Publications by authors named "Andrew M Davis"

128 Publications

Public-Private Partnerships: Compound and Data Sharing in Drug Discovery and Development.

SLAS Discov 2021 Feb 13:2472555220982268. Epub 2021 Feb 13.

Molecular AI, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Collaborative efforts between public and private entities such as academic institutions, governments, and pharmaceutical companies form an integral part of scientific research, and notable instances of such initiatives have been created within the life science community. Several examples of alliances exist with the broad goal of collaborating toward scientific advancement and improved public welfare. Such collaborations can be essential in catalyzing breaking areas of science within high-risk or global public health strategies that may have otherwise not progressed. A common term used to describe these alliances is (PPP). This review discusses different aspects of such partnerships in drug discovery/development and provides example applications as well as successful case studies. Specific areas that are covered include PPPs for sharing compounds at various phases of the drug discovery process-from compound collections for hit identification to sharing clinical candidates. Instances of PPPs to support better data integration and build better machine learning models are also discussed. The review also provides examples of PPPs that address the gap in knowledge or resources among involved parties and advance drug discovery, especially in disease areas with unfulfilled and/or social needs, like neurological disorders, cancer, and neglected and rare diseases.
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http://dx.doi.org/10.1177/2472555220982268DOI Listing
February 2021

The fall, recovery, classification, and initial characterization of the Hamburg, Michigan H4 chondrite.

Meteorit Planet Sci 2020 Nov 27;55(11):2341-2359. Epub 2020 Oct 27.

Department of Earth Sciences University of Toronto 22 Russell St Toronto Ontario M5S 3B1 Canada.

The Hamburg meteorite fell on January 16, 2018, near Hamburg, Michigan, after a fireball event widely observed in the U.S. Midwest and in Ontario, Canada. Several fragments fell onto frozen surfaces of lakes and, thanks to weather radar data, were recovered days after the fall. The studied rock fragments show no or little signs of terrestrial weathering. Here, we present the initial results from an international consortium study to describe the fall, characterize the meteorite, and probe the collision history of Hamburg. About 1 kg of recovered meteorites was initially reported. Petrology, mineral chemistry, trace element and organic chemistry, and O and Cr isotopic compositions are characteristic of H4 chondrites. Cosmic ray exposure ages based on cosmogenic He, Ne, and Ar are ~12 Ma, and roughly agree with each other. Noble gas data as well as the cosmogenic Be concentration point to a small 40-60 cm diameter meteoroid. An Ar-Ar age of 4532 ± 24 Ma indicates no major impact event occurring later in its evolutionary history, consistent with data of other H4 chondrites. Microanalyses of phosphates with LA-ICPMS give an average Pb-Pb age of 4549 ± 36 Ma. This is in good agreement with the average SIMS Pb-Pb phosphate age of 4535.3 ± 9.5 Ma and U-Pb Concordia age of 4535 ± 10 Ma. The weighted average age of 4541.6 ± 9.5 Ma reflects the metamorphic phosphate crystallization age after parent body formation in the early solar system.
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http://dx.doi.org/10.1111/maps.13584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820957PMC
November 2020

Pancreatic Cysts-An Overview and Summary of Society Guidelines, 2021.

JAMA 2021 Jan;325(4):391-392

Center for Endoscopic Research and Therapeutics (CERT), University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2020.18678DOI Listing
January 2021

Initiating Pharmacologic Treatment in Tobacco-Dependent Adults.

JAMA 2021 Jan;325(3):301-302

General Internal Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2020.24790DOI Listing
January 2021

ACR Appropriateness Criteria® Blunt Chest Trauma-Suspected Cardiac Injury.

J Am Coll Radiol 2020 Nov;17(11S):S380-S390

Specialty Chair, UT Southwestern Medical Center, Dallas, Texas.

Blunt cardiac injuries range from myocardial concussion (commotio cordis) leading to fatal ventricular arrhythmias to myocardial contusion, cardiac chamber rupture, septal rupture, pericardial rupture, and valvular injuries. Blunt injuries account for one-fourth of the traumatic deaths in the United States. Chest radiography, transthoracic echocardiography, CT chest with and without contrast, and CT angiography are usually appropriate as the initial examination in patients with suspected blunt cardiac injury who are both hemodynamically stable and unstable. Transesophageal echocardiography and CT heart may be appropriate as examination in patients with suspected blunt cardiac injuries. This publication of blunt chest trauma-suspected cardiac injuries summarizes the literature and makes recommendations for imaging based on the available data and expert opinion. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2020.09.012DOI Listing
November 2020

ACR Appropriateness Criteria® Acute Nonspecific Chest Pain-Low Probability of Coronary Artery Disease.

J Am Coll Radiol 2020 Nov;17(11S):S346-S354

Specialty Chair, UT Southwestern Medical Center, Dallas, Texas.

Patients with acute nonspecific chest pain and low probability for coronary disease remain an important clinical management dilemma. We focus on evidence for imaging, in an integrated decision-making setting. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2020.09.006DOI Listing
November 2020

Cardiac phenotype in -related syndromes: A multicenter cohort study.

Neurology 2020 11 10;95(21):e2866-e2879. Epub 2020 Sep 10.

From the Department of Clinical and Experimental Epilepsy (S.B., S.M.S.), UCL Queen Square Institute of Neurology, London; Chalfont Centre for Epilepsy (S.B., S.M.S.), Bucks, UK; Division of Pediatric Neurology (M.A.M., A.S.H., B.K., M.M., L.P.), Department of Neurobiology, and Division of Cardiology (M.C.), Department of Pediatrics, Duke University, School of Medicine, Durham, NC; Centre for Inherited Cardiovascular Diseases (R.A.G.-R., J.P.K.), Great Ormond Street Hospital for Children NHS Foundation Trust; Institute of Cardiovascular Science(R.A.G.-R., J.P.K.), University College London, London, UK; Child Neuropsychiatry Unit (E.D.G., A.G., L.P., M.S., E.V.), IRCCs Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, DINOG-MI, University of Genoa; Department of Pediatric Neuroscience (A.G., T.G., N.N., F.R.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Child Neuropsychiatry (L.P.), ASST Fatebenefratelli Sacco, Milan, Italy; Paediatric Neurology Department (J.C., C.F., L.P.-P., A.A.), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona University, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Barcelona, Spain; Department of Neurology (A.B., C.M.), Wake Forest School of Medicine, Winston-Salem, NC; Neurology Department (R.S.), Centro Hospitalar e Universitario do Porto-Hospital de Santo António, Porto, Portugal; Clinic for Child Neurology and Psychiatry (V.B., A.P.), Department of Child Neurology, Medical Faculty University of Belgrade, Serbia; Department of Human Genetics (Q.S.P.), Graduate School of Public Health, University of Pittsburgh, PA; Department of Pediatric Neurology (J.P.), Medical University of Silesia, Katowice, Poland; Clinical Neurosciences (K.V., J.H.C.), Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, London, UK; Sydney Children's Hospital (A.M.E.B.), Randwick; Department of Cardiology (A.M.D.), The Royal Children's Hospital, Melbourne, University of Melbourne; Department of Neurology (M.M.R.), Royal Children's Hospital, Melbourne; Agnes Ginges Centre for Molecular Cardiology (C.S.), Centenary Institute, University of Sydney; Epilepsy Research Centre (G.H., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC; Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Australia; Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children (A.A., E.P.), University Hospitals of Lyon (HCL), Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Lyon, France; Paediatric Neurology Unit (I.C.), CMIN, Centro Hospitalar e Universitario Porto, Porto, Portugal; Clinical Neurophysiology Unit (C.Z.), IRCCS "E. Medea," Bosisio Parini (LC), Italy; Department of Neurology (J.N.), CHUV and Université de Lausanne, Switzerland; Second Department of Neurology (K.D.), Institute Psychiatry and Neurology, Warsaw, Poland; Association AHC18+ e. V. (Germany) and Polish Association for People Affected by AHC, ahc-pl (M.P.); Department of Developmental Neurology (M.M.B.), Medical University of Gdańsk, Poland; Neurology Department (S.W.), University Hospital Antwerp; Neurogenetics Group (S.W.), University Antwerp, Belgium; First Department of Pediatrics (R.P.), "Agia Sofia" Children Hospital, National & Kapodistrian University of Athens, Greece; Department of Neurology (S.G.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Ion Channel Research Unit (D.S.S.), Department of Medicine/Cardiology and Pharmacology, Duke University Medical Center, Durham, NC; Cardiovascular Research Institute (G.S.P.), Weill Cornell Medical College, New York, NY; The Heart Centre (A.T.), Queen Mary University of London; Department of Pathology (M.A.), Great Ormond Street Hospital for Children NHS Foundation Trust; Department of Neuropathology (Z.M., M.T.), Institute of Neurology, University College London, UK; and ICT and Data Analysis Section (R.V.), Euro-Mediterranean Institute of Science and Technology (I.E.ME.S.T.), Palermo, Italy.

Objective: To define the risks and consequences of cardiac abnormalities in -related syndromes.

Methods: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an knock-in mouse (Mashl) to determine the sequence of events in seizure-related cardiac death.

Results: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.

Conclusions: We found increased prevalence of ECG dynamic abnormalities in all -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine -related disease. -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
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http://dx.doi.org/10.1212/WNL.0000000000010794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734736PMC
November 2020

A MALT1 inhibitor suppresses human myeloid DC, effector T-cell and B-cell responses and retains Th1/regulatory T-cell homeostasis.

PLoS One 2020 1;15(9):e0222548. Epub 2020 Sep 1.

Research & Early Development, Respiratory, Inflammation & Autoimmune, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden.

The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) regulates nuclear-factor-kappa-B (NF-κB) activation downstream of surface receptors with immunoreceptor tyrosine-based activation motifs (ITAMs), such as the B-cell or T-cell receptor and has thus emerged as a therapeutic target for autoimmune diseases. However, recent reports demonstrate the development of lethal autoimmune inflammation due to the excessive production of interferon gamma (IFN-ɣ) and defective differentiation of regulatory T-cells in genetically modified mice deficient in MALT1 paracaspase activity. To address this issue, we explored the effects of pharmacological MALT1 inhibition on the balance between T-effector and regulatory T-cells. Here we demonstrate that allosteric inhibition of MALT1 suppressed Th1, Th17 and Th1/Th17 effector responses, and inhibited T-cell dependent B-cell proliferation and antibody production. Allosteric MALT1 inhibition did not interfere with the suppressive function of human T-regulatory cells, although it impaired de novo differentiation of regulatory T-cells from naïve T-cells. Treatment with an allosteric MALT1 inhibitor alleviated the cytokine storm, including IFN-ɣ, in a mouse model of acute T-cell activation, and long-term treatment did not lead to an increase in IFN-ɣ producing CD4 cells or tissue inflammation. Together, our data demonstrate that the effects of allosteric inhibition of MALT1 differ from those seen in mice with proteolytically inactive MALT1, and thus we believe that MALT1 is a viable target for B and T-cell driven autoimmune diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222548PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462277PMC
October 2020

Patients With Genetic Heart Disease and COVID-19: A Cardiac Society of Australia and New Zealand (CSANZ) Consensus Statement.

Heart Lung Circ 2020 Jul 30;29(7):e85-e87. Epub 2020 Apr 30.

Waikato Hospital, Hamilton, New Zealand.

In the context of the current global COVID-19 pandemic, this Consensus Statement provides current recommendations for patients with, or at risk of developing, genetic heart disease, and for their health care management and service provision in Australia and New Zealand. Apart from general recommendations, there are specific recommendations for the following conditions: cardiomyopathy, Brugada syndrome (including in children), long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Other recommendations are relevant to patient self-care and primary health care.
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http://dx.doi.org/10.1016/j.hlc.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192105PMC
July 2020

Management of Critically Ill Adults With COVID-19.

JAMA 2020 May;323(18):1839-1841

General Internal Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2020.4914DOI Listing
May 2020

Diagnosis and Treatment of Adults With Community-Acquired Pneumonia.

JAMA 2020 03;323(9):885-886

Section of General Internal Medicine, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.21118DOI Listing
March 2020

Lifetimes of interstellar dust from cosmic ray exposure ages of presolar silicon carbide.

Proc Natl Acad Sci U S A 2020 Jan 13;117(4):1884-1889. Epub 2020 Jan 13.

Institute of Geochemistry and Petrology, ETH Zürich, 8092 Zürich, Switzerland.

We determined interstellar cosmic ray exposure ages of 40 large presolar silicon carbide grains extracted from the Murchison CM2 meteorite. Our ages, based on cosmogenic Ne-21, range from 3.9 ± 1.6 Ma to ∼3 ± 2 Ga before the start of the Solar System ∼4.6 Ga ago. A majority of the grains have interstellar lifetimes of <300 Ma, which is shorter than theoretical estimates for large grains. These grains condensed in outflows of asymptotic giant branch stars <4.9 Ga ago that possibly formed during an episode of enhanced star formation ∼7 Ga ago. A minority of the grains have ages >1 Ga. Longer lifetimes are expected for large grains. We determined that at least 12 of the analyzed grains were parts of aggregates in the interstellar medium: The large difference in nuclear recoil loss of cosmic ray spallation products He and Ne enabled us to estimate that the irradiated objects in the interstellar medium were up to 30 times larger than the analyzed grains. Furthermore, we estimate that the majority of the grains acquired the bulk of their cosmogenic nuclides in the interstellar medium and not by exposure to an enhanced particle flux of the early active sun.
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http://dx.doi.org/10.1073/pnas.1904573117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995017PMC
January 2020

Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP).

JAMA 2020 Feb;323(5):468-469

Department of Medicine, Section of General Internal Medicine, University of Chicago Medical Center, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.18411DOI Listing
February 2020

Can an Evidence-Based Approach Improve the Patient-Physician Relationship?

JAMA 2020 01;323(1):31-32

Section of General Internal Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.19427DOI Listing
January 2020

50 Years of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) - Time to Explore the Dark Side of the Moon.

Heart Lung Circ 2020 Apr 6;29(4):520-528. Epub 2019 Dec 6.

Department of Cardiology, The Royal Children's Hospital, Melbourne, Vic, Australia; Murdoch Children's Research Institute, Melbourne, Vic, Australia; The University of Melbourne, Melbourne, Vic, Australia.

Despite significant progress in understanding catecholaminergic polymorphic ventricular tachycardia (CPVT), there are still multiple uncertainties and gaps in our knowledge. Like the dark side of the moon, we cannot see them directly. Unfortunately, clinicians must make diagnostic and therapeutic decisions without solid evidence. Instead of summarising the current state of science and reiterating the guidelines, we review difficulties in understanding the disease mechanism, diagnosis and therapy. Highlighting these truths helps to avoid misconceptions, think clearly about our patients and direct future research efforts. It has become clear that CPVT encompasses more than just uniformly expressed ryanodine receptor mutations leading to bidirectional ventricular tachycardia, rather it is a disease caused by different genetic mutations, overlapping with other entities and possibly affecting not only the heart. Treatment in addition to beta blockers is often necessary: flecainide and left cardiac sympathetic denervation are therapies that come before consideration of defibrillator implantation and new treatment options are on the horizon.
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http://dx.doi.org/10.1016/j.hlc.2019.10.013DOI Listing
April 2020

Assessment and Management of Heavy Menstrual Bleeding.

JAMA 2020 Jan;323(3):270-271

Department of Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.17383DOI Listing
January 2020

Medical Management of Opioid-Induced Constipation.

JAMA 2019 Nov 4. Epub 2019 Nov 4.

Section of General Internal Medicine, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.15852DOI Listing
November 2019

Primary Prevention of Cardiovascular Disease.

JAMA 2019 Oct 4:1-3. Epub 2019 Oct 4.

University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.15915DOI Listing
October 2019

Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1,2)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic Acid (AZD9898) as a New Treatment for Asthma.

J Med Chem 2019 09 30;62(17):7769-7787. Epub 2019 Aug 30.

Orexo AB , Virdings allé 32A , SE-75450 Uppsala , Sweden.

While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl leukotriene cascade. Starting from a screening hit (), a program to discover oral inhibitors of LTC4S led to (1,2)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (), a picomolar LTC4S inhibitor (IC = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC = 34 nM). Compound mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound with a human dose predicted to be 30 mg once daily.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00555DOI Listing
September 2019

An Angle on MK2 Inhibition-Optimization and Evaluation of Prevention of Activation Inhibitors.

ChemMedChem 2019 10 13;14(19):1701-1709. Epub 2019 Aug 13.

Clinical Pharmacology and Safety Sciences, R&D Biopharmaceuticals, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.

The mitogen-activated protein kinase p38α pathway has been an attractive target for the treatment of inflammatory conditions such as rheumatoid arthritis. While a number of p38α inhibitors have been taken to the clinic, they have been limited by their efficacy and toxicological profile. A lead identification program was initiated to selectively target prevention of activation (PoA) of mitogen-activated protein kinase-activated protein kinase 2 (MK2) rather than mitogen- and stress-activated protein kinase 1 (MSK1), both immediate downstream substrates of p38α, to improve the efficacy/safety profile over direct p38α inhibition. Starting with a series of pyrazole amide PoA MK2 inhibitor leads, and guided by structural chemistry and rational design, a highly selective imidazole 9 (2-(3'-(2-amino-2-oxoethyl)-[1,1'-biphenyl]-3-yl)-N-(5-(N,N-dimethylsulfamoyl)-2-methylphenyl)-1-propyl-1H-imidazole-5-carboxamide) and the orally bioavailable imidazole 18 (3-methyl-N-(2-methyl-5-sulfamoylphenyl)-2-(o-tolyl)imidazole-4-carboxamide) were discovered. The PoA concept was further evaluated by protein immunoblotting, which showed that the optimized PoA MK2 compounds, despite their biochemical selectivity against MSK1 phosphorylation, behaved similarly to p38 inhibitors in cellular signaling. This study highlights the importance of selective tool compounds in untangling complex signaling pathways, and although 9 and 18 were not differentiated from p38α inhibitors in a cellular context, they are still useful tools for further research directed to understand the role of MK2 in the p38α signaling pathway.
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http://dx.doi.org/10.1002/cmdc.201900303DOI Listing
October 2019

Colorectal Cancer Screening.

JAMA 2019 May;321(20):2022-2023

Department of Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.4842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285652PMC
May 2019

Management of Blood Cholesterol.

JAMA 2019 02;321(8):800-801

Department of Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2019.0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679800PMC
February 2019

Patient-provider communications about pharmacogenomic results increase patient recall of medication changes.

Pharmacogenomics J 2019 12 4;19(6):528-537. Epub 2019 Feb 4.

Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA.

Effective doctor-patient communication is critical for disease management, especially when considering genetic information. We studied patient-provider communications after implementing a point-of-care pharmacogenomic results delivery system to understand whether pharmacogenomic results are discussed and whether medication recall is impacted. Outpatients undergoing preemptive pharmacogenomic testing (cases), non-genotyped controls, and study providers were surveyed from October 2012-May 2017. Patient responses were compared between visits where pharmacogenomic results guided prescribing versus visits where pharmacogenomics did not guide prescribing. Provider knowledge of pharmacogenomics, before and during study participation, was also analyzed. Both providers and case patients frequently reported discussions of genetic results after visits where pharmacogenomic information guided prescribing. Importantly, medication changes from visits where pharmacogenomics influenced prescribing were more often recalled than non-pharmacogenomic guided medication changes (OR = 3.3 [1.6-6.7], p = 0.001). Case patients who had separate visits where pharmacogenomics did and did not, respectively, influence prescribing more often remembered medication changes from visits where genomic-based guidance was used (OR = 3.4 [1.2-9.3], p = 0.02). Providers also displayed dramatic increases in personal genomic understanding through program participation (94% felt at least somewhat informed about pharmacogenomics post-participation, compared to 61% at baseline, p = 0.04). Using genomic information during prescribing increases patient-provider communications, patient medication recall, and provider understanding of genomics, important ancillary benefits to clinical use of pharmacogenomics.
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http://dx.doi.org/10.1038/s41397-019-0076-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980369PMC
December 2019

Diagnosis and Management of Nonalcoholic Fatty Liver Disease.

JAMA 2018 Dec;320(23):2474-2475

University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2018.17365DOI Listing
December 2018

An Update on the Diagnosis and Management of Catecholaminergic Polymorphic Ventricular Tachycardia.

Heart Lung Circ 2019 Mar 7;28(3):366-369. Epub 2018 Nov 7.

The Royal Children's Hospital Melbourne, Melbourne, Vic, Australia; University of Melbourne, Melbourne, Vic, Australia; The Murdoch Children's Research Institute, Melbourne, Vic, Australia.

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http://dx.doi.org/10.1016/j.hlc.2018.10.016DOI Listing
March 2019

Guidelines on Glycemic Targets for Persons With Type 2 Diabetes-Reply.

JAMA 2018 11;320(18):1937-1938

Chicago Center for Diabetes Translation Research, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2018.13421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607888PMC
November 2018

Incidental Pulmonary Nodules Detected on CT Images.

JAMA 2018 Dec;320(21):2260-2261

University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2018.16336DOI Listing
December 2018

Collision-avoiding imaging trajectories for linac mounted cone-beam CT.

J Xray Sci Technol 2019 ;27(1):1-16

Department of Radiation and Cellular Oncology, University of Chicago, Chicago.

Background: Some patients cannot be imaged with cone-beam CT for image-guided radiation therapy because their size, pose, or fixation devices cause collisions with the machine.

Objective: To investigate imaging trajectories that avoid such collisions by using virtual isocenter and variable magnification during acquisition while yielding comparable image quality.

Methods: The machine components most likely to collide are the gantry and kV detector. A virtual isocenter trajectory continuously moves the patient during gantry rotation to maintain an increased separation between the two. With dynamic magnification, the kV detector is dynamically moved to increase clearance for an angular range around the potential collision point while acquiring sufficient data to maintain the field-of-view. Both strategies were used independently and jointly with the resultant image quality evaluated against the standard circular acquisition.

Results: Collision avoiding trajectories show comparable contrast and resolution to standard techniques. For an anthropomorphic phantom, the RMSE is <7×10- 4, multi-scale structural similarity index is >0.97, and visual image fidelity is >0.96 for all trajectories when compared to a standard circular scan.

Conclusions: The proposed trajectories avoid machine-patient collisions while providing comparable image quality to the current standard thereby enabling CBCT imaging for patients that could not otherwise be scanned.
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http://dx.doi.org/10.3233/XST-180401DOI Listing
July 2020

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Eur Heart J 2018 08;39(31):2879-2887

L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification.

Methods And Results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE.

Conclusion: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.
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http://dx.doi.org/10.1093/eurheartj/ehy412DOI Listing
August 2018

Glycemic Control in Nonpregnant Adults With Type 2 Diabetes.

JAMA 2018 06;319(23):2430-2431

Chicago Center for Diabetes Translation Research, Section of General Internal Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jama.2018.6798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555416PMC
June 2018