

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English Learners (ELs), students from non-English-speaking backgrounds, are a fast-growing, understudied, group of students in the U.S. with unique learning challenges. Cognitive flexibility—the ability to switch between task demands with ease—may be an important factor in learning for ELs as they have to manage learning in their non-dominant language and access knowledge in multiple languages. We used functional MRI to measure cognitive flexibility brain activity in a group of Hispanic middle school ELs (N = 63) and related it to their academic skills. We found that brain engagement during the cognitive flexibility task was related to both out-of-scanner reading …