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1. Creating and Teaching a Web-Based, University-Level Introductory Chemistry Course that Incorporates Laboratory Exercises and Active Learning Pedagogies

Author

Phipps, Linda R.

Abstract

An introductory, nonscience-majors chemistry course was converted to a Web-based course. The differences in student populations, teaching strategies, laboratory methods, and learning outcomes are described. Practical information is also given on the use of software and other online technology to implement course conversion. (Contains 2 tables.)

Published
2013
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4. The climate effects of increasing ocean albedo: an idealized representation of solar geoengineering

Author

B. Kravitz, P. J. Rasch, H. Wang, A. Robock, C. Gabriel, O. Boucher, J. N. S. Cole, J. Haywood, D. Ji, A. Jones, A. Lenton, J. C. Moore, H. Muri, U. Niemeier, S. Phipps, H. Schmidt, S. Watanabe, S. Yang, and J.-H. Yoon

Subjects
Physics, QC1-999, Chemistry, QD1-999
Abstract

Geoengineering, or climate intervention, describes methods of deliberately altering the climate system to offset anthropogenic climate change. As an idealized representation of near-surface solar geoengineering over the ocean, such as marine cloud brightening, this paper discusses experiment G1ocean-albedo of the Geoengineering Model Intercomparison Project (GeoMIP), involving an abrupt quadrupling of the CO2 concentration and an instantaneous increase in ocean albedo to maintain approximate net top-of-atmosphere radiative flux balance. A total of 11 Earth system models are relatively consistent in their temperature, radiative flux, and hydrological cycle responses to this experiment. Due to the imposed forcing, air over the land surface warms by a model average of 1.14 K, while air over most of the ocean cools. Some parts of the near-surface air temperature over ocean warm due to heat transport from land to ocean. These changes generally resolve within a few years, indicating that changes in ocean heat content play at most a small role in the warming over the oceans. The hydrological cycle response is a general slowing down, with high heterogeneity in the response, particularly in the tropics. While idealized, these results have important implications for marine cloud brightening, or other methods of geoengineering involving spatially heterogeneous forcing, or other general forcings with a strong land–ocean contrast. It also reinforces previous findings that keeping top-of-atmosphere net radiative flux constant is not sufficient for preventing changes in global mean temperature.

Published
2018
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5. Response to marine cloud brightening in a multi-model ensemble

Author

C. W. Stjern, H. Muri, L. Ahlm, O. Boucher, J. N. S. Cole, D. Ji, A. Jones, J. Haywood, B. Kravitz, A. Lenton, J. C. Moore, U. Niemeier, S. J. Phipps, H. Schmidt, S. Watanabe, and J. E. Kristjánsson

Subjects
Physics, QC1-999, Chemistry, QD1-999
Abstract

Here we show results from Earth system model simulations from the marine cloud brightening experiment G4cdnc of the Geoengineering Model Intercomparison Project (GeoMIP). The nine contributing models prescribe a 50 % increase in the cloud droplet number concentration (CDNC) of low clouds over the global oceans in an experiment dubbed G4cdnc, with the purpose of counteracting the radiative forcing due to anthropogenic greenhouse gases under the RCP4.5 scenario. The model ensemble median effective radiative forcing (ERF) amounts to −1.9 W m−2, with a substantial inter-model spread of −0.6 to −2.5 W m−2. The large spread is partly related to the considerable differences in clouds and their representation between the models, with an underestimation of low clouds in several of the models. All models predict a statistically significant temperature decrease with a median of (for years 2020–2069) −0.96 [−0.17 to −1.21] K relative to the RCP4.5 scenario, with particularly strong cooling over low-latitude continents. Globally averaged there is a weak but significant precipitation decrease of −2.35 [−0.57 to −2.96] % due to a colder climate, but at low latitudes there is a 1.19 % increase over land. This increase is part of a circulation change where a strong negative top-of-atmosphere (TOA) shortwave forcing over subtropical oceans, caused by increased albedo associated with the increasing CDNC, is compensated for by rising motion and positive TOA longwave signals over adjacent land regions.

Published
2018
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6. Regioselective Radical Arene Amination for the Concise Synthesis of ortho-Phenylenediamines

Author

James E Gillespie, Robert J. Phipps, Charlotte Morrill, Phipps, Robert J [0000-0002-7383-5469], Apollo - University of Cambridge Repository, and Phipps, Robert [0000-0002-7383-5469]

Subjects
chemistry.chemical_classification, 34 Chemical Sciences, Communication, Radical, Substrate (chemistry), Regioselectivity, 3405 Organic Chemistry, General Chemistry, 010402 general chemistry, 01 natural sciences, Biochemistry, Combinatorial chemistry, Catalysis, 0104 chemical sciences, 3. Good health, chemistry.chemical_compound, Colloid and Surface Chemistry, Aniline, Radical ion, chemistry, Non-covalent interactions, Selectivity, Amination
Abstract

The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactive N-centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the arene ortho position. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly to ortho-phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuable ortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.

Published
2021
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7. Small volume retinol binding protein measurement by liquid chromatography-tandem mass spectrometry

Author

Jill Irvine, Clark M. Henderson, Jane A. Dickerson, Anna E. Merrill, Thomas J. Laha, Pratistha Ranjitkar, William S. Phipps, Dina N. Greene, Hannah Pflaum, and Andrew N. Hoofnagle

Subjects
Male, Chromatography, medicine.diagnostic_test, Chemistry, Clinical Biochemistry, Infant, Newborn, General Medicine, Mass spectrometry, Article, Retinol-Binding Proteins, Retinol binding protein, Nutrition Assessment, Tandem Mass Spectrometry, Liquid chromatography–mass spectrometry, Immunoassay, Intensive care, medicine, Humans, Distribution (pharmacology), Female, Retinol Binding Protein Measurement, Nephelometry, Chromatography, Liquid
Abstract

Background The measurement of plasma concentrations of retinol binding protein is a component of nutritional assessment in neonatal intensive care. However, serial testing in newborns is hampered by the limited amount of blood that can be sampled. Limitations are most severe with preterm infants, for whom close monitoring may be most important. Methods We developed an assay to quantify retinol binding protein using trypsin digestion and liquid chromatography-tandem mass spectrometry, which requires a serum or plasma volume of 5 µl. Additionally, we validated the method according to current recommendations and performed comparison with a standard nephelometry platform in clinical use. Results The assay demonstrated linearity from below 1 mg/dL (0.48 µM) to more than 20 mg/dL (9.7 µM), and an imprecision of 11.8% at 0.43 mg/dL (0.21 µM). The distribution of results observed with the new method was different when compared with nephelometry. Conclusion Liquid chromatography-tandem mass spectrometry facilitated testing a smaller sample volume, thereby increasing the ability to monitor key nutritional markers in premature infants. The differences in results compared with a commercially-available nephelometric assay revealed questionable results for lower concentrations by immunoassay.

Published
2022
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8. Hydrogen Atom Transfer-Driven Enantioselective Minisci Reaction of Amides

Author

Robert J. Phipps, Rupert S. J. Proctor, Padon Chuentragool, Avene C. Colgan, Proctor, Rupert SJ [0000-0002-2296-448X], Colgan, Avene C [0000-0003-3842-6077], Phipps, Robert J [0000-0002-7383-5469], and Apollo - University of Cambridge Repository

Subjects
34 Chemical Sciences, Communication, Enantioselective synthesis, 3405 Organic Chemistry, General Chemistry, Hydrogen atom, 010402 general chemistry, 01 natural sciences, Biochemistry, Combinatorial chemistry, Catalysis, 0104 chemical sciences, 3. Good health, Stereocenter, 3402 Inorganic Chemistry, chemistry.chemical_compound, Colloid and Surface Chemistry, chemistry, Reagent, Amide, Oxidative coupling of methane, Minisci reaction
Abstract

Minisci-type reactions constitute one of the most powerful methods for building up complexity around basic heteroarenes. The most desirable variants involve formal oxidative coupling of a C-H bond on each partner, leading back to the simplest possible starting materials. We herein disclose a method that enables such a coupling of linear amides and heteroarenes with full control of enantioselectivity at the newly formed stereocenter as well as site selectivity on both the heteroarene and the amide. This is achieved by the use of a chiral phosphoric acid catalyst in conjunction with diacetyl as a combined hydrogen atom transfer reagent and oxidant. Diacetyl is directly photoexcitable, and thus, no extraneous photocatalyst is required: an added feature that contributes to the simplicity and practicality of the protocol.

Published
2021
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9. Prevalence and Social Acceptability of Cannabis, Tobacco, and Alcohol Use in Adult Women

Author

Nicole W. Karjane, Anna Beth Parlier-Ahmad, Lisa B. Phipps, Jaclyn S. Sadicario, Patricia Coughenour, and Dace S. Svikis

Subjects
cannabis, medicine.medical_specialty, Population, Alcohol, tobacco, Adult women, chemistry.chemical_compound, Intervention (counseling), medicine, Psychiatry, education, Depression (differential diagnoses), education.field_of_study, attitudes, biology, business.industry, biology.organism_classification, chemistry, Social acceptability, Anxiety, Original Article, women, Cannabis, social acceptability, medicine.symptom, business
Abstract

Background: As more US states legalize cannabis use, prevalence of use continues to rise and attitudes toward use are changing. This study examined (1) the relationship between cannabis use and social acceptability of use and (2) how social acceptability and use of cannabis relate to anxiety, depression, and several pain conditions. Materials and Methods: Participants were n = 210 nonpregnant women recruited from two women's health clinics for an anonymous survey of complementary and integrative health practices. Survey domains included demographics, recent and lifetime cannabis, cigarette, and alcohol use, depression, anxiety, pain, and social acceptability of substances studied. Results: The sample had a mean age of 38.7 years and was 50.0% Black. Approximately 12.9% of the sample endorsed recent cannabis use, 17.2% endorsed recent cigarette use, and 57.5% endorsed recent alcohol use. Acceptability of use varied by substance. One-third (33.3%) of women found cannabis use to be socially acceptable. Higher social acceptability scores for cannabis were correlated with higher acceptability scores for each of the other substances studied, with the strongest correlation for e-cigarettes (R 2 of 0.395, p < 0.001) and the weakest for alcohol (R 2 of 0.296, p < 0.001). Women reporting anxiety (38.9%) and recent acute pain (28.6%) rated cannabis use as more socially acceptable than those without such symptoms. Conclusions: Women with recent cannabis use were more likely to find use of alcohol, tobacco, and cannabis to be socially acceptable than those not reporting cannabis use. More research is needed to better understand these relationships, as they might help to identify opportunities for education and intervention in this population.

Published
2021
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10. The molecular identity of the characean OH− transporter: a candidate related to the SLC4 family of animal pH regulators

Author

Ilse Foissner, Bianca N. Quade, Mark D. Parker, Mary A. Bisson, Mary J. Beilby, Shaunna Phipps, and Marion C. Hoepflinger

Subjects
0106 biological sciences, 0301 basic medicine, Chara, biology, Chemistry, Xenopus, Zygnematophyceae, Transporter, Cell Biology, Plant Science, General Medicine, Hyperpolarization (biology), biology.organism_classification, 01 natural sciences, Cell biology, Chloroplast, 03 medical and health sciences, 030104 developmental biology, Algae, Cytoplasm, 010606 plant biology & botany
Abstract

Characeae are closely related to the ancient algal ancestors of all land plants. The long characean cells display a pH banding pattern to facilitate inorganic carbon import in the acid zones for photosynthetic efficiency. The excess OH−, generated in the cytoplasm after CO2 is taken into the chloroplasts, is disposed of in the alkaline band. To identify the transporter responsible, we searched the Chara australis transcriptome for homologues of mouse Slc4a11, which functions as OH−/H+ transporter. We found a single Slc4-like sequence CL5060.2 (named CaSLOT). When CaSLOT was expressed in Xenopus oocytes, an increase in membrane conductance and hyperpolarization of resting potential difference (PD) was observed with external pH increase to 9.5. These features recall the behavior of Slc4a11 in oocytes and are consistent with the action of a pH-dependent OH−/H+ conductance. The large scatter in the data might reflect intrinsic variability of CaSLOT transporter activation, inefficient expression in the oocyte due to evolutionary distance between ancient algae and frogs, or absence of putative activating factor present in Chara cytoplasm. CaSLOT homologues were found in chlorophyte and charophyte algae, but surprisingly not in related charophytes Zygnematophyceae or Coleochaetophyceae.

Published
2021
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11. Urate-induced epigenetic modifications in myeloid cells

Author

Tony R. Merriman, O. I. Gaal, Boris Novakovic, Tania O. Crişan, Donia Macartney-Coxson, Viola Klück, Charles A. Dinarello, M. M. A. Helsen, L. A. B. Joosten, Nicola Dalbeth, Amanda Phipps-Green, M. Badii, Ehsan Habibi, Lisa K. Stamp, Maartje C. P. Cleophas, Samuel T. Keating, Mihai G. Netea, Robab Davar, and Hendrik G. Stunnenberg

Subjects
0301 basic medicine, Gout, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Hyperuricemia, Diseases of the musculoskeletal system, Peripheral blood mononuclear cell, Monocytes, Epigenesis, Genetic, 03 medical and health sciences, Mice, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, medicine, Animals, Humans, Epigenetics, Molecular Biology, 030203 arthritis & rheumatology, DNA methylation, biology, Chemistry, Membrane Proteins, RNA-Binding Proteins, medicine.disease, Molecular biology, Chromatin, Uric Acid, 030104 developmental biology, Histone, RC925-935, biology.protein, Leukocytes, Mononuclear, H3K4me3, Cytokines, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Research Article
Abstract

Objectives Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1β. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. Methods Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. Results High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. Conclusion Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

Published
2021

12. Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin

Author

Janet K. Lighthouse, John M. Ashton, Wojciech Wojciechowski, Jeffrey D. Alexis, Richard P. Phipps, Ronald A. Dirkx, Eric M. Small, Ryan M. Burke, Amy Mohan, Meghann O’Brien, Collynn F. Woeller, and Pearl Quijada

Subjects
Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Cell Survival, Physiology, Myocardial Infarction, Cardiomyopathy, Gene Expression, Cardiomegaly, p38 Mitogen-Activated Protein Kinases, Article, Extracellular matrix, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, medicine, Animals, Humans, Myocardial infarction, Myofibroblasts, Fibroblast, Salinomycin, Pyrans, Heart Failure, rho-Associated Kinases, Ventricular Remodeling, business.industry, Angiotensin II, Myocardium, medicine.disease, Extracellular Matrix, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, NIH 3T3 Cells, Antifibrotic Agents, Cardiology and Cardiovascular Medicine, business, Deposition (chemistry), Myofibroblast
Abstract

Rationale: Cardiomyopathy is characterized by the deposition of extracellular matrix by activated resident cardiac fibroblasts called myofibroblasts. There are currently no therapeutic approaches to blunt the development of pathological fibrosis and ventricle chamber stiffening that ultimately leads to heart failure. Objective: We undertook a high-throughput screen to identify small molecule inhibitors of myofibroblast activation that might limit the progression of heart failure. We evaluated the therapeutic efficacy of the polyether ionophore salinomycin in patient-derived cardiac fibroblasts and preclinical mouse models of ischemic and nonischemic heart failure. Methods and Results: Here, we demonstrate that salinomycin displays potent anti-fibrotic activity in cardiac fibroblasts obtained from heart failure patients. In preclinical studies, salinomycin prevents cardiac fibrosis and functional decline in mouse models of ischemic and nonischemic heart disease. Remarkably, interventional treatment with salinomycin attenuates preestablished pathological cardiac remodeling secondary to hypertension and limits scar expansion when administered after a severe myocardial infarction. Mechanistically, salinomycin inhibits cardiac fibroblast activation by preventing p38/MAPK (mitogen activated protein kinase) and Rho signaling. Salinomycin also promotes cardiomyocyte survival and improves coronary vessel density, suggesting that cardioprotection conferred by salinomycin occurs via the integration of multiple mechanisms in multiple relevant cardiac cell types. Conclusions: These data establish salinomycin as an antifibrotic agent that targets multiple cardioprotection pathways, thereby holding promise for the treatment of heart failure patients.

Published
2021
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14. DP1 prostanoid receptor activation increases the severity of an acute lower respiratory viral infection in mice via TNF-α-induced immunopathology

Author

Sonja Rittchen, Jia Li, Simon Phipps, Ashik Ullah, and Sumaira Z. Hasnain

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, Neutrophils, Immunology, Receptors, Prostaglandin, Severity of Illness Index, Virus, Article, Monocytes, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immunopathology, Immunology and Allergy, Medicine, Animals, Receptor, Respiratory Tract Infections, Innate immune system, business.industry, Tumor Necrosis Factor-alpha, Acquired immune system, medicine.disease, Disease Models, Animal, 030104 developmental biology, chemistry, Bronchiolitis, Virus Diseases, Acute Disease, Cytokines, Prostaglandin D2, Disease Susceptibility, business, Viral load, Biomarkers, 030215 immunology
Abstract

Respiratory syncytial virus (RSV) bronchiolitis is a leading cause of infant hospitalization and mortality. We previously identified that prostaglandin D2 (PGD2), released following RSV infection of primary human airway epithelial cells or pneumonia virus of mice (PVM) infection of neonatal mice, elicits pro- or antiviral innate immune responses as a consequence of D-type prostanoid receptor 2 (DP2) or DP1 activation, respectively. Here, we sought to determine whether treatment with the DP1 agonist BW245c decreases the severity of bronchiolitis in PVM-infected neonatal mice. Consistent with previous findings, BW245c treatment increased IFN-λ production and decreased viral load in week 1 of the infection. However, unexpectedly, BW245c treatment increased mortality in week 2 of the infection. This increased morbidity was associated with viral spread to the parenchyma, an increased cellular infiltrate of TNF-α-producing cells (neutrophils, monocytes, and CD4+ T cells), and the heightened production of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. These phenotypes, as well as the increased mortality, were significantly attenuated following the administration of anti-TNF-α to PVM-infected, BW245c-treated mice. In summary, pharmacological activation of the DP1 receptor in PVM-infected neonatal mice boosts antiviral innate and adaptive immunity, however, this is ultimately detrimental, as a consequence of increased TNF-α-induced morbidity and mortality.

Published
2021

15. The effect of microfibrillated cellulose on the wet-web strength of paper

Author

Diana Tanase, Mark Paradis, Tom Larson, and Jonathan Phipps

Subjects
chemistry.chemical_compound, Materials science, chemistry, Polymer science, Mechanical Engineering, General Chemical Engineering, Media Technology, General Materials Science, General Chemistry, Cellulose
Abstract

The wet-web strength of paper immediately after the press section of a paper machine is a critical factor in determining machine runnability. However, it is difficult to determine at commercial scale, because the web has to be broken and production interrupted in order to obtain a sample for measurement. The use of microfibrillated cellulose (MFC) is believed to increase wet-web strength, as it has allowed filler level increases of 10% or more on many commercial paper machines. In this paper, we describe a laboratory method for estimating the effect of MFC on wet sheet strength after pressing, as well as actual measurements of wet-web strength from a pilot paper machine trial. These experiments have demonstrated the positive effect of MFC. At solids contents in the range typically observed after pressing, sheets with MFC at fixed filler content are significantly stronger, but also wetter, than those without it. When the use of MFC is combined with a typical increase in filler content, the wet web remains slightly stronger, but also becomes drier than the reference condition. These results are compatible with the theory put forward by van de Ven that wet-web strength is mainly a result of friction between entangled fibers, and they also suggest that the presence of MFC increases this friction.

Published
2021
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16. Co-ground mineral/microfibrillated cellulose composite materials: Recycled fibers, engineered minerals, and new product forms

Author

Tom Larson, Jonathan Phipps, and David Skuse

Subjects
Materials science, Mineral, business.industry, Mechanical Engineering, General Chemical Engineering, General Chemistry, chemistry.chemical_compound, Chemical engineering, chemistry, New product development, Media Technology, General Materials Science, Cellulose, business
Abstract

When pulp and minerals are co-processed in suspension, the mineral acts as a grinding aid, allowing cost-effective production of mineral/microfibrillated cellulose (MFC) composite materials. This processing uses robust milling equipment and is practiced at industrial scale. The resulting products can be used in many applications, including as wet- and dry-strength aids in paper and board production. Previously, we have reported that use of these MFC composite materials in fiber-based applications allow generally improved wet and dry mechanical properties with concomitant opportunities for cost savings, property improvements, or grade developments. Mineral/MFC composites made with recycled pulp feedstocks were shown to offer at least equivalent strength aid performance to composites made using virgin fibers. Selection of mineral and fiber allows preparation of mineral/MFC composites with a range of properties. For example, the viscosity of such formulations was shown to be controlled by the shape factor of the mineral chosen, effective barrier formulations were prepared, and mineral/MFC composites with graphite as the mineral were prepared. High-solids mineral/MFC composites were prepared at 75% total solids (37% fibril solids). When resuspended and used for papermaking, these high-solids products gave equivalent performance to never-dried controls.

Published
2021
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18. Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors

Author

Darren Bentley, Nassim Djebli, Andreas Brink, Edna Chow-Maneval, Elena Guerini, Karey Kowalski, Vincent Buchheit, Francois Mercier, Georgina Meneses-Lorente, Alex Phipps, and Li Yu

Subjects
Adult, Male, 0301 basic medicine, Indazoles, Metabolite, ADME Study, Antineoplastic Agents, Capsules, Entrectinib, Pharmacology, Bioequivalence, Feces, Food-Drug Interactions, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Neoplasms, Phase I Studies, Humans, Distribution (pharmacology), Medicine, Pharmacology (medical), Protein Kinase Inhibitors, Active metabolite, Aged, ADME, Cross-Over Studies, business.industry, Fasting, Middle Aged, Food effect, Healthy Volunteers, 030104 developmental biology, Therapeutic Equivalency, Oncology, chemistry, 030220 oncology & carcinogenesis, Benzamides, Female, business, TRK/ROS1/ALK
Abstract

SummaryBackground: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics. Methods: The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100–400 mg/m2, and 600–800 mg) once daily with food in continuous 28-day cycles. In the ADME study, volunteers received a single oral dose of [14C]entrectinib 600 mg. In the third study, volunteers received single doses of entrectinib 600 mg as the research and marketed formulations in the fasted state (Part 1), and the marketed formulation in the fed and fasted states (Part 2). Entrectinib and its major active metabolite M5 were assessed in all studies. Results: Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics. Conclusions: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food.

Published
2021
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19. Conformational control via sequence for a heteropeptoid in water: coupled NMR and Rosetta modelling

Author

Robert D. Gilbertson, Jurgen G. Schmidt, Jennifer S. Martinez, Ryszard Michalczyk, Jacob C. Miner, M. Lisa Phipps, Trideep Rajale, Charlie E. M. Strauss, and Robert F. Williams

Subjects
Circular dichroism, Peptidomimetic, Monte Carlo method, Metals and Alloys, Stacking, Sequence (biology), Peptoid, General Chemistry, Catalysis, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, chemistry.chemical_compound, Crystallography, chemistry, Materials Chemistry, Ceramics and Composites, Carboxylate, Conformational isomerism
Abstract

We report a critical advance in the generation and characterization of peptoid hetero-oligomers. A library of sub-monomers with amine and carboxylate side-chains are combined in different sequences using microwave-assisted synthesis. Their sequence-structure propensity is confirmed by circular dichroism, and conformer subtypes are enumerated by NMR. Biasing the ψ-angle backbone to trans (180°) in Monte Carlo modelling favors i to i + 3 naphthyl-naphthyl stacking, and matches experimental ensemble distributions. Taken together, high-yield synthesis of heterooligomers and NMR with structure prediction enables rapid determination of sequences that induce secondary structural propensities for predictive design of hydrophilic peptidomimetic foldamers and their future libraries.

Published
2021
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20. Systematic Variation of Ligand and Cation Parameters Enables Site-Selective C–C and C–N Cross-Coupling of Multiply Chlorinated Arenes through Substrate–Ligand Electrostatic Interactions

Author

Robert J. Phipps, Hendrik L. Schmitt, and William A. Golding

Subjects
chemistry.chemical_classification, Ligand, Substrate (chemistry), General Chemistry, 010402 general chemistry, Electrostatics, 01 natural sciences, Biochemistry, Combinatorial chemistry, Catalysis, 0104 chemical sciences, Coupling (electronics), chemistry.chemical_compound, Colloid and Surface Chemistry, chemistry, Non-covalent interactions, Molecule, Selectivity, Phosphine
Abstract

Use of attractive noncovalent interactions between ligand and substrate is an emerging strategy for controlling positional selectivity. A key question relates to whether fine control on molecules with multiple, closely spaced reactive positions is achievable using typically less directional electrostatic interactions. Herein, we apply a 10-piece "toolkit" comprising of two closely related sulfonated phosphine ligands and five bases, each possessing varying cation size, to the challenge of site-selective cross-coupling of multiply chlorinated arenes. The fine tuning provided by these ligand/base combinations is effective for Suzuki-Miyaura coupling and Buchwald-Hartwig coupling on a range of isomeric dichlorinated and trichlorinated arenes, substrates that would produce intractable mixtures when typical ligands are used. This study develops a practical solution for site-selective cross-coupling to generate complex, highly substituted arenes.

Published
2020
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21. Electrostatically-directed Pd-catalysis in combination with C-H activation: site-selective coupling of remote chlorides with fluoroarenes and fluoroheteroarenes

Author

Robert J. Phipps, William A. Golding, Golding, William A [0000-0001-6956-4961], Phipps, Robert J [0000-0002-7383-5469], and Apollo - University of Cambridge Repository

Subjects
inorganic chemicals, 34 Chemical Sciences, 010405 organic chemistry, Metalation, chemistry.chemical_element, 3405 Organic Chemistry, General Chemistry, 010402 general chemistry, 01 natural sciences, Oxidative addition, Combinatorial chemistry, 0104 chemical sciences, 3. Good health, Catalysis, Rhodium, 3402 Inorganic Chemistry, Metal, Chemistry, chemistry, visual_art, visual_art.visual_art_medium, Iridium, Selectivity, Palladium
Abstract

Systems incorporating catalyst–substrate non-covalent interactions are emerging as a versatile approach to address site-selectivity challenges in remote functionalization reactions. Given the achievements that have been made in this regard using metals such as iridium, manganese and rhodium, it is surprising that non-covalent catalyst direction has not been utilized in reactions incorporating palladium-catalyzed C–H activation steps, despite palladium being arguably the most versatile metal for C–H activation. Herein, we demonstrate that electrostatically directed, site-selective C–Cl oxidative addition is compatible with a subsequent C–H activation step, proceeding via a concerted metalation deprotonation-type mechanism. This results in site-selective cross-coupling of dichloroarenes with fluoroarenes and fluoroheteroarenes, with selectivity controlled by catalyst structure. This study demonstrates that Pd-catalyzed C–H activation can be used productively in combination with a non-covalently-directed mode of catalysis, with important implications in both fields., Electrostatically-directed oxidative addition is compatible with a subsequent C–H activation step, enabling site-selective coupling of remote chlorides with fluoroarenes and fluoroheteroarenes.

Published
2021

23. Acid and Solvent Effects on the Regioselectivity of Minisci-Type Addition to Quinolines Using Amino Acid Derived Redox Active Esters

Author

Barbara W. Hadrys and Robert J. Phipps

Subjects
chemistry.chemical_classification, 010405 organic chemistry, Radical, Organic Chemistry, Regioselectivity, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences, Amino acid, Catalysis, Solvent, chemistry, Organic chemistry, Solvent effects, Brønsted–Lowry acid–base theory, Minisci reaction
Abstract

Minisci-type reactions comprise an important class of reactions for the direct functionalization of basic heterocyclic compounds. On certain heterocycles, such as quinolines, Minisci-type reactions face a regioselectivity choice which often results in mixtures of regioisomers at the C2 and C4 positions, limiting utility. We present a study of the effect of solvent and Brønsted acid catalyst on regioselectivity in the addition of N-acetyl-substituted, α-amino alkyl radicals to quinolines. By tuning the solvent and acid combination we identify conditions that strongly favour C2 and strongly favour C4 and present a small scope of compatible substrates.

Published
2020
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24. Value Added Impact of Both Point-of-Care and Laboratory Lactic Acid Analysis When Emergently Evaluating Cancer Patients

Author

Georges T Bouobda, Ron A. Phipps, Lavinia P. Middleton, and Carmen E. Gonzalez

Subjects
medicine.medical_specialty, Emergency department, business.industry, Point-of-care testing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Lactic acid, Retrospective cohort study, medicine.disease, Sepsis, Tumor lysis syndrome, chemistry.chemical_compound, Oncology, chemistry, Point-of-care, Internal medicine, Medicine, business, RC254-282, Original Research, Point of care
Abstract

Introduction Cancer patients are immunosuppressed and may present to an emergency department with atypical symptoms. In the emergency setting, it is important ascertain rapidly if lactic acid levels are high, either due to sepsis or tumor lysis syndrome, to effectively manage symptoms. Therefore, it is critical to determine the blood lactic acid level to timely identify who is at risk of sepsis and provide early intervention. We have compared blood lactic acid concentrations (BLAC) in cancer patients obtained by point-of-care testing (POCT) and those measured by laboratory analysis in blood samples drawn within a short time of each other. Methods This was a retrospective study in cancer patients whose BLAC had been determined by POCT and laboratory analysis. Only those patients who had blood withdrawn for both testing methods within a 2-h timeframe were included in the study. Regressions were performed together with an analysis categorizing the BLAC from both testing methods. Results A total of 274 patients met the criteria for the study. The BLAC from POCT correlated well with the values from laboratory testing (R = 0.925). Categorization of BLAC showed that 88.32% of the patients had BLAC that directly matched between the two tests; 28 (10.22%) patients had a normal BLAC according to laboratory analysis but a high BLAC on POCT; and four (1.46%) patients had a high BLAC according laboratory analysis but normal BLAC on POCT. Conclusions There was a high correlation between POCT and laboratory analysis values of BLAC in cancer patients, with the results from both testing methods agreeing 96% of the time. This finding suggests that POCT would suffice in most cases. Importantly, in 2% of the cancer patients who presented emergently, BLAC determined by POCT and laboratory analysis did not agree. Therefore, in subsequent decision-making, we recommend that if sepsis is suspected and BLAC determined by POCT is normal, nucleic acids, proteins, circulating cells, and interleukin-3 levels should also be obtained by POCT to confirm sepsis and/or rule out tumor lysis syndrome in patients with cancer. Electronic Supplementary Material The online version of this article (10.1007/s40487-020-00118-0) contains supplementary material, which is available to authorized users.

Published
2020
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25. Using fibre property measurements to predict the tensile index of microfibrillated cellulose nanopaper

Author

Richard W. Greenwood, David Skuse, Stuart Blackburn, Jonathan Phipps, and Lewis Taylor

Subjects
0106 biological sciences, Grinding process, Materials science, Polymers and Plastics, 02 engineering and technology, Raw material, 021001 nanoscience & nanotechnology, 01 natural sciences, chemistry.chemical_compound, chemistry, Breakage, Cellulosic ethanol, 010608 biotechnology, Ultimate tensile strength, Hemicellulose, Cellulose, Composite material, 0210 nano-technology
Abstract

A wide variety of wood and non-wood cellulosic fibre sources were used as a feed to produce microfibrillated cellulose (MFC) using a grinding process. Nanopaper was formed using this product, and the tensile index was measured. The hemicellulose content of the feed fibres was measured, and was found to correlate with the production of finer microfibrils and a higher MFC tensile strength. The correlation with tensile strength was improved by the inclusion of a measurement of the MFC particle lengths as measured by a fibre image analyser, with the resulting relation fitting a modified Page Equation. It was hypothesised that the frequency of flaws in the feed fibre cross-section influences the length of the MFC particles produced, and so the zero-span tensile index of the fibres was measured as a proxy for this since it forces cross-sectional fibre breakage. The fibre zero-span tensile index was found to correlate with MFC particle length and so was used in its place in the equation. The resultant equation can predict MFC tensile strength from zero-span tensile index and hemicellulose content measurements of cellulosic fibres and can aid in optimising feedstock selection for mechanical MFC production processes.

Published
2020
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26. Evaluation of the procoagulant properties of a newly developed platelet modified lysate product

Author

Chad A. Hudson, Majed A. Refaai, Grace Conley, Sherry L. Spinelli, Hannah L McRae, Neil Blumberg, Craig N. Morrell, and Richard P. Phipps

Subjects
Blood Platelets, Lysis, Sonication, Immunology, Kinetics, Drug Evaluation, Preclinical, Platelet Transfusion, 030204 cardiovascular system & hematology, Andrology, 03 medical and health sciences, 0302 clinical medicine, Cell-Derived Microparticles, In vivo, medicine, Humans, Immunology and Allergy, Platelet, Blood Coagulation, Coagulants, Chemistry, Hematology, medicine.disease, Thrombosis, Platelet transfusion, Hemolytic reactions, 030215 immunology
Abstract

Background Platelet transfusion is associated with logistical problems with the national storage guidelines of platelets. This results in decreased function in vivo as a result of the platelet storage lesion, and complications such as allergic or hemolytic reactions and thrombosis. We evaluated a new, freshly prepared platelet modified lysate (PML) product designed to be more procoagulant than fresh and stored platelets. Methods Fresh platelets were concentrated, sonicated, and centrifuged to produce PML. Samples of both washed and unwashed PML were evaluated for particle size, concentration, and activity, and then tested for clot kinetics and thrombin generation. PML samples were also stored at various temperatures for durations up to 6 months and evaluated for clot kinetics and thrombin generation throughout. Results PML showed significantly higher concentration of platelet microparticles, increased procoagulant properties, and increased thrombin generation as compared to fresh and stored platelets. In addition, PML maintained its clot kinetics over a 6-month storage period with variable storage conditions. Conclusions The newly proposed PML product is more procoagulant, stable, and has additional potential applications than currently available platelet products. Further studies will be performed to assess its functions in vivo and to assess thrombotic potential.

Published
2020
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27. Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus

Author

Fernando Perez-Ruiz, Alexander So, Anne-Katherin Tausche, Fina A S Kurreeman, Philip Riches, Amanda Phipps-Green, Geraldine M. McCarthy, Greg G. Gamble, Jeffrey N. Miner, Leo A. B. Joosten, Faseeh Zaidi, Ravi K. Narang, Nicola Dalbeth, T.L.Th.A. Jansen, Matthijs Janssen, Lisa K. Stamp, Tony R. Merriman, Michael Doherty, Mariano Andrés, and Rosa J. Torres

Subjects
Adult, Male, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Gout, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Single-nucleotide polymorphism, Logistic regression, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Rheumatology, Internal medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Humans, Medicine, Genetic Predisposition to Disease, Pharmacology (medical), Age of Onset, Genetic association, Creatinine, business.industry, Tophus, nutritional and metabolic diseases, Odds ratio, Symptom Flare Up, medicine.disease, Neoplasm Proteins, Uric Acid, Europe, chemistry, Female, business, Body mass index
Abstract

Objective The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. Methods Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout Results In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). Conclusion In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Published
2020

28. Rad51 filaments assembled in the absence of the complex formed by the Rad51 paralogs Rad55 and Rad57 are outcompeted by translesion DNA polymerases on UV-induced ssDNA gaps

Author

Laurent Maloisel, Émilie Ma, Jamie Phipps, Alice Deshayes, Stefano Mattarocci, Stephane Marcand, Karine Dubrana, and Éric Coïc

Subjects
Cancer Research, biology, DNA polymerase, DNA damage, Mutagenesis, DNA replication, RAD51, Cell biology, chemistry.chemical_compound, chemistry, biology.protein, Genetics, Homologous recombination, Molecular Biology, DNA, Polymerase, Genetics (clinical), Ecology, Evolution, Behavior and Systematics
Abstract

The bypass of DNA lesions that block replicative polymerases during DNA replication relies on DNA damage tolerance pathways. The error-prone translesion synthesis (TLS) pathway depends on specialized DNA polymerases that incorporate nucleotides in front of base lesions, potentially inducing mutagenesis. Two error-free pathways can bypass the lesions: the template switching pathway, which uses the sister chromatid as a template, and the homologous recombination pathway (HR), which also can use the homologous chromosome as template. The balance between error-prone and error-free pathways controls the mutagenesis level. Therefore, it is crucial to precisely characterize factors that influence the pathway choice to better understand genetic stability at replication forks. In yeast, the complex formed by the Rad51 paralogs Rad55 and Rad57 promotes HR and template-switching at stalled replication forks. At DNA double-strand breaks (DSBs), this complex promotes Rad51 filament formation and stability, notably by counteracting the Srs2 anti-recombinase. To explore the role of the Rad55-Rad57 complex in error-free pathways, we monitored the genetic interactions between Rad55-Rad57, the translesion polymerases Polζ or Polη, and Srs2 following UV radiation that induces mostly single-strand DNA gaps. We found that the Rad55-Rad57 complex was involved in three ways. First, it protects Rad51 filaments from Srs2, as it does at DSBs. Second, it promotes Rad51 filament stability independently of Srs2. Finally, we observed that UV-induced HR is almost abolished in Rad55-Rad57 deficient cells, and is partially restored upon Polζ or Polη depletion. Hence, we propose that the Rad55-Rad57 complex is essential to promote Rad51 filament stability on single-strand DNA gaps, notably to counteract the error-prone TLS polymerases and mutagenesis.Author summaryProcessive and accurate DNA polymerases replicate genomic DNA during the S phase of each cell cycle. DNA base lesions on template DNA block these polymerases and result in an accumulation of single-stranded DNA gaps behind moving replication forks. These gaps are filled-in by error-prone and error-free pathways. In this work, we show that the complex made by the Rad51 paralogs Rad55 and Rad57 is essential for the error-free homologous recombination gap-filling pathway when DNA replication is stalled by UV-induced DNA lesions, but not for DNA double strand break repair. Interestingly, we found that homologous recombination is efficiently outcompeted by error-prone translesion DNA polymerases in Rad55-Rad57-deficient cells. We propose that the Rad55-Rad57 complex is essential for Rad51 filament stability at UV-induced DNA gaps to promote efficient error-free homologous recombination. Furthermore, our study in yeast predicts that inhibitors of error-prone DNA polymerases might selectively target cancer cells in which RAD51 paralogs are mutated.

Published
2023
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29. Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy

Author

Elena Ivanova, Connie H Wong, Bang V. Bui, Gene Venables, Samuel A Mills, Michael A Dixon, Flora Hui, Zheng He, Kirstan A. Vessey, Vickie Hy Wong, Josh Tonc, James C Young, Botir T. Sagdullaev, Andrew I Jobling, Ursula Greferath, Erica L. Fletcher, and Joanna A. Phipps

Subjects
retina, microglia, Tetrazoles, Streptozocin, Renin-Angiotensin System, chemistry.chemical_compound, Mice, 03 medical and health sciences, 0302 clinical medicine, fractalkine, CX3CR1, Medicine, Animals, 030304 developmental biology, Neurons, Retina, 0303 health sciences, Diabetic Retinopathy, Multidisciplinary, Microglia, diabetes, business.industry, Chemokine CX3CL1, Gene Expression Profiling, Biphenyl Compounds, Retinal Vessels, Retinal, Diabetic retinopathy, Cell Biology, Biological Sciences, capillary regulation, medicine.disease, Streptozotocin, Cell biology, Rats, Candesartan, medicine.anatomical_structure, chemistry, Vasoconstriction, Benzimidazoles, medicine.symptom, business, Pericytes, 030217 neurology & neurosurgery, medicine.drug, Signal Transduction
Abstract

Significance This work identifies a role for microglia, the innate immune cells of the CNS, in the local control of the retinal vasculature and identifies deficits early in diabetes. Microglia contact neurons and vasculature and express several vasoactive agents. Activation of microglial fractalkine-Cx3cr1 signaling leads to capillary constriction and blocking the renin-angiotensin system (RAS) with candesartan abolishes microglial-mediated vasoconstriction in the retina. In early diabetes, reduced retinal blood flow is coincident with capillary constriction, increased microglial–vessel association, loss of microglial–capillary regulation, and altered microglial expression of the RAS pathway. While candesartan restores retinal capillary diameter early in diabetes, targeting of microglial–vascular regulation is required to prevent coincident dilation of large retinal vessels and reduced retinal blood flow., Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial–capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial–vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.

Published
2021
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31. Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

Author

Daniel C. Okoye, Adeline M. Fanni, M. Lisa Phipps, Jennifer S. Martinez, Florencia A. Monge, Julia J. Hammond, Eva Y. Chi, Gabriella Brinkley, Tye D. Martin, David G. Whitten, Fahimeh Maghsoodi, and Deborah G. Evans

Subjects
Amyloid, Singlet oxygen, medicine.medical_treatment, Photodynamic therapy, macromolecular substances, Fibril, chemistry.chemical_compound, Monomer, chemistry, medicine, Biophysics, Photosensitizer, Methylene blue, Histidine
Abstract

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer’s disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylene-based compounds (OPEs) exhibit selective binding and fluorescence turn-on in the presence of pre-fibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-β (Aβ) and α-synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of toxic Aβ aggregates and compared its efficacy to the well-known but non-selective photosensitizer methylene blue (MB). Our results show that while MB photo-oxidized both monomeric and fibrillar conformers of Aβ40, OPE oxidized only Aβ40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed, but retained the characteristic β-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE’s photosensitizing activity overcomes the limitation of off-target oxidation of currently available photosensitizers, and represents a significant advancement of PDT as a viable strategy to treat neurodegenerative disorders.

Published
2021
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32. Rhodium(III)-Catalyzed Three-Component 1,2-Diamination of Unactivated Terminal Alkenes

Author

Tomislav Rovis, Honghui Lei, Sumin Lee, Erik J. T. Phipps, and Young Jin Jang

Subjects
010405 organic chemistry, Chemistry, Nitrene, Organic Chemistry, One-pot synthesis, chemistry.chemical_element, Regioselectivity, 010402 general chemistry, Ring (chemistry), 01 natural sciences, Combinatorial chemistry, Catalysis, Article, 0104 chemical sciences, Rhodium, Electrophile, Amine gas treating
Abstract

We report a three-component diamination of simple unactivated alkenes using an electrophilic nitrene source and amine nucleo­philes. The reaction provides rapid access to 1,2-vicinal diamines from terminal alkenes through a one-pot protocol. The transformation proceeds smoothly with excellent tolerance for a broad array of primary and secondary amines, affording the desired products in good yield and regioselectivity. The mechanism is proposed to proceed through a Rh(III)-catalyzed aziridination of alkenes with subsequent ring opening by primary or secondary amines.

Published
2021

33. Quantitative amino acid analysis by liquid chromatography‐tandem mass spectrometry using low cost derivatization and an automated liquid handler

Author

Eric Crossley, Patricia M. Jones, Richard L. Boriack, Khushbu Patel, and William S. Phipps

Subjects
Research Report, Analyte, lcsh:QH426-470, Endocrinology, Diabetes and Metabolism, inborn errors of metabolism, Tandem mass spectrometry, Mass spectrometry, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Biochemistry, Genetics and Molecular Biology (miscellaneous), chemistry.chemical_compound, Liquid chromatography–mass spectrometry, Internal Medicine, liquid chromatography, Sample preparation, Derivatization, mass spectrometry, lcsh:RC648-665, Chromatography, Chemistry, Research Reports, isotope‐coded derivatization, triple quadrupole, Triple quadrupole mass spectrometer, lcsh:Genetics, Ninhydrin, amino acid
Abstract

Amino acid analysis is central to newborn screening and the investigation of inborn errors of metabolism. Ion‐exchange chromatography with ninhydrin derivatization remains the reference method for quantitative amino acid analysis but offers slow chromatography and is susceptible to interference from other co‐eluting compounds. Liquid‐chromatography tandem mass spectrometry (LC‐MS/MS) provides a rapid and highly specific alternative, but sample preparation is frequently laborious and sometimes cost prohibitive. To address these limitations, we validated an LC‐MS/MS method using the aTRAQ Reagents Application Kit with a modified protocol consuming only half reagents. Adequate performance for clinical specimen measurement of 26 amino acids with high clinical relevance was achieved. An automated liquid handler and modified calibration and normalization approaches were used to ensure reproducible assay performance. Linear measurement between 5 and 2000 μM was achieved for most analytes despite use of a small, 10 μl sample size. Overall the method achieved near substantially improved throughput and enabled use of smaller samples volumes for batched analyses of clinical samples.

Published
2019
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34. Improving biodiesel yield of animal waste fats by combination of a pre-treatment technique and microwave technology

Author

Patryk Kot, Ibijoke Idowu, David Phipps, Steve Wylie, Montserrat Ortoneda Pedrola, Andy Shaw, and K.H. Teng

Subjects
Biodiesel, 060102 archaeology, Renewable Energy, Sustainability and the Environment, 020209 energy, 06 humanities and the arts, 02 engineering and technology, Transesterification, Raw material, Pulp and paper industry, chemistry.chemical_compound, chemistry, Tallow, Yield (chemistry), Biodiesel production, 0202 electrical engineering, electronic engineering, information engineering, 0601 history and archaeology, Methanol, Fatty acid methyl ester
Abstract

Recently, due to its low cost there has been increased attention on Animal Waste Fats (AWFs) as a feedstock for biodiesel production. Advanced microwave technology has also been reported by many researchers to enhance the transesterification in biodiesel production. However, esterification of free fatty acids in the feedstock reported here has not attracted so much attention. AWFs come with its challenges namely, high free fatty acid (FFA) content and high water content. This study utilizes AWFs (tallow) containing very large amount of FFA; (25 wt%, 18 wt%, and 9.4 wt% FFA/AWFs) as feedstock for fatty acid methyl ester (FAME) production. A simple thermal pre-treatment technique followed microwave assisted esterification with methanol (MeOH) was conducted in a batch process to reduce the FFA content to as low as 1 wt% FFA, which is then suitable for the alkaline transesterification process. The pre-treatment of AWFs at 88 °C to first reduce water and decrease viscosity, followed by an operating microwave power of 70 W producing a power density 1.147 mW/m3, achieved a 15% increase in reduction of FFA over 30 W microwave power and conventional thermal method. Under optimum conditions, using 2.0 wt.wt% sulphuric acid catalyst/AWFs and 1:6 M ratio AWF/MeOH, the FFA conversion of 93 wt % was achieved. The results indicated that the pre-treatment and microwave application provided a faster route to high FFA reduction of AWFs during esterification process. The proposed technology is promising for the potential scale up industrial application.

Published
2019
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35. Eu(III) and Tb(III) Complexes of Octa- and Nonadentate Macrocyclic Ligands Carrying Azide, Alkyne, and Ester Reactive Groups

Author

K. Eszter Borbas, Andreas Orthaber, Salauat R. Kiraev, Dulcie Phipps, and Daniel Kovacs

Subjects
Inorganic Chemistry, Lanthanide, chemistry.chemical_classification, chemistry.chemical_compound, 010405 organic chemistry, Chemistry, Polymer chemistry, Alkyne, Azide, Physical and Theoretical Chemistry, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences
Abstract

Azide- and alkyne-functionalized bioconjugable luminescent lanthanide complexes are reported. Reactive handles were introduced into the complexes by the late-stage modification of a methylenecarboxylic acid antenna pendent group. Tb and Eu quantum yields (11-13% and 3.4-3.6%, respectively) were not greatly affected by the presence of the azide or the alkyne compared to the parent complex (Φ

Published
2019
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36. Toxicological safety evaluation of a novel highly bioavailable turmeric extract formulation

Author

Kirt R. Phipps, Killian Privat, Nicolas Quesnot, Nigel Baldwin, Eugene Ahlborn, and Pascale Fança-Berthon

Subjects
Male, Biological Availability, 010501 environmental sciences, Toxicology, medicine.disease_cause, 01 natural sciences, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Ingredient, Curcuma, Quillaia, Animals, Humans, Medicine, Ingestion, Cells, Cultured, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Plants, Medicinal, Traditional medicine, biology, Mutagenicity Tests, Plant Extracts, business.industry, biology.organism_classification, Rats, Bioavailability, chemistry, Micronucleus test, Curcumin, Female, France, business, Genotoxicity
Abstract

Turmeric (Curcuma longa L.) extracts have a long history of use worldwide, but a major limitation of these extracts is their extremely low oral bioavailability, caused by low absorption, rapid metabolism and rapid excretion following ingestion. Thus, a new highly bioavailable turmeric extract formulation (comprising turmeric extract, acacia gum, sunflower oil and quillaia extract) has been developed and is intended for use as a food ingredient. Safety of this novel extract was evaluated using the standard Tier 1 battery of in vitro genotoxicity tests (bacterial reverse mutation test and an in vitro mammalian cell micronucleus test) followed by repeated-dose 28- and 90-day oral toxicity studies in rats. In the 90-day study, male and female Sprague-Dawley rats were dosed once daily, by oral gavage, either with the vehicle or the test item at 500, 1500 or 3000 mg/kg body weight/day. Clinical examinations were conducted regularly, and body weights and food consumption were recorded weekly throughout the study. At the end of the study, blood samples were analyzed for clinical pathology parameters, before a macroscopic necropsy was conducted and a full list of tissues were examined histopathologically. There was no evidence of genotoxicity in vitro. No test item-related adverse effects were observed in the 28- or 90-day studies; therefore, 3000 mg/kg body weight/day (the maximum feasible dose and highest dose tested in rats) was established as the no-observed-adverse-effect level.

Published
2019
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37. Toxicological safety assessment of the human‐identical milk oligosaccharide 3′‐sialyllactose sodium salt

Author

Marta H. Mikš, Christoph H. Röhrig, Barry Lynch, Nigel Baldwin, Kirt R. Phipps, Diane R. Stannard, Alica Šoltésová, and Ben Gilby

Subjects
Adult, Male, Population, Oligosaccharides, 010501 environmental sciences, Biology, Toxicology, medicine.disease_cause, 01 natural sciences, 03 medical and health sciences, Ingredient, medicine, Animals, Humans, Food science, education, 030304 developmental biology, 0105 earth and related environmental sciences, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, Milk, Human, Mutagenicity Tests, Fructooligosaccharide, Infant, Newborn, Infant, Oligosaccharide, Infant Formula, Rats, Infant formula, chemistry, Models, Animal, Toxicity, Female, Hazard Analysis and Critical Control Points, Genotoxicity, Hormone
Abstract

Human breastmilk is a mixture of nutrients, hormones and bioactive molecules that are vital for infant growth and development. Infant formula (IF) lacks many of these compounds, most notably human milk oligosaccharides (HMOs), which are abundant in breastmilk but scarce in IF. Sialyllactoses, such as 3'-sialyllactose, constitute a large portion of the HMO fraction. To produce IF that matches breastmilk more closely, biosynthesized human-identical milk oligosaccharides (structurally identical to HMOs) such as 3'-sialyllactose sodium salt (3'-SL) are proposed for use in IF and foods for the general population. The safety assessment of 3'-SL comprised in vitro genotoxicity tests and a 90-day oral (gavage) toxicity study. This is the first 90-day study conducted with 3'-SL using neonatal rats (7 days old at the start of dosing-equivalent age to newborn human infants in terms of central nervous system and reproductive development), demonstrating the safety of 3'-SL for consumption by infants, the most sensitive age group. The neonatal rats received 3'-SL at doses up to 5,000 mg/kg body weight (BW)/day and reference controls received 5,000 mg/kg BW/day of fructooligosaccharide (an ingredient approved for use in IF) for comparison with the high-dose 3'-SL group, followed by a 4-week recovery period. There was no evidence of genotoxicity in vitro. In the absence of any test item-related adverse effects in the 90-day study, the high dose (5,000 mg/kg BW/day) was established as the no-observed-adverse-effect level. This confirms the safety of 3'-SL for use in IF for infants, as well as in functional foods for the general population.

Published
2019
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38. Toxicological safety evaluation of the human‐identical milk oligosaccharide 6′‐sialyllactose sodium salt

Author

Marta H. Mikš, Alica Šoltésová, Kirt R. Phipps, Ben Gilby, Diane R. Stannard, Barry Lynch, Christoph H. Röhrig, and Nigel Baldwin

Subjects
Adult, Male, Population, Oligosaccharides, 010501 environmental sciences, Toxicology, medicine.disease_cause, 01 natural sciences, 03 medical and health sciences, Ingredient, medicine, Animals, Humans, Food science, education, Adverse effect, 030304 developmental biology, 0105 earth and related environmental sciences, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, Milk, Human, Mutagenicity Tests, Fructooligosaccharide, Infant, Newborn, Infant, Oligosaccharide, Infant Formula, Rats, Infant formula, chemistry, Models, Animal, Toxicity, Female, Hazard Analysis and Critical Control Points, Genotoxicity
Abstract

Human milk oligosaccharides (HMOs) are abundant in breastmilk, but their presence in infant formula is negligible. Sialylated HMOs, such as 6'-sialyllactose, constitute a significant portion of the HMO fraction of human milk and are linked to important biological functions. To produce infant formula that is more comparable with human milk, biosynthesized sialyllactoses known as human-identical milk oligosaccharides (structurally identical counterparts to their respective naturally occurring HMOs in breastmilk) are proposed for use in infant formula and other functional foods for the general population. To support the safety of 6'-sialyllactose sodium salt (6'-SL), a 90-day oral (gavage) toxicity study and in vitro genotoxicity tests were conducted. The 90-day study is the first to be conducted with 6'-SL using neonatal rats (day 7 of age at the start of dosing), thus addressing safety of 6'-SL for consumption by the most sensitive age group (infants). In the 90-day study, neonatal rats received 6'-SL at doses up to 5000 mg/kg body weight (BW)/day and reference controls received 5000 mg/kg BW/day of fructooligosaccharide (an ingredient approved for use in infant formula) for comparison with the high-dose 6'-SL group, followed by a 4-week recovery period. There was no evidence of genotoxicity in vitro. No test item-related adverse effects were observed on any parameter in the 90-day study, thus the high dose (5000 mg/kg BW/day) was established as the no-observed-adverse-effect level. These results confirm that 6'-SL is safe for use in formula milk for infants and in other functional foods for the general population.

Published
2019
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39. Multicomponent Synthesis of Diversified Chromeno[3,2-d]oxazoles

Author

Faizan Cheema, M. Hassan Beyzavi, Jiyun Hu, Ahmad Reza Khosropour, Abdol-Khalegh Bordbar, Hadi Amiri Rudbari, Joshua Phipps, and Parisa Zamani

Subjects
chemistry.chemical_compound, 010405 organic chemistry, Chemistry, Scientific method, Propylene carbonate, General Chemistry, General Medicine, 010402 general chemistry, 01 natural sciences, Combinatorial chemistry, 0104 chemical sciences
Abstract

A practical and efficient synthetic procedure to novel chromeno[3,2-d]oxazoles through a one-pot sequential multistep process is presented. This procedure proceeds efficiently in propylene carbonat...

Published
2019
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40. Rh(III)-Catalyzed C–H Activation-Initiated Directed Cyclopropanation of Allylic Alcohols

Author

Tomislav Rovis and Erik J. T. Phipps

Subjects
Cyclopropanes, Annulation, Allylic rearrangement, Olefin fiber, Propanols, Cyclopropanation, Chemistry, Stereoisomerism, General Chemistry, Alkenes, Ketones, Allylic alcohol, 010402 general chemistry, 01 natural sciences, Biochemistry, Medicinal chemistry, Article, Catalysis, 0104 chemical sciences, Colloid and Surface Chemistry, Coordination Complexes, Cyclization, Rhodium
Abstract

We have developed a Rh(III)-catalyzed diastereoselective [2+1] annulation onto allylic alcohols initiated by alkenyl C–H activation of N-enoxyphthalimides to furnish substituted cyclopropyl-ketones. Notably, the traceless oxyphthalimide handle serves three functions: directing C–H activation, oxidation of Rh(III), and, collectively with the allylic alcohol, in directing cyclopropanation to control diastereoselectivity. Allylic alcohols are shown to be highly reactive olefin coupling partners leading to a directed diastereoselective cyclopropanation reaction, providing products not accessible by other routes.

Published
2019
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41. Total plasma heme concentration increases after red blood cell transfusion and predicts mortality in critically ill medical patients

Author

Sherry L. Spinelli, Jill M. Cholette, Richard P. Phipps, Kelly F. Henrichs, Anthony P. Pietropaoli, Neil Blumberg, and Majed A. Refaai

Subjects
medicine.medical_specialty, business.industry, Critically ill, Immunology, Hematology, Odds ratio, 030204 cardiovascular system & hematology, Gastroenterology, Confidence interval, 03 medical and health sciences, chemistry.chemical_compound, Red blood cell, 0302 clinical medicine, medicine.anatomical_structure, chemistry, Interquartile range, Intensive care, Internal medicine, Immunology and Allergy, Medicine, business, Prospective cohort study, Heme, 030215 immunology
Abstract

BACKGROUND Relationships between red blood cell (RBC) transfusion, circulating cell-free heme, and clinical outcomes in critically ill transfusion recipients are incompletely understood. The goal of this study was to determine whether total plasma heme increases after RBC transfusion and predicts mortality in critically ill patients. STUDY DESIGN AND METHODS This was a prospective cohort study of 111 consecutive medical intensive care patients requiring RBC transfusion. Cell-free heme was measured in RBC units before transfusion and in the patients' plasma before and after transfusion. RESULTS Total plasma heme levels increased in response to transfusion, from a median (interquartile range [IQR]) of 35 (26-76) μmol/L to 47 (35-73) μmol/L (p

Published
2019
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42. Lipoxin B4 Enhances Human Memory B Cell Antibody Production via Upregulating Cyclooxygenase-2 Expression

Author

Katie L. Lannan, Richard P. Phipps, Nina Kim, Stephen J. Pollock, Thomas H. Thatcher, and Collynn F. Woeller

Subjects
0301 basic medicine, Lipoxin, education.field_of_study, XBP1, Immunology, Population, Acquired immune system, In vitro, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, chemistry, Plasma cell differentiation, medicine, Immunology and Allergy, Memory B cell, education, B cell, 030215 immunology
Abstract

Vaccination has been the most effective way to prevent or reduce infectious diseases; examples include the eradication of smallpox and attenuation of tetanus and measles. However, there is a large segment of the population that responds poorly to vaccines, in part because they are immunocompromised because of disease, age, or pharmacologic therapy and are unable to generate long-term protection. Specialized proresolving mediators are endogenously produced lipids that have potent proresolving and anti-inflammatory activities. Lipoxin B4 (LXB4) is a member of the lipoxin family, with its proresolving effects shown in allergic airway inflammation. However, its effects on the adaptive immune system, especially on human B cells, are not known. In this study, we investigated the effects of LXB4 on human B cells using cells from healthy donors and donors vaccinated against influenza virus in vitro. LXB4 promoted IgG Ab production in memory B cells and also increased the number of IgG-secreting B cells. LXB4 enhanced expression of two key transcription factors involved in plasma cell differentiation, BLIMP1 and XBP1. Interestingly, LXB4 increased expression of cyclooxygenase-2 (COX2), an enzyme that is required for efficient B cell Ab production. The effects of LXB4 are at least partially COX2-dependent as COX2 inhibitors attenuated LXB4-stimulated BLIMP1 and Xpb-1 expression as well as IgG production. Thus, our study reveals for the first time, to our knowledge, that LXB4 boosts memory B cell activation through COX2 and suggests that LXB4 can serve as a new vaccine adjuvant.

Published
2018
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43. Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication

Author

Elizabeth Ahern, Nabila Seddiki, Thuy T. Le, Amanda L. Bain, Lambros T. Koufariotis, Nicola Waddell, Emily M. Cross, Daniel J. Rawle, Robert D. McCuaig, Jade K. Forwood, Kexin Yan, Sudha Rao, Michelle Melino, Wen Juan Tu, Andreas Suhrbier, Simon Phipps, Sofiya Tsimbalyuk, Natasha Collinson, and Rebecca L Johnston

Subjects
animal structures, viruses, Immunology, Cell, Importin, Biochemistry, Article, Transcription (biology), Genetics, medicine, Molecular Biology, QH573-671, biology, Chemistry, RNA, Cell Biology, Cell biology, medicine.anatomical_structure, Viral replication, Cell culture, Cytoplasm, biology.protein, Demethylase, Epigenetics, Cytology, hormones, hormone substitutes, and hormone antagonists, Post-translational modifications
Abstract

Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

Published
2021
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44. Current State of Targeted Radiometal-Based Constructs for the Detection and Treatment of Disease in the Brain

Author

Melissa A. Deri, Michael D. Phipps, and Vanessa A. Sanders

Subjects
Pharmacology, Brain Diseases, 010405 organic chemistry, Chemistry, business.industry, Organic Chemistry, Biomedical Engineering, Pharmaceutical Science, Bioengineering, 02 engineering and technology, Disease, 021001 nanoscience & nanotechnology, 01 natural sciences, 0104 chemical sciences, Brain disease, Metals, Humans, Personalized medicine, Radiopharmaceuticals, 0210 nano-technology, business, Neuroscience, Biotechnology, Chelating Agents
Abstract

The continual development of radiopharmaceutical agents for the field of nuclear medicine is integral to promoting the necessity of personalized medicine. One way to greatly expand the selection of radiopharmaceuticals available is to broaden the range of radionuclides employed in such agents. Widening the scope of development to include radiometals with their variety of physical decay characteristics and chemical properties opens up a myriad of possibilities for new actively targeted molecules and bioconjugates. This is especially true to further advance the imaging and treatment of disease in the brain. Over the past few decades, imaging of disease in the brain has heavily relied on agents which exploit metabolic uptake. However, through utilizing the broad range of physical characteristics that radiometals offer, the ability to target other processes has become more available. The varied chemistries of radiometals also allows for them to incorporated into specifically designed diverse constructs. A major limitation to efficient treatment of disease in the brain is the ability for relevant agents to penetrate the blood-brain barrier. Thus, along with efficient disease targeting, there must be intentional thought put into overcoming this challenge. Here, we review the current field of radiometal-based agents aimed at either imaging or therapy of brain disease that have been evaluated through at least in vivo studies.

Published
2021

45. Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients

Author

Andrew D Beggs, Oliver Phipps, Austin G. Acheson, Mohammed Nabil Quraishi, Edward A Dickson, Aditi Kumar, HO Al-Hassi, Helen Steed, Matthew J Brookes, and Jonathan Segal

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Anemia, Colorectal cancer, Metabolite, gut microbiome, colorectal cancer, Gastroenterology, lcsh:RC254-282, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, iron deficiency, tumor microbiota, Internal medicine, medicine, 16S rRNA, biology, Lactobacillales, business.industry, Clostridiales, iron supplementation, Iron deficiency, medicine.disease, biology.organism_classification, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, anemia, stomatognathic diseases, 030104 developmental biology, Oncology, chemistry, Iron-deficiency anemia, 030220 oncology & carcinogenesis, Complication, business
Abstract

Simple Summary Anemia is commonly associated with colorectal cancer and often requires intervention with therapeutic iron. However, iron is required for growth by the majority of colonic bacteria, leading to competition for free luminal iron. Hence, this leaves the potential for the route of iron administration to lead to differential gut bacterial populations. This study aimed to investigate the differences in on- and off-tumor bacterial populations following oral and intravenous therapy in anemic colorectal cancer patients. The following iron therapies were shown to be differential to bacterial diversity, microbial populations, and predictive metagenomics, inferring that oral iron-treated patients may have a potentially more procarcinogenic microbiota compared to intravenous iron-treated patients. Overall, this suggests that intravenous iron may be a more beneficial treatment for anemia in colorectal cancer, in order to limit microbial perturbations associated with oral iron. Abstract Iron deficiency anemia is a common complication of colorectal cancer and may require iron therapy. Oral iron can increase the iron available to gut bacteria and may alter the colonic microbiota. We performed an intervention study to compare oral and intravenous iron therapy on the colonic tumor-associated (on-tumor) and paired non-tumor-associated adjacent (off-tumor) microbiota. Anemic patients with colorectal adenocarcinoma received either oral ferrous sulphate (n = 16) or intravenous ferric carboxymaltose (n = 24). On- and off-tumor biopsies were obtained post-surgery and microbial profiling was performed using 16S ribosomal RNA analysis. Off-tumor α- and β-diversity were significantly different between iron treatment groups. No differences in on-tumor diversity were observed. Off-tumor microbiota of oral iron-treated patients showed higher abundances of the orders Clostridiales, Cytophagales, and Anaeroplasmatales compared to intravenous iron-treated patients. The on-tumor microbiota was enriched with the orders Lactobacillales and Alteromonadales in the oral and intravenous iron groups, respectively. The on- and off-tumor microbiota associated with intravenous iron-treated patients infers increased abundances of enzymes involved in iron sequestration and anti-inflammatory/oncogenic metabolite production, compared to oral iron-treated patients. Collectively, this suggests that intravenous iron may be a more appropriate therapy to limit adverse microbial outcomes compared to oral iron.

Published
2021
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46. CRISPR/Cas9 generated knockout mice lacking phenylalanine hydroxylase protein as a novel preclinical model for human phenylketonuria

Author

Beth L. Thurberg, Michael Phipps, Gulbenk Anarat-Cappillino, Cathleen S. Cornell, Katie Malley, Jennifer Johnson, Errin Roberts, Tim Devlin, Kuldeep Singh, Xiaoyou Ying, Matthew DeRiso, Srinivas Rao, Susan Ryan, Sirkka Kyostio-Moore, Yao V. Zhang, Sarah Geller, Robert B. Jackson, Dinesh S. Bangari, Mostafa Kabiri, Robert Fogle, Patricia Berthelette, and Mitul Desai

Subjects
Male, medicine.medical_specialty, Phenylalanine hydroxylase, Science, Diseases, Pathogenesis, Article, Gene Knockout Techniques, Mice, Internal medicine, Phenylketonurias, medicine, Animals, Tyrosine, Hypopigmentation, chemistry.chemical_classification, Mice, Knockout, Multidisciplinary, biology, Phenylalanine Hydroxylase, Translational research, medicine.disease, Enzyme assay, Stop codon, Experimental models of disease, Hypocholesterolemia, Disease Models, Animal, Enzyme, Endocrinology, chemistry, Preclinical research, Knockout mouse, biology.protein, Medicine, medicine.symptom, CRISPR-Cas Systems
Abstract

Phenylketonuria (PKU) is an autosomal recessive inborn error of l-phenylalanine (Phe) metabolism. It is caused by a partial or complete deficiency of the enzyme phenylalanine hydroxylase (PAH), which is necessary for conversion of Phe to tyrosine (Tyr). This metabolic error results in buildup of Phe and reduction of Tyr concentration in blood and in the brain, leading to neurological disease and intellectual deficits. Patients exhibit retarded body growth, hypopigmentation, hypocholesterolemia and low levels of neurotransmitters. Here we report first attempt at creating a homozygous Pah knock-out (KO) (Hom) mouse model, which was developed in the C57BL/6 J strain using CRISPR/Cas9 where codon 7 (GAG) in Pah gene was changed to a stop codon TAG. We investigated 2 to 6-month-old, male, Hom mice using comprehensive behavioral and biochemical assays, MRI and histopathology. Age and sex-matched heterozygous Pah-KO (Het) mice were used as control mice, as they exhibit enough PAH enzyme activity to provide Phe and Tyr levels comparable to the wild-type mice. Overall, our findings demonstrate that 6-month-old, male Hom mice completely lack PAH enzyme, exhibit significantly higher blood and brain Phe levels, lower levels of brain Tyr and neurotransmitters along with lower myelin content and have significant behavioral deficit. These mice exhibit phenotypes that closely resemble PKU patients such as retarded body growth, cutaneous hypopigmentation, and hypocholesterolemia when compared to the age- and sex-matched Het mice. Altogether, biochemical, behavioral, and pathologic features of this novel mouse model suggest that it can be used as a reliable translational tool for PKU preclinical research and drug development.

Published
2021

47. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Author

Eugenia Abaleke, Mustafa Abbas, Sadia Abbasi, Alfie Abbott, Ashraf Abdelaziz, Sherif Abdelbadiee, Mohamed Abdelfattah, Basir Abdul, Althaf Abdul Rasheed, Rezan Abdul-Kadir, Abdulfatahi Abdulmumeen, Niyaz Abdulshukkoor, Kula Abdusamad, Yazeed Abed El Khaleq, Mai Abedalla, Abeer UA Abeer Ul Amna, Adebanke Aboaba, Hani Abo-Leyah, Ahmed Abou-Haggar, Mahmoud Abouibrahim, Miriam Abraham, Tizzy Abraham, Abraheem Abraheem, Judith Abrams, Hyacinth-John Abu, Ahmad Abu-Arafeh, Syed M Abubacker, Akata Abung, Yaa Aceampong, Devikumar Acharya, Janet Acheson, Andres Acosta, Catherine Acton, Jacqueline Adabie-Ankrah, Fiona Adam, Matthew Adam, Huzaifa Adamali, Carol Adams, Kate Adams, Richard Adams, Tim Adams, Malgorzata Adamus, Kirsty Adcock, Aderonke Adebiyi, Ken Adegoke, Vicki Adell, Aldrin Adeni, Sherna Adenwalla, Oluwasegun A Adesemoye, Emmanuel O Adewunmi, Joyce Adeyemi, Elizabeth Adeyeye, Gabrielle Adkins, Adnan Adnan, John Aeron-Thomas, Lynn Afari, Debbie Affleck, Carmel Afnan, Deborah Afolabi, Muhammad Afridi, Rachel Agbeko, Chris Agbo, Sunil Aggarwal, Arameh Aghababaie, Judith Agwada-Akeru, Kwame A Agyapong, Shafana Ahamed Sadiq, Mohamed H Ahammed Nazeer, Jonathan Ah-Chuen, Mahin Ahmad, Ashar Ahmed, Bilal Ahmed, Forizuddin Ahmed, Iram Ahmed, Irshad Ahmed, Liban Ahmed, Maria C Ahmed, Muhammad S Ahmed, Naseer Ahmed, Nausheen Ahmed, Osama Ahmed, Rajia A Ahmed, Rizwan Ahmed, Saif Ahmed, Sammiya Ahmed, Sara Ahmed, Syed H Ahmed, Roa Ahmed Ali, Sana Ahmer, Dhiraj Ail, Adam Ainsley, Mark Ainsworth, Myriam Aissa, Lucy Aitchson, Lindianne Aitken, Bini Ajay, Abdulakeem Ajibode, Ayesha Ajmi, Muhammad N Akhtar, Nasim Akhtar, Suha Akili, Oludoyinsola Akindolie, Yinka Akinfenwa, Olugbenga Akinkugbe, Ibrahim Akinpelu, Umeh Akudo, Asma Al Balushi, Majd Al Dakhola, Narendra Aladangady, Sajid Alam, Abbas Al-Asadi, Kyriaki Alatzoglou, Lorraine Albon, Stephen Alcorn, Aggie Aldana, David Alderdice, Rayan Aldouri, Jonathan Aldridge, Nicolas Aldridge, Ana Alegria, Alison Alexander, John Alexander, Peter DG Alexander, Julyan Al-Fori, Bahij Al-Hakim, Shams Al-Hity, Ali Ali, Anyat Ali, Fawzia R Ali, Jawad Ali, Mariam Ali, Mohammad Ali, Oudai Ali, Sakina Ali, Syed Ali, Abid Alina, Katrin Alizaedeh, Maithem Al-Jibury, Moutaz Alkhusheh, Alison Allanson, Robert Allcock, Eireann Allen, Jonathan Allen, Kerry Allen, Louise Allen, Rebecca Allen, Sam Allen, Sharon Allen, Simon Allen, Kathryn Allison, Bethan Allman, Lynne Allsop, Christine Almadenboyle, Hassan Al-Moasseb, Magda Al-Obaidi, Lina Alomari, Akram Al-Rabahi, Bahar Al-Ramadhani, Zayneb Al-Saadi, Warkaq Al-Shamkhani, Bashar Al-Sheklly, Mary Alvarez, Maysaa Alzetani, Susan Amamou, Sakarai Ambalavanan, Sarah-Jayne Ambler, Robert Ambrogetti, Chris Ambrose, Amir Ameen, Maria R Amezaga, Allison Amin, Amina Amin, Kanish Amin, Amjad Amjad, Victoria Amosun, Khaled Amsha, Atul Anand, Samantha Anandappa, Julie Anderson, Laura Anderson, Michelle Anderson, Nicola Anderson, Rachel Anderson, Rory Anderson, Prematie Andreou, Angela Andrews, Jill Andrews, Kanayochukwu Aneke, Andrew Ang, Wan Wei Ang, Tammy Angel, Paola Angelini, Lazarus Anguvaa, Oleg Anichtchik, Millicent Anim-Somuah, Krishnan Aniruddhan, Alpha Anthony, Aaron Anthony-Pillai, Philip Antill, Zhelyazkova Antonina, Varghese Anu, Muhammad Anwar, Aristeidis Apostolopoulos, Sarah Appleby, Diane Appleyard, Bianca Araba, Angela Aramburo, Ann Archer, Denise Archer, Simon Archer, Christian Ardley, Ana-Maria Arias, Ryoki Arimoto, Charlotte Arkley, Charlotte Armah, Ilianna Armata, Adam Armitage, Ceri Armstrong, Maureen Armstrong, Sonia Armstrong, Philippa Armtrong, Heike Arndt, Clare Arnison-Newgass, David Arnold, Rachael Arnold, Dhawal Arora, Pardeep Arora, Rishi Arora, Arslam Arter, Ganesh Arunachalam, Rita Arya, Salma Asam, Denisa Asandei, Adeeba Asghar, Catherine Ashbrook-Raby, Helen Ashby, Jan Ashcroft, John Ashcroft, Ayesha Ashfaq, Abdul Ashish, Sally Ashman-Flavell, Sundar Ashok, Muhammad Z Ashraf, Saima Ashraf, Mohammad B Ashraq, Deborah Ashton, Susan Ashton, Andrew Ashworth, Rebecca Ashworth, Harshini Asogan, Julia Asplin, Atif Asrar, Omar Assaf, Raine Astin-Chamberlain, Deborah Athorne, Christopher Atkins, Stacey Atkins, John Atkinson, Vicki Atkinson, Ahmed Attiq, Paula Aubrey, Suzannah August, Aye CT Aung, Hnin Aung, Kyaw Thu Aung, Nini Aung, Zaw Myo Aung, Emily Austin, Karen Austin, Miriam Avery, Joanne Avis, Cristina Avram, Paula Avram, Gabriel Awadzi, Aszad Aya, Eman Ayaz, Amanda Ayers, Vivek Ayra, Jawwad Azam, Mohammed Azharuddin, Ghazala Aziz, Ashaari Azman Shah, Giada Azzopardi, Hocine Azzoug, Nasaruilla Babajan, Fiyinfoluwa Babatunde, Melvin Babi, Babiker Babiker, Gayna Babington, Matthew Babirecki, Adetona O Babs-Osibodu, Gina Bacon, Jenny Bacon, Bibi Badal, Gurpreet R Badhan, Shreya Badhrinarayanan, Joseph Bae, Alice Baggaley, Amy Baggott, Graham Bagley, Dinesh Bagmane, Kasra Bahadori, Gayathri Baijiu, Charles Bailey, Julie Bailey, Katie Bailey, Lindsey Bailey, Liz Bailey, Morgan Bailey, Peter Bailey, Hamish Baillie, Kenneth Baillie, Jennifer Bain, Karen Bain, Becky Bainton, David Baird, Yolanda Baird, Aiysha Bajandouh, Evelyn Baker, Johanne Baker, Kenneth Baker, Pearl Baker, Hugh Bakere, Nawar Bakerly, Michelle Baker-Moffatt, Panos Bakoulas, Abhijit Bal, Niranjan Balachandran, Irvin Balagosa, Andrea Balan, Theodosios Balaskas, Madhu Balasubramaniam, Alison Balcombe, Cheryl Baldwick, Alexander Baldwin, Ashley Baldwin, Danielle Baldwin, Lisa Baldwin, Rebekah Baldwin-Jones, James Balfour, Ceri Ball, Craig Balmforth, Gabby Bambridge, Alasdair Bamford, Amy Bamford, Peter Bamford, Adefunke Bamgboye, Kasun Bamunuarachchi, Elizabeth Bancroft, Hollie Bancroft, Joyce Banda, Srini Bandi, Nageswar Bandla, Somaditya Bandyopadhyam, Ritwik Banerjee, Sandip Banerjee, Harrison Banks, Luke Banks, Daniel Banner, Oliver Bannister, Christopher Bannon, Laura Banton, Mariamma Baptist, Tanya Baqai, Ananya M Baral, Desislava Baramova, Russell Barber, Emma Barbon, Monica Barbosa, Jamie Barbour, Alexander Barclay, Charlotte Barclay, Stephanie Bareford, Shahedal Bari, Amy Barker, Debbie Barker, Joseph B Barker, Leon Barker, Oliver Barker, Kerry Barker-Williams, Sinha Barkha, Juliana Barla, Gavin Barlow, Richard Barlow, James Barnacle, Alex Barnard, Debi Barnes, Nicky Barnes, Amy Barnett, Debra Barnett, Ashton Barnett-Vanes, William Barnsley, Andrew Barr, David Barr, Shaney Barratt, Manuella Barrera, Fiona Barrett, Jessica Barrett, Jazz Bartholomew, Sarah Bartholomew, Claire Bartlett, Georgina Bartlett, Greg Barton, Jill Barton, Rachael Barton, Rosaleen Baruah, Sonia Baryschpolec, Archana Bashyal, Betsy Basker, Ayten Basoglu, Amira Bassaly, G Bassett, Bengisu Bassoy, Anupam Basumatary, Adam Bataineh, Freddie Batalla, Tristan Bate, Harry John Bateman, Kathryn Bateman, Vhairi Bateman, Eleanor Bates, Hayley Bates, Michelle Bates, Rizvan Batha, Sally Batham, Ana Batista, Amit Batla, Dushyant Batra, Harry Batty, Thomas Batty, Miranda Baum, Carina Bautista, Fatima S Bawani, Simon Bax, Matt Baxter, Nicola Baxter, Hannah Bayes, Farid Bazari, Rohit Bazaz, Ahmad Bazli, Laura Beacham, Hannah Beadle, Wendy Beadles, Philip Beak, Andy Beale, Kathy Beardsal, Jack Bearpark, Karen Beaumont, Matthew Beaumont, Dawn Beaumont-Jewell, Theresa Beaver, Sarah Beavis, Christy Beazley, Sarah Beck, Virginia Beckett, Rosie Beckitt, Heidi Beddall, Seonaid Beddows, Deborah Beeby, Michelle Beecroft, Sally Beer, Jane Beety, Gabriela Bega, Alison Begg, Susan Begg, Sara Beghini, Ayesha Begum, Safia Begum, Teresa Behan, Roya Behrouzi, Jon Beishon, Claire Beith, James Belcher, Holly Belfield, Katherine Belfield, Ajay Belgaumkar, Dina Bell, Gareth Bell, Gillian Bell, Lauren Bell, Louise Bell, Nicholas Bell, Stephanie Bell, Jennifer L Bell, Mary Bellamy, Arianna Bellini, Amanda Bellis, Fionn Bellis, Lesley Bendall, Naveena Benesh, Nicola Benetti, Leonie Benham, Guy Benison-Horner, Ann Bennett, Caroline Bennett, Gillian Bennett, Kristopher Bennett, Lorraine Bennett, Sara Bennett, Vivienne Benson, Andrew Bentley, Ian Benton, Eva Beranova, Matthew Beresford, Colin Bergin, Malin Bergstrom, Jolanta Bernatoniene, Thomas Berriman, Zoe Berry, Kimberley Best, Yvonne Beuvink, Emily Bevan, Sarah Bevins, Tom Bewick, Helen Bexhell, Andrew Bexley, Sonay Beyatli, Fenella Beynon, Arjun Bhadi, Sanjay Bhagani, Shweta Bhagat, Shiv Bhakta, Rekha Bhalla, Mahesh Bhalme, Khushpreet Bhandal, Kulbinder Bhandal, Ravina Bhanot, Prashanth Bhat, Nikhil Bhatia, Rahul Bhatnagar, Janki Bhayani, Deepika Bhojwani, Salimuzzaman Bhuiyan, Anna Bibby, Naheeda Bibi, Salma Bibi, Tihana Bicanic, Julie Bigg, Sarah Biggs, Alphonsa Biju, Andras Bikov, Sophie Billingham, Jessica Billings, Alice Binns, Oliver Bintcliffe, Catherine Birch, Janine Birch, Jenny Birch, Katherine Birchall, Sam Bird, Sumedha Bird, Mark Birt, Kilanalei Bishop, Linda Bishop, Lisa Bishop, Nibedan Biswas, Sahar Biuk, Karen Blachford, Ethel Black, Helen Black, Karen Black, Mairead Black, Polly Black, Sabrina Black, Bethan Blackledge, Joanne Blackler, Samantha Blackley, Helen Blackman, Caroline Blackstock, Francesca Blakemore, Helen Blamey, Sujata Blane, Simon Blankley, Parry Blaxill, Jane Blazeby, Natalie Blencowe, Ben Bloom, Angela Bloss, Hannah Bloxham, Louise Blundell, Susara Blunden, Mark Blunt, Ian Blyth, Kevin Blyth, Andrew Blythe, Karen Bobruk, Pritesh Bodalia, Neena Bodasing, Gabriele Boehmer, Marta Boffito, Sumit Bokhandi, Maria Bokhar, Saba Bokhari, Sakina Bokhari, Syed Owais Bokhari, Ambrose Boles, Matthew Bolton, Helena Bond, Stuart Bond, Thomas Bond, Alice Bone, Georgia Boniface, Lizzy Bonney, Joanne Borbone, Stephanie Borg, Catherine Borra, Samuel Bosompem, Liam Botfield, Fiona Bottrill, Hannah Bouattia, Laura Bough, Hayley Boughton, Zoe Boult, Miriam Bourke, Karen Bourne, Michelle Bourne, Rachel Bousefield, Lucy Boustred, Alexandra Bowes, Amy Bowes, Philip Bowker, Louise Bowman, Simon Bowman, Angie Bowring, Geetha Boyapati, Jenny Boyd, Laura Boyd, Namoi Boyle, Pauline Boyle, Rosalind Boyle, Louise Boyles, Leanna Brace, Jodie Bradder, Clare J Bradley, Pamela Bradley, Patrick Bradley, Joanne Bradley-Potts, Lynne Bradshaw, Zena Bradshaw, Rebecca Brady, Shirin Brady, Marie Branch, Emily Brandl-Salutz, Christina Branfield, Jamie Brannigan, Louise Brassington, Fiona Bray, Nancy Bray, Manny Brazil, Lucy Brear, Tracy Brear, Stephen Brearey, Morwenna Brend, Andrew Brereton, Chris Brewer, Gavin Bridgwood, Sara Brigham, John Bright, Christopher Brightling, Elaine Brinkworth, Robin Brittain-Long, Vianne Britten, Lauren Broad, Sarah Broad, Rosie Broadhurst, Andrew Broadley, Marie Broadway, Christopher Brockelsby, Megan Brocken, Tomos Brockley, Fiona Brogan, Felicity Brokke, Jacob Brolly, David Bromley, Hannah Brooke-Ball, Verity Brooker, Matthew Brookes, Alison Brooks, Kate Brooks, Nicole Brooks, Rachel Brooks, Sophie Brooks, Natalie Broomhead, Chloe Broughton, Nathaniel Broughton, Matt Brouns, Alison Brown, Carly Brown, Catrin Brown, Ellen Brown, Heather Brown, Janet Brown, Louise Brown, Niall Brown, Pauline Brown, Richard Brown, Robert Brown, Steven Brown, Tom Brown, Charlotte Browne, Duncan Browne, Rachel Browne, Stephen Brownlee, David Bruce, Johanna Bruce, Michelle Bruce, Wojciech Brudlo, Nigel Brunskill, Luke Brunton, Margaret Brunton, Jade Bryant, Mark Bryce, Maya Buch, Ruaridh Buchanan, Amanda Buck, Elizabeth Buckingham, Laura Buckley, Philip Buckley, Sarah Buckley, Carol Buckman, George Bugg, Ramadan Bujazia, Shanzay Bukhari, Richard Bulbulia, Alex Bull, Damian Bull, Rhian Bull, Thomas Bull, Sam Bullard, Naomi Bulteel, Katherine Bunclark, Roneleeh Bungue-Tuble, Caroline Burchett, Christy Burden, Thomas G Burden, Sarah Burge, Mika Burgess, Sophia Burgess, Emma Burke, Sara Burnard, Caroline Burnett, Amy Burns, Collette Burns, James Burns, Karen Burns, Daniel Burrage, Kate Burrows, Claire Burston, Ben Burton, Fiona Burton, Angus Butchart, Aaron Butler, Jo Butler, Joanne Butler, Joshua Butler, Peter Butler, Susan Butler, Al-Tahoor Butt, Caryl Butterworth, Nicola Butterworth-Cowin, Robert Buttery, Heather Button, Daniel Buttress, Jane Byrne, Wendy Byrne, Victoria Byrne-Watts, Ruth Cade, Donna Cairney, Claire Calderwood, James Calderwood, Giorgio Calisti, Debbie Callaghan, Jennifer Callaghan, Claire Callens, Caroline Calver, Melissa Cambell-Kelly, Tracey Camburn, David R Cameron, Eleanor Cameron, Fraser Cameron, Sheena Cameron, Christian Camm, Renee FD Cammack, Alison Campbell, Amy Campbell, Barbara Campbell, Bridget Campbell, Debbie Campbell, Helen Campbell, Hilary Campbell, Jonathan Campbell, Mark Campbell, Robyn Campbell, Wynny Campbell, Quentin Campbell Hewson, Laura Camrasa, Julie Camsooksai, Shaula M Candido, Cielito Caneja, Johnathon Cann, Ruby Cannan, Emma Cannon, Michael Cannon, Petra Cannon, Vivienne Cannons, Jane Cantliff, Ben Caplin, Angelika Capp, Thomas Capstick, Simon Carley, Tammy Carlin, Samantha Carmichael, Margaret Carmody, Mandy Carnahan, Charlotte Caroline, Patrick Carr, Sharon Carr, Anna Carrasco, Zoe Carrington, Jonathan Carter, Paul Carter, Penny Carter, Douglas Cartwright, Claire Carty, Jaime Carungcong, Paula Carvelli, Aisling Cashell, Barbara Cassimon, Teresa Castiello, Gail Castle, Melanie Caswell, Ana Maria Catana, Heidi Cate, Susanne Cathcart, Katrina Cathie, Christine Catley, Laura Catlow, Kerry Causer, Luke Cave, Frianne Cawa, Kathryn Cawley, Philippa Cawley, Chloe Caws, Hankins Cendl, Jeva Cernova, Ed Cetti, Stephanie Chabane, Manish Chablani, Cathleen Chabo, David Chadwick, Julie Chadwick, Robert Chadwick, Ela Chakkarapani, Arup Chakraborty, Mallinath Chakraborty, Mollika Chakravorty, James Chalmers, Georgina Chamberlain, Sarah Chamberlain, Carol Chambers, Emma Chambers, Jonathan Chambers, Lucy Chambers, Naomi Chambers, Shreekant Champanerkar, Carmen Chan, Cheuk Chan, Evelyn Chan, Kimberley Chan, Ping Chan, Rebekah (Pui-Ching) Chan, Xin H Chan, Chris Chandler, Kim J Chandler, Zoe Chandler, Badrinathan Chandrasekaran, Josephine Chaplin, Graeme Chapman, John Chapman, Katie Chapman, Laura Chapman, Lianne Chapman, Polly Chapman, Timothy 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Dermody, Amisha Desai, Purav Desai, Sanjeev Deshpande, Vai Deshpande, Sirjana Devkota, Prakash Dey, Vishal Dey, Rogin Deylami, Gurlove K Dhaliwal, Kevin Dhaliwal, Sundip Dhani, Amandeep Dhanoa, Mili Dhar, Sukhjit Dhariwal, Devesh Dhasmana, Ekanjali Dhillon, Reiss Dhillon, Kayleigh Diaz-Pratt, Pamela Dicks, Matthew Dickson, Sean Dillane, Sarah Diment, Paul Dimitri, Alex Dipper, Laura Dirmantaite, Lisa Ditchfield, Sarah Diver, Nandita Divikar, Lavanya Diwakar, Masroor Diwan, Caroline Dixon, Catherine Dixon, Petr Dlouhy, Paul Dmitri, Marinela Dobranszky Oroian, Charlotte Dobson, Lee Dobson, Marie Docherty, Morven Dockery, Emma Docks, James Dodd, Jackie Dodds, Rebecca Dodds, Steve Dodds, Richi Dogra, Erin Doherty, Warren Doherty, Yumiko Doi, Iain Doig, Daniel Dolan, Mark Dolman, Rozzie Dolman, Lisa Donald, Callum Donaldson, Denise Donaldson, Kate Donaldson, Sinead Donlon, Joanne Donnachie, Christopher Donnelly, Eilish Donnelly, Emma Dooks, Andrew Dooley, Kane Dorey, Sharon Dorgan, Davinder Dosanjh, Paula Dospinescu, Andrew Dougherty, Katie Douglas, Lucy Dowden, Michelle Dower, Sud Dowling, Hayley Downe, Nicola Downer, Charlotte Downes, Rob Downes, Thomas Downes, Damian Downey, Louise Downs, Simon Dowson, Cornel Dragan, Cristina Dragos, Chelsea Drake, Victoria Drew, Olivia Drewett, Celine Driscoll, Helena Drogan, Ronald Druyeh, Simon Drysdale, Hazel Dube, Judith Dube, Stephen Duberley, Simon Dubrey, Roger Duckitt, Hayley Duckles-Leech, Nicola Duff, Helen Duffy, Lionel Dufour, Annette Duggan, Parveen Dugh, Janice Duignan, Simon Dummer, Andrew Duncan, Barrie Duncan, Christopher Duncan, Fullerton Duncan, Alessia Dunn, Damian Dunn, Laura Dunn, Karen Dunne, Fiona Dunning, Aidan Dunphy, Venkat Duraiswamy, Beatriz Duran, Ingrid DuRand, Alison Durie, Emily Durie, Laura Durrans, Hannah Durrington, Akshay Dwarakanath, Laasya Dwarakanath, Ellen Dwyer, Claudia Dyball, Harvey Dymond, Tom Dymond, Chris Eades, Melissa Earwaker, Nicholas Easom, Clare East, Jack Easton, Ruth Eatough, Oluwadamilola Ebigbola, Martin Ebon, Sinan Eccles, Chloe Eddings, Michael Eddleston, Maureen Edgar, Katharine Edgerley, Mary Edmondson, Tracy Edmunds, Alexandra Edwards, Andrea Edwards, Catherine Edwards, Joy Edwards, Kennedy Edwards, Mandy Edwards, Steven Edwards, Jenny Eedle, Dawn Egginton, Sarah Eisen, Ugochukwu Ekeowa, Mohamed Ekoi, Ayomide Ekunola, Kate El Bouzidi, Ashley Elden, Jennifer Elder, Haifa Eldew, Diana Eleanor, Maysoon Elfadil, Eman Elfar, Mayy M Elgamal, Amr Elgohary, Stellios Elia, Jennifer Elias, Tania Elias, Nadia Elkaram, Amin Elkhawad, Andrew V Elkins, Julie Ellam, Nikki Ellard, Laura Nicola Ellerton, Amy Elliott, Fiona Elliott, Kerry Elliott, Valmai Elliott, Annie Ellis, Hayley Ellis, Kaytie Ellis, Tak-Yan Ellis, Yvette Ellis, Rahma Elmahdi, Einas Elmahi, Omer Elneima, Mohamed Elokl, Ahmed Elradi, Mohamed Elsaadany, Sally El-Sayeh, Hana El-Sbahi, Tarek Elsefi, Karim El-Shakankery, Sarah Elyoussfi, Jonathan Emberson, John Emberton, Julian Emmanuel, Ingrid Emmerson, Charis Emmett, Michael Emms, Marieke Emonts, Angila Engden, Katy English, Nicola Entwistle, Hene Enyi, Ruth Erin Jones, Agota Ermenyi, Hanif Esmail, Ajmal Eusuf, Brynach Evans, Chris Evans, Debra Evans, Gail Evans, Gareth Evans, Jennifer Evans, Lynn Evans, Melanie Evans, Mim Evans, Morgan Evans, Ranoromanana Evans, Teriann Evans, Terry J Evans, Caroline Everden, Lynsey Evison, Jacqueline Faccenda, Leila Fahel, Youstina Fahmay, Sara Fairbairn, Andy Fairclough, Louise Fairlie, Anne Fajardo, Euan Falconer, John Fallon, David Faluyi, Qayyum Farah, Novin Fard, Amr Farg, Adam Farmer, Katie Farmer, Toni Farmery, Frances Farnworth, Samantha Farnworth, Faiyaz Farook, Hadia Farooq, Sidrah Farooq, Fiona Farquhar, Aaron Farrell, Barbara Farrell, James Farthing, Syeda Farzana, Rahmatu Fasina, Azam Fatemi, Mina Fatemi, Nibah Fatimah, Saul N Faust, Joe Fawke, Sinmidele Fawohunre, Alex Feben, Federico Fedel, Christopher Fegan, Mae Felongco, Lynsey Felton, Tim Felton, Kate Fenlon, Andrea Fenn, Isabelle Fenner, Ciara Fenton, Melisa Fenton, Cameron Ferguson, Jenny Ferguson, Kathryn Ferguson, Katie Ferguson, Lisa Ferguson, Susan Ferguson, Susie Ferguson, Victoria Ferguson, Denzil Fernandes, Candida Fernandez, Eduardo Fernandez, Sonia Fernandez Lopez, Ahmed Feroz, Pietro Ferranti, Thais Ferrari, Catarina Ferreira-De Almeida, Alexandra Ferrera, Emma Ferriman, Nicholas Fethers, Ben Field, Janet Field, Andra Fielding, Julie Fielding, Sarah Fielding, Asma Fikree, Sarah Ann Filson, Joanne Finch, Laurie Finch, Natalie Fineman, Adam Finn, Joanne Finn, Sofia Fiouni, Jo Fiquet, James Fisher, Neil Fisher, Daniel Fishman, Krystofer Fishwick, Marie Fisk, Jan Flaherty, Michael Flanagan, Charles Flanders, Julie Fleming, Lucy Fleming, Paul Fleming, William Flesher, Alison Fletcher, Lucy Fletcher, Sophie Fletcher, Christopher Flood, Jonathan Flor, Vincent Florence, Sharon Floyd, Adama Fofana, Georgina Fogarty, Linda Folkes, Aiwyne Foo, Andrew Foot, Jayne Foot, Jane Forbes, Kathryn Forcer, Jamie Ford, Jennifer Foreman, Caroline Fornolles, Adam Forrest, Ellie Forsey, Thomas Forshall, Elliot Forster, Julian Forton, Emily Foster, Joseph Foster, Rachel A Foster, Tracy Foster, Angela Foulds, Ian Foulds, Folakemi Fowe, Emily Fowler, Robert Fowler, Stephen Fowler, Caroline Fox, Claire Fox, Heather Fox, Jonathan Fox, Lauren Fox, Natalie Fox, Simon Fox, Sarah-Jane Foxton, Rebecca Frake, Alex Francioni, Olesya Francis, Rebecca Francis, Sarah Francis, Theodora Francis-Bacon, Victoria Francois, Sharon Frayling, Martyn Fredlund, Michael Freeborn, Carol Freeman, Elaine Freeman, Hannah Freeman, Nicola Freeman, Clare Freer, Eleanor French, Anastasia Fries, Matthew Frise, Renate Fromson, Claire Froneman, John Frost, Victoria Frost, Rachel Frowd, Arun Fryatt, Bridget Fuller, Elizabeth Fuller, Tracy Fuller, Duncan Fullerton, Sarah Funnell, John Furness, Hassina Furreed, Waqas Gaba, Elizabeth Gabbitas, Claire Gabriel, Joshua Gahir, Katarzyna Gajewska-Knapik, Christopher Gale, Hugo Gale, 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Julia Greig, Rebecca Grenfell, Teena Grenier, Susan Grevatt, Glaxy Grey, Andrew Gribbin, Ben Griffin, Denise Griffin, Mel Griffin, Sian Griffith, Andrew Griffiths, Daniel Griffiths, David Griffiths, Donna Griffiths, Isabel Griffiths, Nicola Griffiths, Oliver Griffiths, Sofia Grigoriadou, Steph Grigsby, Russell Gritton, Evelina Grobovaite, Clarissa Grondin, Rachel Groome, Liliana Grosu, Jenny Grounds, Jayne Groves, Neil Grubb, Julie Grundy, Francesca Guarino, Sharada Gudur, Shivang Gulati, Vikas Gulia, Pumali Gunasekera, Kirun Gunganah, Jessica Gunn, Emma Gunter, Alok Gupta, Atul Gupta, Rajeev Gupta, Richa Gupta, Tarun Gupta, Vineet Gupta, Ankur Gupta-Wright, Sambasivarao Gurram, Ishy Gurung, Shraddha Gurung, Hazel Guth, Ruth Habibi, Pamela Hackney, Christian Hacon, Aiman Haddad, Denise Hadfield, Michalis Hadjiandreou, Anna Haestier, Nauman Hafiz, Rana Hafiz-Ur-Rehman, Samantha Hagan, Jack W Hague, Rosemary Hague, Andrew Haigh, Kate Haigh, Christina Haines, Scott Hainey, Morton Hair, Brigid Hairsine, Juraj Hajnik, Anne Haldeos, Carmel Halevy, William Halford, Alistair Hall, Anthony Hall, Chloe Hall, Claire Hall, Emily Hall, Helen Hall, Jennifer Hall, Kathryn Hall, Toni Hall, Jan Hallas, Kyle Hallas, Charles Hallett, Heather Halls, Maryam Hamdollah-Zadeh, Bilal Hameed, Imran Hamid, Mohamad Hamie, Bethany Hamilton, Fergus Hamilton, Leigh Hamilton, Ruth Hamlin, Eleanor Hamlyn, Shirley Hammersley, Kate Hammerton, Bev Hammond, Leah Hammond, Rachel Hammond-Hall, Fiona Hammonds, Nidal Hammoud, Ibrahim Hamoodi, Karen Hampshire, Jude Hampson, Shi Han Lee, Ozan Hanci, James Hand, Soran Handrean, Georgina Hands, Sheharyar Hanif, Amy Hannington, Merhej Hannun, Aidan Hanrath, Jane Hanson, Kathryn Hanson, Mazhar U Haq, Ala Haqiqi, Monjurul Haque, Zoe Harding, Simon Hardman, Kumar Haresh, Rachel Harford, Beverley Hargadon, Carolyn Hargreaves, James Hargreaves, Alice Harin, Mohammed Haris, Helen Harizaj, Edward Harlock, Paula Harman, Tracy Harman, Mark Harmer, Muhammad A Haroon, Charlie H Harper, Heather Harper, Peter Harper, Rosemary Harper, Sarah Harrhy, Sian Harrington, Yasmin Harrington-Davies, Claire Harris, Jade Harris, Julie Harris, Laura Harris, Marie-Clare Harris, Nichola Harris, David Harrison, Laura Harrison, Melanie Harrison, Rowan Harrison, Susie Harrison, Tom Harrison, Wendy Harrison, Elizabeth Harrod, Ciaran Hart, Dominic Hart, Rosemary Hartley, Ruth Hartley, Tom Hartley, William Hartrey, Hans Hartung, Alice Harvey, Angela Harvey, Max Harvey, Catherine Harwood, Helen Harwood, Neda Hasan, Brigitte Haselden, Mohammed Hashimm, Imranullah Hashmi, Zena Haslam, Abdulhakim Hassan, Adil Hassan, Ali Hassan, Waqar Ul Hassan, Philip Hassell, Alex Hastings, Bethany Hastings, Jonathan Hatton, Jennifer Haugh, May Havinden-Williams, Stefan Havlik, Dan Hawcutt, Liz Hawes, Nicola Hawes, Annie Hawkins, Nancy Hawkins, Daniel Hawley, Edward Haworth, Cathy Hay, Jamal Hayat, Anne Hayes, Melony Hayes, Fiona Hayes, Antara Hayman, Melanie Hayman, Matthew Haynes, Richard 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Nicola Hornby, Sophie Horrocks, Latoya Horsford, Megan Horsford, Valana Horsham, Alex Horsley, Ashley Horsley, Elizabeth Horsley, Sarah Horton, Jane Hosea, Toby Hoskins, Ejaz Hossain, Muhammad S Hossain, Rashed Hossain, Maxine Hough, Sarah Hough, Kathryn Houghton, Rebecca Houlihan, Gordon Houston, Hamish Houston, Eleanor Hoverd, Roseanna Hovvels, Lee How, Laura Howaniec, Laura Howard, Linda Howard, Lucy Howard, Sarah Howard, Richard Howard-Griffin, Serena Howe, Mark Howells, Lyn Howie, Alex Howlett, Sophie Howlett, Josh Hrycaiczuk, Desmond Hsu, Hein Htet, Zaw Htet, Naing Z Htoon, Su Htwe, Ying Hu, Abby Huckle, Shahzya Huda, Alison Hudak, Lisa Hudig, Heather Hudson, Alison Hufton, Conor Huggins, Alistair Hughes, Emma Hughes, Gareth Hughes, Heather Hughes, Luke Hughes, Rachel Hughes, Rhian Hughes, Samantha Hughes, Stephen Hughes, Vikki Hughes, Wesley Hughes, Lukas Huhn, Ching Hui, Ruth Hulbert, Diana Hull, Robert Hull, Amanda Hulme, Peter Hulme, Wendy Hulse, George Hulston, Ryan Hum, Charlotte Humphrey, Alasdair Humphries, Joanne Humphries, David Hunt, Fiona Hunt, Jane Hunt, Kristen Hunt, Luke Hunt, Karl Hunter, Neil Hunter, Elizabeth Hurditch, Cian Hurley, Katrina Hurley, Mohammed A Husain, Syeda Y Husaini, Coralie Huson, Ibraar Hussain, Mohammad Hussain, Muhammad Hussain, Reda Hussain, Sajid Hussain, Samia Hussain, Sanniah Hussain, Yasmin Hussain, Mohammed Hussam El-Din, Rebecca Hussey, Christopher Hutchcroft, Camille Hutchinson, Dorothy Hutchinson, Elizabeth Hutchinson, John Hutchinson, Claire Hutsby, Paula Hutton, Daniella Hydes, Jamie Hyde-Wyatt, Niamh Hynes, Megan Hyslop, Ahmed Ibrahim, Asil Ibrahim, Kamal Ibrahim, Mohamed Ibrahim, Wadah Ibrahim, Muhammad Idrees, Hina Iftikhar, Chukwuemeka Igwe, Mohammad Ijaz, Amaju Ikomi, Clare Iles, Stamatina Iliodromiti, Lorna Ilves, La'ali Imam-Gutierrez, Christopher Imray, Haider Imtiaz, Jack Ingham, Julie Ingham, Rory Ingham, Tejas Ingle, Anne Ingram, Luke Ingram, Peter Inns, Ken Inweregbu, Andreea A Ionescu, Ana 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Sabrina Jansz, Deepa Japp, Catherine Jardine, Ellie Jarvie, Rosina Jarvis, Patrycja Jastrzebska, Hafsa Javed, Lona Jawaheer, Dinakaran Jayachandran, Deepak Jayaram, Geeshath Jayasekera, Lalith Jayasekera, Saman Jeddi, Mohammad S Jeelani, Katie Jeffery, Rachel Jeffrey, Nathan Jeffreys, Benjamin Jeffs, Debbie Jegede, Taylor Jemima, Ifan Jenkin, Alison Jenkins, David Jenkins, Elinor Jenkins, Sarah Jenkins, Sian Jenkins, Stephen Jenkins, Edward Jenner, David Jennings, Jacqui Jennings, Louise Jennings, Virginia Jennings, Ellen Jerome, Douglas Jerry, Ellen Jessup-Dunton, Jorge A Jesus Silva, Kishan Jethwa, Abi Jeyabalan, Akhilesh Jha, Shaman Jhanji, Khoo Jian, Zhixin Jiao, Ana Jimenez Gil, Jithin Jith, Teishel Joefield, Navraj Johal, Karine Johannessen, Aisyah Johari, Annie John, Anu John, Emma Johns, Margaret Johns, Antoinette Johnson, Gillian Johnson, Kathryn Johnson, Luke Johnson, Mark Johnson, Claire Johnston, Janet Johnston, Susan Johnston, Victoria Johnston, Dawn Johnstone, Ed 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Vivien Price, Anne Priest, Kate Priestley, Lorraine Primrose, Judith Prince, Laura Prince, Shirley Pringle, Veronika Pristopan, Kelly Pritchard, Lucy Pritchard, Simon Pritchard, Verma Priyash, Andrew Procter, Clare Proctor, Rebecca Proudfoot, Heather Prowse, Benjamin Prudon, David Pryor, Solomon Pudi, Amy Pugh, Joanne Pugh, Mark Pugh, Nichola Pugh, Richard Pugh, Veronika Puisa, Kirandip Punia, Saleel Punnilath Abdulsamad, Laura Purandare, Martha Purcell, Corrina Purdue, Bally Purewal, Molly Pursell, Gregory Purssord, Sarah Purvis, Kathryn Puxty, Michael Pynn, Tariq Qadeer, Sheena Quaid, Alice Quayle, Ian Quayle, Siobhan Quenby, Xinyi Qui, Vanessa Quick, Julie Quigley, Tom Quinn, Quratulain Quratulain, Danya Qureshi, Hasanain Qureshi, Khadija Qureshi, Nawaz Qureshi, Qurratulain Qurratulain, Saad Qutab, Muhammad S Rabbani, Madalina Raceala, Laura Rad, Jane Radford, Liz Radford, Jayachandran Radhakrishnan, Michael Raffles, Cecillia Rafique, Muhammad Rafique, Ravi Ragatha, Sarika Raghunath, Aiswarya Raghunathan, Abigail Raguro, Shankho D Raha, Sana Rahama, Karen Rahilly, Faisal Rahim, Haseena R Rahimi, Muhammad Rahman, Salim Ur Rahman, Lenka Raisova, Mehul Raithatha, Arjun Raj, Pradeep Rajagopalan, Nithy Rajaiah, Arvind Rajasekaran, Aylur Rajasri, Jyothi Rajeswary, Gayathri Rajmohan, Matsa Ram, Balaji Ramabhadran, Niranjani Ramachandran, Iyad Ramadan, Mohamed Ramali, Athimalaipet Ramanan, Shashikira Ramanna, Maheshi Ramasamy, Dhanishta Ramdin, Jozel Ramirez, Lidia Ramos, Shanthi Ramraj, Lisa Ramsawak, Alex Ramshaw, Aleem Rana, Ghulam F Rana, Rehman Rana, Abby Rand, James Rand, Georgina Randell, Poonam Ranga, Manu Rangar, Harini Rangarajan, Sameer Ranjan, Poormina Ranka, Christopher Ranns, Anita Rao, Deepak Rao, Sandhya Rao, Sanjay Rao, Khalid Rashid, Simbisai Ratcliff, Sam Ratcliffe, Sophy Ratcliffe, Sanjeev Rath, Mohmad I Rather, Selina Rathore, Aravinden Ratnakumar, Jonathan Ratoff, Deepa Rattehalli, Jason Raw, Gautam Ray, Samiran Ray, Adam Raymond-White, 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Riordan, Naomi Rippon, Chloe Rishton, Michael Riste, Jane Ritchie, Andrew Ritchings, Pilar Rivera Ortega, Vanessa Rivers, Syed AS Rizvi, Syed HM Rizvi, Ian Roberts, Karen Roberts, Mark Roberts, Nicky Roberts, Rebecca Roberts, Calum Robertson, Nichola Robertson, Stuart Robertson, Caroline Robinson, Emily Robinson, Emma Robinson, Gisela Robinson, Hannah Robinson, Jemima Robinson, Kate Robinson, Matthew Robinson, Sandra Robinson, Steve Robson, Lisa Roche, Samantha Roche, Natalie Rodden, Alistair Roddick, Jack Roddy, Marion Roderick, Alison Rodger, Faye Rodger, Megan Rodger, Alicia Rodgers, Natasha Rodgers, Penny Rodgers, Sarah Rodrigues, Rocio Rodriguez-Belmonte, Nicholas Roe, Charles C Roehr, Gill Rogers, Jason Rogers, Joanne Rogers, John Rogers, Leigh Rogers, Lindsay Rogers, Michaela Rogers, Naomi Rogers, Paula Rogers, Thomas Rogers, Sakib Rokadiya, Lee Rollins, Jennifer Rollo, Catherine Rolls, Claire Rook, Kevin Rooney, Laura Rooney, Lynsey Rooney, Lace Rosaro, Alastair Rose, Annie 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Mfon Sam, Sally Sam, Tinashe Samakovna, Razan Saman, Renaldo Samlal, Emily Sammons, David Sammut, Mark Sammut, Sunitha Sampath, Julia Sampson, Anda Samson, Debbie Samuel, Johnson Samuel, Reena Samuel, Thomas DL Samuel, Elsward Samuels, Theo Samuels, Joanna Samways, Manjula Samyraju, Ilves Sana, Aabid Sanaullah, Veronica Sanchez, Amada Sanchez, Tom Sanctuary, Peter Sandercock, Amy Sanderson, Paul Sanderson, Tom Sanderson, Kuljinder Sandhu, Loveleen Sandhu, Victoria Sandrey, Sarah Sands, Mirriam Sangombe, Matthew Sanju, Rojy Santosh, Jayanta Sanyal, Aureo F Sanz-Cepero, Najam Saqib, Sarbjit Sarai, Dinesh Saralaya, Arun Saraswatula, Avishay Sarfatti, Rebecca Sargent, Beatrix Sari, Rahul Sarkar, Sruthi Sarma, Varun Sarodaya, Zainab Sarwar, Thea Sass, Sonia Sathe, Sobitha Sathianandan, Abilash Sathyanarayanan, Thozhukat Sathyapalan, Prakash Satodia, Rachel Saunders, Samantha Saunders, Anne Saunderson, Heather Savill, Karishma Savlani, Matthew Saxton, Amrinder Sayan, Diane Scaletta, Lyndsay 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Peter Tsang, Kyriaki K Tsilimpari, Georgios Tsinaslanidis, Simon Tso, Sally Tucker, Aisha Tufail, Redmond Tully, Killian Turbitt, Rezon Turel, Tolga Turgut, Claudia Turley, Alison Turnbull, Aine Turner, Ash Turner, Charlotte Turner, Gail Turner, Kate Turner, Kelly Turner, Lucy Turner, Mark Turner, Patricia Turner, Sally Turner, Samantha Turner, Victoria Turner, Sharon Turney, Jon Turvey, Emma Twohey, Bhavya Tyagi, Vedang Tyagi, Abigail Tyer, Jayne Tyler, Jennifer Tyler, Alison Tyzack, Petros Tzavaras, Mohammad S Uddin, Ruhama Uddin, Salamat Ullah, Sanda Ullah, Athavan Umaipalan, Judith Umeadi, Akudo Umeh, Wilfred Umeojiako, Lizzie Undrell, Adam Unsworth, Veerpal SU Uppal, Gerry Upson, Alison Uriel, Sebastian Urruela, Hiromi Uru, Miranda Usher, Rebecca Usher, Andrew Ustianowski, Linda C Vaccari, Abhay Vaidya, Erika Vainieri, Bernardas Valecka, Jennifer Valentine, Balan Valeria, Luke Vamplew, Ekaterini Vamvakiti, Joannis Vamvakopoulos, Maud van de Venne, Alex van der Meer, Nora van der 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School of Medicine, Horby, PW, Roddick, A, Spata, E, Staplin, N, Emberson, JR, Pessoa-Amorim, G, Peto, L, Day, J, Thwaites, G, Mafham, M, Haynes, R, and Landray, MJ

Subjects
Male, medicine.medical_treatment, 030204 cardiovascular system & hematology, Azithromycin, ResearchInstitutes_Networks_Beacons/humanitarian_conflict_response_institute, Rate ratio, chemistry.chemical_compound, 0302 clinical medicine, RA0421, Oxygen therapy, RA0421 Public health. Hygiene. Preventive Medicine, 030212 general & internal medicine, Hospital Mortality, 11 Medical and Health Sciences, azithromycin, education.field_of_study, Covid19, clinical trial, General Medicine, 3rd-DAS, Middle Aged, Hospitalization, Survival Rate, Treatment Outcome, Humanitarian and Conflict Response Institute, Female, Life Sciences & Biomedicine, medicine.medical_specialty, RM, Population, COVID-19/drug therapy, Azithromycin/therapeutic use, 03 medical and health sciences, Pharmacotherapy, Tocilizumab, Medicine, General & Internal, SDG 3 - Good Health and Well-being, Internal medicine, General & Internal Medicine, medicine, Humans, education, Survival rate, Mechanical ventilation, Science & Technology, business.industry, COVID-19, NIS, Length of Stay, R1, United Kingdom, COVID-19 Drug Treatment, RM Therapeutics. Pharmacology, RECOVERY Collaborative Group, chemistry, Relative risk, business, RA, Anaesthesia Pain and Critical Care
Abstract

The RECOVERY trial is supported by a grant to the University of Oxford from UK Research and Innovation (Medical Research Council) and NIHR (MC_PC_19056) and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill & Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. TJ is supported by a grant from UK Medical Research Council (MC_UU_0002/14) and an NIHR Senior Research Fellowship (NIHR-SRF-2015-08-001). WSL is supported by core funding provided by NIHR Nottingham Biomedical Research Centre. Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods: In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87-1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98-1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87-1·03; p=0·24). Interpretation: In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Publisher PDF

Published
2021
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48. Xanthohumol Microbiome and Signature in Healthy Adults (the XMaS Trial): Safety and Tolerability Results of a Phase I Triple-Masked, Placebo-Controlled Clinical Trial

Author

Ryan Bradley, Blake O. Langley, Thomas O. Metz, J. Frederik Stevens, Emily Stack, John Phipps, Jennifer J. Ryan, and Douglas Hanes

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Vital signs, Phases of clinical research, Placebo, Article, Placebos, 03 medical and health sciences, chemistry.chemical_compound, Quality of life, Internal medicine, medicine, Humans, Adverse effect, Flavonoids, Propiophenones, 030109 nutrition & dietetics, business.industry, Body Weight, Healthy Volunteers, Clinical trial, 030104 developmental biology, chemistry, Tolerability, Xanthohumol, Quality of Life, Female, business, Biomarkers, Food Science, Biotechnology
Abstract

SCOPE Xanthohumol, a prenylflavonoid from hops, has been extensively studied preclinically but has undergone limited research in human subjects. A triple-masked, placebo-controlled phase I clinical trial was conducted to examine the safety and tolerability of xanthohumol. METHODS AND RESULTS Thirty healthy volunteers were randomized to 24 mg day-1 xanthohumol (99.8% pure) or placebo for eight weeks. Comprehensive metabolic panels, complete blood counts, body weight, vital signs, and health-related quality of life questionnaires were assessed every two weeks. Participants were interviewed for adverse events (AEs) throughout the trial. Thirteen of 14 (93%) and 14 of 16 (88%) participants completed the trial in the placebo and xanthohumol groups, respectively. There were no withdrawals due to AEs. There were no clinically relevant, between-group differences in laboratory biomarkers, body weight, vital signs, or health-related quality of life. There were no severe or FDA-defined serious AEs, but non-serious AEs are documented in both the placebo (n = 42) and xanthohumol (n = 58) groups. CONCLUSION Over an eight-week period, 24 mg daily xanthohumol was safe and well-tolerated by healthy adults.

Published
2021

49. Sources of indoor air pollution at a New Zealand urban primary school; a case study

Author

Mikael Boulic, Perry Davy, Yu Wang, Philippa Howden-Chapman, Robyn Phipps, Nevil Pierse, Julie Bennett, and Bill Trompetter

Subjects
Atmospheric Science, 010504 meteorology & atmospheric sciences, Air pollution, 010501 environmental sciences, medicine.disease_cause, 01 natural sciences, Atmospheric Sciences, chemistry.chemical_compound, Indoor air quality, medicine, Nitrogen dioxide, Waste Management and Disposal, Air quality index, 0105 earth and related environmental sciences, 90799 Environmental Engineering not elsewhere classified, Elemental composition, Environmental engineering, FOS: Environmental engineering, Humidity, FOS: Earth and related environmental sciences, Particulates, Pollution, chemistry, Carbon dioxide, Environmental science, 50299 Environmental Science and Management not elsewhere classified
Abstract

Children are particularly vulnerable to the health effects of air pollution and as they spend a large proportion of time at school, this is an important environment for children's exposure to air pollution. Understanding the factors that influence indoor air quality in schools is critical for the assessment and control of indoor air pollution. This study analysed the concentration and sources of air pollution at an urban primary school (5–11 years) in Wellington, the capital of New Zealand. Over a three-week period during spring, indoor measures of particulate matter (PM 2.5 , PM 10 ), temperature, humidity, carbon dioxide (CO 2 ) and nitrogen dioxide (NO 2 ) were taken and hourly air particulate matter samples (PM 2.5 , PM 10-2.5 ) were collected inside and outside for elemental speciation analysis. Indoor PM 10 concentrations during the school day were significantly (p < 0.001) higher than outdoor concentrations 30.1 (range 10.0–75.0, SD 1.9) μg m −3 c.f. 8.9 (range

Published
2021
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50. Mechanical Feed-Forward Loops Contribute to Idiopathic Pulmonary Fibrosis

Author

Patricia J. Sime, Thomas H. Thatcher, Apostolos Perelas, Jane K. Rebman, Richard P. Phipps, and Margaret A.T. Freeberg

Subjects
0301 basic medicine, Feedback, Physiological, Chemistry, Review, Fibroblasts, medicine.disease, Mechanotransduction, Cellular, Idiopathic Pulmonary Fibrosis, Pathology and Forensic Medicine, Cell biology, Extracellular matrix, 03 medical and health sciences, Transient receptor potential channel, Idiopathic pulmonary fibrosis, 030104 developmental biology, 0302 clinical medicine, 030228 respiratory system, Fibrosis, Pulmonary fibrosis, medicine, Animals, Humans, Mechanotransduction, Myofibroblast, Transcription factor
Abstract

Idiopathic pulmonary fibrosis is a progressive scarring disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Recent studies support the hypothesis that these compositional and mechanical changes create a progressive feed-forward loop in which enhanced matrix deposition and tissue stiffening contribute to fibroblast and myofibroblast differentiation and activation, which further perpetuates matrix production and stiffening. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. Although our understanding of mechanotransduction pathways associated with pulmonary fibrosis remains incomplete, recent progress has allowed us to begin to elucidate the specific mechanisms supporting fibrotic feed-forward loops. The mechanosensors discussed here include integrins, Piezo channels, transient receptor potential channels, and nonselective ion channels. Also discussed are downstream transcription factors, including myocardin-related transcription factor and Yes-associated protein/transcriptional coactivator with PDZ-binding motif. This review describes mechanosensors and mechanotransduction pathways associated with fibrosis progression and highlights promising therapeutic insights.

Published
2021

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