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Corrigendum
, Nicholas J. Scott, Rachel A. Matson, Mark E. Everett, Elise Furlan, Crystal L. Gnilka, David R. Ciardi, Kathryn V. Lester
Frontiers in Astronomy and Space Sciences, Volume 8; https://doi.org/10.3389/fspas.2021.696011

Abstract:
A Corrigendum on The NASA High-Resolution Speckle Interferometric Imaging Program: Validation and Characterization of Exoplanets and Their Stellar Hosts by Steve B. Howell, Nicholas J. Scott, Rachel A. Matson, Mark E. Everett, Elise Furlan, Crystal L. Gnilka, David R. Ciardi, Kathryn V. Lester. (2021). Front. Astron. Space Sci. 10:635864. doi: 10.3389/fspas.2021.635864 In the original article, there were incorrect parameters listed in the last paragraph of Section 2. A correction has been made to that paragraph as follows: “As an aside, Robo-AO is another high-resolution imaging technique used in the optical wavelength range. Ziegler et al. (2017) discuss their results using this method for exoplanet host stars. Unlike speckle imaging, Robo-AO uses the mechanical deformable mirror techniques of IR/AO and applies them to optical light. See Ziegler et al. (2018) for details. Ref is: @ARTICLE2018AJ....156...83Z, author = Ziegler, Carl and Law, Nicholas M. and Baranec, Christoph and Howard, Ward and Morton, Tim and Riddle, Reed and Duev, Dmitry A. and Salama, Ma¨ıssa and Jensen-Clem, Rebecca and Kulkarni, S. R., title = ”Robo-AO Kepler Survey. V. The Effect of Physically Associated Stellar Companions on Planetary Systems”, journal =, keywords = binaries: close, instrumentation: adaptive optics, methods: data analysis, methods: observational, planets and satellites: fundamental parameters, techniques: high angular resolution, Astrophysics - Earth and Planetary Astrophysics, year = 2018, month = aug, volume = 156, number = 2, eid = 83, pages = 83, doi = 10.3847/1538-3881/aace59, archivePrefix = arXiv, eprint = 1804.10208, primaryClass = astro-ph.EP, adsurl = https://ui.adsabs.harvard.edu/abs/2018AJ....156...83Z, adsnote = Provided by the SAO/NASA Astrophysics Data System.” The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Ziegler, C., Law, N. M., Baranec, C., Howard, W., Morton, T., Riddle, R., et al. (2018). Robo-AO Kepler Survey. V. The Effect of Physically Associated Stellar Companions on Planetary Systems. AJ 156 (2), 83. doi:10.3847/1538-3881/aace59 CrossRef Full Text | Google Scholar Keywords: exoplanets, exoplanetary systems, binary host stars, speckle interferometry, high-resolution imaging Citation: Howell SB, Scott NJ, Matson RA, Everett ME, Furlan E, Gnilka CL, Ciardi DR and Lester KV (2021) Corrigendum: The NASA High-Resolution Speckle Interferometric Imaging Program: Validation and Characterization of Exoplanets and Their Stellar Hosts. Front. Astron. Space Sci. 8:696011. doi: 10.3389/fspas.2021.696011 Received: 30 April 2021; Accepted: 07 May 2021;Published: 30 September 2021. Edited and reviewed by: Copyright © 2021 Howell, Scott, Matson, Everett, Furlan, Gnilka, Ciardi and Lester. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Steve B. Howell, [email protected]
Sina Jasim
Published: 28 August 2021
AACE Clinical Case Reports, Volume 7; https://doi.org/10.1016/j.aace.2021.08.003

Abstract:
Thank you for being part of our journal and welcome to another issue of AACE Clinical Case Reports. The current issue includes many interesting and educational case reports to share. We will provide a summary of those cases. For more details, please access ACCR online journal available at https://www.aaceclinicalcasereports.com/
Published: 27 August 2021
by Zenodo
Abstract:
These are the results files for the following peer-reviewed article: Price, M.H., J.M. Capriles, J. Hoggarth, R.K. Bocinsky, C.E. Ebert, and J.H. Jones, (2021). End-to-end Bayesian analysis for summarizing sets of radiocarbon dates. Journal of Archaeological Science. They were generated inside a Docker container as outlined in the README of this github repository: https://github.com/MichaelHoltonPrice/price_et_al_tikal_rc The analyses rely on an R package located in this github repository: https://github.com/eehh-stanford/baydem For the results archived here, the commits for each repository are: price_et_al_tikal_rc 3ac1e35f4277ef878f8e3aac3d05159928a09a2b baydem 1220a60a860633b51f9f07cbff3eb78f458efc1a
Published: 27 August 2021
by Zenodo
Abstract:
These are the results files for the following peer-reviewed article: Price, M.H., J.M. Capriles, J. Hoggarth, R.K. Bocinsky, C.E. Ebert, and J.H. Jones, (2021). End-to-end Bayesian analysis for summarizing sets of radiocarbon dates. Journal of Archaeological Science. They were generated inside a Docker container as outlined in the README of this github repository: https://github.com/MichaelHoltonPrice/price_et_al_tikal_rc The analyses rely on an R package located in this github repository: https://github.com/eehh-stanford/baydem For the results archived here, the commits for each repository are: price_et_al_tikal_rc 3ac1e35f4277ef878f8e3aac3d05159928a09a2b baydem 1220a60a860633b51f9f07cbff3eb78f458efc1a
Imaekhai Lawrence
Published: 16 August 2021
by Zenodo
Abstract:
{"references": ["Arditi, D., Akan, G. T., & Gurdamar, S. (1985). Cost overruns in public projects. International Journal of Project Management, 3(4), 218-224.", "Dlakwa MM, Culpin MF (1990) Reasons for overrun in public sector construction projects in Nigeria. International Journal of Project Management 1990;8(4):237\u201341.", "Frimpong, Y. (2000). Project management in developing countries: causes of delay and cost overruns in construction of groundwater projects. Unpublished Masters Research Project, University of Technology, Sydney, Australia.", "Giridhar P, Ramesh K. (1998) Effective management of Turnkey projects. Aace Transactions, PM7- PM11 1998.", "Khalil ALMI, AL-Ghafly MA. (1999) Delay in public Utility projects in Saudi Arabia. International Journal of Project Management,17(2):101\u20136.", "Mansfield NR, Ugwu OO, Doran T. (1994) Causes of delay and cost overruns in Nigeria construction projects. International Journal of Project Management,12(4):254\u201360.", "Ogunlana SO, Promkuntong K, Vithool J. (1996) Construction delays in a fast-growing growing economy: comparing Thailand with other economies. International Journal of Project Management; 14(1):37\u201345.", "Ogunlana SO, Olomolaiye PO. (1989) A survey of site management practice on some selected sites in Nigeria. Building Environ, 24(2):191\u20136.", "Oglesby C, Parker H, Howell G. (1989) Productivity improvement in construction. New York: McGraw-Hill; 1989.", "Okpala DC, Aniekwu AC. (1988) Causes of high costs of construction in Nigeria. Journal of Management in Engineering, ASCE, 114:233\u201344."]}
Imaekhai Lawrence
Published: 16 August 2021
by Zenodo
Abstract:
{"references": ["Arditi, D., Akan, G. T., & Gurdamar, S. (1985). Cost overruns in public projects. International Journal of Project Management, 3(4), 218-224.", "Dlakwa MM, Culpin MF (1990) Reasons for overrun in public sector construction projects in Nigeria. International Journal of Project Management 1990;8(4):237\u201341.", "Frimpong, Y. (2000). Project management in developing countries: causes of delay and cost overruns in construction of groundwater projects. Unpublished Masters Research Project, University of Technology, Sydney, Australia.", "Giridhar P, Ramesh K. (1998) Effective management of Turnkey projects. Aace Transactions, PM7- PM11 1998.", "Khalil ALMI, AL-Ghafly MA. (1999) Delay in public Utility projects in Saudi Arabia. International Journal of Project Management,17(2):101\u20136.", "Mansfield NR, Ugwu OO, Doran T. (1994) Causes of delay and cost overruns in Nigeria construction projects. International Journal of Project Management,12(4):254\u201360.", "Ogunlana SO, Promkuntong K, Vithool J. (1996) Construction delays in a fast-growing growing economy: comparing Thailand with other economies. International Journal of Project Management; 14(1):37\u201345.", "Ogunlana SO, Olomolaiye PO. (1989) A survey of site management practice on some selected sites in Nigeria. Building Environ, 24(2):191\u20136.", "Oglesby C, Parker H, Howell G. (1989) Productivity improvement in construction. New York: McGraw-Hill; 1989.", "Okpala DC, Aniekwu AC. (1988) Causes of high costs of construction in Nigeria. Journal of Management in Engineering, ASCE, 114:233\u201344."]}
Charneal L. Dixon,
Published: 19 July 2021
Journal of Lipid Research, Volume 62; https://doi.org/10.1016/j.jlr.2021.100097

Abstract:
NOD2 (nucleotide-binding and oligomerization domain containing protein 2) is a cytosolic pattern recognition receptor that detects intracellular peptidoglycan (muramyl dipeptide) from bacteria. Membrane association of NOD2 is essential for its ability to activate nuclear factor κB and mitogen-activated protein kinase signaling pathways via the kinase, receptor-interacting serine/threonine-protein kinase 2. The post-translational addition of palmitate to NOD2 results in an acylated protein with increased affinity for membrane bilayers (1Lu Y. Zheng Y. Coyaud É. Zhang C. Selvabaskaran A. Yu Y. Xu Z. Weng X. Chen J.S. Meng Y. Warner N. Cheng X. Liu Y. Yao B. Hu H. Xia Z. Muise A.M. Klip A. Brumell J.H. Girardin S.E. Ying S. Fairn G.D. Raught B. Sun Q. Neculai D. Palmitoylation of NOD1 and NOD2 is required for bacterial sensing.Science. 2019; 366: 7Crossref Scopus (26) Google Scholar). Palmitoylation of cysteine residues (shown in orange) at positions C395 and C1033 en face of the structural model (A) based on the crystal structure of rabbit NOD2 (PDB 5IRL) (2Maekawa S. Ohto U. Shibata T. Miyake K. Shimizu T. Crystal structure of NOD2 and its implications in human disease.Nature Communications. 2016; 7: 11813Crossref PubMed Scopus (74) Google Scholar) is mediated by the protein acyltransferase enzyme zDHHC5 (1Lu Y. Zheng Y. Coyaud É. Zhang C. Selvabaskaran A. Yu Y. Xu Z. Weng X. Chen J.S. Meng Y. Warner N. Cheng X. Liu Y. Yao B. Hu H. Xia Z. Muise A.M. Klip A. Brumell J.H. Girardin S.E. Ying S. Fairn G.D. Raught B. Sun Q. Neculai D. Palmitoylation of NOD1 and NOD2 is required for bacterial sensing.Science. 2019; 366: 7Crossref Scopus (26) Google Scholar). The model suggests that this face of the protein is juxtaposed to the plasmalemmal surface. Palmitoylation of the expressed GFP-NOD2WT and GFP-NOD2C395,1033S in HCT116 cells was further characterized using a biorthogonal chemical reporter assay (B) (3Yap M.C. Kostiuk M.A. Martin D.D.O. Perinpanayagam M.A. Hak P.G. Siddam A. Majjigapu J.R. Rajaiah G. Keller B.O. Prescher J.A. Wu P. Bertozzi C.R. Falck J.R. Berthiaume L.G. Rapid and selective detection of fatty acylated proteins using ω-alkynyl-fatty acids and click chemistry.Journal of Lipid Research. 2010; 51: 1566-1580Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Here,15-hexadecynoic acid (15-HDYA), also referred to as alkynyl palmitic acid, was metabolically incorporated into cells. The 15-HDYA covalently attached to the immunocaptured GFP-NOD2 proteins was reacted with azide-PEG3-FLAG via a copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The proteins were resolved by SDS-PAGE and subsequently detected by an anti-FLAG antibody. The metabolic label, which was incorporated into NOD2WT and was notably absent in the double cysteine mutant, was removed by treatment with 2.5% hydroxylamine (HAM) that hydrolyzes the 15-HDYA – protein thioester linkage. Finally, the palmitoylation-deficient GFP-NOD2C395,1033S does not localize to the plasma membrane in HCT116 cells (C). Mutations that disrupt S-palmitoylation are associated with severe immunologic and inflammatory diseases such as Crohn’s disease whereas mutations associated with Blau syndrome demonstrate increased S-palmitoylation and membrane localization (1Lu Y. Zheng Y. Coyaud É. Zhang C. Selvabaskaran A. Yu Y. Xu Z. Weng X. Chen J.S. Meng Y. Warner N. Cheng X. Liu Y. Yao B. Hu H. Xia Z. Muise A.M. Klip A. Brumell J.H. Girardin S.E. Ying S. Fairn G.D. Raught B. Sun Q. Neculai D. Palmitoylation of NOD1 and NOD2 is required for bacterial sensing.Science. 2019; 366: 7Crossref Scopus (26) Google Scholar).
Thomas Kovacs
American Journal of Speech-Language Pathology, Volume 30, pp 1038-1048; https://doi.org/10.1044/2020_ajslp-20-00224

Abstract:
Purpose The aim of the study was to collect information about American speech-language pathologists' preprofessional training, practice, self-perceived competence, adequacy of resources, and interest in continuing education related to augmentative and alternative communication (AAC) assessment and intervention strategies addressing each of the five language domains: semantics, pragmatics, phonology, morphology, and syntax. Method An anonymous online survey of American speech-language pathologists was conducted. Results A majority of participants rated their preprofessional training for assessing semantic and pragmatic skills positively. Otherwise, a majority of participants rated preprofessional training for assessment and intervention negatively across language domains. High interest in continuing education opportunities addressing assessment and intervention was found across language domains. A discrepancy between responses to questions addressing semantic and pragmatic skills and responses to questions addressing phonological, morphological, and syntactic skills was consistently found for ratings of preprofessional training, practice, perceived competence, and adequacy of resources. In all cases, higher frequencies of positive ratings were found for questions addressing semantic and pragmatic skills. Conclusions Improved preprofessional training and continuing education opportunities are needed to support AAC assessment and intervention across language domains. Perspectives and practice patterns reflect a historical emphasis on semantic and pragmatic skills in the external evidence base, even though there are several recent journal articles addressing morphology and syntax in clients who use AAC.
Junjun Li, Yanan Chen, Zhanxi Fan,
Frontiers in Energy Research, Volume 9; https://doi.org/10.3389/fenrg.2021.676876

Abstract:
Editorial on the Research TopicEmerging Technologies for Materials Design and Characterization in Energy Conversion and Storage The increasing consumption of fossil fuels leads to energy crisis and environmental issues, which seriously affects human daily life. To date, great efforts have been made to explore sustainable, eco-friendly and renewable energy alternatives to fossil fuels. In the past few decades, various energy conversion and storage technologies, such as water splitting (Zhang F. et al., 2019; Hu et al., 2021; Wu et al., 2021), proton exchange membrane fuel cells (Edwards et al., 2008; Park et al., 2012), nitrogen reduction reaction (NRR) (Wan et al., 2019; Zhang W. et al., 2019; Yang et al., 2020b; Li et al., 2021), CO2 reduction reaction (CO2RR) (Ozdemir et al., 2019; Liu et al., 2020; Yang et al., 2020a; Ma et al., 2021; Wang et al., 2021), and metal-air batteries (Cheng and Chen, 2012) have shown promising potential due to the high efficiency, energy security, and environmental protection. In these fields, more attention has been paid to preparing advanced materials with outstanding performance, and developing advanced technologies for prediction, characterization and detection (Centi, 2020). Electrocatalytic NRR to NH3 has been regarded as an attractive alternative to the traditional Haber-Bosch process owing to its lower energy consumption under ambient conditions (Tang and Qiao, 2019; Yang et al., 2020b). The development of advanced NRR catalysts with outstanding performance and low costs is highly desired. Recently, Wang et al. reported that the ringlike V2O3 nanostructures could effectively convert N2 to NH3 under ambient conditions. Scanning electron microscopy analysis shows that the ringlike structure is uniform with outer diameter of 350–500 nm. Transmission electron microscopy (TEM) analysis confirms that such nanoring possesses a rough surface, displaying more active sites. The high-resolution TEM image of an individual nanoring indicates a contracted interplanar distance of 0.211 nm, corresponding to the (113) plane. This work presents a facile strategy to fabricate the advanced non-noble-metal catalysts for NRR. It is believed that more effective and stable electrocatalysts would be developed for boosting the NRR in the future. Energy efficiency is another efficacious way to alleviate the energy crisis. In the field of energy-saving optoelectronics, electrochromic devices (ECDs) have shown great advantages. Among various fabrication materials for ECDs, coordination polymer (CP) shows a broad application prospect due to good cycle stability, high color rendering efficiency, and fast switching speed. Liu et al. present a comprehensive survey of the current achievements and progresses of CP in energy efficient ECDs from the aspect of influence of composition, coordination bonding and microstructure of pyridine-based CP on the performance of ECDs. This work is expected to provide the guideline for achieving a substantial enhancement in electrochromic and other optoelectronic fields. Nevertheless, one of the paramount challenges to develop new high-efficiency energy transformation materials is the long span from experiment to practical application, due to the complexity of research objects and methods, insufficient personal accumulated experience, etc. (Luo et al.) Artificial intelligence (AI) has potential for solving the problems mentioned above. Luo et al. investigated and summarized research works on energy storage materials for capacitors and Li-ion batteries. They pointed out that machine learning (ML), as a subset of AI, algorithms can reduce test number of cycles and required experiments, which greatly reduces time consumption and accelerates every stage of development. In addition, they summarized the status and progress of AI in energy storage materials and present solutions to relevant deficiencies, such as the establishment of a database, extracting data from unstructured literature with automaticity and high efficiency and accuracy, etc. Apart from saving time, AI can predict the performance of materials, monitor reaction processes, and explore reaction mechanisms (Luo et al.; Yang et al.). Focusing on the superiority of AI in predicting experiments, Yang et al. reviewed the situation and application of AI in respects of optoelectronic materials, hydrogen peroxidation catalysts, water electrolysis catalysts and microbial fuel cells. It indicates that the relationship between prediction and actual experiments is mutually facilitating. In other words, the efficiency of actual material processing can be promoted with accurate prediction, and the database for AI is extended. In conclusion, the development of advanced materials and technologies for energy conversion and storage are of vital importance. Until now, various promising materials with excellent performance have been prepared, such as carbon nanomaterials [nanofibers (Zhao et al., 2018; Lee et al., 2020), nanotubes (Ma et al., 2019; Sun et al., 2020; Tuo et al., 2020; Zhang et al., 2020), graphene (Chen et al., 2020), etc.], reticular structure [metal-organic framework (Nam et al., 2018), covalent organic framework (Lin et al., 2015)], and tandem catalyst (Morales-Guio et al., 2018), etc. It is worth mentioning that traditional technologies in detection and characterization are gradually substituted with new and advanced solutions, such as computer science (AI, ML, etc.), and in-situ characterization (In-situ/operando synchrotron radiation, in-situ/operando morphology/spectrum, etc.). 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Mater. 8:1702524. doi: 10.1002/aenm.201702524 CrossRef Full Text | Google Scholar Keywords: energy conversion and storage, electrocatalysis, water splitting, CO2 reduction, nitrogen reduction reaction, fuel cell Citation: Li J, Chen Y, Fan Z and Zhang Z (2021) Editorial: Emerging Technologies for Materials Design and Characterization in Energy Conversion and Storage. Front. Energy Res. 9:676876. doi: 10.3389/fenrg.2021.676876 Received: 06 March 2021; Accepted: 12 April 2021; Published: 10 May 2021. Edited by: Reviewed by: Copyright © 2021 Li, Chen, Fan and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Zhicheng Zhang, [email protected]
Frontiers in Environmental Science, Volume 9; https://doi.org/10.3389/fenvs.2021.664313

Abstract:
The year 2021 offers a critical opportunity for concerted action to influence the future of freshwater biodiversity, ecosystem services and human well-being. The United Nations Decade on Biodiversity 2011–2020 has ended, and governments around the world are reviewing major international agreements relevant to biodiversity conservation, including the Convention on Biological Diversity (CBD)1, the Sustainable Development Goals (SDGs)2, and the UN Framework Convention on Climate Change (UNFCCC)3. A Post-2020 Global Biodiversity Framework4 is under development, with the grand mission to “Halt the loss of species, ecosystems and genetic diversity by 2030; restore and recover biodiversity to ensure a world of people “living in harmony with nature' by 2050”. Freshwater ecologists have acted quickly to draw attention to the global dimensions of the freshwater biodiversity crisis and address the lack of a comprehensive framework to guide policy responses (Bunn, 2016; Darwall et al., 2018). An Emergency Recovery Plan for freshwater biodiversity, published by 25 authors from 14 organizations (Tickner et al., 2020), sets out six major priorities for global action and policy development to “bend the curve of freshwater biodiversity loss.” It has been submitted to the working committees of the Post-2020 Global Biodiversity Framework, and further promoted as a dramatic OUPblog “Bring living waters back to our planet5” Comprehensive reviews have since enumerated many research questions, actions and policy refinements needed to “bend the curve” and protect the world's freshwater ecosystems (van Rees et al., 2020; Buxton et al., 2021; Harper et al., 2021; Maasri et al., 2021). Each review cuts across important scientific, societal, management and policy issues. The purpose of this brief challenge paper is, likewise, to strengthen and support the Emergency Recovery Plan, but in a different way, by advocating a broader package of strategic activities that too often operate in silos, with patchy coverage of the world's freshwater ecosystem types and biogeographic diversity. This package presents traditional areas of scientific and societal activity that require more strategic, integrated and collaborative global effort to deliver evidence-based freshwater conservation outcomes, conjoined with terrestrial and estuarine/marine conservation, depending on context: (i) inventory, evaluation and research; (ii) restoration and rehabilitation; (iii) protected area design and management; and (iv) socio-ecological science and governance. The paper is intended to motivate greater interest, commitment and collaboration of all stakeholders in the most urgent and ambitious conservation enterprise of the next decade—to protect and sustain freshwater biodiversity in the socio-ecological systems of the Anthropocene. Evidence-based ecosystem restoration and biodiversity protection depend upon a credible foundation of scientific and sociological data, process understanding and a capacity to model, predict and evaluate ecological/societal outcomes from natural processes, pressures and management actions. Notwithstanding a huge body of erudite freshwater research, there remains an ongoing need to increase understanding of the biodiversity, biophysical processes and ecosystem services of the world's freshwater and connected terrestrial and estuarine/marine ecosystems. The IUCN Commission on Ecosystem Management has developed a globally consistent, spatially explicit Ecosystem Typology for conservation purposes (Keith et al., 2021). It is designed to help identify the ecosystems most critical to conservation of biodiversity and supply of ecosystem services, as well as structuring global risk assessments for the Red List of Ecosystems and reporting against CBD and SDG targets and other framings. The typology distinguishes 28 natural freshwater ecosystem types within subterranean systems, palustrine wetlands, streams, rivers, freshwater and saline lakes, artesian springs, oases, and transitional waters (fjords, estuaries, intermittently closed and open lakes and lagoons–ICOLLS). Depending on ecosystem type, geography and knowledge gaps, freshwater inventory and research is traditionally integrated around taxonomy, genetics and organismal biology, population and community ecology, and ecosystem functions, the latter including the processes that link landscapes, connected boundary systems (riparian areas, floodplains, wetlands/lakes, and groundwater systems) and freshwater ecosystems (Geist, 2011; Reis et al., 2017; Flitcroft et al., 2019). Likewise, the pathways and processes that connect rivers and estuaries via surface flows and submarine groundwater discharges are vital dimensions of interconnected freshwater and coastal ecosystems. The IUCN Ecosystem Typology provides a geographic framing and scientific resource to help guide priorities for basic inventory and ecological research on understudied ecosystem types and biogeographic regions. For example, groundwater-dependent ecosystems such as artesian springs and oases are relatively poorly studied but coming to attention globally (Cantonati et al., 2020). Intermittent rivers and ephemeral streams (IRES) and episodic arid-zone floodplains are of growing interest because even when dry they perform multiple ecosystem services that complement those of nearby perennial rivers (Datry et al., 2018). Given the exceptional biodiversity of the Amazon Basin and poor knowledge of many aquatic taxa (e.g., migratory fishes), there is an outstanding need for inventory, knowledge synthesis and risk assessment to guide recovery and conservation (Duponchelle et al., 2021). Innovative biodiversity assessment techniques (remote sensing, GIS, environmental DNA, camera traps, sound recordings, radiotelemetry) can be integrated with established field methods to document biodiversity patterns and hotspots, and track flagship, umbrella and endangered species of high conservation value (Harper et al., 2021). Systematic reviews, meta-analysis, natural and laboratory experiments and modeling offer scope to relate biodiversity patterns and processes with dominant environmental drivers (climate, hydrological regime and water quality, etc). Broad stakeholder engagement is essential across the spectrum of biodiversity inventories, identification of knowledge gaps and research priorities, evaluation of ecosystem services and formulation of targets for restoration and protection of species, ecosystem processes and valued services. The major threats to freshwater ecosystems have been comprehensively synthesized in six main categories: hydrological alterations, habitat degradation and loss, pollution, overexploitation, invasive species, and climate change (Dudgeon et al., 2006). These have been mapped at global scale (Vörösmarty et al., 2010; Reis et al., 2017; Grill et al., 2019), elaborated as new pollutants and configurations of stress emerge (Reid et al., 2019) and widely publicized (Bunn, 2016; Flitcroft et al., 2019). Yet despite prodigious management efforts, biodiversity loss and ecosystem degradation continue, creating huge deprivation for millions of people whose diets and livelihoods depend directly on freshwater biota (Lynch et al., 2016). Biodiversity decline has significant implications for ecosystem resilience, recovery potential and adaptation to climate change. The Emergency Recovery Plan offers a blueprint focused on reducing biodiversity decline and recovering from these major threats, a well as a new threat category on connectivity to highlight the implications of habitat fragmentation for freshwater biota and ecosystems (Grill et al., 2019). Numerous methods and sound protocols already enable mitigation of these major threats, as demonstrated in successful ecological restoration projects around the world (Palmer et al., 2005). For example, the restoration of connectivity patterns and processes has contributed to recovery of biodiversity and ecosystem processes in many regulated rivers (Horne et al., 2017; Opperman et al., 2019). The bolder objective of the Emergency Recovery Plan is to transition from local freshwater restoration successes to a strategic approach that achieves biodiversity and ecological recovery at larger spatial scales. The European Water Framework Directive6 offers one well-established jurisdictional framing for freshwater ecosystem recovery to good ecological status. Building on European case studies, challenges and successes under this and other directives, van Rees et al. (2020) extend the ideas of the freshwater Emergency Recovery Plan into 15 special recommendations with potential to protect freshwater life globally. Beyond the main categories of threat to freshwater biodiversity and ecosystems lie new kinds of stress and new configurations of familiar stressors (Reid et al., 2019). Many, if not most, freshwater ecosystems are affected by several types of stress that interact, often with effects greater than (synergism), less than (antagonism) or equal to the sum of their individual effects (Sabater et al., 2018). The daunting scientific challenge is to identify the most significant causes of stress and define the most beneficial blend, geographic placement and timing of management actions (Omerod et al., 2010; Craig et al., 2017). This approach has worked reasonably well for the urban stream “syndrome” (Sheldon et al., 2012; Booth et al., 2016). Other multiple-stressor syndromes that threaten freshwater ecosystems include irrigated agriculture, forestry, mining, energy production, transport systems and the recreation and tourism sectors. Climate change, itself a complex mix of stressors, already compounds multiple stressor syndromes (Sabater et al., 2018), by altering river flow and flooding regimes, while rising temperatures are driving higher evaporation rates, water scarcity, and aquatic habitat loss. Shifting climatic regimes intensify the urgency of multiple stressor research and adaptive management solutions. In multiple-stressor contexts, Tickner et al. (2020) recommend the assembly of “strategic portfolios of measures” rather than relying on interventions that address individual stressors, although these will always be necessary in particular contexts. Methods for mapping individual and cumulative stressors are well-developed (e.g., Vörösmarty et al., 2010), and analytical tools for prioritizing ecological restoration among sites in multi-stressor landscapes are emerging (Hermoso et al., 2015; Neeson et al., 2016). Strategic portfolios of restoration measures require development of cause-and-effect relationships to understand and predict the responses of species and communities to individual and multiple-stressor configurations. Maasri et al. (2021) recommend assessment of restoration outcomes using large-scale replication of before-after-control-impact (BACI) designs, and long-term post-monitoring phases. Relatively few restoration projects meet these stringent design and monitoring requirements (Palmer et al., 2005; Geist and Hawkins, 2016). Meta-analyses of results from post-monitoring can help to identify restoration failures (often under-reported, Geist, 2011) as well as successes, extract learnings and guide adaptation toward more effective strategies. In many situations with a long history of anthropogenic stress it is important to be realistic about the potential for restoration of near-natural ecological systems (Geist and Hawkins, 2016). Rehabilitation or remediation to recover and sustain selected ecosystem values and species may be the only feasible approach, especially where novel ecosystems with well-established alien species have replaced natural system structures, biodiversity and processes, as in many impounded rivers and degraded floodplain wetlands (Acreman et al., 2014; Poff et al., 2017). These novel circumstances require careful development of explicit and realistic targets for the recovery of the system at project onset (Geist, 2011, 2015; Geist and Hawkins, 2016). A framing termed Strategic Adaptive Management (SAM) offers a structured step-wise process from development of a shared vision and hierarchy of objectives linked to management actions, monitoring, evaluation and publication of outcomes (Kingsford et al., 2021). It amply meets the criteria for measuring restoration and management success from an ecological perspective (Palmer et al., 2005) and provides a powerful model of effective stakeholder collaboration. Broad stakeholder engagement throughout project design, implementation and monitoring strengthens comprehension of the multiple challenges of ecosystem restoration, and encourages appreciation of what can be achieved and is worthy of investment. Freshwater ecosystem restoration, rewilding, rehabilitation and remediation are technically feasible with existing and emerging technologies, collaborative human commitment and adequate resourcing. The IUCN ecosystem typology provides a template for identification of risks and restoration priorities at global scale. As an example, severe threats to freshwater biodiversity in the Amazon Basin (overexploitation, deforestation, extensive hydroelectric dam development and climate change) demand a portfolio of recovery actions (Duponchelle et al., 2021) and spatially explicit prioritization of future hydropower developments to minimize loss of aquatic connectivity and biodiversity (Winemiller et al., 2016). Ecosystem restoration is challenging, expensive and may require decades of sustained effort to maintain the desired outcomes. Prevention of biodiversity loss is a far better option than struggling for cures. Perfectly located, designed and managed freshwater protected areas (PAs) represent the pinnacle of global conservation policy. Many categories of area-based protected ecosystems (IUCN I–VI PAs, Ramsar list of Wetlands of International Importance, private protected areas, landholder covenants, indigenous stewardship) play significant roles in freshwater biodiversity conservation. In 2010, the Convention on Biological Diversity (CBD) included an area target of 17% protection for inland waters. However, 70% of river reaches (by length) have no protected areas in their upstream catchments, and only 11.1% (by length) achieve full integrated protection (Abell et al., 2017). Seasonal inland wetlands represent ~6% of the world's land surface, yet around 89% are unprotected by IUCN PAs and Ramsar sites (Reis et al., 2017). Urgent calls for increased protection of freshwater ecosystems and biodiversity include free-flowing rivers (Perry et al., 2021), river-wetland mosaics (Reis et al., 2017), springs (Cantonati et al., 2020) and other groundwater-dependent ecosystems, as well as integrated terrestrial-freshwater-estuary/marine protection coordinated across spatial scales, jurisdictions and sectors (Abell et al., 2017; Leal et al., 2020; Buxton et al., 2021). Systematic conservation planning offers data-driven methods for prioritizing restoration and protected area strategies (Abell et al., 2017; Linke et al., 2019). Applications of these approaches have addressed vital issues for freshwater conservation planning (source catchment condition, dimensions of river connectivity, integrated river, wetland and aquifer protection, threatening processes, species distribution shifts under climate change, and trade-offs between freshwater biodiversity conservation and human water requirements). Other tools that can aid similar spatial analysis, provide insights into trade-offs, and inform strategic multi-objective decision-making include pareto-optimal assessments (Hurford and Harou, 2014), Strategic Environmental Assessment (Lazarus et al., 2018) and system-scale infrastructure planning (Winemiller et al., 2016; Opperman et al., 2019). Significant improvements in the placement, spatial configuration and connectivity of protected areas are feasible using these techniques. Recent studies have sought to evaluate the benefits of freshwater protected areas for conservation of freshwater biodiversity. A systematic review found that only 51% of 75 case studies demonstrated beneficial outcomes relative to comparable unprotected areas (Acreman et al., 2020). Activities within and external to protected areas were held responsible, including landscape modifications, riparian loss, alterations to hydrological regimes, loss of floodplain connectivity, habitat alterations, chemical contamination, fishing, harvesting (e.g., turtle eggs) and the presence of non-native species. Over-exploited and degraded protected areas add to the burden of ecosystem restoration and recovery facing many societies. Ecological principles and guidelines for improved use, management and monitoring of freshwater protected areas and their surrounding landscapes warrant far wider appreciation and application (Finlayson, 2018; Acreman et al., 2020). Strengthening the conservation benefits of freshwater protected areas requires engagement and collaboration among scientists, management agencies and the people who visit, know and use these areas. Increased public engagement, citizen science and participatory monitoring of trends in condition or species abundance by committed stakeholders can raise the profile of freshwater biodiversity and help to change behaviors that might otherwise lead to ecosystem damage. Positive socio-economic outcomes as well as biodiversity conservation are important, and more likely to occur when PAs adopt co-management regimes (e.g., fisheries), empower local people, reduce economic inequalities, and maintain cultural and livelihood benefits (Oldekop et al., 2016). Freshwater ecosystems and their catchments are increasingly viewed as coupled human and natural systems, wherein setting objectives and devising management solutions, require engagement and collaboration among engineers and hydrologists, ecologists, social scientists and citizens (Bunn, 2016). This has been advocated and implemented in the field of environmental water management for decades (Poff et al., 2003, 2017) and is a strong element of The Brisbane Declaration and Global Action Agenda on Environmental Flows (Arthington et al., 2018; Anderson et al., 2019). Ecosystem-based Management (EBM), also referred to as the ‘Ecosystem Approach', jointly considers societal and ecological goals and scenarios in an impressive modeling framework (Langhans et al., 2019). The EBM and similar framings (e.g., SAM) recognize the need for coupling of social and ecological systems, and engagement of all stakeholders. The concept of “stakeholders” has often meant token representation of indigenous, marginalized or poorly recognized societal groups. Yet increasingly, solving complex conflicts about water use and management, especially in times of scarcity and uncertainty, requires collaboration and enduring partnerships among all stakeholders with indigenous, societal and scientific knowledge, technical expertise, and credentials at all levels of governance. Recent reviews consistently call for improved practices to enhance communication, understanding and respect for different “ways of knowing,” and methods for blending of stakeholder knowledge (especially indigenous knowledge) with conventional science (Anderson et al., 2019; Buxton et al., 2021; Maasri et al., 2021; Perry et al., 2021). Others call for evidence-based and targeted guidance to facilitate working with the complex dynamic interactions of ecological and societal systems (Harper et al., 2021). The framing termed Coupled Human and Natural Systems (CHANS) is especially relevant. It proposes strategic integration of patterns and processes that connect human and natural systems, as well as within-scale and cross-scale interactions and feedbacks between human and natural components of such systems (Liu et al., 2021). Interesting applications to freshwater systems include evaluation of water availability, use, quality, management and governance in Canadian agricultural watersheds (Liu et al., 2019) and fisheries management (Lynch and Liu, 2014). CHANS, SAM and EBM embrace important principles of socio-ecological collaboration and governance, including building trust, maintaining respectful interactions, upholding rights, embracing mutual understanding, and development of enduring partnerships. These integrated socio-ecological frameworks and partnership models offer fundamental tools to guide understanding and management of increasingly degraded Anthropocene ecosystems, in which societal and ecological processes are deeply entwined and interact. Socio-ecological systems in turn require participatory management and governance regimes that can foster biodiversity conservation alongside societal benefits and social justice. For example, a “Just Aquatic Governance” framework has been proposed for the Amazon Basin, based on three pillars of social justice: recognitional, procedural and distributional (Lopes et al., 2021). The need for inclusive socio-ecological freshwater science and governance is particularly acute in the biodiverse, multicultural Amazon Basin (Castello, 2021). The Post-2020 Global Biodiversity Framework is visionary and compelling, and especially relevant to the recovery of freshwater biodiversity—the most overlooked and urgent conservation challenge of the next decade. The IUCN has distinguished 28 global freshwater ecosystem types, a powerful framing for activities to promote the recovery and conservation of freshwater biodiversity. This challenge paper supports the freshwater Emergency Recovery Plan by promoting a broader package of strategic activities that too often operate in silos, with patchy coverage of the world's freshwater ecosystem types and biogeographic diversity and cultural heritage. This portfolio urges integration of biodiversity inventory and basic ecosystem science, stressor assessment and mapping with systematic restoration and protected area management in a strategic global freshwater conservation strategy, with links to terrestrial and estuarine/marine realms as required. An overarching and integrative theme is the coupling of ecological and human systems, and the importance of collaboration among all stakeholders with indigenous, societal and scientific knowledge, technical expertise, and experience with governance models and policy development. There is an urgent need to build shared knowledge, trust, mutual understanding and enduring respectful partnerships in coupled human-ecological systems if we want a world of people “living in harmony with nature.” The author confirms being the sole contributor of this work and has approved it for publication. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1. ^ https://www.cbd.int/convention/guide/?id=web4 2. ^ https://sustainabledevelopment.un.org/sdgs 3. ^ https://www.iucn.org/theme/global-policy/our-work/united-nations-framework-convention-climate-change-unfccc 4. ^ http://www.fao.org/forestry/48209-0cb7240cc9f200dcf507a40e71c39a591.pdfs 5. ^ https://blog.oup.com/2020/09/bring-living-waters-back-to-our-planet/ 6. ^ https://ec.europa.eu/environment/pubs/pdf/factsheets/wfd/en.pdf Abell, R., Lehner, B., Thieme, M., and Linke, S. (2017). 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B., Gessner, M. O., Dudgeon, D., Prusevich, A., Green, P. A., et al. (2010). Global threats to human water security and river biodiversity. Nature 467, 555–561. doi: 10.1038/nature09440 PubMed Abstract | CrossRef Full Text | Google Scholar Winemiller, K. O., McIntyre, P. B, Castello, L., Fluet-Chouinard, E., Giarrizzo, T., Nam, S., et al. (2016). Balancing hydropower and biodiversity in the Amazon, Congo, and Mekong. Science 351, 128–129. doi: 10.1126/science.aac7082 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: biodiversity, ecosystem services, multiple stressors, restoration, protected areas, socio-ecological governance, stakeholders Citation: Arthington AH (2021) Grand Challenges to Support the Freshwater Biodiversity Emergency Recovery Plan. Front. Environ. Sci. 9:664313. doi: 10.3389/fenvs.2021.664313 Received: 05 February 2021; Accepted: 06 April 2021; Published: 10 May 2021. Edited by: Reviewed by: Copyright © 2021 Arthington. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Angela H. Arthington, [email protected]
Erika M. Timpe, , Cathy Binger, , Nancy Harrington, Jamie B. Schwartz
Augmentative and Alternative Communication, Volume 37, pp 113-128; https://doi.org/10.1080/07434618.2021.1921025

Abstract:
Three parents of preschool-aged children with Down syndrome using mobile augmentative and alternative communication (AAC) technologies to communicate participated indirect, systematic communication-partner instruction. Intervention featured an adaptation of the ImPAACT Program (Improving Partner Applications of Augmentative Communication Techniques; Kent-Walsh, Binger, & Malani, 2010) that included six face-to-face and three telepractice sessions. Parents learned to use the evidence-based Read–Ask–Answer (RAA) instructional strategy (Kent-Walsh, Binger, & Hasham, 2010 Kent-Walsh, J. , Binger, C. , & Hasham, Z. (2010). Effects of parent instruction on the symbolic communication of children using augmentative and alternative communication during storybook reading. American Journal of Speech-Language Pathology, 19(2), 97–107. doi:10.1044/1058-0360(2010/09-0014) [Crossref], [PubMed], [Web of Science ®] , [Google Scholar] ) during shared storybook reading with their children. A single-case, multiple-probe across participants design was used to assess parents’ accurate implementation of the instructional strategy and children’s multimodal communicative turns. All three parents increased their use of the RAA strategy and maintained strategy use over time, and all three children increased their frequency of communicative turns taken and maintained higher turn-taking rates. Results support the use of the ImPAACT Program with parents of children with complex communication needs, including the integration of hybrid learning as part of the instructional approach.
Sulaiman Ali Al Yousef
Acta fytotechnica et zootechnica, Volume 24; https://doi.org/10.15414/afz.2021.24.01.1-8

Abstract:
Article Details: Received: 2020-07-09 | Accepted: 2020-10-14 | Available online: 2021-03-31 https://doi.org/10.15414/afz.2021.24.01.1-8Extended-spectrum β-lactamases (ESBL) are enzymes produced by Gram-negative microorganisms, which may be resistant to commonly used antibiotics. The purpose of this research was to estimate the bactericidal effects of cinnamon oil on ESBLproducing bacteria. In this study, 227 water samples were collected from wells in Hafr Al-Batin, Saudi Arabia. The samples were cultured on a cystine lactose electrolyte-deficient (CLED) medium. A MicroScan system was used to identify bacteria and also for antimicrobial susceptibility test. Activity of crud cinnamon oil and its fractions were detected by determining the minimum inhibitory concentration (MIC) against the ESBL-producing bacteria. Morphological changes of the treated bacteria were observed and oil compounds was investigated. The culture was positive on the CLED medium in 170 out of 227 water samples. In 170 CLED-positive isolates, E. coli was the most common organism, followed by K. pneumoniae. The results showed that 100% of K. pneumoniae isolates were completely resistant to ampicillin (100%), then by mezlocillin (92.5%), cefazolin, and cefuroxime (77.5%). Also, 86.9% of E. coli isolates were the most resistant to ampicillin, followed by mezlocillin (83%). 82% of K. pneumoniae and 89% of E. coli isolates were confirmed by phenotypic confirmatory disc diffusion test (PCDDT) as ESBL-producers. The cinnamon oil activity was only concentrated in the oxygenated fraction. The MICs of the oxygenated fraction were 80 and 20 µl/mL at 105 CFU of ESBL-producing E. coli and K. pneumoniae, respectively. This study indicated the antibacterial effects of cinnamon essential oil to eliminate some antibiotic-resistant bacteria from water.Keywords: water, Escherichia coli, Klebsiella pneumoniae, antibiotic resistance, essential oil References ADEYEMI, A.O. et al. (2014). Antibiotics susceptibility patterns of some uropathogens to nitrofurantoin and nalidixic acid among pregnant women with urinary tract infections in federal medical centre, Bida, Niger-State, North Central, Nigeria. American Journal of Epidemiology and Infectious Disease, 2, 88–92. http://dx.doi.org/10.12691/ajeid-2-4-1AL YOUSEF, S. A. et al. (2016). Control. Detection of extended spectrum beta-lactamase producing Escherichia coli on water at Hafr Al Batin, Saudi Arabia. Journal of Pollution Effects & Control, 4(01). http://dx.doi.org/10.4172/2375-4397.1000155BRADFORD, P.A. (2001). Extended-spectrum β-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clinical Microbiology Reviews, 14(4), 933–951. http://dx.doi.org/10.1128/cmr.14.4.933-951.2001BRENES, A. and ROURA, E. (2010). Essential oils in poultry nutrition: Main effects and modes of action. Animal Feed Science and Technology, 158, 1–14. http://dx.doi.org/10.1016/j.anifeedsci.2010.03.007BURT, S. (2004). Essential oils: their antibacterial properties and potential applications in foods – a review. International Journal of Food Microbiology, 94(2), 223–253. http://dx.doi.org/10.1016/j.ijfoodmicro.2004.03.022CHANG, C.W. et al. (2008). Antibacterial activities of plant essential oils against Legionella pneumophila. Water Research, 42, 278–286. http://dx.doi.org/10.1016/j.watres.2007.07.008DIAO, W.R. et al. (2013). Chemical composition and antibacterial activity of the essential oil from green huajiao (Zanthoxylum schinifolium) against selected foodborne pathogens. J. Agric. Food Chem., 61(25), 6044–6049. http://dx.doi.org/10.1021/jf4007856DOI, Y. et al. (2007). Community-acquired extended-spectrum β-lactamase producers, United States. Emerging Infectious Diseases, Centers for Disease Control and Prevention (CDC), 13(7),1121–1123. http://dx.doi.org/10.3201/eid1307.070094DORMAN, H. and DEANS, S.G. (2000). Antimicrobial agents from plants: antibacterial activity of plant volatile oils. Journal of Applied Microbiology, 88(2), 308–416. http://dx.doi.org/10.1046/j.1365-2672.2000.00969.xGASPARI, R.J. et al. (2005). Antibiotic resistance trends in paediatric uropathogens. International Journal of Antimicrobial Agents, 26(4), 267–271. https://doi.org/10.1016/j.ijantimicag.2005.07.009JONES R.N. (1986). NCCLS standards: approved methods for dilution antimicrobial susceptibility tests. Antimicrobic Newsletter, 3(1), 1–3. http://dx.doi.org/10.1016/0738-1751(86)90022-5KOHANSKI, M.A. et al. (2007). A common mechanism of cellular death induced by bactericidal antibiotics. Cell, 130(5), 797–810. http://dx.doi.org/10.1016/j.cell.2007.06.049LAL, P. et al. (2007). Occurrence of TEM & SHV gene in extended spectrum β-lactamases (ESBLs) producing Klebsiella sp. isolated from a tertiary care hospital. Indian J. Med. Res., 125, 173–178.LIN, L. et al. (2017). Antibacterial poly (ethylene oxide) electrospun nanofibers containing cinnamon essential oil/ beta-cyclodextrin proteoliposomes. Carbohydrate Polymers, 178, 131–140. http://dx.doi.org/10.1016/j.carbpol.2017.09.043MAcKENZIE, F. et al. (2002). Comparison of screening methods for TEM-and SHV-derived extended-spectrum β-lactamase detection. Clinical Microbiology and Infection, 8(11), 715–724. http://dx.doi.org/10.1046/j.1469-0691.2002.00473.xMOLAND, E.S et al. (2002). Occurrence of newer β-lactamases in Klebsiella pneumoniae isolates from 24 US hospitals. 2002. American Society for Microbiology, 46(12), 3837–3842. http://dx.doi.org/10.1128/aac.46.12.3837-3842.2002NARAYANASWAMY, A. and MALLIKA M.E. (2011). Prevalence and Susceptibility of extended spectrum beta-lactamases in urinary isolates of Escherichia coli in a Tertiary Care Hospital, Chennai-South India. Internet Journal of Medical Update, 6(1), 39–43. http://dx.doi.org/10.4314/ijmu.v6i1.63975OJAGH, S.M. et al. (2010)....
Published: 11 March 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.635371

Abstract:
The magnitude of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the repurposing of several drugs to quickly stop the morbidity, mortality, and spread of this new disease. Repurposed drugs tested to fight COVID-19 have been chosen mainly on the basis of promising in vitro efficacy against SARS-CoV-2 or on previous therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) (1). Numerous clinical trials have already been completed, but no repurposed drug evaluated to date has been found that could significantly impact the course of COVID-19 pandemic (2). Our experience with previous viral pandemics, such as human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV), has taught us that precise design and target specificity will be essential to obtaining potent and successful antivirals against SARS-CoV-2. Repurposed drugs that have been explored more thoroughly since the beginning of the COVID-19 pandemic include remdesivir, favipiravir, lopinavir-ritonavir, ribavirin, interferon, and hydroxychloroquine (1). Favipiravir, a purine nucleoside analog broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp), approved for treatment of influenza virus infection in Japan, was chosen due to its in vitro activity against SARS-CoV-2, nevertheless, there is no evidence of its clinical efficacy. A prospective, randomized, open-label trial of early vs. late favipiravir in hospitalized patients with COVID-19 has shown that favipiravir did not significantly improve viral clearance (3). Lopinavir-ritonavir, a HIV-1 protease inhibitor, was investigated due to its SARS-CoV antiviral activity in tissue culture and infected patients. However, the lopinavir-ritonavir combination exhibited no clinical benefit against SARS-CoV-2 (4). From the very beginning of the COVID-19 pandemic, remdesivir has been the most promising drug against SARS-CoV-2. This adenosine nucleotide analog prodrug, a potentially inhibitor of RdRp, was initially developed by Gilead Sciences to treat filoviruses, such as the Ebola virus, and was explored due to its broad-spectrum antiviral activity in tissue culture and animal models against filoviruses, paramyxoviruses, pneumoviruses, and pathogenic coronaviruses, including SARS-CoV and MERS-CoV. Randomized controlled trials (RCTs) have found no effect of remdesivir on mortality (5). This drug has been approved to treat COVID-19 in the USA and Europe, but conclusive results to support the use of remdesivir are lacking (6, 7). The use of aminoquinoline drugs chloroquine and hydroxychloroquine is paradigmatic of the failure of repurposed drugs to treat COVID-19. These cheap drugs are generic antimalarials used to treat amoebic liver abscess and rheumatic disease. The early promising results with these two drugs showing antiviral activity against SARS-CoV-2 at micromolar concentrations in tissue culture and their clinical benefit in dubious observational trials of a few patients positioned them at the forefront of possible treatments for COVID-19. However, large observational clinical trials and RCTs have shown no effect of hydroxychloroquine in reducing mortality and/or mobility (2). Moreover, in some studies, a worse infection course was observed in hospitalized patients treated with these aminoquinolines (8). Importantly, recent studies have demonstrated that chloroquine does not inhibit infection of human lung cells with SARS-CoV-2 (9). Previous studies have shown that chloroquine and hydroxychloroquine inhibit the ability of SARS-CoV-2 to infect African green monkey kidney-derived Vero cells. However, when Vero cells were engineered to express TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells rendered SARS-CoV-2-infected Vero cells insensitive to chloroquine (9). Furthermore, chloroquine does not block infection with SARS-CoV-2 in TMPRSS2-expressing human lung Calu-3 cells, indicating that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS-CoV-2. These results emphasize the necessity of being cautious with observed drug inhibition of viral replication in tissue culture. Ivermectin, another cheap antiparasitic drug with in vitro efficacy against SARS-CoV-2, is being prescribed as a preventative against COVID-19. However, the evidence that ivermectin protects people from COVID-19 is limited (10). We should be prudent using ivermectin, or other potential drugs, outside clinical trials. In some countries, ivermectin is being also administered to SARS-CoV-2 infected patients. Different doses and posology have been used and confounding results have been reported. A recent pilot clinical trial found no significant differences in detection of SARS-CoV-2 RNA from nasopharyngeal swabs at days four and seven after treating with a single oral dose of 400 mcrg/Kg of ivermectin (11). Virus target specificity (e.g., isolation or drug-resistant viruses) should be tested and demonstrated before initiating treatments in virus-infected patients. As hydroxychloroquine showed no effect in SARS-CoV-2 infection in non-human primates (12), testing animal models will be preferable before translating these drugs to humans. In addition to drugs specifically aimed to inhibit SARS-CoV-2 replication, therapeutics that modulate inflammation have also been tested and, in this case, they seem to be a more effective therapeutic strategy for treating COVID-19 morbidity and mortality. Immunomodulators are being tested in several clinical trials for the treatment of SARS-CoV-2-generated cytokine storm. However, data to support the use of one of the most explored compounds to modulate inflammation, tocilizumab, a monoclonal antibody against interleukin-6 receptors, come largely from observational studies (13). Large RCTs with tocilizumab should provide answers regarding its clinical benefit. Immunomodulators that appear to work are corticosteroids. A recent RTC performed with dexamethasone showed that, in patients with moderate or severe COVID-19, dexamethasone plus standard care significantly increases survival and reduces morbidity (14, 15). Other drugs that could offer clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens, statins, N-acetyl cysteine, ACE2 inhibitors, angiotensin receptor blockers, and direct TMPRSS-2 inhibitors (16). Although immunomodulators may be an excellent clinical tool, it is desirable to potently and specifically stop SARS-CoV-2 replication after the onset of the first COVID-19 symptoms to avoid the pathogenic course of the disease. Ideally, we should stop SARS-CoV-2 in the first days of the infection. For example, neuraminidase inhibitors may not produce any detectable effect in a patient hospitalized with severe influenza virus infection, but can be useful in preventing the development of severe disease. The most appropriate therapy goal of an acute viral infection is therefore not to cure severe disease, but to keep the disease from becoming severe, and prevent hospitalization. Treatment early in the course of illness could also limit person-to-person transmission. A way to stop the early spread of SARS-CoV-2 will be through a sterilizing vaccine. SARS-CoV-2-neutralizing antibodies have been associated with protection (17). This is not surprising as natural infection induces both mucosal antibody responses (secretory IgA) and systemic antibody responses (IgG). The upper respiratory tract is mostly protected by secretory IgA, whereas the lower respiratory tract is mostly protected by IgG. Because most vaccines currently in development will be administered intramuscularly or intradermally, they will induce mostly IgG, but no secretory IgA (18). Therefore, these vaccines would probably prevent disease but not generate sterilizing immunity; that is, they may still allow for transmission of the virus (18). In this scenario, the current pandemic will require different strategies utilized in concert, including an effective vaccine and competent antivirals. HIV therapy is arguably among the most successful in treating any single human disease. The success of HIV therapeutics is illustrated by the number of antiretroviral agents and unique drug classes available (19). To date, the Food and Drug Administration (FDA) has approved 23 drugs to treat HIV infection. Based on their molecular mechanism and drug-resistance profile, antiretrovirals are classified into eight different classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors that block HIV entering CD4+ cells, CCR5 antagonists that block the CCR5 co-receptor that HIV needs to enter the cells, integrase inhibitors, attachment inhibitors that bind HIV glycoprotein 120, and post-attachment inhibitors that block cellular CD4 receptor. In addition to antiretrovirals, one pharmacokinetic enhancer has been approved to increase antiretroviral effectiveness. In contrast to the diffuse viral targets of most of the repurposed drugs mentioned above, antiretroviral target specificity was defined through the in vitro or in vivo selection of HIV-resistant variants for the different drugs. No antiretroviral has been approved in the absence of a specific viral target. Although the virus was discovered in 1983, few antiretroviral treatment options existed for HIV infection before 1996. HIV therapeutics consisted mainly of prophylaxis against common opportunistic pathogens and managing AIDS-related illnesses. The development of HIV reverse transcriptase and protease inhibitors in the mid-1990s, and the introduction of drug regimens that combined these two classes of inhibitors to increase their efficacy, completely revolutionized the clinical approach to HIV. These combination treatments transformed HIV infection from a life-threatening disease to a manageable chronic disease. The success of antiretroviral therapies has strongly impacted the development of therapies against other viral infections. The best example is HCV, another pandemic, life-threatening, human viral infection discovered in 1989. The first generation of FDA-approved HCV drugs included interferon alfacon-1 (approval year: 1997, discontinued in 2013 due to severe adverse events), ribavirin (1998), pegylated interferon alfa-2b (2001), and pegylated interferon alfa-2a (2002) (20). Although these drugs had low cure rates, a treatment duration of 48 weeks, and may cause severe adverse events, they were the only standard-of-care treatments over a decade. Interferons and ribavirin were chosen because they exhibited a certain inhibitory capacity against other viral infections, and their low effectivity is largely due to their low specificity against HCV. Fortunately, the development of direct-acting antivirals (DAAs) targeting the two main HCV enzymes, NS3 protease and RdRp (20), has decreased treatment duration to 8 weeks and increased the cure rate to nearly 100%. DAA therapy is among the best examples of success in the fight against viral infections. DAAs have transformed HCV management and opened the door to the global eradication of HCV. Patients infected with HIV or HCV have a prolonged course of infection measured in months or years, during which they are asymptomatic or only mildly ill, providing ample opportunity to intervene with an antiviral drug. Because viremia is prolonged and relatively steady, a patient can serve as his own control to measure a drug effect. Although the situation is quite different for patients who have developed COVID-19, a rapidly progressive disease in whom might be more difficult to expect an antiviral to provide detectable benefit and more difficult to diagnose in its earlier stages when antiviral approaches would be more likely to be effective, HIV-1 and HCV examples should be mirrors in which we should look for antiviral solutions. It can be argue that a repurposed drug that has not shown any benefit in hospitalized COVID-19 patients might still be useful in slowing the development of illness, preventing severe disease and making hospitalization unnecessary. In the absence of vaccines, a repurposed drug with limited antiviral activity might be given to persons who have been exposed to an infected individual, or are in a situation in which exposure is likely to occur (post- or pre-exposure prophylaxis). However, such benefit would be more difficult to demonstrate than a standard RCT, but could still be tested. A combinatorial approach of repurposing drugs targeting both the virus and host target mechanisms has been also proposed for the management of COVID-19 severity (21). The recent resolution of the crystal structures of the three most likely SARS-CoV-2 targetable proteins (spike, RdRp, and the main protease) is allowing the identification of first-generation SARS-CoV-2-specific antivirals (22–24). Even if the benefits of SARS-CoV-2-specific antivirals remain to be elucidated, we should quickly move these first-generation specific and potent antivirals to the clinic. Antiviral drugs approved for the treatment of human virus infectious diseases have saved tens of millions of human beings over the last decades. It is a challenge to pursue effective, low-toxicity, and well-tolerated drugs that enhance patient compliance and drug administration. Nevertheless, effective antivirals will positively impact COVID-19 therapy, and SARS-CoV-2 transmission and eradication. 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Le Anh Tuan, Bui Son Nhat, Nguyen Hong Long, Nguyen Thi Ngan, Nguyen Thi Lien Huong, Le Thi Luyen
VNU Journal of Science: Medical and Pharmaceutical Sciences, Volume 37; https://doi.org/10.25073/2588-1132/vnumps.4278

Abstract:
The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of isoniazid (INH) and to identify factors influencing INH pharmacokinetic variability. Pubmed and Embase databases were systematically searched from inception to July, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of INH written in English, conducted in human (either healthy subjects or pulmonary tuberculosis patients) were included in this review. Ten studies were included in this review. Most studies characterized a two-compartment model with first-order kinetics for INH with a transit-compartment model for absorption suggested. Frequently reported significant predictors for INH clearance is NAT2 acetylator types (slow/intermediate/fast), while weight is a significant covariate for INH volume of distribution (both central and peripheral). In children, enzyme maturation had a profound affect on INH clearance. Keywords: Population pharmacokinetics, Isoniazid. References [1] World Health Organization, Global Tuberculosis Report 2019. https://apps.who.int/iris/bitstream/handle/10665/329368/9789241565714-eng.pdf (accessed 18 December 2019).[2] United Nations, Transforming our world: The 2030 agenda for sustainable development, New York, USA, 2015.[3] K. Takayama, L. Wang, H.L. David, Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis, Antimicrob Agents Chemother 2.1 (1972) 29-35. https://doi.org/10.1128/aac.2.1.29 [4] A. Jindani, V.R. Aber, E. A. Edwards, D. A. Mitchison, The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 121(6) (1980) 939-49. https://doi.org/10.1164/arrd.1980.121.6.939 [5] P.R. Donald, The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid. Clin Infect Dis 39(10) (2004) 1425-30. https://doi.org/10.1086/424999 [6] D.A. 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Peloquin et al., Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide, Antimicrobial Agents and Chemotherapy 41(12) (1997) 2670-2679. https://doi.org/10.1128/aac.41.12.2670 [20] K.Y. Seng et al., Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers, Antimicrobial Agents and Chemotherapy 59(11) (2015) 6791-6799. https://doi.org/10.1128/aac.01244-15 [21] J.J. Wilkins et al., Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients, British Journal of Clinical Pharmacology 72(1) (2011) 51-62. https://doi.org/10.1111/j.1365-2125.2011.03940.x [22] S.P. Zvada et al., Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: In silico evaluation of currently recommended doses, Journal of Antimicrobial Chemotherapy 69(5) (2014) 1339-1349. https://doi.org/10.1093/jac/dkt524 [23] World Health Organization, Guidance for national tuberculosis programmes on the management of tuberculosis in children (No. WHO/HTM/TB/2014.03). World Health Organization, 2014.[24] World Health Organization, & Stop TB Initiative (World Health Organization), Treatment of...
, George M. Eliopoulos
Antimicrobial Agents and Chemotherapy, Volume 65; https://doi.org/10.1128/aac.02295-20

Abstract:
Since its inaugural issue nearly half a century ago, Antimicrobial Agents and Chemotherapy has served as a premier source for reports on scientific and clinical advances in the field of antimicrobial chemotherapy. As a follow-up to the previous “History of Antimicrobial Agents and Chemotherapy from 1972 to 1998” written by George A. Jacoby (Antimicrob Agents Chemother 43:999–1002, 1999, https://doi.org/10.1128/AAC.43.5.999 ), we herein highlight the further evolution of this comprehensive and authoritative journal in response to changing science, demographics, and information technology.
Annals of Advances in Chemistry, Volume 5, pp 001-003; https://doi.org/10.29328/journal.aac.1001022

Abstract:
In recent years polyolefin nanocomposites are of great interest because of their high potential as materials with novel properties [1,2].
, Farhana Sarker, Tom Chau, Khondaker A. Mamun
Abstract:
Augmentative and Alternative Communication (AAC) emerged as a combination of methods or strategies that constitute any device, such as Speech Generating Device (SGD), Program (mobile applications), Procedure (PECS, Picture Exchange Communication System), which enhances individual’s communication ability. Autism Spectrum Disorder (ASD) is a spectrum of comprehensive neurodevelopment disorder that leads to speech impairments, repetitive behavior, and social communication difficulties; therefore, it is imperative to underscore that at the core of all impediments are communication impairment. This article represents a systematic review of research initiatives that investigate multi-modal AAC strategies and functionality, features of mobile applications to reinforce communication and communal skills in verbally challenged ASD children because other researches are focused only on low or high-tech AAC or interventions to provide insights on ASD children respond to a particular approach. Following the PRISMA method, a total of 60 (January 2015 to October 2020) research articles were reviewed, indexed by Springer, Science Direct, Scopus, ACM, IEEE databases, and published in the AAC journal. The selected research articles are categorized into different themes where most of them focused on interactive mobile applications to improve emotional, social, learning, and overall communication skills in verbally challenged ASD children. This systematic review provides an outline of the paradigm shift in AAC modalities from PECS to Artificial Intelligence (AI), Machine Learning (ML), and Augmented Reality (AR) based applications. It opens up underline future opportunities to integrate intelligent analytics features in mobile applications to strengthen communication skills in verbally undermined ASD children.
Pedro Réquio
Cadernos de Literatura Comparada pp 275-290; https://doi.org/10.21747/2183-2242/cad44a16

Abstract:
This article aims to evaluate the creation and literary dissemination of students from the Academic Association of Coimbra (AAC) during the period between 1958 and 1962. The chronological limits are justified by Humberto Delgado’s candidacy to the 1958 presidential elections, which brings with it the politicization of different sectors of society, and the first academic crisis, in 1962. During the period mentioned in the AAC magazine, Via Latina, many short stories and literary essays by university students were published. This production denotes a clear influence of the artistic currents that dominated the Portuguese cultural panorama at the time. Inspired by neo-realism and existentialism, as well as by democratizing political opportunities, these authors carried out a transformation of the university and Coimbra’s cultural panorama. For a richer analysis, Via Latina is compared with other academic journals of the time. This article has used interviews with members of the magazine.
Varun J Sharma, Minesh Prakash, Zaw Lin, Casey Lo
Interactive Cardiovascular and Thoracic Surgery, Volume 32, pp 106-110; https://doi.org/10.1093/icvts/ivaa215

Abstract:
Summary A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was ‘in patients with ascending aortic or aortic arch disease what are the outcomes with endovascular repair in terms of survival, complications and reintervention?’ Altogether 585 papers were found using the reported search, of which 9 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We found that the endovascular operative techniques with the greatest evidence were ascending aortic chimney grafts (AACs), branched thoracic endovascular aortic repair (bTEVAR) aortic grafts and fenestrated TEVAR (fTEVAR) aortic grafts. The best evidence available were small case-series or retrospective cohort studies (n < 100), with 1 systematic review, at a short follow-up period (range 0–5 years). Intraoperatively, these techniques have a high technical success rate (84–100%). We found rates of endoleak comparable between AAC (7.4–16%) and bTEVAR/fenestrated TEVAR (11.1–21.4%). Stroke rates are higher in bTEVAR (3.1–42% vs 1–26% in AACs), attributed to more proximal pathology and technically challenging procedures. Following the immediate postoperative period, the 30-day mortality is 0–10.8% and patency is 97–100%. Stroke and reintervention rates remain higher in the bTEVAR group (3.1–42.0% and 0.5–33.3%) compared to the AAC group (1.0–11.1% and 6.7–16.7%). The 3- and 5-year survival ranges from 59% to 90%, but is driven by non-aortic pathology in a high-risk population; 3-year freedom from aortic death is 93–97%. Patency is 97–100% at up to 3 years, conformation and supra-aortic occlusions thereafter remain unknown. We conclude that AACs, bTEVARs and fenestrated TEVARs are safe endovascular options in high-risk elective patients, with results comparable to open or hybrid repair. They remain unverified in acute settings or in patients fit for open intervention.
, Catherine P Bondonno, , Lauren C Blekkenhorst, Reindolf Anokye, Emma Connolly, Nicola P Bondonno, John T Schousboe, Richard J Woodman, Kun Zhu, et al.
Published: 11 November 2020
by BMJ
Abstract:
IntroductionMost cardiovascular disease (CVD)-related events could be prevented or substantially delayed with improved diet and lifestyle. Providing information on structural vascular disease may improve CVD risk factor management, but its impact on lifestyle change remains unclear. This study aims to determine whether providing visualisation and pictorial representation of structural vascular disease (abdominal aortic calcification (AAC)) can result in healthful diet and lifestyle change.Methods and analysisThis study, including men and women aged 60–80 years, is a 12-week, two-arm, multisite randomised controlled trial. At baseline, all participants will have AAC assessed from a lateral spine image captured using a bone densitometer. Participants will then be randomised to receive their AAC results at baseline (intervention group) or a usual care control group that will receive their results at 12 weeks. All participants will receive information about routinely assessed CVD risk factors and standardised (video) diet and lifestyle advice with three simple goals: (1) increase fruit and vegetable (FV) intake by at least one serve per day, (2) improve other aspects of the diet and (3) reduce sitting time and increase physical activity. Clinical assessments will be performed at baseline and 12 weeks.OutcomesThe primary outcome is a change in serum carotenoid concentrations as an objective measure of FV intake. The study design, procedures and treatment of data will adhere to Standard Protocol Items for Randomized Trials guidelines.Ethics and disseminationEthics approval for this study has been granted by the Edith Cowan University and the Deakin University Human Research Ethics Committees (Project Numbers: 20513 HODGSON and 2019-220, respectively). Results of this study will be published in peer-reviewed academic journals and presented in scientific meetings and conferences. Information regarding consent, confidentiality, access to data, ancillary and post-trial care and dissemination policy has been disclosed in the participant information form.Trial registration numberAustralian New Zealand Clinical Trial Registry (ACTRN12618001087246).
Ankita Bhatt, Pratham Arora, Sanjeev Kumar Prajapati
Published: 11 November 2020
Frontiers in Microbiology, Volume 11; https://doi.org/10.3389/fmicb.2020.596374

Abstract:
Microalgae are defined as photosynthetic and unicellular organisms that demonstrate a wide range of adaptability to adverse environmental conditions like temperature extremes, photooxidation, high or low salinity, and osmotic stress (Holzinger and Karsten, 2013; Singh et al., 2019). Alternatively, macroalgae or seaweed includes multicellular, macroscopic, and marine algae belonging mostly to two phyla, namely, Rhodophyta and Phaeophyta (Peng et al., 2015). The micro/macro-algae have recently emerged as a source of various bioactive compounds like phycocyanin, lutein, vitamin E, B12 and K1, polyunsaturated fatty acids, polysaccharides and phenolics (Peng et al., 2015; Costa et al., 2020). These secondary metabolites have been studied for their anti-microbial, anti-inflammatory, immunosuppressive, anti-cancer and other pharmacologically important activities (Sathasivam et al., 2019). Thus, the algal metabolites find wide applicability in a vast array of biotechnological and pharmaceutical fields. In view of the ongoing COVID-19 pandemic caused by a novel coronavirus, designated as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), increased efforts are being made for developing efficient treatment options to tackle the disease. The SARS-CoV-2 has been identified as a single-stranded, positive-sense RNA virus belonging to the Betacoronavirus family (Yeo et al., 2020). Further, various structural (spike glycoprotein), non-structural (3-chymotrypsin-like protease, helicase, papain-like protease, and RNA-dependent RNA polymerase), and accessory proteins are encoded by SARS-CoV-2 genome (Li and De Clercq, 2020). The spike glycoprotein has been considered to be involved in the interaction between viruses and receptors present on the host cell (Li and De Clercq, 2020). Since this glycoprotein is an essential requirement for the entry of virus in host cells, many recent studies are focused on this structural protein (Zumla et al., 2016). It has been further concluded that the above mentioned five proteins also emerged as attractive targets for antiviral studies against SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East respiratory syndrome) (Zumla et al., 2016). Considering all the facts related to exploration of algae for bioactive molecules, the present study provides an insight into the utilization of micro/macro-algal metabolites as therapeutic compounds against SARS-CoV-2 and like viruses. The key antiviral metabolites, namely, phycocyanobilins, lectins, and, sulphated polysaccharides have been discussed. Phycocyanobilins (PCBs) are tetrapyrrole chromophores present in certain cyanobacteria, rhodophytes, and are classified as blue phycobilinis (Figure 1) (Guedes et al., 2019). These light-capturing pigments are now widely studied for their antioxidative, antiviral (Hirata et al., 2000; Ramakrishnan, 2013) and NADPH-oxidase inhibitory activity (McCarty, 2007). Recently, Pendyala and Patras (2020) discussed the possible utilization of PCBs (source—Spirulina sp.) as inhibitors for the SARS-CoV-2 infection. The study involved in-silico screening (by the COVID-19 Docking Server) of the bioactive compounds for their activity against SARS-CoV-2. It was observed that the phycocyanobilin demonstrates a high binding affinity toward the potential targets, namely, the Main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The Main protease is involved in the processing of polyproteins (translated from SARS-CoV-2 RNA) while the replication of viral RNA is catalyzed by the polymerase. High binding energy of −8.6 kcal/mol was observed for PCB-Mpro while −9.3 kcal/mol for PCB-RdRp. Noteworthy, the PCB demonstrated a superior binding to target enzymes as compared to antiviral drugs like remdesivir (−8.1 kcal/mol for Mpro, −9.0 kcal/mol for RdRp), lopinavir (−7.9 kcal/mol) and nelfinavir (−7.9 kcal/mol for Mpro, −9.3 kcal/mol for RdRp). Thus, the study highlighted the significant potential of PCB as antiviral. However, as recommended by Pendyala and Patras (2020), further in-vitro and/or in-vivo studies will be crucially needed to support the obtained docking results and unravel the underlying potential of PCB as therapeutic for COVID-19. Additionally, the purified allophycocyanin obtained from Spirulina platensis has been demonstrated to exhibit significant activity against enterovirus 71 (Singh et al., 2020). It was observed that the cytopathic effects of the viral infection were neutralized and the viral RNA synthesis was delayed by the microalgal pigment allophycocyanin. Likewise, results of an in-silico study reported that the PCB expressed by Arthrospira sp. could serve as a potent antiviral against SARS-CoV-2 (Petit et al., 2020). The study evaluated the interaction between the Arthrospira sp. PCB and the receptor binding domain (RBD) of SARS-CoV-2 spike glycoprotein. It was observed that five Van der Waals interactions (involving residues ARG403, TYR453, LEU492, GLN493, and ASN501) contributed to the PCB/Spike RBD complex. The five π-alkyl bonds between the PCB and spike RBD involved the residues TYR449, TYR495, PHE497, and TYR505 with a hydrogen-bond on TYR449. The other residues involving the hydrogen-bond were SER494, GLY496, and GLN498 with the GLY496 linked to PCB by a π-donor hydrogen bond. Finally, a competitive binding energy (−7.2 kcal/mol) demonstrated the possibility to employ PCB as a potential antiviral agent (Petit et al., 2020). A recent study also reported the probability to utilize phycocyanobilin containing cyanobacteria like Spirulina sp. to control the RNA virus infections (Nikhra, 2020). A decrease in mortality rate in influenza-infected mice has been observed when administered orally with phycocyanin rich cold-water Spirulina sp. extracts in animal experimentation studies. The cold-water extract was well-tolerated even at high concentrations of 3,000 mg/kg/day in animal models for a period of 14 days (Chen et al., 2016). The PCB extracts thus demonstrated a substantial reduction in the survival of zoonotic RNA viruses by enhancing the type 1 interferon response of host immune system (Nikhra, 2020). Hence, it is likely possible that PCB producing microalgae may demonstrate substantial activity against SARS-CoV-2 as well (Cascella et al., 2020; Zhou et al., 2020). Moreover, further research along with in-vivo studies is necessary to understand the specific bioactivity of PCBs for the development of therapeutic strategies against human pathogenic viruses, including SARS-CoV-2. Figure 1. Algal antiviral metabolites (a) phycocyanobilin; (b) lectin; (c) fucoidan (a representative SP); (d) SPs-mediated humoral activation; (e) activation of host cellular immune response by SPs; (f) SPs-driven inhibition of virus entry/attachment to the host cell receptor. The macroalgae are rich in certain carbohydrate-binding proteins called lectins that demonstrate high specificity for sugar groups of other molecules like the oligosaccharide chains of the viral glycoproteins (Figure 1). Thus, lectins have been widely employed in various pharmacological and medical applications (Breitenbach Barroso Coelho et al., 2018). The mannose-binding lectins (MBL) are the predominant proteins to be studied in the viral infection pathways (Mitchell et al., 2017). The self-assembly of viruses during replication is interrupted by MBLs (Liu et al., 2015); thus, they have also emerged as a potential therapy against Ebola (Michelow et al., 2011). The red algae-derived lectins were initially brought to the limelight when griffithsin was discovered by Watson and Waaland (1983) from Griffithsia sp. Since then, it has been widely studied for various applications (Mori et al., 2004). It has been observed to possess high specificity for mannose residues present on viral glycoproteins. Some studies have demonstrated its antiviral activity against HIV-1 (Lusvarghi et al., 2016), Hepatitis C (Meuleman et al., 2011), and SARS-CoV glycoprotein (Zumla et al., 2016). A recent study analyzed the anti MERS-CoV activity of griffithsin and concluded that the lectin inhibits the entry of the virus while imparting negligible cellular toxicity (Millet et al., 2016). The inhibitory effect of griffithsin at the binding step during virus infection was assayed by time-course experiments. Thus, the study by Millet et al. (2016) demonstrated the griffithsin-mediated inhibition of MERS-CoV infectivity in-vitro. Additionally, various studies have reported the in-vivo antiviral activity of griffithsin against Japanese encephalitis virus (Ishag et al., 2013), herpes simplex virus 2 (Nixon et al., 2013) and human papillomavirus (Levendosky et al., 2015). For instance, the impact of an anti-HIV griffithsin containing microbicide on the rectal microbiome was assessed in the non-human primates (Rhesus macaques) (Girard et al., 2018). It was observed that 0.1% of griffithsin gel did not negatively impact the rectal mucosal proteome or microbiome. Further, O'Keefe et al. (2010) reported a 100% survival of model mice infected with a high dose of SARS-CoV upon providing a griffithsin dose of 10 mg/kg(b.w.)/day. Based on griffithsin activity against SARS-CoV, it may be investigated as a therapeutic option for SARS-CoV-2. Likewise, a novel D-mannose-binding lectin was identified from the red macroalgae Grateloupia chianggi and designated as GCL (Grateloupia chianggi lectin) (Hwang et al., 2020). The study focussed on GCL purification, its molecular and functional characterization, and subsequent analysis of its antiviral activity against influenza virus, herpes simplex virus and HIV. A quantity of 1–20 nM GCL was required for effective inhibition of HSV. Thus, it may be concluded that GCL also holds the potential to be utilized in virology and biomedical research. It is significant to note here that the SARS-CoV-2 is similar to the influenza virus as both are characterized as enveloped RNA viruses (Noda, 2012; Yeo et al., 2020). Based on the activity of GCL against the influenza virus, its activity may be explored against SARS-CoV-2 as well. Various researchers have demonstrated the beneficial effects of algal sulphated polysaccharides (SPs) under defined in-vitro and/or in-vivo conditions. Both the cellular and/or the humoral response of the immune system can be activated by these compounds (de Paniagua-Michel et al., 2014) (Figure 1). A recent study emphasized on the purification and structural characterization of two fucoidans from the brown macroalgae Sargassum henslowianum (Sun et al., 2020). These fucoidans designated as SHAP-1 and SHAP-2 were studied for their activity against two strains of herpes simplex virus, i.e., HSV-1 and HSV-2. It was observed that both compounds possessed significant anti-HSV activity with the IC50 value estimated to be 0.89 and 0.82 μg/mL for SHAP-1 and SHAP-2, respectively, against HSV-1 strain. Surprisingly, the IC50 values for both polysaccharides against HSV-2 were very low, i.e., 0.48 μg/mL. Also, time-of-addition experiments revealed that more efficient anti-HSV activities were obtained when fucoidans were added during the infection stage, thereby signifying their role at the early stages of viral infection. The adsorption and penetration assays further demonstrated that the fucoidans were involved in interruption of HSV adsorption to the host cell. Hence, it may be concluded that fucoidans could serve as promising candidates for inhibition of HSV-2 viruses and may be successfully utilized for various clinical applications. Similarly, a sulphated polysaccharide was isolated from the green macroalgae Monostroma nitidum (Wang et al., 2020). The compound isolated from M. nitidum was identified as a water-soluble sulphated glucuronorhamnan and thus designated as MWS. Various cytotoxicity and antiviral assays were performed to estimate the activity of MWS against EV71, a strain of human pathogenic enterovirus. It was observed that MWS was not toxic to the used cell lines and demonstrated a broad-spectrum of antiviral activity, especially against EV71 under defined in-vitro conditions. Further, it was concluded that MWS inhibits the EV71 infection by either targeting the host signaling pathway (down-regulation of host phosphoinositide 3-kinase/protein kinase B signaling pathway) in EV71 early life cycle and/or interrupting adsorption of virus to the host cell. The former mechanism has been concerned with the suppression of viral infection. The study also involved animal experiments, and a significant reduction in the viral titers was observed upon intramuscular administration of MWS in EV71 infected mice (Wang et al., 2020). Additionally, the SPs obtained from macroalgae Cladosiphon okamuranus and Ulva clathrata were also observed to demonstrate significant antiviral activity against the Newcastle disease virus under defined in-vitro conditions (Aguilar-Briseño et al., 2015). Another study elaborated the antiviral activity of SPs obtained from Ulva pertusa, Grateloupia filicina, and Sargassum qingdaoense against the avian influenza virus under in-vitro and in-vivo conditions (Song et al., 2016). A recent review highlighted the possibility of utilizing the SPs obtained from Porphyridium sp. (red microalga) as a potential therapeutic to combat COVID-19 disease (Gaikwad et al., 2020). Based on the antiviral activity of Porphyridium polysaccharides against a wide range of viruses including HSV (Huheihel et al., 2002), varicella zoster virus (Raposo et al., 2013), hepatitis B virus, vaccinia virus (Radonić et al., 2010) and retroviruses (Xiao and Zheng, 2016), this microalga has been considered to hold immense potential for the development of an antiviral pharmaceutical composition against SARS-CoV-2 as well (Gaikwad et al., 2020). Also, the effective inhibition (in-vitro) of SARS-CoV-2 by SPs (fucoidans) obtained from macroalgae Saccharina japonica was reported by Kwon et al. (2020). The fucoidans labeled as RPI-27 and RPI-28 demonstrated significant activity against SARS-CoV-2 with RPI-27 being more potent than the antiviral drug remdesivir. These highly branched fucoidans were observed to interfere with the binding of viral S protein to the heparan sulfate co-receptor of the host cells, thereby, inhibiting the viral infection. Thus, the study suggested the possibility of utilizing fucoidans alone or in combination with other antivirals as a promising therapeutic strategy against SARS-CoV-2 infection (Kwon et al., 2020). These studies indicate the potential therapeutic role of algal sulphated polysaccharides. There has been a substantial increase in evidence that reveals the antiviral activity of various microalgal and macroalgal metabolites like lectins, sulphated polysaccharides, and phycocyanobilins. Recent studies have reported that these compounds demonstrate substantial activity against a wide array of DNA and RNA viruses, including the influenza virus known to be associated with respiratory illnesses. As discussed, the bioactive molecules could serve as a novel therapeutic option to tackle SARS-CoV-2 and alike viruses. Considering the dire need for the development of therapeutics against SARS-CoV-2, there is a necessity to screen through the myriad of algae-derived potential antivirals which demands further evaluation and research. AB: conceptualization, data curation, visualization, and writing - original draft. PA: validation, writing - review & editing. SP: conceptualization, writing - review & editing, and supervision. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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Drug Discov. 15, 327–347. doi: 10.1038/nrd.2015.37 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: microalgae, seaweed, antiviral, COVID-19, sulphated polysaccharides Citation: Bhatt A, Arora P and Prajapati SK (2020) Can Algal Derived Bioactive Metabolites Serve as Potential Therapeutics for the Treatment of SARS-CoV-2 Like Viral Infection? Front. Microbiol. 11:596374. doi: 10.3389/fmicb.2020.596374 Received: 19 August 2020; Accepted: 05 October 2020; Published: 11 November 2020. Edited by: Reviewed by: Copyright © 2020 Bhatt, Arora and Prajapati. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Sanjeev Kumar Prajapati, [email protected]; [email protected]
Published: 9 September 2020
Frontiers in Neurology, Volume 11; https://doi.org/10.3389/fneur.2020.00960

Abstract:
The ability of MOG antibody (MOG-Ab) to induce autoimmune disease in animals has been known for decades (1), but it is only recently since the cell-based assay for MOG-Ab IgG1 has been developed and commercialized, that it became possible to characterize clinical syndromes associated with MOG-Ab in humans. Early reports of MOG Associated Disease (MOGAD) emphasized its similarity to Neuromyeliits Optica Spectrum Disorder (NMOSD) (2–4). Indeed, a minority of patients with Aquaporin-4 antibody (AQ4-ab)-seronegative NMOSD−42% in one series–test positive for MOG-Ab (5). However, because the spectrum of MOGAD encompasses many NMOSD-atypical presentations, and because of differences in pathophysiology–AQ4-ab-positive NMOSD being an astrocytopathy and MOGAD being an oligodendrocytopathy—there is an increasing tendency to recognize AQ4-Ab-positive NMOSD and MOGAD as distinct entities (6–10). In this review, we organize the clinical presentations of MOGAD by neuroanatomic compartments, while emphasizing the wide range of reported presentations. While this organization is useful for didactic purposes, it should be borne in mind that MOGAD may involve multiple regions of the CNS simultaneously– much more often than other CNS inflammatory diseases, and that half of MOGAD patients have active lesions in more than one location at the time of initial presentation (11–14). While no phenotype is restricted to any specific age group, some generalizations about clinical presentations of MOGAD in children and adults are possible. In children under the age of 11, ADEM-like phenotypes (encephalopathy, multifocal neurologic deficits and “fluffy” supratentorial cerebral lesions in a bilateral distribution) predominate, while in adolescents and adults, focal syndromes of optic neuritis or longitudinally extensive myelitis are more common (11, 15, 16). Unlike Multiple Sclerosis (MS), where relapse rates are higher in children and decline with older age, in MOGAD the majority of children are not prone to frequent relapses, with 80% of having a monophasic course (17). However, the high rate of monophasic disease may be an overestimate due short follow up (right censoring) as recent case reports documented disease reemergence years and even decades after the initial episode in childhood (18, 19). Given the important differences in pediatric and adult MOGAD, we will qualify discussion of specific syndromes with reference to the respective age group (with the caveat that the clinical distinctions across age groups are only generalizations). Optic neuritis (ON) is the most common initial presentation of MOGAD in adolescence and adulthood, and a frequent presentation in pediatric patients (11, 16, 20). It is associated with a higher risk of subsequent relapse compared to other clinical presentations (11–13, 18). At the onset, vision loss is often severe and up to 80% of patients have bilateral optic nerve involvement, which is highly unusual in MS (12, 14, 21–24). Despite the severity of vision loss in the acute phase, recovery is usually good, especially in children: 89–98% of children had visual acuity to 20/25 or better at 6 months (14, 25). In adults, 6–14% of patients had permanent loss of vision (≤ 20/200) in the affected eye (11, 13, 24). Optic disc edema is rare in MS or NMOSD but is present in up to 86% of patients with MOGAD-ON (13, 21, 22, 24, 26, 27). Rarely, bilateral ON with disc edema can be mistaken for idiopathic intracranial hypertension especially if the patient also complains of headache and has elevated opening pressure on lumbar puncture; however lymphocytic pleocytosis in CSF and enhancement of optic nerve on orbital MRI point toward an inflammatory etiology and should prompt testing for MOG-Ab (28). Fulminant disc edema with peripapillary hemorrhages and “macular star” have been described in MOGAD-ON (29–31). Both of these findings are considered highly atypical for other inflammatory-demyelinating diseases and are more often associated with infectious and ischemic etiologies (29, 30). Up to 50% of adults with MOG-ON have a recurrence of optic neuritis (11–13, 18), which may be the only manifestations of MOGAD. Two rare previously described phenotypes, chronic relapsing inflammatory optic neuropathy (CRION)– a rare condition characterized by relapsing, steroid-dependent optic neuritis (32), and relapsing isolated optic neuritis (RION), have been associated with MOG-Ab in some cases (33, 34). MRI of the orbits during acute MOG-ON typically shows longitudinally extensive optic nerve enhancement with a predilection for the anterior portion of optic nerves; the chiasm and optic tracts are less frequently affected (21, 31). “Optic perineuritis,” characterized by inflammation of the optic nerve sheath and surrounding structures on MRI (35), is seen in up to 50% of cases of MOGAD-ON (Figure 1A) (13, 21, 25, 36, 37). Perineural enhancement is a feature that can help differentiate MOGAD from NMOSD or MS (13, 21, 25, 36, 37). Isolated cases of MOGAD perineuritis, involving the nerve sheath and surrounding structures but not the optic nerve, have also been reported (38, 39). Rarely, uveitis and keratitis can occur simultaneously or subsequently to MOG-ON (38). Figure 1. (A) MRI brain T1 coronal post gadolinium contrast showing contrast enhancement of bilateral optic nerves and right optic nerve sheath consistent with perioptic neuritis. (B) MRI spine sagittal STIR showing longitudinal extensive patchy lesion spaning from cervical to thoracic cord. (C) MRI spine sagittal T2 showing hyperintense longitudinally extensive “pseudo-dilation” of central canal. (D) MRI spine sagittal T1 post gadolinium contrast showing patchy enhancement of the conus medullaris. (E) MRI brain axial FLAIR showing large subcortical and septal white matter lesions in a pediatric patient presenting with ADEM. (F) MRI brain axial T2 with hyperintense “H” sign outlining the central gray matter of the upper cervical cord in a teenager with myelitis. (G) MRI brain axial T2 with “fluffy” hyperintense lesion of gray and white matter of the left caudate and left occipital parietal regions in a pediatric patient who presenting with ADEM. (H) MRI brain axial T2 showing unilateral FLAIR hyperintensity and edema of right mesial frontal cortex in a patient with FLAMES syndrome. (I) MRI brain axial T1 post gadolinium contrast showing leptomeningeal enhancement of the midrain and right mesial temporal lobe. (J) MRI brain axial T1 post gadolinium contrast showing a lesion adjacent to the cerebellar vermis and dorsal medulla in a patient with brainstem syndrome and no other lesions. MOG-Ab associated acute transverse myelitis is a relatively common presentation of MOGAD in adults, and can be seen in children as well (11). In some cases of MOG-TM, there is an antecedent history of infection or vaccination, but in most patients, no such history can be elicited (11, 18, 40). While MOG-TM is typically steroid-responsive with favorable long-term recovery, around 9% of patients have poor recovery (11). Recurrent myelitis, without any other syndromes of MOGAD, is reported in up to 5% of patients (41). MOG-TM can affect any segments of the spinal cord but has a greater predilection for conus medullaris–reported in 11–41% patients–than other CNS inflammatory-demyelinating diseases (11, 18, 40, 42). The involvement of the conus (Figure 1D) may explain the high incidence of neurogenic bowel and bladder symptoms (83%), and erectile dysfunction (54%) during acute phase (40), as well as in the long-term (11). There are also reports of a steroid-dependent myeloradiculitis in MOGAD with a longitudinally extensive transverse lesion from T12 to the conus with sacral nerve root enhancement (43). Radiographically, MOG-TM is usually associated with a longitudinally extensive lesion spanning 3-4 vertebral segments (Figure 1B) (2, 18, 40, 44). In this respect, MOG-TM is similar to NMO-TM, but there are several radiographic differences between the two diseases. First, cord lesion of MOG-TM during the acute phase are much less likely to demonstrate gadolinium enhancement than in NMOSD: only 26% of MOG patients show enhancement vs. 78% of AQ4-ab-seropositive NMOSD (40). Secondly, spinal cord lesions in MOGAD can be multifocal: 62% of patients had ≥2 non-contiguous spinal cord lesions (40). The radiographic multifocality is in line with the notion that MOGAD has a tendency to affect multiple areas of CNS simultaneously. MOG-TM affects both gray and white matter of the cord. The involvement of gray matter can manifest as linear hyperintensity of the central spinal canal (“pseudo-dilation,” Figure 1C) (44), or as H-shaped T2-hyperintensity that outlines the anterior and posterior horns (“H-sign,” Figure 1F) (2, 18, 40). The “H-sign” is suggestive, but not specific for MOGAD, reported in 29% of patients with MOG-TM and 8% of patients with NMO-TM (40). The predilection for the gray matter may explain why MOG-TM sometimes presents as acute flaccid paralysis (AFM) (45): in one series 10 out of 47 MOGAD patients (21%) met clinical criteria for AFM (40). In young children, MOGAD frequently presents as ADEM or an ADEM-like syndrome (ADEM with optic neuritis, multiphasic disseminated encephalomyelitis) (16, 46–49). MRI of the brain typically shows large, ill-defined bilateral lesions frequently involving cortical and deep gray matter structures (Figure 1G) (50). Lesions may also involve subcortical white matter and corpus callosum as seen in Figure 1E. Optic nerves and spinal cord may be involved concurrently with brain (51). Recurrent ADEM or ADEM associated with recurrent optic neuritis (52, 53) are especially suggestive of MOGAD. Importantly, in children with clinical syndrome of encephalitis, MOGAD diagnosis is possible even when MRI findings are not compatible with ADEM—for example, exclusive cortical or symmetric thalamic/basal ganglia involvement, or even normal MRI (54). Cerebral involvement in adults is both less common and more restricted than in children, though there are exceptions (55). Syndrome of encephalitis with steroid-responsive seizures, also termed FLAMES (FLAIR-hyperintense Lesions and Anti-MOG-associated Encephalitis with Seizures), appears to be specific to MOGAD (20, 56–58). FLAMES patients present with focal-onset, tonic-clonic seizures, and have unilateral FLAIR hyperintensities with edema on MRI (Figure 1H). A review by Budhram et al. found 20 cases of FLAMES in the literature. The most common symptoms were seizures (85%), headache (70%), and fever (55%). CSF pleocytosis and cortical leptomeningeal enhancement (Figure 1I) were present in a minority of patients (57). All patients with FLAMES responded to high dose steroids with resolution of FLAIR changes. Of note, a number of patients developed ON either before or after seizures (56, 58, 59). Thus, the emergence of seizures in the context of ON or focal brain inflammatory lesions should prompt testing for MOG-Ab (52). Isolated seizures may rarely be an index event in MOGAD. In one case, an adult patient presented with aphasic status epilepticus with initial MRI showing no abnormalities. Six months later the patient developed a tumefactive demyelinating lesion, with MOG-Ab testing positive several months later (60). A similar presentation has been described in four pediatric patients who presented with isolated seizures and normal brain MRI and developed MRI brain lesions months, and in one case years, later (61). Several studies document an association between MOGAD and autoimmune encephalitis with NMDA-antibody (62–64). In a retrospective case review by Titulaer et al., 12 of 691 with NMDAR encephalitis patients (1.6%) tested positive for MOG-Ab. Some patients presented with MOGAD syndrome followed by encephalitis, others with encephalitis followed by MOGAD, and in some NMDA encephalitis and MOGAD were diagnosed concurrently. Three patients with NMDAR encephalitis and no clinical or MRI features to suggest MOGAD also tested positive for MOG-Ab (62). Finally, mention should be made of rare cases when MOG-Ab was found in patients with pathologically-proven CNS vasculitis (65, 66). Two patients presented with fever, headache, confusion, and focal neurologic deficits (66), and the third had 9 months of progressive cognitive and behavioral decline (65). MRI showed multifocal lesions in both the gray and white matter in two cases, one of whom also had open-ring contrast-enhancing lesions. The third case had findings of focal cortical encephalitis with gyriform FLAIR hyperintensities with edema, similar to findings seen in FLAMES. All three cases underwent brain biopsy, which showed small vessel perivascular inflammation, consistent with CNS vasculitis. However, fibrinoid necrosis, a pathologic requirement for small vessel CNS vasculitis, was absent in two of the cases (66, 67). Whether vasculitis should be regarded as a primary or secondary manifestation of MOGAD, or MOG-Ab is unrelated to vasculitis diagnosis, is difficult to determine given rarity of the association. Brainstem involvement is seen in 30% of MOGAD patients, and is a risk factor for a higher disability at long-term follow-up and more active disease (68). In one large series brainstem inflammation occurred concomitantly with inflammation in optic nerves in 40% of cases, spinal cord in 89% cases and cerebrum in 66% of cases (68). However, there are reports of isolated brainstem inflammation as well (Figure 1J) (68). Any part of the brainstem can be affected, medulla being the most common (11, 68). Brainstem lesions are usually associated with disabling symptoms—weakness, cranial nerve deficits, ataxia, hypoventilation syndrome, impaired consciousness and, and, exceptionally, a fatal outcome (68). Area postrema syndrome (APS), one of the core syndromes of NMOSD, has also been described in MOGAD (11, 68–70). MOGAD can mimic infective rhomboencephalitis when a patient presents with fever, CSF leukocytosis, brainstem enhancing lesions and leptomeningeal enhancement (44, 68), or Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS), when MRI shows punctate, curvilinear enhancement in the pons (71–73). Whether CLIPPERS is a form of MOGAD or elicits an immune response to MOG-Ab is uncertain (73). Since the first reports of MOG-Ab associated neurologic diseases appeared just a few years ago (4), the floodgates of case reporting have been opened and our understanding of MOGAD has grown exponentially. We now recognize certain clinical and radiologic features that help to differentiate MOG-ON and MOG-TM from NMOSD syndromes; that pediatric ADEM is frequently associated with MOG-Ab, especially if followed by episodes of ADEM or ON; that in adults, MOG can be associated with seizures and focal cerebral edema (“FLAMES syndrome,” which appears to be unique to MOGAD); that brainstem inflammation is seen in a significant minority of MOGAD patients and may be an isolated finding; that MOG Ab is a common mimicker of infectious encephalitis (54) that MOG antibody is exceptionally rare in MS or AQ4 Ab positive NMOSD, but may co-exist with NMDA and other autoimmune encephalidites (64, 74). But many important questions remain. We need to determine sensitivity, specificity, positive and negative predictive value of MOG-Ab in the various neurologic syndromes; whether MOG-Ab shoud be tested in CSF, if it is negative in serum (75); whether various ultrarare presentions, such as isolated seizures without brain lesions, CLIPPERS, and a MOG-Ab-associated CNS vasculitis-type syndrome should be subsumed under MOGAD rubric. Most importantly, we need to better stratify risk of disease recurrence after the first or second episode and determine best treatments to prevent recurrence. With the rapid pace of progress, we can expect to answer these and other questions, and, no doubt, find new surprises along the way. EP and IK wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version. 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Edited by: Reviewed by: Copyright © 2020 Parrotta and Kister. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Erica Parrotta, [email protected]
Peter Thomas Malcolm
2013 ASEE Annual Conference & Exposition Proceedings pp 23.1165.1-23.1165.15; https://doi.org/10.18260/1-2--22550

Abstract:
The Spatial Estimator: Design Feedback and the Fundamental Engineering Abilities of Mental Rotation and ApproximationThe White House has called educators to action around "science, technology, engineering andmath" ([STEM] Obama, 2010) in K-12 schools in the U.S. Meanwhile the absence of the "e" inSTEM from the traditional American curriculum is being remedied by the movement tostandardize engineering knowledge for pre-college learners (NAE, 2010). There are several keyprerequisites to engineering learning, and this paper addresses ways of teaching two thesefundamental prerequisite abilities in middle school. The abilities addressed here are: (1) mentalrotation ability, often included among a more broad set of spatial skills (Sorby, 2009) and (2) theability to make multi-step estimates. The research proposed is situated in project-basedenvironment for digital fabrication.Mental rotation ability predicts a host of engineering abilities and has been found to be mutableand teachable (Sorby, 2009). This is the ability to mentally rotate shapes and to imagine them indifferent orientations. Chemical, mechanical, and even software engineers use this ability.Numerical approximation (estimation) is a ubiquitous skill (Usiskin, 1986) used mostly in theearly stages of a project. For example, establishing feasibility depends upon using estimates.Erico Fermi (1901-1954) coined the term "back of the envelope" to refer to large estimates basedon a series of smaller estimates. These so-called Fermi problems are useful in engineeringeducation (e.g., Barak, Raviv & VanEpps, 2009; Dunn-Rankin, 2001; French & Leiffer, 2012).The Spatial Estimator is a new online tool designed to help students estimate properties of three-dimensional shapes as an early step in digital fabrication (Bell et al, 2010; Berry et al., 2010).Digital fabrication involves the design and creation of tangible objects by way of digital devices,and can include die-cutting and three-dimensional (3D) printing. As manufacturing becomessmall-scale and computer-aided-design (CAD) programs become more accessible, widespreadeducational uses of digital fabrication have great educational potential. Early research withdigital fabrication in K-12 education shows promise (Tillman, 2011).This research is based on the hypothesis that students can learn to make practical estimates aboutthe amount of time and materials needed for digital fabrication. Feedback in software willencourage students to explore aspects of their own designs to establish properties such as volumeand the necessary density of their materials. Currently, 3D printers must be used judiciously inclassrooms because of the requisite costs of time and access to fabrication materials such asplastic. These real-world constraints can be assets to a teacher since they provide authenticdesign specifications.Students will revise estimates based on interaction with three-dimensional shapes in software.This will require spatial thinking and mental rotation, in addition to the point-and-click rotationof the shapes on screen. Students' iterative estimates will elicit feedback from the computer, andstudent actions will be recorded as log files for analysis. It is anticipated that student estimatesbecome more accurate with practice and that their solutions will benefit from work with theSpatial Estimator.REFERENCES:Bell, B. L., Brown, A., Bull, G., Conly, K., Johnson, L., Mcanear, … Sprague, D., (2010). A special editorial: Digital fabrication revolution, TechTrends 54(5).Berry, R. Q., III, Bull, G., Browning, C., Thomas, C. D., Starkweather, K., & Aylor, J. H. (2010). Preliminary considerations regarding use of digital fabrication to incorporate engineering design principles in elementary mathematics education. Contemporary Issues in Technology and Teacher Education, 10(2). Retrieved from http://www.citejournal.org/vol10/iss2/editorial/article1.cfmBull, G., & Groves, J. (2009). The democratization of production. Learning and Leading with Technology, 37(3), 36-37.Dunn-rankin, D. (2001). Evaluating design alternatives – the role of simple engineering analysis and estimation. 2001 ASEE Annual Conference & Exposition.French, J. J., & Leiffer, P. R. (2012). The genesis of transformation: Preventing “failure to launch” syndrome in generation in first-year engineering students. 2012 ASEE Annual Conference & Exposition.Kolodner, J. L., Camp, P. J., Crismond, D., Fasse, B., Gray, J., Holbrook, J., Puntambekar, S., et al. (2003). Problem-based learning meets case-based reasoning in the middle-school science classroom: Putting learning by design™ into practice. Journal of the Learning Sciences, 12(4), 495–547. doi:10.1207/S15327809JLS1204_2Obama, B. (2010). Remarks by the president at the announcement of the “Change the Equation” initiative. Retrieved from the White House Web site: http://www.whitehouse.gov/the- press- office/2010/09/16/remarks - president- announcement- change- equation- initiativeRaviv, D., Barak, M., Sheva, B., Vanepps, T. J., & Raton, B. (2009). Teaching innovative thinking: Future directions. 2009 ASEE Annual Conference & Exposition.Tillman, D. (2011). Performance assessment of digital fabrication activities with embedded mathematics pedagogy. In M. Koehler & P. Mishra (Eds.), Proceedings of Society for Information Technology & Teacher Education International Conference 2011 (pp. 898– 901). Chesapeake, VA: AACE.
Silvia Husted, Judith Virginia Gutierrez, , ,
2014 ASEE Annual Conference & Exposition Proceedings pp 24.922.1-24.922.17; https://doi.org/10.18260/1-2--22855

Abstract:
Multidimensional Assessment of Creativity in an Introduction to Engineering Design CourseRecently University ABC generated new curricula for its undergraduate degrees in chemical(CE), food (FE), and environmental engineering (EE). These new “integrated and spiral”curricula includes seven departmental courses considered chemical, food, and environmentalengineering “pillars”, which will be designed to enhance the development of 21st centuryexpertise in students from each of the undergraduate degrees. Creative thinking includes thecapacity to combine or synthesize existing ideas, images, or expertise in original ways and theexperience of thinking, reacting, and working in an imaginative way characterized by a highdegree of innovation, divergent thinking, and risk taking1. If we are to produce engineers whocan solve society's most pressing technological problems we must provide our students withopportunities to exercise and augment their natural creative abilities and we must createclassroom environments that make these exercises effective2-4. This paper will describe in detailhow a second semester cornerstone (and pillar) course (Introduction to Chemical, Food, andEnvironmental Engineering Design) for CE, FE, and EE is helping to achieve these objectives, aswell as its alignment with the Investment Theory of Creativity (ITC) developed by Sternberg andLubart5-8. This theory comprises six resources for creativity: intellectual processes, knowledge ofdomain, intellectual style, personality, motivation, and environmental context. Creativeperformance results from a confluence of these elements6-8.Creativity assessment was grounded on the Consensual Assessment Technique9, which is basedon the idea that the best measure of creativity regardless of what is being evaluated, is theassessment by experts in that field. Course two major projects were presented to experts in thefield that assessed student creative thinking by means of a rubric adapted from ITC6-8, whichprovides a multidimensional assessment of creativity. Possible performance levels were fromexemplar (value of 4) to benchmark (value of 1). Instructor, peer-, and self-assessments werealso performed throughout the course on several assignments (formative) as well as on two majorprojects (summative).Mean values from rubric assessment of two major projects were 3.00 for creative performance,3.00 for knowledge of domain (application of formal and informal knowledge), 3.00 forintellectual style (includes indicators such as autonomy and rules), 3.44 for motivation (level ofcommitment, project pride, and interest in task), 3.33 for intellectual processes (which includesindicators such as sensitivity, problem identification, ideation, ability to recognize ideas thathave potential to be valued, as well as ability to sell your ideas effectively and persuade of itsvalue), 3.25 for creative personality (with indicators such as tolerance for ambiguity, risk taking,will, and perseverance), and 2.38 for the product itself (which includes originality, quality,importance, and feasibility) that in these cases are the two designed products for correspondingprojects. The vast majority of students attained projects’ expected outcomes at an intermediatelevel. Therefore, it is suggested to further integrate creativity in subsequent pillar courses inorder to foster meaningful development of students’ creative thinking.[1] AAC&U. 2013. Creative Thinking Value Rubric. Washington, DC: Association of American Colleges and Universities (AAC&U). Available online at http://www-.aacu.org/value/- rubrics/pdf/All_Rubrics.pdf[2] Felder, R. M. 1988. Creativity In Engineering Education. Chemical Engineering Education, 22(3): 120–125.[3] Felder, R. M. 1987. On Creating Creative Engineers. Engineering Education, 77(4): 222-227.[4] Felder, R. M. 1982. Does Engineering Education Have Anything to Do with Either One? Toward a Systems Approach to Training Engineers. Raleigh, NC: North Carolina State University. Available online at http://www.ncsu.edu/felder-public/Papers/RJR- Monograph.pdf[5] Fernández, F. L. and Peralta, L. F. 1998. Estudio de tres modelos de creatividad: criterios para la identificación de la producción creativa. Faisca: Revista de Altas Capacidades, 6: 67- 85.[6] Sternberg, R. J., Lubart, T. I., Kaufman, J. C. and Prelz, J. E. 2005. Creativity. In K. J. Holyoak and R. G. Morrison (Eds.) The Cambridge Handbook of Thinking and Reasoning (pp. 351-369). New York: Cambridge University Press.[7] Sternberg, R. J. and O' Hara L. 2005. Creatividad e Inteligencia. Cuadernos de Información y Comunicación, 10: 113-149.[8] Sternberg, R. J. and Lubart, T. I. 1993. Creative Giftedness: A Multivariate Approach Investment. Gifted Child Quarterly, 37(1): 7-15.[9] Amabile, T. M. 1982. Social Psychology of Creativity: A Consensual Assessment Technique. Journal of Personality and Social Psychology, 43(5): 997-1013.
2014 ASEE Annual Conference & Exposition Proceedings pp 24.40.1-24.40.14; https://doi.org/10.18260/1-2--19932

Abstract:
A Creative Experience for Chemical, Food, and Environmental Engineering Students in a Material Balances CourseCreative thinking includes the capacity to combine or synthesize existing ideas, images, orexpertise in original ways and the experience of thinking, reacting, and working in animaginative way characterized by a high degree of innovation, divergent thinking, and risktaking1. The challenging problems facing our society are not likely to be solved by conventionalmeans. To the extent that these problems are technological, creative engineers are needed tosolve them2. Despite all that has been demonstrated regarding problem solving and creativethinking, many engineering schools are still relying on the traditional lecture-homework-quizformat of well-defined problems and single correct answers. Unfortunately, while efficient, thisformat has not shown to be effective at producing the critical, innovative thinking skills neededto solve difficult technological problems2, 3.This paper will describe a module for promoting students’ creativity in a Material Balancessecond semester required course for Chemical, Food, and Environmental Engineering atUniversity ABC. Major goals include to stimulate and strengthen student cognitive flexibilitythat could allow them to be creative thinkers. The proposed four class-sessions module is anactive and cooperative experience that was implemented as course final project. Studentsexplored creativity through multiple representations of a problem that should be presented inwritten, graphic, and audio-visual manner to an expert audience for its evaluation. According tothe Cognitive Flexibility Theory4, 5, multiple representations of knowledge promote the transferof abstract knowledge to different contexts while cognitive flexibility is one of the four baseelements of creativity6. For the design of the learning environments of the module, we followJonassen7. Final projects were presented to experts in the field that assessed student creativethinking by means of a rubric adapted from the investment theory of creativity developed bySternberg and Lubart6, 8, 9, which provide a multidimensional assessment of creativity. Instructor,peer-, and self-assessments were also performed. Possible performance levels were fromexemplar (value of 4) to benchmark (value of 1).Students were able to build concrete examples of a material balance in an everyday situation andrepresent them in many ways (physically, verbally, symbolically, and by means of a multimediapresentation). Integrated reflections present in final project dossiers, suggest that this projectallowed them to strengthen their learning and understanding of main concepts included in courselearning outcomes. Mean values from rubric assessment of final projects were 3.13 for creativeperformance, 3.80 for knowledge of domain (application of formal and informal knowledge),3.31 for intellectual style (includes indicators such as autonomy and rules), 3.28 for motivation(level of commitment, project pride, and interest in task), 3.02 for intellectual processes (whichincludes indicators such as sensitivity, problem identification, ideation, ability to recognize ideasthat have potential to be valued, as well as ability to sell your ideas effectively and persuade ofits value), 2.90 for creative personality (with indicators such as tolerance for ambiguity, risktaking, will, and perseverance), and 2.76 for the product itself (which includes originality,quality, importance, and feasibility) that in this case is the example of an everyday situation. Thevast majority of students attained final project expected outcomes at an acceptable level.[1] AAC&U. 2013. Creative Thinking Value Rubric. Washington, DC: Association of American Colleges and Universities (AAC&U). Available online at http://www-.aacu.org/value/- rubrics/pdf/All_Rubrics.pdf[2] Felder, R. M. 1987. On Creating Creative Engineers. Engineering Education, 77(4): 222-227.[3] Jonassen, D. H., Strobel, J., and Lee, C. B. 2006. Everyday problem solving in engineering: Lessons for engineering educators. Journal of Engineering Education, 95(2): 1–14.[4] Spiro, R., Coulson, R., Feltovich, P., and Anderson, D. 1988. Cognitive Flexibility Theory: Advanced knowledge acquisition in ill-structured domains. In Proceedings of the 10th Annual Conference of the Cognitive Science Society. Hillsdale, NJ: Lawrence Erlbaum.[5] Spiro, R., Vispoel, W., and Schmitz, J. 1997. Knowledge Acquisition for Application: Cognitive Flexibility and Transfer in Complex Content Domains. In Readings in Executive Control Processes. Hillsdale, NJ: Lawrence Erlbaum.[6] Sternberg, R. J. and Lubart, T. I. 1993. Creative Giftedness: A Multivariate Approach Investment. Gifted Child Quarterly, 37(1): 7-15.[7] Jonassen, D. H. 2011. Learning to Solve Problems: A Handbook for Designing Problem- Solving Learning Environments. New York: Routledge.[8] Sternberg, R. J., Lubart, T. I., Kaufman, J. C. and Prelz, J. E. 2005. Creativity. In K. J. Holyoak and R. G. Morrison (Eds.) The Cambridge Handbook of Thinking and Reasoning (pp. 351-369). New York: Cambridge University Press.[9] Sternberg, R. J. and O' Hara L. 2005. Creatividad e Inteligencia. Cuadernos de Información y Comunicación, 10: 113-149.
2014 ASEE Annual Conference & Exposition Proceedings pp 24.338.1-24.338.12; https://doi.org/10.18260/1-2--20229

Abstract:
Creativity and its Assessment in a Design and Development of Food Products and Processes CourseThe main task of a food engineer is to design and operate processes to transform raw materialsinto final products, particularly with the aim to control, prevent, or delay spoilage caused bychemical reactions, physical effects, and/or biological activity1. At ABC University foodengineering (FE) students apply their knowledge and skills required to function in the differentfields of FE in the capstone course entitled Design and Development of Food Products andProcesses, which outcomes include that students will be able to: a) Identify consumer andcommercial factors that should be considered when designing a new product, b) Describe theproduct to be developed, c) Develop and evaluate potential product formulations, d) Propose themanufacturing process for the product to be developed, e) Choose the most suitable packagingfor the product, f) Evaluate the shelf-life of the product, g) Locate and describe the lawsapplicable to the ingredients used to ensure the safety of the developed product, h) Develop anutritional label for the product, h) Identify critical control points and limits of the proposedprocess, and i) Estimate operating costs and investment required to start the production line. Creative thinking in higher education can only be expressed productively within a particulardomain. The student must have a strong foundation in the strategies and skills of the domain inorder to make connections and synthesize. While demonstrating solid knowledge of the domain'sparameters, the creative thinker, at the highest levels of performance, pushes beyond thoseboundaries in new, unique, or atypical re-combinations, uncovering or critically perceiving newsyntheses and using or recognizing creative risk-taking to achieve a solution2. With sights set onthis, the full paper will present with further detail the didactic intervention whose purpose was toenhance creative thinking, make the food product design and development processes moreefficient as well as to overall improve the creative experience in the studied capstone course3-6. Creativity assessment was grounded on the Consensual Assessment Technique7 (CAT), whichis based on the idea that the best measure of creativity regardless of what is being evaluated, isthe assessment by experts in that field. Therefore, a group of experts in the FE field were invitedto evaluate capstone course final projects and developed food products by means of the CreativeThinking VALUE Rubric, which is made up of a set of attributes that are common to creativethinking across disciplines2. Possible performance levels were entitled capstone or exemplar(value of 4), milestones (values of 3 or 2), and benchmark (value of 1). Instructor, peer-, and self-assessments were also performed throughout the course and on final project. Evaluators werefurther encouraged to assign a value of zero if work did not meet benchmark level performance.Mean values from rubric assessment of final projects were 2.35 for Acquiring Competencies(attaining strategies and skills within a particular domain), 2.42 for Taking Risks (may includepersonal risk, fear of embarrassment or rejection, or risk of failure in successfully completingassignment, i.e. going beyond original parameters of assignment, introducing new materials andforms, tackling controversial topics, advocating unpopular ideas or solutions), 2.44 for SolvingProblems, 2.44 for Embracing Contradictions, 2.40 for Innovative Thinking (novelty oruniqueness of idea, claim, question, form, etc.), and 2.24 for Connecting, Synthesizing, andTransforming. Students’ creative thinking was at an intermediate level in both the capacity tocombine or synthesize existing ideas or expertise in original ways and the experience of thinking,reacting, and working in an imaginative way.[1] XXX [For blind review purposes]. 2013. Proceedings of the 2013 ASEE Annual Conference and Exposition, Atlanta, GA, June 23 – 26.[2] AAC&U. 2013. Creative Thinking Value Rubric. Washington, DC: Association of American Colleges and Universities (AAC&U). Available online at http://www-.aacu.org/value/- rubrics/pdf/All_Rubrics.pdf[3] Baer, J. 1993. Creativity and diverge/if thinking: A task-specific approach. Hillsdale, NJ: Lawrence Erlbaum Associates.[4] Fogler, H. S. and LeBlanc S. E. 2007. Strategies for creative problem solving. 2nd Ed. Upper Saddle River, NJ: Pearson Education.[5] Guilford, J. P. 1950. Creativity. American Psychologist, 5: 444-154.[6] Sternberg, R. J. and Lubart, T. I. 1993. Creative Giftedness: A Multivariate Investment Approach. Gifted Child Quarterly, 37(1): 7-15.[7] Amabile, T. M. 1982. Social Psychology of Creativity: A Consensual Assessment Technique, Journal of Personality and Social Psychology, 43(5): 997-1013.
Veronica Udeogalanya
International Journal of Higher Education Management, Volume 7; https://doi.org/10.24052/ijhem/v07n01/art-1

Abstract:
Academic Success, Graduation Rates, Students, Teaching, Undergraduate Education All students who enroll have success as their main goal. However, most institutions focus their resources on programs for students on honor roll, Dean’s list and those progressing academically. Little resources remain for those students who stumble. In 2015, 36.2% of white students, 22.5% of black students, and 15.5% of Hispanic students had completed four years of college. This shows a 13.7% gap between black and white students and a 20.7% gap between Hispanic and white students (Wellman, 2017). How do we close this gap in educational completion? This study believes that all students can learn. Consequently, there needs to be educational equity and the development of a basis for instruction and assessment of all students’ learning outcomes. This paper represents an exploratory fundamental and qualitative research that aims to present a refocus on the role of faculty in teaching and learning to reach all students in classrooms. It examines a holistic and collaborative approach to increasing student success using evidence -based qualitative analysis of best practices. This approach has four component parts. Part 1 is the Holistic Component that involves engaging all students in the institution; communicating purposefully to them in a timely manner; and providing all-inclusive comprehensive support services (HC). This part develops and implements measurable benchmarks that motivate, encourage, and enable all students. Part 2 is the Collaborative Component which involves bringing six working teams together: faculty, industry, current majors, alumni, career services, and the community (CC). This part engages the team in maintaining a living curriculum that reflects the ever-changing global economy. Part 3 is Celebration of Student Success (CSS) which entails the collaborative team owning each milestone, reaffirming teamwork while building trust and persistence. Part 4 is the Assessment of Student Progress (ASP) using the holistic and collaborative approach. The paper concludes that holistic and collaborative teamwork that includes, respects, and empowers all students is the key to reducing the college completion gaps that exist among blacks and Hispanic students. Adelman, C. (2006). The Toolbox revisited: Paths to degree completion from high school though college. U.S. Department of Education. Washington, D.C: Office of Vocational and Adult Education. American College Testing Program (ACT) 2006. Anoopkumar, M., & Rahman, A. M. J. M. Z. (2016). A Review on Data Mining techniques and factors used in Educational Data Mining to predict student amelioration. In 2016 International Conference on Data Mining and Advanced Computing (SAPIENCE), (pp. 122–133). Asif, R., Merceron, A., Abbas, S., & Ghani, N. (2017). Analyzing undergraduate students’ performance using educational data mining. Computers in Education, 113, 177–194. Asif, R., Merceron, A., & Pathan, M. K. (2015). Predicting student academic performance at degree level: A case study. International Journal of Intelligent Systems and Applications, 7(1), 49–61. Astin, A.W. (1993). What matters in college: Four critical years revisited? San Francisco: Jossey-Bass Bailey, T.R., & Leinbach, D.T. (2005). Is student success considered institutional failure?? The accountability debate at community colleges. New York, NY: Community College Research Center, Teachers College, Columbia University Bailey, T., Jaggars, S., & Jenkins, D. (2015). Redesigning America’s community colleges: A clearer path to student success. Cambridge, MA: Harvard University Press. Bauman, G. L., Bustillos, L.T., Bensimon, E.M., Brown, M.C., & Bartee, R.D. (2005). Achieving Equitable Educational Outcomes with All Students: The Institution’s Roles and Responsibilities. AAC&U/Ford Foundation. Baum, S., & Payea, K. (2004). Education pays: The benefits of higher education for individuals and society. Washington, DC: The College Board.Bensimon 2004 Bensimon, E.M., Dowd, A.C., & Witham, K. (2016). Five principles for enacting equity by design. Diversity & Democracy, 19(1). Brame, C. J. (2019). Inclusive teaching: Creating a welcoming, supportive classroom environment. In Science teaching essentials: Short guides to good practice (pp. 3–14). San Diego: Elsevier/Academic Press. Calvet Liñán, L., & Juan Pérez, Á. A. (2015). Educational Data Mining and Learning Analytics: differences, similarities, and time evolution. International Journal of Educational Technology in Higher Education, 12(3), 98. Center for Community College Student Engagement. (2013). A matter of degrees: Engaging practices, engaging students (High-impact practices for community college student engagement). Austin, TX: The University of Texas at Austin, Community College Leadership Program. Chen, X. (2015). STEM attrition among high-performing college students: Scope and potential causes. Journal of Technology and Science Education, 5(1), 41–59. Dadgar, M., Venezia, A., Nodine, T., & Bracco, K. R. (2013). Providing structured pathways to guide students toward completion. San Francisco: WestEd. Dewsbury, B. M. (2017). Context determines strategies for “activating” the inclusive classroom. Journal of Microbiology & Biology Education, 18(3). 18.3.66. Dewsbury, B. M. (2019). Deep teaching: A conceptual model for inclusive approaches to higher education STEM pedagogy. Cultural Studies in Science Education. doi.org/10.1007/s11422-018-9891-z. Accessed 3/30/2019 Dutt, A., Ismail, M. A., & Herawan, T. (2017). A systematic review on educational data mining. IEEE Access, 5, 15991–16005. Estrada, M., Burnett, M., Campbell, A. G., Campbell, P. B., Denetclaw, W. F., Gutiérrez, C. G., ... Okpodu, C. M. (2016). Improving underrepresented minority student persistence in STEM. CBE—Life Sciences Education, 15(3), es5. Finley, A. & McNair,...
, Ioana A. Cristea
Published: 10 July 2020
Frontiers in Psychology, Volume 11; https://doi.org/10.3389/fpsyg.2020.01786

Abstract:
The COVID-19 pandemic is a serious public health crisis that is causing major worldwide disruption. So far, the most widely deployed interventions have been non-pharmacological (NPI), such as various forms of social distancing, pervasive use of personal protective equipment (PPE), such as facemasks, shields, or gloves, and hand washing and disinfection of fomites. These measures will very likely continue to be mandated in the medium or even long term until an effective treatment or vaccine is found (Leung et al., 2020). Even beyond that time frame, many of these public health recommendations will have become part of individual lifestyles and hence continue to be observed. Moreover, it is implausible that the disruption caused by COVID-19 will dissipate soon. Analysis of transmission dynamics suggests that the disease could persist into 2025, with prolonged or intermittent social distancing in place until 2022 (Kissler et al., 2020). Human behavior research will be profoundly impacted beyond the stagnation resulting from the closure of laboratories during government-mandated lockdowns. In this viewpoint article, we argue that disruption provides an important opportunity for accelerating structural reforms already underway to reduce waste in planning, conducting, and reporting research (Cristea and Naudet, 2019). We discuss three aspects relevant to human behavior research: (1) unavoidable, extensive changes in data collection and ensuing untoward consequences; (2) the possibility of shifting research priorities to aspects relevant to the pandemic; (3) recommendations to enhance adaptation to the disruption caused by the pandemic. Data collection is very unlikely to return to the “old” normal for the foreseeable future. For example, neuroimaging studies usually involve placing participants in the confined space of a magnetic resonance imaging scanner. Studies measuring stress hormones, electroencephalography, or psychophysiology also involve close contact to collect saliva and blood samples or to place electrodes. Behavioral studies often involve interaction with persons who administer tasks or require that various surfaces and materials be touched. One immediate solution would be conducting “socially distant” experiments, for instance, by keeping a safe distance and making participants and research personnel wear PPE. Though data collection in this way would resemble pre-COVID times, it would come with a range of unintended consequences (Table 1). First, it would significantly augment costs in terms of resources, training of personnel, and time spent preparing experiments. For laboratories or researchers with scarce resources, these costs could amount to a drastic reduction in the experiments performed, with an ensuing decrease in publication output, which might further affect the capacity to attract new funding and retain researchers. Secondly, even with the use of PPE, some participants might be reluctant or anxious to expose themselves to close and unnecessary physical interaction. Participants with particular vulnerabilities, like neuroticism, social anxiety, or obsessive-compulsive traits, might find the trade-off between risks, and gains unacceptable. Thirdly, some research topics (e.g., face processing, imitation, emotional expression, dyadic interaction) or study populations (e.g., autistic spectrum, social anxiety, obsessive-compulsive) would become difficult to study with the current experimental paradigms (Table 1). New paradigms can be developed, but they will need to first be assessed for reliability and validated, which will undoubtedly take time. Finally, generalized use of PPE by participants and personnel could alter the “usual” experimental setting, introducing additional biases, similarly to the experimenter effect (Rosenthal, 1976). Table 1. Possible consequences of non-pharmacological interventions for COVID-19 on human behavior research. Data collection could also adapt by leveraging technology, such as running experiments remotely via available platforms, like for instance Amazon's Mechanical Turk (MTurk), where any task that programmable with standard browser technology can be used (Crump et al., 2013). Templates of already-programmed and easily customizable experimental tasks, such as the Stroop or Balloon Analog Risk Task, are also available on platforms like Pavlovia. Ecological momentary assessment is another feasible option, since it was conceived from the beginning for remote use, with participants logging in to fill in scales or activity journals in a naturalistic environment (Shiffman et al., 2008). Increasingly affordable wearables can be used for collecting physiological data (Javelot et al., 2014). Web-based research was already expanding before the pandemic, and the quality of the data collected in this way is comparable with that of laboratory studies (Germine et al., 2012). Still, there are lingering issues. For instance, for some MTurk experiments, disparities have been evidenced between laboratory and online data collection (Crump et al., 2013). Further clarifications about quality, such as consistency or interpretability (Abdolkhani et al., 2020), are also needed for data collected using wearables. Beyond updating data collection practices, a significant portion of human behavior research might change course to focus on the effects of the pandemic. For example, the incidence of mental disorders or of negative effects on psychological and physical well-being, particularly across populations of interest (e.g., recovered patients, caregivers, and healthcare workers), are crucial areas of inquiry. Many researchers might feel hard-pressed to not miss out on studying this critical period and embark on hastily planned and conducted studies. Multiplication and fragmentation of efforts are likely, for instance, by conducting highly overlapping surveys in widely accessible and oversampled populations (e.g., university students). Moreover, rushed planning is bound to lead to taking shortcuts and cutting corners in study design and conduct, e.g., skipping pre-registration or even ethical committee approval or using not validated measurement tools, like ad hoc surveys. Surveys using non-probability and convenience samples, especially for social and mental health problems, frequently produce biased and misleading findings, particularly for estimates of prevalence (Pierce et al., 2020). A significant portion of human behavior research that re-oriented itself to study the pandemic could result in to a heap of non-reproducible, unreliable, or overlapping findings. Human behavior studies could also aim to inform the planning and enforcement of public health responses in the pandemic. Behavioral scientists might focus on finding and testing ways to increase adherence to NPIs or to lessen the negative effects of isolation, particularly in vulnerable groups, e.g., the elderly or the chronically ill and their caretakers. Studies could also attempt to elucidate factors that make individuals uncollaborative with recommendations from public health authorities. Though all of these topics are important, important caveats must be considered. Psychology and neuroscience have been affected by a crisis in reproducibility and credibility, with several established findings proving unreliable and even non-reproducible (Button et al., 2013; Open Science Collaboration, 2015). It is crucial to ensure that only robust and reproducible results are applied or even proposed in the context of a serious public health crisis. For instance, the possible influence of psychological factors on susceptibility to infection and potential psychological interventions to address them could be interesting topics. However, the existing literature is marked by inconsistency, heterogeneity, reverse causality, or other biases (Falagas et al., 2010). Even for robust and reproducible findings, translation is doubtful, particularly when these are based on convenience samples or on simplified and largely artificial experimental contexts. For example, the scarcity of medical resources (e.g., N-95 masks, drugs, or ventilators) in a pandemic with its unavoidable ethical conundrum about allocation principles and triage might appeal to moral reasoning researchers. Even assuming, implausibly, that most of the existent research in this area is robust, translation to dramatic real-life situations and highly specialized contexts, such as intensive care, would be difficult and error-prone. Translation might not even be useful, given that comprehensive ethical guidance and decision rules to support medical professionals already exist (Emanuel et al., 2020). The COVID-19 pandemic and the corresponding global public health response pose significant and lasting difficulties for human behavior research. In many contexts, such as laboratories with limited resources and uncertain funding, challenges will lead to a reduced research output, which might have further domino effects on securing funding and retaining researchers. As a remedy, modifying data collection practices is useful but insufficient. Conversely, adaptation might require the implementation of radical changes—producing less research but of higher quality and more utility (Cristea and Naudet, 2019). To this purpose, we advocate for the acceleration and generalization of proposed structural reforms (i.e., “open science”) in how research is planned, conducted, and reported (Munafò et al., 2017; Cristea and Naudet, 2019) and summarize six key recommendations. First, a definitive move from atomized and fragmented experimental research to large-scale collaboration should be encouraged through incentives from funders and academic institutions alike. In the current status quo, interdisciplinary research has systematically lower odds of being funded (Bromham et al., 2016). Conversely, funders could favor top-down funding on topics of prominent interest and encourage large consortia with international representativity and interdisciplinarity over bottom-up funding for a select number of excellent individual investigators. Second, particularly for research focused on the pandemic, relevant priorities need to be identified before conducting studies. This can be achieved through assessing the concrete needs of the populations targeted (e.g., healthcare workers, families of victims, individuals suffering from isolation, disabilities, pre-existing physical and mental health issues, and the economically vulnerable) and subsequently conducting systematic reviews so as to avoid fragmentation and overlap. To this purpose, journals could require that some reports of primary research also include rapid reviews (Tricco et al., 2015), a simplified form of systematic reviews. For instance, The Lancet journals require a “Research in context” box, which needs to be based on a systematic search. Study formats like Registered Reports, in which a study is accepted in principle after peer review of its rationale and methods (Hardwicke and Ioannidis, 2018), are uniquely suited for this change. Third, methodological rigor and reproducibility in design, conduct, analysis, and reporting should move to the forefront of the human behavior research agenda (Cristea and Naudet, 2019). For example, preregistration of studies (Nosek et al., 2019) in a public repository should be widely employed to support transparent reporting. Registered reports (Hardwicke and Ioannidis, 2018) and study protocols are formats that ensure rigorous evaluation of the experimental design and statistical analysis plan before commencing data collection, thus making sure shortcuts and methodological shortcomings are eliminated. Fourth, data and code sharing, along with the use of publicly available datasets (e.g., 1000 Functional Connectomes Project, Human Connectome Project), should become the norm. These practices allow the use of already-collected data to be maximized, including in terms of assessing reproducibility, conducting re-analyses using different methods, and exploring new hypotheses on large collections of data (Cristea and Naudet, 2019). Fifth, to reduce publication bias, submission of all unpublished studies, the so-called “file drawer,” should be encouraged and supported. Reporting findings in preprints can aid this desideratum, but stronger incentives are necessary to ensure that preprints also transparently and completely report conducted research. The Preprint Review at eLife (Elife, 2020), in which the journal effectively takes into review manuscripts posted on the preprint server BioRxiv, is a promising initiative in this direction. Journals could also create study formats specifically designed for publishing studies that resulted in inconclusive findings, even when caused by procedural issues, e.g., unclear manipulation checks, insufficient stimulus presentation times, or other technical errors. This would both aid transparency and help other researchers better prepare their own experiments. Sixth, peer review of both articles and preprints should be regarded as on par with the production of new research. Platforms like Publons help track reviewing activity, which could be rewarded by funders and academic institutions involved in hiring, promotion, or tenure (Moher et al., 2018). Researchers who manage to publish less during the pandemic could still be compensated for the onerous activity of peer review, to the benefit of the entire community. Of course, individual researchers cannot implement such sweeping changes on their own, without decisive action from policymakers like funding bodies, academic institutions, and journals. For instance, decisions related to hiring, promotion, or tenure of academics could reward several of the behaviors described, such as complete and transparent publication regardless of the results, availability of data and code, or contributions to peer review (Moher et al., 2018). Academic institutions and funders should acknowledge the slowdown of experimental research during the pandemic and hence accelerate the move toward more “responsible indicators” that would incentivize best publication practices over productivity and citations (Moher et al., 2018). Funders could encourage submissions leveraging existing datasets or developing tools for data re-use, e.g., to track multiple uses of the same dataset. 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The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Claudio Gentili, [email protected]
, Joshua J. Bon, Kristin L. Sainani, Brenton J. Baguley, Nicholas J. Tierney, Christopher Drovandi
Published: 23 May 2020
Sports Medicine, Volume 50, pp 1551-1553; https://doi.org/10.1007/s40279-020-01298-5

The publisher has not yet granted permission to display this abstract.
Aimee K. Murray
Frontiers in Microbiology, Volume 11; https://doi.org/10.3389/fmicb.2020.01020

Abstract:
We are in the midst of the novel coronavirus (COVID-19) pandemic, the most significant global health event since Spanish influenza in the early 20th century. Increasingly draconian measures are being implemented worldwide to try to slow the spread of the virus. Antimicrobial resistance (AMR) has been cited as the most significant threat to the global health and global economy in recent years, but is now likely to be eclipsed by COVID-19 for some time. However, the emergence of COVID-19 also presents some important consequences for the development of AMR. This piece will highlight how managing the COVID-19 crisis could impact AMR in the clinic, beyond the clinic in the community, in the environment and in relation to public awareness. When civilization emerges from the other side of this global health emergency, efforts should be made to understand these potential effects on AMR, the other significant, and constant global health issue of our time. Healthcare systems around the world are under increasingly immense pressure. This is leading to several changes in practice that may have impacts on, or relevance to, AMR. For example, the UK government have published several documents relating to COVID-19 management in clinical settings. In the guidance for primary care, it is recommended that any room that has been used for a patient with a suspected SARS-CoV-2 (the causative agent of COVID-19) infection should remain closed and ventilation switched off until full sterilization has taken place (HM Government, 2020a). With regards to infection prevention and control procedure, additional measures are recommended regarding transmission prevention. These include precautions around direct contact with potentially contaminated surfaces, droplets and aerosols (HM Government, 2020b). These may not become routine management options within clinical settings following the COVID-19 pandemic, however, many of these practices may also reduce dissemination of AMR bacteria at a local and global scale. In particular, extra vigilance around hygiene and additional sterilization procedures may reduce the spread of AMR bacteria. It would be interesting to gather data on the prevalence of AMR infections before and after the outbreak to determine if this is the case. Comparison of whole genome sequences of clinical pathogens before, during and after the pandemic is one potential technique that could elucidate changes in carriage of AMR mechanisms circulating in clinical settings. Databases such as BacWGSTdb (Ruan and Feng, 2016) could also be used to track outbreaks of key AMR pathogens to the species, clonal complex or isolate level. With regards to COVID-19 patients contracting secondary bacterial infections, there are very few data so far. However, 1 to 10% of patients have been reported to contract secondary bacterial infections in two separate studies (Lai et al., 2020). This in comparison to infection with pandemic H1N1, where around 12–19% of hospitalized patients with pneumonia developed secondary bacterial infections (Kim, 2020). Given current data it is not possible to predict whether the cases of secondary bacterial infection following development of COVID-19 will increase or decrease overtime. Clinical microbiologists, as well as radiologists, will be key for making these distinctions (Kim, 2020). However, despite the relatively low confirmation of secondary bacterial infections, there have been comparatively more reports of antibiotic usage when treating COVID-19 patients (Lai et al., 2020), including up to 45% of patients receiving antibiotic treatment (Xu et al., 2020). This is even though the World Health Organization recommended against the use of antibiotics during COVID-19 treatment (Cascella et al., 2020). It has also been suggested that certain antibiotics, such as tecioplanin (a glycopeptide antibiotic) could be used as an antiviral after exhibiting activity against coronaviruses (amongst others) previously (Baron et al., 2020). However, great caution should be used given that inappropriate use or overuse of antibiotics is known to be a significant driver of the emergence of AMR. This is why significant focus on AMR revolves around reducing inappropriate or overuse of antibiotics (NICE, 2018). Countries which have made progress in this area may face less AMR secondary bacterial infections than countries that have experienced limited success in reducing antibiotic consumption. Again, it would be interesting to analyse this data, when available. The second reason use of antibiotics should be considered very carefully is that it may lead the public to assume that all antibiotics are suitable for treatment of viral infections (see “Public Awareness,” below). Outside the clinic, countries are employing measures aimed at reducing transmission of COVID-19 that range from social distancing, to full-on lock down and closing borders. One piece of advice to the public that has remained constant from the beginning, however, is for the public to regularly wash their hands with soap and water (or to use hand sanitiser, when these are unavailable). Use of antimicrobial soaps and disinfectant cleaners by members of the community and in the hospital will have increased hugely over the last few months. Higher usage is likely to continue, and may even remain high following the outbreak due to changes in infection and control policy or individual habits. As discussed above, these increased/improved hygiene practices may reduce the spread of AMR, which is a very positive outcome. However, there is also a potential negative impact that could arise from increased use of such products, as many of them contain biocides. Biocides are antimicrobials found in surface disinfectants and household cleaners (Buffet-Bataillon et al., 2012) that may also lead to the emergence of AMR (Levy, 2002; Maillard, 2005; Pal et al., 2015; Webber et al., 2015). Due to the COVID-19 pandemic, higher concentrations of biocides are likely to be detected in wastewater treatment plants and receiving waters. This may increase levels of AMR in the environment, posing a human health risk for individuals exposed to these environments. The final concentration of biocide in the wastewater treatment plant and its receiving environments is key. If very high, it is likely most bacteria will be completely inhibited. This could cause significant impacts on key ecosystem services performed by bacteria but prevent the selection for or development of AMR. Conversely, if concentrations increase but remain below the minimum inhibitory concentration for the majority of bacteria present, this increase in selective pressure could provide an opportunity for the evolution of AMR (McBain et al., 2002). The phenomenon of sub-inhibitory selection is comparatively well-studied for antibiotics, with significantly fewer experimental studies on biocides. Increased antibiotic consumption to treat or prevent secondary bacterial infections in COVID-19 patients, or as a potential therapy for COVID-19, will also result in increased concentrations of antibiotics in the wastewater system and receiving environments. Again, this increased selective pressure may result in selection for AMR. However, unlike with biocides, it is highly doubtful that completely inhibitory concentrations of antibiotics could be reached, due to metabolism by the patient and a greater dilution factor. Furthermore, it has been shown previously that low concentrations of antibiotics can select for AMR just as much as high, clinically relevant concentrations (Murray et al., 2018). These increased concentrations of biocides and antibiotics in wastewater as a result of the COVID-19 pandemic and their impacts would form an interesting area of research. Significant reductions in travel (in addition to resulting in a much-needed reduction in carbon dioxide emissions) will also have impacts for the spread of AMR. Movement of key AMR genes between countries in undeniable. For example, one of the key genes conferring resistance to last resort carbapenem antibiotics (NDM-1) was first isolated in India (Liang et al., 2011), and has since been detected worldwide (Nordmann et al., 2011). Similarly, emergence of the mcr1 gene that confers resistance to another last resort antibiotic, colistin, was first detected in China (Liu et al., 2016) but has since been found worldwide (Castanheira et al., 2016). Transferable tigecycline resistance gene tet(X4) was also detected in China for the first time last year (Bai et al., 2019). The CTX-M genes originated in environmental bacteria (Humeniuk et al., 2002; Olson et al., 2005; Cantón et al., 2012) but have since been labeled a “pandemic” (Canton and Coque, 2006). Whilst a viral pandemic has the more immediate outcome of infection, often with symptoms, transmission of AMR may result in infection, or colonization and shedding. For example, it has been shown that following travel to countries with high rates of AMR, travelers can become colonized by new AMR genes or bacteria. Following travel to China, India or northern Africa, colonization of Swedish travelers with extended-spectrum beta-lactamase producing Enterobacteriaceae increased from 2.4 to 68%, and this took weeks to months (and up to 1 year) to return to a pre-travel level (ÖstholmBalkhed et al., 2018). Reduction of travel on such a massive scale should have also slowed the spread of AMR. There is no denying the understandably extensive media coverage of the COVID-19 pandemic. In particular, how the outbreak has crossed international borders so rapidly to become the current crisis facing all countries. AMR has been reportedly described as a problem that “knows no borders.” According the WHO, the definition of a pandemic is human-to-human spread of microorganisms and community-level outbreaks in three countries, one of which must be within a different WHO region (WHO, 2009). Arguably, AMR can also be considered as a pandemic, although a more insidious one that has fewer immediate effects on everyday life but potentially more far reaching negative impacts. According to the European Center for Disease Control and Prevention, at the time of writing, 190, 236 lives have sadly been lost to COVID-19 globally over the past 4 months (ECDC, 2020). AMR currently kills an estimated 700, 000 people each year (IACG, 2019). For a crude comparison, assuming both figures are accurate estimates and COVID-19 death rates remain constant for the remainder of the year, AMR will result in 130,000 more deaths this year alone. In addition, AMR deaths are predicted to increase to 10 million deaths per year by 2050 (O'Neill, 2014), whereas it is hoped COVID-19 can be managed in a much shorter time frame. In future, COVID-19 may be a useful comparison for describing the spread of AMR and highlighting how difficult it is to control, once it has emerged. According to a study performed by the WHO, a very common misconception amongst the public is that antibiotics can be used for viral infections (i.e., the common cold) (WHO, 2015). Media coverage of the COVID-19 outbreak has highlighted there is no “cure” for infection, often stating antibiotics are ineffective and antiviral treatments are being trialed in certain countries. Using terms like “antiviral” may also help with understanding there are different medications for different types of infection. Furthermore, people who are self-isolating due to suspected or confirmed infection with COVID-19 may have previously asked for antibiotics. If they have adhered to the self-isolation protocol, they would not have been able to visit their family doctor to request such a prescription. It is possible that the public may now have greater awareness of suitable use of antibiotics, which should be capitalized on once the outbreak has been controlled. A long-term, potential benefit could be reduced antibiotic use that should be considered when discussing potential antibiotic therapies for COVID-19. Repeating studies that examine public understanding of appropriate antibiotic use, such as the one above, would be useful to see if the outbreak has caused a shift in public awareness of AMR. Potential implications, both good and bad, of some of the current management practices and practicalities of managing the novel coronavirus outbreak in relation to AMR have been discussed. This is by no means a comprehensive list and without doubt, further impacts will become apparent as the situation rapidly progresses. This pandemic will be considered a significant event in human history. Both emerging infectious diseases and AMR are included in the UK government's National Risk Registry of Civil Emergencies (HM Government, 2017). The global issue of AMR will persist beyond the COVID-19 outbreak, and understanding some of the impacts the management strategies employed globally had, or will have, on AMR in the clinic, the environment and regarding public awareness should be investigated, when the time is right. In the mean time, everyone should wash their hands. The author confirms being the sole contributor of this work and has approved it for publication. The author was supported by a NERC Industrial Innovation Fellowship NE/R01373X/. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Baron, S. A., Devaux, C., Colson, P., Raoult, D., and Rolain, J. M. (2020). Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19? Int. J. Antimicrob. 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, Arnaldo Fabricio Dos Santos Queiroz, Leonardo Mario Siqueira Morais, Carolina Cardoso De Azevedo, José Eduardo Martinelli Filho
Journal of Coastal Research, Volume 95, pp 12-17; https://doi.org/10.2112/si95-003.1

Abstract:
Leite, A.A.C.; Queiroz, A.F.S.; Morais, L.M.S.; Azevedo, C.C., and Martinelli Filho, J.E., 2020. Zooplankton at the Northern Brazilian Coast: Evaluation and gaps. In: Malvárez, G. and Navas, F. (eds.), Global Coastal Issues of 2020. Journal of Coastal Research, Special Issue No. 95, pp. 12–17. Coconut Creek (Florida), ISSN 0749-0208.Research on planktonic communities in the Brazilian Northern coast started since the XIX century by foreigners, most of it being taxonomical surveys. The only literature reviews for the area are a technical report and a book chapter published in Portuguese by 2005. This article aimed to analyze the existing literature about zooplanktonic communities at the Northern coast of Brazil from a decade after the last review (2005 to 2015), to update and elucidate possible knowledge patterns and identify existing gaps. The bibliographic review considered the three states of the Brazilian North coast (Maranhão, Pará and Amapá), in the libraries of educational and research institutions, indexing platforms and databases on the internet (Web of Knowledge, Scopus, Scielo and Google Scholar). The most important parameters extracted from the publications were: year and language of publication, zooplankton density, dominant species, sampling mesh size, study area (by state), type of publication, coordinates, and research subject. A total of 222 publications were found, 45 (20.3%) referred to white publications (national and international scientific articles) and 177 (79.7%) referred to gray literature (do not published by peer review system). The Pará state showed a higher number of publications than Amapá and Maranhão sates together. The publications were mostly about zooplanktonic community description, copepod ecology and taxonomy or experimental approaches, and sampling took place mostly on estuarine environments (87.5%). Richness varied from 4 to 68 taxa, while density varied from 0.01 to 962,400 org.m-3. Despite the numerous research in the period, there are important knowledge gaps, mainly in relation to collection sites, target organisms, and research subjects. Future research should focus primarily on oceanic areas (outer shelf) and on themes such as experimental ecology, biogeochemistry and long temporal scale surveys, so that a more comprehensive knowledge about zooplankton on the Brazilian Northern coast can be achieved.
, Suparno
JPUD - Jurnal Pendidikan Usia Dini, Volume 14, pp 43-57; https://doi.org/10.21009/jpud.141.04

Abstract:
One form of early mathematical recognition is to introduce the concept of geometric shapes. Geometry is an important scientific discipline for present and future life by developing various ways that fit 21st century skills. This study aims to overcome the problem of early mathematical recognition of early childhood on geometry, especially how to recognize geometric forms based on computer learning. A total of 24 children aged 4-5 years in kindergarten has to carrying out 2 research cycles with a total of 5 meetings. Treatment activities in each learning cycle include mentioning, grouping and imitating geometric shapes. There were only 7 children who were able to recognize the geometric shapes in the pre-research cycle (29.2%). An increase in the number of children who are able to do activities well in each research cycle includes: 1) The activities mentioned in the first cycle and 75% in the second cycle; 2) Classifying activities in the first cycle were 37.5% and 75% in the second cycle; 3) Imitation activities in the first cycle 54.2% and 79.2% in the second cycle. The results of data acquisition show that computer learning application can improve the ability to recognize geometric shapes, this is because computer learning provides software that has activities to recognize geometric shapes with the animation and visuals displayed. Keywords: Early Childhood Computer Learning, Geometry Forms, Early Math Skills Reference Alia, T., & Irwansyah. (2018). Pendampingan Orang Tua pada Anak Usia Dini dalam Penggunaan Teknologi Digital. A Journal of Language, Literature, Culture and Education, 14(1), 65– 78. https://doi.org/10.19166/pji.v14i1.639 Ameliola, S., & Nugraha, H. D. (2013). Perkembangan Media Informasi dan Teknologi Terhadap Anak di Era Globalisasi. International Conferences in Indonesian Studies : “Etnicity and Globalization.” Anderson, L. W., Krathwohl, D. R., & Bloom, B. S. (2001). A taxonomy for learning, teaching, and assessing: a revision of Bloom’s taxonomy of educational objectives. New York: Longman. Arikunto, S. (2010). Prosedur Penelitian Suatu Pendekatan Praktik. Jakarta: Asdi Mahasatya. Arsyad, N., Rahman, A., & Ahmar, A. S. (2017). Developing a self-learning model based on open-ended questions to increase the students’ creativity in calculus. Global Journal of Engineering Education, 19(2), 143–147. https://doi.org/10.26858/gjeev19i2y2017p143147 Asiye, I., Ahmet, E., & Abdullah, A. (2018). Developing a Test for Geometry and Spatial Perceptions of 5-6 Year-Old. Kastamonu Education Journal, 26(1). Aslan, D., & Yasare, A. (2007). Three to Six Years OldChildren’s Recognition of Geometric Shapes. International Journal of Early Years Education, 15 :1, 83–104. Ben-Yehoshua, D., Yaski, O., & Eilam, D. (2011). Spatial behavior: the impact of global and local geometry. Animal Cognition Journal, 13(3), 341–350. https://doi.org/10.1007/s10071- 010-0368-z Charlesworth, R., & Lind, K. K. (2010). Math and Sciend for Young Children. Canada: Wadsworth/Cengage Learning. Chen, J.-Q., & Chang, C. (2006). using computers in early childhood classrooms teachers’ attitudes,skills and practices. Early Childhood Research. Clements, D. H., & Samara. (2003). Strip mining for gold: Research and policy in educational technology—a response to “Fool’s Gold.” Association for the Advancement of Computing in Education (AACE) Journal, 11(1), 7–69. Cohen, L., & Manion, L. (1994). Research Methods in Education (fourth edi). London: Routledge. Conorldi, C., Mammarela, I. C., & Fine, G. G. (2016). Nonverbal Learning Disability (J. P. Guilford, Ed.). New York. Corey, S. M. (1953). Action Research to Improve School Practice. New York: Teachers College, Columbia University. Couse, L. J., & Chen, D. W. (2010). A tablet computer for young children? Exploring its viability for early childhood education. Journal of Research on Technology in Education, 43(1), 75– 98. https://doi.org/10.1080/15391523.2010.10782562 Delima, R., Arianti, N. K., & Pramudyawardani, B. (2015). Identifikasi Kebutuhan Pengguna Untuk Aplikasi Permainan Edukasi Bagi Anak Usia 4 sampai 6 Tahun. Jurnal Teknik Informatika Dan Sistem Informasi, 1(1). Depdiknas. (2007). Permainan Berhitung Permulaan Di Taman Kanak-kanak. In Pedoman Pembelajaran. Jakarta: Depdiknas. Djadir, Minggi, I., Ja’faruddin., Zaki, A., & Sidjara, S. (2017). Sumber Belajar PLPG 2017: Bangun Datar. In Modul PLPG. Jakarta: Kementrian Pendidikan dan Kebudayaan Direktorat Jenderal Guru dan Tenaga Kependidikan.Dooley, T., Dunphy, E., & Shiel, G. (2014). Mathematics in Early Childhood and Primary Education (3-8 years). Duncan, G. J., Dowsett, C. J., Claessens, A., Magnuson, K., Huston, A. C., Klebanov, P., ... Japel, C. (2007). School Readiness and Later Achievement. Developmental Psychology, 43(6), 1428–1446. https://doi.org/10.1037/0012-1649.43.6.1428 Duncan, G. J., & Magnuson, K. (2011). The nature and impact of early achievement skills, attention skills, and behavior problems. Whither Opportunity?: Rising Inequality, Schools, and Children’s Life Chances, (0322356), 47–69. Edwards, S. (2009). Early Childhood Education and Care: a sociocultural Approach. New South Wales: Pademelon Press. Feliyanah, Norman, S., & Yulidesni. (2014). Meningkatkan Kemampuan Matematika dengan Menggunakan Teknik Mengurutkan dan Membandingkan. Universitas Bengkulu. Gardner, H. (2011). Frame of Mind ; The theory of Multiple Intelegences. New York: Basic Book. Gimbert, B., & Cristol, D. (2004). Teaching Curriculum with Technology: Enhancing Children’s Technological Competence During Early Childhood. Early Childhood Education Journal, 31(1). Gulay, H. (2011a). The evaluation of the relationship between the computer using habits and proso_cial and aggressive behaviours of 5–6 years old children. International Journal of Academic Research, 3(2), 252. Gulay, H. (2011b). The...
, Jorge Bielsa
Published: 3 February 2020
Frontiers in Plant Science, Volume 10; https://doi.org/10.3389/fpls.2019.01742

Abstract:
Estimates of crop evapotranspiration (ET) to measure the freshwater use indicator water footprint (WF) have undoubtedly been popular and implemented (Chapagain and Hoekstra, 2004), as well as the more recent extension to subnational regions and watersheds (Mekonnen and Hoekstra, 2010a; Hoekstra and Mekonnen, 2012; Mekonnen and Hoekstra, 2012). As reviewed by (Chenoweth et al., 2014; Lovarelli et al., 2016), these studies have gone from estimating products’ water trade on a global scale, to rigorous quantification for specific crops and geographical areas. Many studies have extended the coverage and precision of estimates. However, when it comes to the implementation of these improvements in local and river-basin water management, we find management problems that are ultimately unaddressed. It is here that, in our opinion, the Plant Water Sciences (PWS) have to shed light on these “blind spots.” We also illustrate these general ideas with two examples. Firstly, defining boundaries on what to account for human appropriation is a multidisciplinary and, to this point, open debate regarding WF calculations. Launiainen et al. (2014) questioned WF’s appropriateness for evaluating the water use in forestry and forest-based production. They pleaded for the exclusion of rain-fed forestry and forest-based production in WF, arguing that managed forest ET is indistinguishable from those of unmanaged forests. At a global level, there were case studies on some forest products such as paper WF (van Oel and Hoekstra, 2012), but these were not as systematic as those for crops and livestock WF. Nevertheless, we do need a clear split between both human and natural water usage in order to manage existing water resources. Secondly, to further improve estimates, we find areas where WF can benefit from more precise studies of plant water ET and dynamics. Recent studies (Schyns et al., 2017; Schyns and Vanham, 2019) have estimated the WF (of production) of wood for lumber, pulp, paper, fuel, and firewood, but more can be done to calculate the WF on the consumer side, computing the responsibility of the demand (typically households/individuals) in the WF. Regarding livestock WF, the challenges involve discerning dry matter composition (concentrates/roughages). Furthermore, WF would probably benefit from updated estimates on roughages ET/WF, especially pasture/grass (estimated and briefly explained in Mekonnen and Hoekstra, 2010a). The relation and distinction of evaporation (E) to transpiration (T), absent in many studies until very recently, is very important from an economic perspective since T is productive and E is not (E can occur from soil but also from intercepted water on leaves). Recently, Nouri et al. (2019) found that mulching reduced irrigation needs by 3.6%, and when combined with drip irrigation, by 4.7%. There is thus an important need for studies on “partitioning” of ET and T (see review in Kool et al., 2014). Thirdly, while there have been great advances in developing spatial and temporally explicit information, there is a divergence between the geographic and temporal units used by natural scientists and those used by social scientists for resource management (typically, river basins and long periods of time). If plant sciences do not provide information for the geographic areas in which decisions are taken, their work will be overlooked by social scientists. Regarding the temporal dimension, there are a lack of studies looking beyond a point in time (even when the evaluations of evapotranspiration are averaged over periods of time), and looking at the effects derived from land use and cover changes. In other words, studies looking at the dynamics of the resource rather than a static picture are needed. In summary, very detailed and methodical studies from the natural sciences coexist with rough approximations and simulations of data, such as those used by hydro-economic models (see for example Harou et al., 2009; Kahil et al., 2018 for a review of this form of work). Fourthly, there are also blind spots regarding the estimation of historical WF time series. Historic economic analyses on water consumption usually rely on multiple sources of information: censuses, statistics on climate, precipitation, irrigation systems, agricultural production, yield, inputs used, water uses, etc. Information on crop water consumption (in m3 per unit of production) was also used in the past, relating it to scarcity and sustainability. How do we estimate the evolution of these coefficients over time? The answer likely lies in developing a methodology that allows us to obtain them from data on changes in irrigation systems, yields, harvest indexes, soils, etc. Dalin et al. (2012) and Duarte et al. (2014) initiated attempts to generalize coefficient changes over time based on yield changes. There is room for improvement in these estimates, e.g., incorporating not only the effect of changes in yield (as crop output per unit area), but also the changes in the harvest index (the ratio of grain yield to biomass when the crop matures), notably being increased (greater part of the biomass allocated to the grain) in many countries with the Green Revolution. As happened previously with the concept of Integrated Water Resources Management (IWRM), a vast literature and discussion of a topic does not directly entail practical utility. One step further is needed. We cannot expect one indicator to be able to resolve everything, but we can provide additional data to complement it (e.g., Vanham et al., 2016, investigated whether the WF indicator addresses the food–energy–water ecosystem nexus, finding potential components to be included). Lund (2015) correctly highlighted that water management has always required not only physical sciences, but also social ones. Indeed, natural sciences have often not counted so much as it should on water management practices. The present and future of the world’s food requirements and water needs have already been at the forefront since studies like those of Rockström et al. (1999). Greater water needs could lead to decisions that affect nature in the future. Derived from this, some researchers have tried to combine policy recommendations that take into account the management of local and global, acknowledging interrelations, especially between use and scarcity through trade (see Vörösmarty et al., 2015). However, the apparent remoteness of some phenomena (indirect chains of impacts) and the absence of monetary valuations beyond their relationship with agricultural production, have impeded their prominence in practice. For the most part, economists’ contributions to the virtual water (VW) and WF literature have not been as comprehensive as it should either. These contributions have focused on: a) computing VW and WF through economic tools such as multi-regional input-output tables and models (Duarte and Yang, 2011; Tian et al., 2018); b) criticize or highlight limitations on the concept of VW based on the theory of comparative advantage (Wichelns, 2011; Gawel, 2014; Mateo-Sagasta et al., 2015; Wichelns, 2015); c) defend it or further explain factors completing the picture (Gawel, 2014; Afkhami et al., 2018; Zhao et al., 2019); and d) relate WF with scarcity and profitability, to obtain a visible ‘water productivity’ (Garrido et al., 2010; Cazcarro et al., 2019). However, although most of these latest studies are focused on trying to reflect the shortage and opportunity costs, the recommendations of Lowe et al. (2018) for incorporating environmental valuation are necessary because it has not really been done. Along these lines, we extend this argument by stating that, in general, both economic valuations have not dealt with WF and economic analysis has not served to make WF socially relevant, which is a very desirable goal. Therefore, we propose to go beyond the recommendations of Lowe et al. (2018), arguing that the economic valuation of water should also be based on measurements of WF, their scarcity, and the equivalence of their opportunity costs when regarding alternative uses or environmental costs generated. There are other ways of making economic valuations of water, such as the literature of environmental valuation and that of ecosystem services (Martin-Ortega et al., 2015; Liu et al., 2016). The literature of hydro-economic models (HE) also pursues that goal (e.g., Escriva-Bou et al., 2018; Kahil et al., 2018). We also emphasize the importance of working together with HE (more biophysical) models, and of incorporating broader perspectives and tools (political, economic, and social ecology). For example, Hellegers and van Halsema (2019) argue that valuation is very useful for decision-making and that it must go beyond economics. We also have examples of more social assessments (Rodríguez-Labajos and Martínez-Alier, 2015; Wright-Contreras, 2018) and more in the realm of ecological economics (Kallis et al., 2013; Gómez-Baggethun and Martín-López, 2015). All this literature has one element in common: it is about following, as Lund (2015) points out, a problem-based approach rather than a discipline-based approach. If the above seems too “ethereal,” we propose a couple of concrete examples below. First example: the management of forests and other types of vegetation. This entails biodiversity, erosion, emissions, lack of management, which affects the risk of fires, but also its effect on water availability (in Blanco (2017), existing paradigms on the relation between forests and water are even challenged). Indeed, existing blue-green water relations and substitutability are often ignored by analyzing them as if they were two distinct areas. As reviewed in D’Odorico et al. (2018), decades of research on deforestation have highlighted the profound hydroclimatic impacts of land use and land cover change (Perugini et al., 2017). Although it is very difficult to generalize conclusions for different kinds of forests, climates, soils, etc. (for which more studies on grassland vs. agroforestry are needed), Kay et al. (2018) show consistently for six case studies in Europe how groundwater recharge rate tends to be higher in agricultural landscapes without agroforestry systems. On rain-fed farmland vs. forestry, the former is found to sustain lower evapotranspiration rates because of the smaller leaf area index, surface roughness, root depth, and greater albedo (Bonan, 2008; Perugini et al., 2017; D’Odorico et al., 2018). On closed vs. open forest, the first reduces more infiltration (Gracia et al., 2011; Di Prima et al., 2017). All in all, both ET and runoff go against infiltration. The reason is that, although truly runoff does not increase on site storing, water remains within the basin, while with ET water escapes from it. For example, in the Ebro basin, Bielsa et al. (2011) and López-Moreno et al. (2008; 2014) found surprisingly small water volumes in downstream gauges which lead them to identify increasing natural revegetation as a potential explanatory factor. We believe plant sciences have a great deal to contribute to river basin water management since land-use changes, particularly forest extent and coverage, can modify forest water demand and hence blue water availability. Some policy makers only take action when they grasp, if roughly, the economic implications of these water losses or water pollution. Consider a second example. As highlighted by Shtull-Trauring et al. (2016), high-resolution studies can provide data to inform policy makers and farmers about the appropriate crops and cultivation practices that lower the WF by increasing water use efficiency and reducing the negative impact on the environment. On that basis, we would also add that policy makers will only take appropriate decisions knowing the whole picture of the benefits and costs for society. We know that the market economic valuation instruments are not usually appropriate for this cost-benefit calculations (see e.g., Van der Zaag and Savenije, 2006). Therefore, a key aspect is the consideration of many water services as public goods. This implies requiring some type of agency that considers social costs and benefits [be they public administrators/non-governmental organizations (NGOs), etc.] to manage it. Only if the water cycle (and thus the green side of it) is fully known, can informed and sound decisions be made. Clearly, plant water dynamics have much to contribute in this area. Table 1 summarizes advances, gaps and relevance for PWS of a selection of the cited literature. Table 1 Selected review of literature on water footprint (WF) notably related to plant water sciences (PWS) and dynamics, and key gaps for water management (WM). As we have argued based on the critical analysis of recent literature on water management and on WF, new advances in the study of plant water dynamics have great potential to improve the understanding and management of the water cycle. 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No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Ignacio Cazcarro, [email protected]
, Meredith Gilman Parrado, John Bradley
Published: 30 January 2020
Frontiers in Pharmacology, Volume 10; https://doi.org/10.3389/fphar.2019.01691

Abstract:
We currently have no approved drugs for the treatment of Ebola virus disease (EVD) or post-Ebola syndrome (PES). A substantial proportion of patients presenting for treatment die, including healthcare workers (HCWs) with hospital-acquired infections. More than 28,000 people were suspected or confirmed with EVD and 11,000 died in the West Africa outbreak during 2014–2016. A new EVD epicenter developed in the Democratic Republic of Congo in mid-2018, and it is likely that new outbreaks will occur in the future. The low survival rate discourages patients from presenting for treatment, and the occupational risk discourages HCWs from caring for highly infectious patients. A substantial proportion of survivors complain of chronic symptoms, such as eye problems (47%) and arthralgias (64%)—a condition that has been termed PES (Wilson et al., 2018). Inflammation may play a role in both the uveitis, which can result in blindness (Shantha et al., 2017) and in arthritis (Amissah-Arthur et al., 2017). Availability of an efficacious adjunctive treatment drug would save lives, increase the number of people presenting for treatment, and increase the willingness of HCWs to care for patients. An efficacious drug for adjunctive treatment of PES could decrease morbidity suffered by survivors. To date, most research efforts have focused on vaccine for prevention and either antivirals or antibody preparations for treatment. However, given the extensive inflammatory component of EVD, adjunctive therapy to decrease inflammation—but not globally downregulate the host immune response in a manner that could be detrimental (e.g., steroids)—may hold promise for better outcomes for those infected. Although drugs such as acetylsalicylic acid, ibuprofen, indomethacin, and celecoxib are also broadly anti-inflammatory, they all inhibit cyclooxygenase and can interfere with platelet aggregation—a characteristic that would be disqualifying for use with hemorrhagic fevers. “Cytokine storm,” a burst in production of inflammatory cytokines, is thought by many to be integral to EVD pathogenesis, and high levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, IL-1β, macrophage inflammatory protein (MIP)-1α, MIP-1β, and macrophage chemoattractant protein (MCP)-1 are associated with fatal infections (Ruibal et al., 2016; Vernet et al., 2017). Nuclear factor of activated T cells (NFAT) is thought to be the key transcriptional regulator of inflammatory mediators (Madelain et al., 2018). Knock-out mice with dampened cytokine response (Tim-1 -/-) are considerably more likely to survive Ebola virus challenge than their wild-type counterparts, despite a limited impact on viremia (Younan et al., 2017). We questioned whether the inflammation associated with cytokine storm could be countered pharmaceutically—and having some familiarity with one antimicrobial (minocycline) with significant anti-inflammatory properties as well as documented antiviral activity—we searched PubMed for articles describing cytokine activity during EVD and during minocycline use. Minocycline is an FDA-approved semisynthetic tetracycline with an established safety profile that has been used for 40 years in the treatment of acne and rosacea (Cullen and Cohan, 1976; Hersle and Gisslen, 1976), and more recently, for multidrug resistant Acinetobacter (Lashinsky et al., 2017). It appears to have activity against certain viral pathogens: It inhibits H7N9 replication in vitro (Josset et al., 2014), attenuates stimulation of interferon-related gene and TRAILΨ in human dendritic cells and PBMCs exposed to HIV or influenza virus (Drewes et al., 2014), reduces West Nile Virus titers in brain-derived cell types in a dose-dependent manner (Michaelis et al., 2007), reduces Japanese encephalitis-induced damage in neuronal cell cultures (Mishra et al., 2009), and, based on molecular dynamics, may possibly inhibit the binding of Congo Crimean hemorrhagic fever virus to host nucleoprotein during cell infection—a host protein that is believed to be pivotal to viral replication (Sharifi et al., 2017). In a randomized controlled trial of patients with dengue hemorrhagic fever, compared to patients who received standard-of-care supportive treatment, those who also received the related tetracycline class antibiotic—doxycycline—had significantly lower mortality [20.9% vs 11.2% (p < 0.05)] and lower TNF and IL6 levels on days 3, 5, and 7 (p < 0.05 for all) (Fredeking et al., 2015). Table 1 compares the effects of Ebola virus and minocycline on selected biomarkers including important cytokines and chemokines. Table 1 Comparison of the Effect of Ebola Virus and Minocycline on Selected Biomarkers. As shown in our table, the anti-inflammatory activity of minocycline opposes those of many gene products of Ebola virus. It also selectively impairs NFAT-mediated transcriptional activation (Szeto et al., 2011). Due to its small size and lipophilic nature, minocycline may reach potentially therapeutic concentrations in tissue compartments for which antibiotic penetration is typically difficult, such as the eye (Abcouwer et al., 2013; Scholz et al., 2015) and joints (McEvoy, 2016). Such spaces appear to be capable of harboring Ebola virus (Varkey et al., 2015; Steptoe et al., 2017; Subissi et al., 2018) and are thought to contribute to the chronic sequelae seen in PES (Shantha et al., 2017; PREVAIL III Study Group, 2019; Heydari-Kamjani et al., 2019). However, pharmacokinetic/pharmacodynamic (PK/PD) data are lacking that would confirm minocycline penetration into such spaces. As previously mentioned, inflammation may play a role in both the potentially blinding uveitis and arthritis of PES. Although there are animal data to suggest that minocycline may have anti-inflammatory effects in the eye (Scholz et al., 2015) and human data to suggest anti-inflammatory activity in joints (Pradier et al., 2018), it is not known whether it has direct antiviral activity against Ebola virus. Given minocycline’s broad anti-inflammatory activity against cytokines/chemokines that appear to be pathologically upregulated by Ebola virus and the safety history, relative availability, and affordability of minocycline, we feel it should be investigated as an adjunctive therapy in animal models of acute EVD. Given that it appears to cross into protected spaces where it may have anti-inflammatory activity, we feel it should also be investigated as adjunctive therapy for chronic sequelae of EVD (i.e., PES). It is likely that the anti-inflammatory benefit would be greater in certain infected populations (starting treatment early vs late in the infection), and it is also possible that, for some, downregulation of inflammation in general could impair host clearance of the virus. These important issues are amenable to investigation in animal models. KH performed the literature review and drafted the table and text. MP helped to synthesize the tabular data and edited the text. JB reviewed the information and edited the text. Use of trade names and commercial sources is for identification only and does not imply endorsement. This is an opinion piece based on literature review. No experiments have been conducted or data collected at this time for the potential adjunct treatment of Ebola virus disease or post-Ebola syndrome. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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Ebola virus binding to Tim-1 on T lymphocytes induces a cytokine storm. mBio 8 (5), e00845–17. doi: 10.1128/mBio.00845-17 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: Ebola virus disease, minocycline, drug discovery, cytokine, chemokine, hepatoprotection Citation: Hendricks K, Parrado MG and Bradley J (2020) Opinion: An Existing Drug to Assess In Vivo for Potential Adjunctive Therapy of Ebola Virus Disease and Post-Ebola Syndrome. Front. Pharmacol. 10:1691. doi: 10.3389/fphar.2019.01691 Received: 31 October 2019; Accepted: 24 December 2019; Published: 30 January 2020. Edited by: Reviewed by: Copyright © 2020 Hendricks, Parrado and Bradley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Katherine Hendricks, [email protected]
Published: 28 January 2020
Frontiers in Microbiology, Volume 11; https://doi.org/10.3389/fmicb.2020.00033

Abstract:
The emergence and dissemination of antibiotic resistance is now understood as an unavoidable aspect of bacterial evolution following the consumption of antibiotics (Courvalin, 2005). This dramatic phenomenon is well illustrated by the relationship existing between the occurrence of resistances and the consumption of antibiotics (Furuya and Lowy, 2006; Davies, 2007; Davies and Davies, 2010). Mechanistically speaking, the increasing occurrence of antibiotic resistant bacteria (ARB) has been widely attributed to the selection of resistant variants that pre-exist in susceptible communities (Andersson and Hughes, 2014). Such resistant bacteria are supposedly outcompeting the rest of the microbial communities in a context where antibiotics are administrated at relatively high levels, which means that local concentrations are well-over the Minimum Inhibitory Concentrations (MICs). Despite the fact that the increasing occurrence of antibiotic resistances among bacteria has been recognized decades ago as resulting from antimicrobial drug consumption, only recently has the seriousness of the situation been considered by international, national and local health organizations/agencies. This awareness led to series of reports and recommendations intending to educate and improve practices of health professionals and consumers, in order to preserve the effectiveness of our therapeutic potential (MSS, 2011; World Health Organization, 2015; O'Neil Report, 2016; EUR-Lex, 2018). Considering the correlation between antibiotic consumption and occurrence of resistances in bacteria (Davies, 2007), most recommendations proposed to take action in the public health and veterinary/farming domains by limiting the inappropriate exposure of bacteria to antibiotics in order to slow down a natural evolution toward resistance and its spread in the downstream environment in a One Health context (World Health Organization, 2015, 2017). Limiting the inappropriate exposure of bacteria to antibiotics implicitly means (i) reducing the need for antibiotics, which can be achieved with infection control measures that would limit the epidemic spread of resistant bacteria, and (ii) a better usage of antibiotics so as to reduce our overall antibiotic consumption when unnecessary. Even if there is a great disparity between countries regarding the consumption of antibiotics (European Centre for Disease Prevention and Control (ECDC), 2017), change in practice remains difficult to implement when public health is concerned. In any case, taking action to reduce antibiotic resistance requires a coordinated and multi-sectorial approach combining political commitment, resources, specific governance mechanisms, and practical managements, as recently reported by World Health Organization (2018). In its 2018 reports, the ECDC indicated that the overall consumption of antibiotics in the EU did not significantly change in the community and the hospital sectors, while a few decreasing and increasing trends were observed for some countries over the 2013–2017 period. Changes in consumption were probably more visible in veterinary medicine. In a report covering the 2011–2016 period on veterinary antibiotics sale, the European Surveillance of Veterinary Antimicrobial Consumption related an overall decrease of 20% aggregated for 25 countries (European Surveillance of Veterinary Antimicrobial Consumption (ESVAC), 2018). This was tentatively explained by the implementation of policies and measures aiming at reducing the misuse of antibiotics. Even if the studied period is too short yet to draw robust conclusion, the first effects of such responsible-use campaigns start to be visible. In France for instance, an unprecedented national plan to reduce the antibiotic consumption in the animal sector has been initiated (Ecoantibio, 2017). This led to a drastic 39% reduction of antibiotic prescription in veterinary medicine in 6 years, all animals considered. The reduction was even stronger for critical antibiotics such as fluoroquinolones (81% reduction) and last generation cephalosporin (75% reduction). According to the French surveillance network of antimicrobial resistance in pathogenic bacteria of animal origin, these measures were followed by a net diminution of pathogenic ARBs (RESAPATH, 2016). As reported by the French National Public Health Agency (Santé Publique France, 2018), using data also presented by the European Food Safety Agency, the proportion of resistant E. coli for C3G went down from 16% to <2% in poultry between 2010 and 2017, which was dramatically increasing before 2010 (Bourély et al., 2018; European Food Safety Agency (EFSA), 2018; Santé Publique France, 2018). Although more results are necessary to comfort these results, they tend to demonstrate that a better use leading to a reduced consumption of antibiotics can rapidly result in a sensible decrease of the relative occurrence of ARBs. If several other reports are rather encouraging to pursue in that direction (Seppala et al., 1997; Aarestrup et al., 2001; Dutil et al., 2010), the relationship between occurrence of resistance and antibiotic consumption does not always follow this trend. Indeed, even if it is not the vast majority of the reported cases, stopping or increasing the consumption of a given antibiotic does not always result in the concomitant decrease or increase of the corresponding resistances, and this may vary according to the studied environment, the public/animal concerned, and the antibiotic and bacteria considered. For instance, Lai et al. (2011) reported a negative correlation between a decreasing consumption of cefotaxime and the rate of cefotaxime resistant-Escherichia coli pathogens isolated in a Taiwanese university hospital. Similar trends were reported for the consumption of ceftriaxone and ceftriaxone-resistant E. coli and Klebsiella spp. in a Turkish hospital setting (Altunsoy et al., 2011). Negative correlations between antibiotic consumptions and development of resistances can also work the other way around, and may depend on the bacterial species considered. In a Korean study covering six university hospitals, Kim et al. (2018) observed contrasted results following an increased consumption of fluoroquinolones, where the resistance rate for ciprofloxacin in E. coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, either increased, remained stable or decreased, respectively over an 8-years period. Surprisingly, the same authors also found negative correlation between decreasing consumptions of aminoglycosides and the resistance rate for third generation cephalosporins and ciprofloxacin, thus disconnecting a given drug consumption from its effect on the corresponding antibiotic resistance, at least for a few documented cases. To go further, it is worth noting that carbapenem-resistant P. aeruginosa could be isolated from animals that have not been previously treated with carbapenems. In this case, the resistance to carbapenem was attributed to an efflux pump dysregulation (rather than a carbapenemase) resulting from mutations possibly selected by disinfectants and other antibiotics in veterinary practices (Haenni et al., 2017), thus showing that resistant phenotypes can emerge independently from the presence of the corresponding antibiotics. On the other hand, the identification of antibiotic resistance genes in metagenomes from 30,000-years old sediments reminds us that resistance phenotypes and their corresponding genes probably existed before the so-called antibiotic era (D'Costa et al., 2011). Taken together, these observations clearly indicate that the emergence and the dissemination of antibiotic resistances in bacteria cannot solely be explained by a simple selective process occurring during antibiotics therapy, even if the latter is an important driving parameter in many instances. Tackling the spread of antibiotic resistance will surely require a better usage of antibiotics in order to slow down the emergence of resistant variants associated to antibiotic therapies. But, considering the indispensability of antibiotics in modern medicine, antibiotic resistances will continue to be released in anthropogenically-impacted environments where ARBs can persist, accumulate, transfer their resistant genes (ARGs) to indigenous microbes, and finally re-enter the food chain and contaminate human and animal guts for a new round of selection (Davies and Davies, 2010). It should be noted here that the environment has been described as a reservoir of ARGs in several occasions (Berendonk et al., 2015). Considering that the dissemination of antibiotic resistances lies on the acquisition of resistance but also implies a transmission, and therefore a contact, between people, or with wastewater, or manure, or animals, tackling the dissemination of ARB and ARGs will surely require controlling both the usage of antibiotics but also the route of transmission, especially at the environmental level. With that respect, Collignon et al. (2018) recently proposed that the transmission of ARB and ARGs was probably the dominant contributor to consider for controlling antibiotic resistance, which implies to act at other levels than the antibiotic consumption as well. The global reduction of consumption is not the sole important measure implemented by national and international organizations for better usage antibiotics. The classification of antimicrobial agents as critically important molecules for human health (WHO classification list), the restriction of their availability/delivery, and the confinement of particular antibiotic usages to human medicine are important measures aiming at preventing the emergence of particular resistances in the animal husbandry sector and their dissemination in the human health sector (EUR-Lex, 2018; OIE: World Organisation for Animal Health, 2018; World Health Organization, 2019). Nevertheless, confining the usage of a given antibiotic is likely to be of limited impact if collateral effects were to be observed between antibiotics of different nature on the emergence and the dissemination of unrelated ARGs. Lately, Scornec et al. (2017) demonstrated that Tn916, a mobile genetic element involved in the dissemination of an ARG for tetracycline, could exhibit a 1,000-fold increase of its transfer frequency when exposed to sub-inhibitory concentrations of tetracyclines, but also macrolides, lincosamides, and streptogramins. This means that not only sub-inhibitory concentrations of an antibiotic could stimulate the dissemination of its corresponding resistant gene, but that collateral stimulation by other antibiotics is also possible. This tends to rule out the effectiveness, at least partially, of any measure that would be based on confining the usage of cross-reacting antibiotics. On another ground, the use of trace metal elements such as zinc oxide or copper sulfate, is frequently used as an antibiotic alternative to promote growth of livestock and poultry. Consequently to such practices, several authors reported a concomitant increase of ARB and ARGs that are likely to result from co-selective processes, as ARGs and metal resistance genes can collocate on the same genetic entities (mobile genetic elements) (Hasman et al., 2006; Yin et al., 2017; van Alen et al., 2018). Collateral effects of antibiotics at sub-inhibitory concentrations and trace metal elements clearly highlight the fact that the antibiotic resistance risk should not be associated with the sole antibiotic therapy practices, and should rather be considered as a multifactorial problem where co-selection and stimulation of horizontal gene transfer also fully applies. Further in depth epidemiological studies should allow determining the extent of such collateral effects outside the context of a Petri dish, and may explain why some antibiotic resistances escape any reduction of occurrence while reducing the corresponding antibiotic consumption. On the other hand determining exhaustively which antibiotic molecules exhibit collateral effects, and at which concentrations, would be an additional step toward antibiotic risk assessment, whether for therapeutic practices or for the effect of antibiotics once diluted in the downstream environments. CM wrote this opinion paper. The author wishes to thank the French National Agency for Research (ANR) (Project ReguloMobile, No. ANR-13-ADAP-0009) and the French Agency for Food, Environmental and Occupational Health & Safety (Project AquaResist, PNREST Anses, 2018/1/052) for research funding. 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The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Christophe Merlin, [email protected]
Comment
Published: 24 January 2020
Frontiers in Psychiatry, Volume 10; https://doi.org/10.3389/fpsyt.2019.00959

Abstract:
A Commentary onA Pilot Digital Intervention Targeting Loneliness in Youth Mental Healthby Lim MH, Rodebaugh TL., Eres R, Long KM, Penn DL, and Gleeson JF. (2019). Front. Psychiatry. 10:604. doi: 10.3389/fpsyt.2019.00604 Positive relationships are fundamental to our physical and psychological health and wellbeing, yet loneliness is now estimated to affect one in four members of the general population to the detriment of their physical and psychological health (1–4). To combat rising rates of loneliness, a number of interventions are available that focus on increasing social connections. However, as Lim et al. (5) suggests, increasing the quantity of relationships is not, by itself, enough. In order to improve feelings of loneliness, it is also necessary to address the quality of relationships. This is the central aim of the +Connect smartphone app. The pilot of +Connect offers exciting preliminary insights into the delivery of an intervention for loneliness in young adults (5). However, design choices in a number of areas—including the digital platform used in the intervention and a focus on current relationships—set boundaries on the utility of the current iteration of the app. I argue that these additional considerations should be reflected upon in the design of future iterations of this app and that Lim and colleagues (5) can fruitfully draw from empirical work in related areas (e.g., belonging, social skills, cognitive-based interventions, and motivation) to create more diverse and tailored offerings. +Connect (5) was created as a 6-week digital intervention program with the goal of a) targeting loneliness by improving relationship quality among young adults with Social Anxiety Disorder (SAD) and b) extending past research (6, 7). The pilot intervention employs a positive psychology approach to help young adults identify their strengths, increase their positive affect, and focus on building intimacy within existing relationships. The intervention yielded positive results, proving to be beneficial. An impressive 75%–100% of participants with SAD reported +Connect to be helpful. However, the researchers also noted a high attrition rate for participants with SAD, which was almost double the rate of those without the disorder (5). An important strength of the app is its use of shared experience videos. The designers of the app have identified and made valuable use of an opportunity to normalize the experience of loneliness as a commonly occurring human emotion. This insight offers an alternative perspective to recent scholarly work that has sought to pathologize loneliness (8). Another strength is that the app offers an alternative to medical approaches that posit that loneliness is a condition that requires pharmaceutical treatment (9). +Connect provides a non-medical, psychologically based intervention that offers users skills that also benefit the general population, irrespective of their mental health status or even whether they are lonely or not (5). Lim and colleagues (5) emphasize that loneliness does not always stem from being alone or physically isolated and they rightly point out that a successful intervention does not simply involve recruiting people to join groups. Instead, the authors suggest that increasing the satisfaction with, and perceived meaning of social connections in addition to focusing on the quality of interactions, rather than the quantity, offers a more helpful approach to addressing perceived loneliness. However, while the aim to improve the quality of current relationships offers considerable value, the focus on current relationships is limiting in that it offers little help for those who are unable to make substantial social connections in the first place. Quantity is not enough by itself, nor is quality. Both are needed together. Other research areas in the empirical literature point toward ways in which this focus could be broadened to improve successful outcomes from the app [e.g., (10–18)]. The +Connect app may also be beneficial for other at-risk youth, such as young people who have a parent with mental illness who indicate that they want more support through digital technology (19). Loneliness and belonging, for example, are considered by many scholars to be distinct but related subjective states that play a role in normal human emotion (20, 21). According to this kind of approach, belonging is a psychological need for interpersonal bonds [e.g., (11)], while loneliness results from the perceived discrepancy between an individual’s actual and desired social relationships (22). When needs for belonging are not met, this leads to perceived loneliness (21). There is evidence that, because loneliness and belonging share similar characteristics and are highly correlated, an increase in feelings of belonging will improve feelings of loneliness (20). Conversely, supporting belonging is associated with decreased loneliness (21). Interventions targeting belonging may, thus, offer rich and new insights and perspectives into ways in which loneliness can be addressed (23). A more balanced and well-rounded intervention might also consider the inclusion of social skills training [to address those users who may be lonely as a result of social skills deficits or limited interpersonal skills; see (10, 13)], cognitive-based interventions [to address those users whose perceptions of their experience of loneliness may be irrational or due to fundamental attribution errors; (17, 18)], and motivation [assuming that some users simply lack the motivation to create more meaningful connections; (11, 15)]. We are seeing increasing evidence for the success of these types of interventions delivered through online technologies for various outcomes [e.g., Growth mindset and social belonging, (12); treating depression, (14)]. However, more research is needed before this approach could be validated as a useful inclusion in the +Connect app. The inclusion of more diverse interventions offers routes by which to reach more people, offer greater variety for users, and allow for the app to engage with a broader audience. It is well established in the literature that positive psychology interventions, such as those included in the +Connect app, are more effective when factors such as personal fit, variety, and dosage are considered in respect to the individual personal features of the user (16). Diversity in intervention delivery may also offer additional ways of developing the cross-cultural applicability of the insights underlying the app. In evaluating the +Connect app, it is necessary to ask whether and to what extent it is capable of doing more than non-specialized, commonly used social media apps (such as Instagram, Twitter, Facebook, or TikTok) that have been found in some research to create opportunities to connect with others and reduce loneliness (24–27). While social media may create digital communities (28), there are good reasons to think that the connection formed does not create the same level of satisfaction that comes from the face-to-face relationships that the +Connect app aims to enhance through specifically improving the perceived quality of relationships. Some recent research also suggests that social media use can add to feelings of loneliness and isolation [e.g., (29)] although other studies suggest that these types of finding are highly dependent on the user and the context, including the frequency of use (16, 30). +Connect differs from common social media apps in that it aims to build skills with the goal of increasing social support systems. It also sidesteps various problems for mental health and wellbeing that research has associated with the use of other social media apps, such as criticisms related to cyberbullying, addiction, and unrealistic social comparisons (31–34). Pittman and Reich (26) have demonstrated that social media platforms based on video and picture content can actually enhance a sense of connection with others, while other research has shown the benefits of gamification for wellbeing interventions (35). The core use of video technology and an interactive platform in +Connect is, thus, likely to be another strength of the app. A central limitation of the +Connect app is that it may not reach all people who could potentially benefit from it, such as those without phones and those who are socially isolated. While the vast majority of young people in developed countries own phones, many still do not. This fact alone excludes a significant number of individuals from receiving help and support for feelings of loneliness and isolation. The focus of +Connect on increasing the quality of existing relationships also sidelines those who do not currently have such relationships or who are looking to explore new relationships. Another possible concern with the primary platform chosen to deliver the +Connect content is that the very technology it uses has been identified by some scholars as problematic for loneliness (27, 28, 36–38). While +Connect aims to address loneliness in young adults, it may also unwittingly promote increased digital screen time and reduced time spent on face-to-face connections. It may be possible to explore other ways of connecting in order to expand upon +Connect’s goal of reaching more people, such as through school programs, university electives, and community-based programs. The core content of the +Connect intervention is delivered through videos. It should, thus, be feasible to consider that this content might usefully be delivered through different platforms in addition to delivery through the app itself, an exclusive focus on which may prove to be unnecessarily restrictive. Future research should address issues with the current intervention and methodology in order to provide more in-app tailored support to address attrition rates of users with mental health difficulties, an investigation into potential use for other age groups who have been identified as most at-risk for loneliness [i.e. adolescence and older adults (2)], cross-cultural applicability, suitable alternatives for people without phones, opportunities for those looking for new relationships, and larger samples for generalizability. An important next step will be a pilot randomized controlled trial. +Connect was developed with the goal of addressing loneliness in young adults and was found to be beneficial for the participants in the study, especially with regards to their overall quality of life. The findings suggest that those with SAD may benefit from such interventions but require tailored support to reduce dropout rates. Lim et al. (5) demonstrate sufficient evidence for the value of further work to examine the effectiveness of +Connect within a pilot randomized controlled trial. This commentary has argued that the app itself could be strengthened by drawing from other fields of research and meeting the needs of a broader audience, especially those without access to digital platforms and those who are physically alone, socially isolated, or ostracized. Interventions such as +Connect show great preliminary promise for targeting loneliness and should be extended urgently to explore utility with other age groups, cultural groups, and with alternative modes of delivery. +Connect plays a role in signaling the urgent need to evaluate systemic factors that may enhance or hinder loneliness in society (e.g., legislation, town planning, architecture, medical approaches, and general public awareness of the importance of belonging to groups and the detrimental effects of chronic loneliness). 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Bowling alone: the collapse and revival of American community. Simon & Schuster: New York (2000). Google Scholar 38. Turkle S. Alone together: why we expect more from technology and less from each other. Basic Books: New York, NY (2011). Google Scholar Keywords: smartphone, mental health, psychosis, belonging, loneliness Citation: Allen K-A (2020) Commentary: A Pilot Digital Intervention Targeting Loneliness in Youth Mental Health. Front. Psychiatry 10:959. doi: 10.3389/fpsyt.2019.00959 Received: 17 August 2019; Accepted: 04 December 2019; Published: 24 January 2020. Edited by: Reviewed by: Copyright © 2020 Allen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Kelly-Ann Allen, [email protected]
Melanie D. M. Hudson, Lucinda S. Spaulding, Angela Y Ford, Laura E Jones
International Journal of Doctoral Studies, Volume 15, pp 705-736; https://doi.org/10.28945/4671

Abstract:
Aim/Purpose: The purpose of this systematic grounded theory study was to generate a model explaining how grit and a growth mindset develop and influence persistence in doctoral completers. Since doctoral attrition has historically plagued institutions of higher learning, with conflicting explanations reported in the literature, program leaders will benefit by understanding factors associated with persistence. Background: Although the initial literature regarding doctoral persistence relied on the more traditional student involvement and integration models of higher education, the changing landscape of doctoral education—a steep increase in the number of distance education programs, as well as students’ time and energy constraints—calls for a closer look at individual student factors over engagement efforts. Methodology: The systematic approach of grounded theory was adopted to fulfill the purpose of constructing a model explaining the process of grit and growth mindset development in doctoral students who persist to completion. Both quantitative data from a total population of 51 completers, in the form of the Short Grit Scale instrument and Dweck’s Mindset Instrument, as well as qualitative data from interviews and reflective journals of a sample of 12 doctoral completers were analyzed to produce the Grit Growth Model suggested by the findings. Contribution: The Grit Growth Model contributes empirical evidence of the antecedents of the characteristics of grit and growth mindset, which has been limited in the literature to date. A unique contribution of this study is the suggestion of a departure from the typical approach of leaders in post-graduate institutions from a student-integration/engagement approach, to a more direct personal development strategy, with specific direction given by the Grit Growth Model, as well as the additional Student Development Model of Doctoral Persistence. Findings: The findings produced the Grit Growth Model, which revealed sub-themes of expectations, engagement, service, and personal loss in the life experiences of the doctoral completers, as well as values surrounding religious faith and passion. Personal characteristics of flexibility and shame resilience were identified, and findings confirmed prior persistence literature that acknowledged the imminent value of personal and academic relationships. The central theme of personal and social responsibility (PSR) carries theoretical, empirical, and practical implications for doctoral or any other leaders who wish to develop grit in others, as well as individuals seeking to develop the trait within themselves. Recommendations for Practitioners: Given the findings of this study, doctoral program leaders should make a concerted effort to add a direct student development focus to their portfolio of strategies to support student persistence, as visualized in the Student Development Model of Doctoral Persistence. Programmatic elements, such as direct provision of grit, growth mindset, and PSR resources through doctoral student communication platforms, could deliver persistence support by means of advancing student metacognition of these principles. Additionally, modules that introduce and inspire growth in these areas using the quantitative instruments for grit and a growth mindset, followed by reflective journaling, direct instruction videos, and post-tests, are suggested. Recommendation for Researchers: Future researchers in any field can build upon this model by replacing doctoral persistence with their own long-term goals or achievements and representing their findings by adjusting the model accordingly. In this way, the significance of the Grit Growth Model lies in its adaptability to future inquiry, providing a meaningful template to illustrate confirmatory or alternative findings. Impact on Society: For educators at any level or individuals who wish to develop grit and a growth mindset within themselves or others studying the array of categories of experiences and beliefs on the Grit Growth Model will illuminate multiple paths to follow on this quest. Accessing resources from Duckworth’s Character Lab (https://characterlab.org/), Dweck’s mindset works© website (https://www.mindsetworks.com/default), or the AAC&U’s Personal and Social Responsibility site (https://www.aacu.org/core_commitments) are suggested concrete starting points. Future Research: In subsequent research along these same lines, it would be desirable to solicit a follow-up interview to dig deeply into more nuanced life experiences that may not emerge in the initial interview. Additionally, due to the limitations of snowball sampling, future confirmatory research should focus on samples from a wider population who completed at a more diverse group of universities. Finally, although the interview sample size of 12 participants produced findings with theoretical saturation, a larger sample from a wider variety of disciplines and demographics, including unmarried doctoral completers, may paint a more complete picture of the common experiences and values of completers from a broader range of personal and professional backgrounds.
Moritz Lönhoff, Hamid Sadegh Azar
International Journal of Masonry Research and Innovation, Volume 5; https://doi.org/10.1504/ijmri.2020.106304

Abstract:
Inderscience Publishers: publishers of distinguished academic, scientific and professional journals.
Bui Son Nhat, Vu Dinh Hoa, Le Anh Tuan, Le Thi Luyen
VNU Journal of Science: Medical and Pharmaceutical Sciences, Volume 35; https://doi.org/10.25073/2588-1132/vnumps.4168

Abstract:
This study aimed to establish a reasonable population pharmacokinetic model for rifampicin taken orally by patients with pulmonary tuberculosis, estimate pharmacokinetic parameters as well as influencing covariates. Blood samples of patients were collected at day 10 – 14 after commencing treatment. Time – concentration data were handled using non-linear mixed-effect model with Monolix 2018. An one-compartment, linear elimination, absorption with transit compartments model was found to be the most suitable for rifampicin. Volume of distribution (33,5 L) and clearance (9,62 L) were found to be influenced by fat-free mass (calculated using Janmahasatian’s method). Absorption-related parameters (Ktr, mean transit time and Ka) were found to have high inter-individual variability. Keywords Rifampicin, population pharmacokinetics, pulmonary tuberculosis. References [1] Christian Lienhardt et al, Target regimen profiles for treatment of tuberculosis: a WHO document (2017).[2] J.G. Pasipanodya et al, Serum drug concentrations predictive of pulmonary tuberculosis outcomes, The Journal of infectious diseases 208(9) (2013) 1464-1473. https://doi.org/10.1093/infdis/jit352[3] Jonathan Reynolds, Scott K Heysell (2014), Understanding pharmacokinetics to improve tuberculosis treatment outcome, Expert opinion on drug metabolism & toxicology 10(6) (2014) 813-823. https://doi.org/10.1517/17425255.2014.895813[4] E.F. Egelund, A.B. Barth, C.A. Peloquin (2011), Population pharmacokinetics and its role in anti-tuberculosis drug development and optimization of treatment, Current pharmaceutical design 17(27) (2017) 2889-2899. https://doi.org/10.2174/138161211797470246.[5] J.F. Murray, D.E. Schraufnagel, P.C. Hopewell, Treatment of tuberculosis. A historical perspective, Annals of the American Thoracic Society 12(12) (2015) 1749-1759. https://doi.org/10.1513/AnnalsATS.201509-632PS[6] K.E. Stott, et al, Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy 73(9) (2018) 2305-2313. https://doi.org/10.1093/jac/dky152.[7] Le Thi Luyen, Ta Manh Hung et al, Simultaneous Determination of Pyrazinamide, Rifampicin, Ethambutol, Isoniazid and Acetyl Isoniazid in Human Plasma by LC-MS/MS Method, Journal of Applied Pharmaceutical Science 8(09) (2018) 061-073. https://doi.org/ 10.7324/JAPS.2018.8910.[8] M.T. Chirehwa et al, Model-based evaluation of higher doses of rifampin using a semimechanistic model incorporating autoinduction and saturation of hepatic extraction, Antimicrobial agents and chemotherapy 60(1) (2016) 487-494. https://doi.org/10.1128/AAC.01830-15.[9] Paolo Denti et al, A population pharmacokinetic model for rifampicin auto-induction, The 3rd international workshop on clinical pharmacology of TB drugs (2010).[10] Y. Jing et al, Population pharmacokinetics of rifampicin in Chinese patients with pulmonary tuberculosis, The Journal of Clinical Pharmacology 56(5) (2016) 622-627. https://doi.org/10.1002/jcph.643.[11] S.R.C. Milán et al, Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis, Journal of clinical pharmacy and therapeutics 38(1) (2013) 56-61. https://doi.org/10.1111/jcpt.12016.[12] Anushka Naidoo et al, Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis, Pharmacogenomics(00) (2013). https://doi.org/10.2217/pgs-2018-0166.[13] Neesha Rockwood et al, HIV-1 coinfection does not reduce exposure to rifampin, isoniazid, and pyrazinamide in South African tuberculosis outpatients, Antimicrobial agents and chemotherapy 60(10) (2016) 6050-6059. https://doi.org/10.1128/AAC.00480-16.[14] Alessandro Schipani et al, A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children, British Journal of Clinical Pharmacology 81(4) (2016) 679-687. https://doi.org/10.1111/bcp.12848.[15] Kok-Yong Seng et al, Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults, Journal of Antimicrobial Chemotherapy 70(12) (2015) 3298-3306. https://doi.org/10.1093/jac/dkv268.[16] J.J. Wilkins et al, Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption, Antimicrobial agents and chemotherapy 52(6) (2008)2138-2148. https://dx.doi.org/10.1128%2FAAC.00461-07.[17] Sylvain Goutelle et al, Population modeling and Monte Carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs, Antimicrobial agents and chemotherapy 53(7) (2009) 2974-2981. https://doi.org/10.1128/AAC.01520-08.[18] R.M. Savic et al, Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies, Journal of pharmacokinetics and pharmacodynamics 34(5) (2007) 711-726. https://doi.org/10.1007/s10928-007-9066-0.[19] B.J. Anderson, N.H.G. Holford, Mechanism-based concepts of size and maturity in pharmacokinetics, Annu. Rev. Pharmacol. Toxicol 48 (2008) 303-332. https://doi.org/10.1146/annurev.pharmtox.48.113006.094708.[20] Kok-Yong Seng et al, Population pharmacokinetic analysis of isoniazid, acetyl-isoniazid and isonicotinic acid in healthy volunteers, Antimicrobial agents and chemotherapy, pp. AAC. (2015) 01244-15. https://doi.org/10.1128/AAC.01244-15.[21] Sarayut Janmahasatian et al, Quantification of lean bodyweight, Clinical pharmacokinetics 44(10), (2005) 1051-1065. https://doi.org/10.2165/00003088-200544100-00004.[22] Kidola Jeremiah et al, Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV, Antimicrobial agents and chemotherapy 58(6) (2014) 3468-3474. https://doi.org/10.1128/AAC.02307-13
Thomas Sécher, Alexie Mayor,
Published: 29 November 2019
Frontiers in Immunology, Volume 10; https://doi.org/10.3389/fimmu.2019.02760

Abstract:
Respiratory tract infections (RTIs) are the third leading cause of morbidity and mortality worldwide, accounting for ~4.25 million deaths in 2010, in either children, adults or the elderlies. RTIs encompass acute infections of the upper (rhinosinusitis, …) and lower airways (pneumonia, bronchiolitis, …) and are also inherently associated with chronic diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). In addition to premature mortality, RTIs result in a huge burden on the society considering quality-adjusted life year loss and additional pressure on the overwhelmed healthcare systems, thereby representing a major public health issue. Antimicrobial chemotherapies (e.g., antibiotics, antivirals) are the standard interventions to prevent and to treat respiratory infections. However, their effectiveness is declining due to increased pathogen resistance, urging alternative or complementary strategies to reinforce the anti-infectious arsenal to fight RTIs. Among those under evaluation, immunomodulatory agents (immunopharmaceutics) like therapeutic antibodies (Ab) or other therapeutic proteins and vaccines may offer novel opportunities for the prevention and treatment of RTIs, by targeting pathogens and boosting the host immune system. When used in a preventive way in patients at risk, or therapeutically to stop or to limit the spread of infection, both immunopropylactics and immunotherapeutics are administered through parenteral routes (including intravenous, subcutaneous, and intramuscular) (Table 1). As demonstrated in preclinical studies, parenteral delivery may not be optimal for large molecular weight entities to treat respiratory diseases (1, 2) since they poorly reach the lung compartment. In contrast, inhalation, comprising the intranasal and oral respiratory routes, targets drugs into the respiratory tract. Currently, inhalation is used both for locally- and systemically-acting drugs as it allows a straight delivery to the diseased organ and a portal to the blood circulation, considering the extensive alveolus-capillary interface. By providing a better therapeutic index, inhalation is the gold standard for small molecules, delivered topically as an aerosol, like corticosteroids/steroids, decongestants or bronchodilators for the treatment of asthma, rhinosinusitis or COPD. Besides, it is also indicated for antibiotics (nasal and oral inhalation), a local-acting protein therapeutic—Dornase alpha (Pulmozyme®, oral inhalation), a mucolytic agent for patients with CF and an influenza live vaccine (FluMist® Quadrivalent, nasal inhalation). Table 1. Marketed immunotherapeutics and immunoprophylactics for infectious diseases. There are accumulating evidences that administration of anti-infectious Abs, protein therapeutics (e.g., cytokines) and vaccines, to the upper and/or lower respiratory tract by inhalation, with the purpose of inducing a local action, is effective (3). Several preclinical studies showed the superiority of immunopharmaceutics administered topically to the respiratory tract in RTI models, in both therapeutic and prophylactic regimens. For instance, inhalation of anti-infectious Abs in models of pneumonia using Pseudomonas aeruginosa or influenza virus conferred higher protection and greater therapeutic response, respectively, compared to parenteral route administration (4, 5). Besides, other immunoprophylactics delivered through the respiratory route such as immunocytokines (e.g., IL-7 Fc) (6) and live-attenuated vaccines (7) showed superior performances over conventional routes against airborne viruses, in mice and non-human primates, respectively. Conversely, restricting the response to the site of action for pleiotropic molecules (e.g., IL-7 Fc), envisioned as adjuvant molecule, may reduce systemic side-effects. As reported for anti-infectious Abs, the inhaled route may also enable a higher efficacy with a lower dose (4). This means that the inhaled route may allow, in the future, to alleviate the financial burden of immunopharmaceutics (in particular Abs), which may exceed the ability of both individual patients and the healthcare systems to sustain them. Additional benefit of the inhaled route includes its non-invasiveness, offering a better comfort for patients, in particular those with chronic respiratory infections, and thus preventing additional healthcare costs. Besides, needle-free vaccination may prevent the risk of cross-contamination and facilitate mass vaccination efforts. However, beyond clear preclinical proofs of concept and obvious theoretical advantages of the inhalation route for immunotherapeutics and -prophylactics, few of these benefits have materialized in the clinic (Table 1). Except for Flumist® Quadrivalent (Astrazeneca), an intranasal live attenuated influenza vaccine, other marketed immunoprophylactics vaccines (including those against Streptococcus pneumoniae, Haemophilus influenza, Mycobacterium tuberculosis, Bordetella pertussis or measles and Ab (anti-RSV Pavilizumab)—are administered systemically. Similarly, none of the protein therapeutics is given by inhalation. Recently, Ablynx developed an inhaled anti-RSV trimeric nanobody® (ALX-0171) for therapeutic purposes. Despite promising results in several animal models, the development has been interrupted due to insufficient evidences of efficacy during Phase 2 trial in children (in Japan). In 2019, only one phase 2 trial with an inhaled anti-infectious protein therapeutics is still ongoing (NCT03570359) assessing the efficacy of topical lung delivery of IFN-β1a (SNG001, Synairgen/Astrazeneca), as an immunostimulant to treat COPD exacerbations. Overall, this highlights the complexity of developing inhaled biopharmaceuticals and points out the persisting hurdles (Figure 1). Figure 1. The multifaceted features from the development of inhaled immunopharmaceutics. The instability of immunopharmaceutics and vaccines often emerges as a challenge for inhalation delivery. Therapeutic proteins and vaccines are sensitive to various conditions which may alter their structure, thereby decrease their activity. Delivering a drug through the inhalation route implies either spraying, drying or aerosolizing, which is associated with multiple stresses (shearing, temperature, air/liquid interface, …) potentially deleterious as widely discussed elsewhere (8, 9). To deal with this, both the device used for the generation of the aerosol and the formulation must be adapted, as successfully reported for Ab-based therapeutics (3, 10). However, the excipients must be adapted for respiratory delivery. The choice of mucosal-licensed adjuvants, which should be exempt of intrinsic immune-toxicity, and the instability of the associated carrier [e.g., nanoparticles, liposomes, immune stimulating complexes (ISCOMs)] is particularly challenging for the inhalation delivery of vaccines, especially those of the latest generation (e.g., T, B-epitope-based vaccines). The drug and device combination yields proper aerodynamical properties (particle size, flow rate, …) to achieve the anticipated deposition in the appropriate area of the respiratory tract. Indeed, appropriate deposition to the anatomical site is mandatory to ensure an optimal efficacy. On one hand, this depends on the drug formulation (e.g., surface tension and viscosity for liquid formulation) (11) and device performances to allow the therapeutic agent to reach the site of infection (Figure 1), by this means the microbe. For lung infections, most pneumonia consists of an aggregate of trachea-bronchitis and alveolar infections. Theoretically, this clinical condition may benefit from a uniform distribution all over the lungs, with a polydisperse aerosol (ranging 1–5 μm). However, several pathogens are associated with specific anatomic localization, like S. pneumoniae, which is mainly found in the alveolar spaces, thereby requiring low-size aerosols (<2–3 μm) to be targeted. On the other hand, delivery to the mucosal-associated lymphoid tissue (MALT), located in the tonsils, would be more adapted for vaccines to induce an adaptive immune response, since MALT plays a central role in the primary respiratory immune defense (Figure 1). Biological barriers are additional hurdles to overcome and apply to all inhaled anti-infectious agents (12). First, a pathogen can “hide” itself inside host cells like M. tuberculosis in alveolar macrophages, thus being more difficult to be targeted by immunopharmaceutics. Other pathogens may produce extracellular barriers like the biofilm matrix produced by P. aeruginosa in the context of chronic lung infections. This biofilm acts as a diffusion barrier, preventing inhaled immunopharmaceutics from reaching their molecular target. Antibody-based fragments, such as fragment antigen-binding (Fab) and single-chain variable fragments (scFv) might be more efficient in crossing over the biofilm, like they penetrate better solid tumors (13), and eradicate P. aeruginosa. Secondly, the host physical defenses, which prevent foreign particles from penetrating into the respiratory tract, may limit the accessibility of inhaled immunopharmaceutics to their target. Among them, the mucus and the mucociliary escalator are highly efficient clearance mechanisms (14, 15). The development of mucoadhesive formulations may be helpful to enhance the bioavailability of inhaled drugs (16). In contrast, anti-adhesive molecules, such as polyethylene glycol may facilitate immunopharmaceutics translocation through the mucus blanket, as shown in vitro (17) and in vivo (18) for other applications. It is noteworthy that, in some pathological conditions (e.g., chronic sinusitis, CF and COPD), the mucus gets thicker. In CF, the mucus exhibited an increased density of disulfide cross-links, further tightening the mucus mesh space, thereby reinforcing its steric barrier potency to immunopharmaceutics (19). To date, overcoming this physical barrier has not been addressed in the design of inhaled immunopharmaceutics. Other biological barriers include alveolar macrophages and the pulmonary surfactant layer in the alveolar region. While the molecular interactions between inhaled particles and the surfactant are largely unknown, some evidences indicate that surfactant proteins may facilitate the uptake of inhaled particles by alveolar macrophages (20). Alveolar macrophages patrol the airways and phagocytose inhaled organic (including pathogens) and inorganic particles ranging between 0.5 and 5μm (21). Interestingly, the size-discriminating property of their phagocytosis potency has led to the development of innovative approaches for inhaled drugs, in which carrier entrapped-particles of smaller or larger size are inhaled to escape the alveolar macrophage phagocytosis and to provide a better controlled drug release [(22, 23); Figure 1]. This strategy is investigated for mucosal vaccines to prevent the degradation or denaturation of the peptide/antigen, to sustain its release and favor delivery and adjuvancy (24). The lung mucosa is a metabolic active environment (25). The presence of proteases [which is more prevalent in the nasal mucosa (26)] may degrade therapeutic proteins before they reach their targets. In addition to host enzymes, bacterial pathogens, like P. aeruginosa, release additional proteases, which may metabolize respiratory-delivered drugs (27). In this context, the presence of protease inhibitors in the formulation of inhaled protein therapeutics may improve their pharmacokinetics and efficacy, as previously demonstrated for inhaled peptides such as insulin and calcitonin (28). Furthermore, the encapsulation of protein therapeutics into liposomes may also improve stability and reduce the frequency of dosing (29). This strategy has already been clinically validated for the pulmonary delivery of antibiotics (30). Of note, respiratory diseases are often associated with an impairment of the protease/anti-protease balance. In CF, high levels of proteases are a result of the chronic infection and inflammation induced by P. aeruginosa (31). This proteolytic environment self-perpetuates the intensity of inflammation, induces mucus hypersecretion and respiratory tissue damage, which may ultimately affect inhaled immunotherapeutics (Figure 1). Compared to the expansion of biopharmaceutics (excluding non-recombinant vaccines) in all medical areas, the field of inhaled protein therapeutics/vaccines has stagnated, with only few drugs approved so far. Despite promising preclinical data and significant advances on macromolecule inhalation, a definitive demonstration that effective and intact inhaled immunopharmaceuticals could be delivered (topically) to humans is still lacking. Although, we cannot rule out that the recent failures of inhaled biopharmaceutics (Exubera and ALX-0171) make it challenging, to our opinion, it may be time for thinking carefully where inhalation may have the edge over other routes: “finding the right use for this modality!” They may be many possibilities considering the unmet clinical needs for respiratory diseases and the growing market of immunopharmaceutics. But the inhalation route must be envisioned and integrated early taking into account the disease/population, the target, the drug and the device (Figure 1), rather than adapting an approved molecule for the inhalation route. RTIs are undoubtedly an appropriate clinical situation for inhalation, if we consider the importance of matching the delivery of immunoprophylatics or immunotherapeutics to their site of action. Anti-infectious macromolecules may certainly benefit from the success of inhaled antibiotics, but it is critical to remember their precise molecular nature associated with a unique pharmacokinetics profile when considering their development for inhalation. Besides, the recent report of a universal flu vaccine, comprised of Ab-based therapeutics (VHH) produced by an adeno-associated virus delivered intranasally pushed further the boundaries of the potential of the inhalation route for immunoprophylactics (32). TS, AM, and NH-V participated in the review of research. NH-V prepared figure. TS and AM prepared table. All authors contributed to the manuscript. This work was supported by the French National Research Agency as part of the Investissements d'Avenir program (LabEx MAbImprove, ANR-10-LABX-53-01), by the Region Centre Val-de-Loire (ARD2020 Biomedicament, PRIMine project/APR IR 2019, Novantinh project), by French Cystic Fibrosis Foundation VLM (Grant No. RF20170502036). 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The role of serine proteases and antiproteases in the cystic fibrosis lung. Mediators Inflamm. (2015) 2015:293053. doi: 10.1155/2015/293053 PubMed Abstract | CrossRef Full Text | Google Scholar 32. Laursen NS, Friesen RHE, Zhu X, Jongeneelen M, Blokland S, Vermond J, et al. Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin. Science. (2018) 362:598–602. doi: 10.1126/science.aaq0620 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: respiratory infection, biopharmaceutics, immune-pharmaceutics, topical delivery, inhalation Citation: Sécher T, Mayor A and Heuzé-Vourc'h N (2019) Inhalation of Immuno-Therapeutics/-Prophylactics to Fight Respiratory Tract Infections: An Appropriate Drug at the Right Place! Front. Immunol. 10:2760. doi: 10.3389/fimmu.2019.02760 Received: 12 September 2019; Accepted: 12 November 2019; Published: 29 November 2019. Edited by: Reviewed by: Copyright © 2019 Sécher, Mayor and Heuzé-Vourc'h. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Nathalie Heuzé-Vourc'h, [email protected] These authors have contributed equally to this work
Jeffrey C. Neely, Mitzi Lewis
The Routledge Companion to American Literary Journalism pp 449-464; https://doi.org/10.4324/9781315526010-31

Abstract:
This chapter presents research findings on teaching literary journalism in higher education, based on five years of survey results and twenty-six interviews with college and university literary journalism instructors. The study employs the Liberal Education and America’s Promise (LEAP) essential learning outcomes developed by the Association of American Colleges and Universities (AAC&U) to suggest that literary journalism is uniquely positioned to help schools across the United States respond to their charge of providing students with a liberal education. Additionally, the authors propose that literary journalism has potential to aid academic departments in communications and humanities as they seek to address national trends in enrollment declines. Literary journalism integrates skills-based learning across a range of topical inquiry within the broader context of personal and social responsibility. It brings together factual information, interpretative understanding, and creative application. Furthermore, its narrative form provides an accessible channel for students to encounter good writing and robust consideration of real-world challenges. Thus, the authors suggest, educators seeking to achieve the goals of a liberal education might benefit from incorporating literary journalism into their curriculum.
Frontiers in Cellular and Infection Microbiology, Volume 9; https://doi.org/10.3389/fcimb.2019.00388

Abstract:
Editorial on the Research TopicBiomarkers in Leishmaniasis Leishmaniasis is one of the most deadly, yet neglected, of all tropical diseases (Alvar et al., 2012). The eco-epidemiological characteristics of leishmaniasis render it a complex problem. There are over 20 species of leishmaniasis pathogens transmitted by different species of sand fly (Phlebotomus spp.). Transmission may be anthroponotic or zoonotic, the latter entailing different animal reservoirs. Depending on the species of Leishmania and the immune response to it, the disease may present as cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), visceral leishmaniasis (VL), or post-kala azar dermal leishmaniasis (PKDL) (Burza et al., 2018). The complexity of leishmaniasis means different strategies are needed if it is to be controlled and eliminated (Matlashewski et al., 2014; Rijal et al., 2019). For example: - Diagnostic methods need to be faster and simpler, but sensitive and robust, and allow early diagnoses to be made. Follow-up methods are also needed that confirm patient responses and help predict the risk of relapse. - Efficient therapies for the different forms of the disease need to be developed, both for the immunocompetent and the immunodepressed. - Methods of controlling animal reservoirs—especially domestic animal reservoirs—need to be developed; alongside better vectorial control these should reduce the transmission of the parasite. - The capacity of asymptomatic carriers to pass on the disease needs to be examined—an important challenge for control programs. - A vaccine against the different forms of leishmaniasis needs to be developed; this might be the best means of control and protection, but work is needed on how to immunize most effectively for the lowest cost. Biomarkers have a central role to play in the above challenges by providing information on patient immune status, the response to treatment, exposure to vectors, the role of animal reservoirs, and the epidemiology of infection, etc. New biomarkers need to be found that will allow the development of tools for assessing the effectiveness of treatments, that can confirm when a cure has been achieved, to identify asymptomatic persons and rates of transmission in endemic areas, to develop rapid, non-invasive tests, and for checking the immune response to experimental vaccines (Ibarra-Meneses et al., submitted). This Research Topic, entitled “Biomarkers in Leishmaniasis”, is a collection of 19 articles, some of which examine the latest advances in biomarkers of the different types of leishmaniasis, while others report original research into biomarker identification and characterization. Several articles in the cited collection examine the identification of new biomarkers useful for understanding the pathogenesis of leishmaniasis, and for improving its diagnosis. The clinical complexity and epidemiology of leishmaniasis is a challenge in the identification of biomarkers able to track the progress of the disease. This is made clear by different review articles that focus on its different clinical forms. The work of Brodskyn and Kamhawi on biomarkers of zoonotic VL in Latin America, focuses on humans and dogs, and addresses the need to examine a combination of inflammatory mediators for the development of a tool that distinguishes between the different stages of the disease. They also discuss the use of serum antibodies against the highly immunogenic salivary proteins of Lutzomyia as biomarkers of exposure to the vector in humans and dogs. In their review, Bahrami et al. highlight the scarcity of specific markers for CL. Apart from abnormalities in the delayed hypersensitivity test, in T cell subpopulations, cytokine levels and enzyme (e.g., adenosine deamidase and L-argininase) concentrations, these authors suggest the need to develop analyses based on comparing the transcriptome of the lesion with that of healthy skin (Christensen et al., 2016; Masoudzadeh et al., 2017). The identification of biomarkers able to predict the result of infection by different species of Leishmania is also a major challenge in CL (Patino and Ramírez, 2017). For example, the physiopathology of PKDL (which follows VL in some treated patients) is different to that of both VL and CL (Kip et al., 2015), and patients show responses to treatment that are difficult to assess (the lesions can take a long time to heal, thus responses may take time to appear). In their review, Zijlstra indicate that current biomarkers for PKDL lesions are unsatisfactory. Certainly, clinical assessment is subjective and not very precise, and while the parasite load can be determined by qPCR, serological tests such as DAT, rK39 ELISA, and rK39 RDT lack specificity since antibodies may hang over from previous bouts of VL. Moreover, the systemic and skin immune responses are different. Zijlstra also questions whether biomarkers in the blood (such as cytokines or cell populations) properly reflect skin-level changes, and declares that new avenues need to be explored. These might include 3D optical scanning and the undertaking of longitudinal studies that can provide a description of PKDL before, during and after cure. Dogs play a major role in the transmission of the parasite to humans (Moreno and Alvar, 2002). The present collection therefore also includes an article by Maia and Campino which is exclusively devoted to canine leishmaniasis. This review discusses the latest advances in the identification of biomarkers associated with infection by L. infantum in dogs. The early detection and treatment of infected animals is a basic requirement in the control of human VL (Alvar et al., 2004). Canine leishmaniasis has a wide spectrum of manifestations, the result of complex host-parasite interactions (Reis et al., 2010), and these authors conclude that no single biomarker is able to confirm a diagnosis, reflect the effectiveness of treatment, or indicate the infectivity of affected dogs. In their contribution, Ontoria et al. report the expression of different genes in the spleens of infected and control Balb/c mice, the final aim of their research being to better understand the immunological mechanisms that lead to protection or disease progression, and the identification of associated biomarkers. d'El-Rei Hermida et al. review the histological changes that occur in the spleen in severe VL, and record the events that eventually lead to its destruction. Garde et al. discuss markers of disease progression, reporting on the antigenicity of Leishmania antigens and the role of the eukaryotic initiation factors F2, F2B, LieIF2, and LieIF2B. These proteins, to which specific antibodies were detected in the serum of patients with VL, and in dogs with canine leishmaniasis, induce a humoral response in a murine model, along with the production of IL-10. IL-10 favors the progression of the disease and therefore could act as an indicator of the same. Piel et al. propose experimentally infecting mice with cosmid-transfected parasites as a means of searching for new genetic markers. This might allow the identification of genetic loci associated, for example, with resistance to medications, or that might act as new treatment targets. Any factors thus identified, however, would have to be validated in specific field studies. Some of the articles included in this Research Topic focus on the identification of new biomarkers associated with the response to treatment, and that provide confirmation of cure. A biomarker that indicates a cure to have been achieved could be used to reduce treatment times and prevent relapses, help adjust doses, and be of use in research into new treatments or combinations of current medications (Alves et al., 2018). Marlais et al. report results obtained in a clinical trial involving patients with VL in which they measured Leishmania-specific IgG1 in the serum before and after treatment. Using the VL Sero K-SeT rapid diagnostic test and ELISA, they show that high post-treatment concentrations of these antibodies are associated with relapse, while low (or no) concentrations are associated with cure. They also report the above rapid diagnostic test may be of help in the diagnosis of PKDL. In the search for biomarkers that indicate the cure of CL, Montoya et al. report the use of a hamster model to analyse skin lesions for the production of the growth factors EGF, TGFbeta1, PDGF, and FGF. They indicate an increase in TGFbeta1 to be associated with active disease, while high EGF levels are associated with the cure of the lesion. They conclude that the EGF/TFGbta1 ratio might provide an excellent biomarker of the establishment of an infection or an adequate response to treatment. Kip et al. investigate the role of neopterin, a marker of macrophage activation, and its association with the response to treatment for VL. These authors examine the plasma neopterin concentration before and after treatment and discuss its potential for identifying patients at risk of suffering an early relapse. Botana et al. compare serological, parasitological and cellular response biomarkers in patients with different forms of leishmaniasis caused by L. infantum. Their work, which was performed with patients with active disease plus others who had been cured, shows significant differences in the results of pre- and post-treatment parasitological tests (they became negative), and in cellular immunity tests (they became positive). However, no changes to the outcome of serological tests were seen. These authors conclude peripheral blood mononuclear cell (PBMC) proliferation following stimulation with Leishmania antigens, and the secretion of IFN-gamma, to be good markers of cure of VL. However, for CL, MCL, and localized leishmanial lymphadenopathy (LLL), these same tests detected no difference between the active and cured phases. Many of the articles in this Research Topic insist on the importance of identifying biomarkers of asymptomatic infection. This is necessary if we are to know the true prevalence of Leishmania infection in any determined area, and for designing strategies to control the disease (Alvar et al., submitted). The search for such biomarkers is limited, however, by the deficient definition of an asymptomatic patient as “someone in an endemic area who has an immune response (antibody- or cell-based) against Leishmania but who remains healthy.” This partly explains why, to date, there is no reference method for detecting asymptomatic infection. This collection of articles contains two original research papers that focus on asymptomatic infection. Best et al. report that in asymptomatic persons who had traveled to areas where American tegumentary leishmaniasis (ATL) is endemic, the expression of IFN-gamma following the stimulation of their PBMC with Leishmania antigens is directly related to the length of time spent in the area. This can provide information on how long the asymptomatic condition can last. In very different work, Coutinho-Abreu and Valenzuela provide a comparative phylogenetic analysis of the proteins in sand fly saliva, and report differences in the amino acid sequence of those of New World and Old World flies, and indeed proteins unique to them, that might serve as biomarkers of infection by a determined species. The search for biomarkers that correlate with the degree of protection achieved are vital in the development of Leishmania vaccines (Moreno, 2019). Several contributions to this Research Topic focus on the immune response to the parasite, and on parasite antigens that might be candidates for use in vaccine production. Egui et al. examine the functional and phenotypic profiles of Leishmania-specific CD4+ and CD8+ cells from patients cured of CL caused by L. panamensis, as well as those of healthy, asymptomatic patients, and report that protection against the disease is associated with an increased cytotoxic T cell response—something that could be very useful when monitoring patients. Boussoffara et al. come to a similar conclusion in their article on CL caused by L. major, and report that high levels of granzyme B are associated with better protection against the development of CL. It could therefore be a useful biomarker for assessing the effectiveness of vaccines. As mentioned by Ontoria et al., combining transcriptomic, proteomic, and metabolomic analyses may be of great interest when studying the factors involved in the cellular response, and for identifying biomarkers of infection. The review by Tavares-Veras et al. goes deeper into this question and discusses large scale studies that have identified and assessed biomarkers in infected macrophages. The parasite alters the protein profile of these cells, rendering them suitable for proteomic studies aimed at identifying new molecular biomarkers that might reveal the destiny of the host cell and pathogen (Jean Beltran et al., 2017). Since many of the biomarkers identified are related to the host immune response, others need to be sought for use in situations in which no immune response occurs. Immunodepression increases the risk of developing leishmaniasis, alters the clinical spectrum of the disease, and increases the risk of therapeutic failure and relapse (van Griensven et al., 2014). Biomarkers for monitoring patients coinfected with Leishmania, and HIV, and who suffer from some other form of immunodepression, are therefore needed (Akuffo et al., 2018). The present collection contains two articles on the search for biomarkers for the former. In their work, aimed at identifying early markers of susceptibility or resistance to VL in patients with HIV, Adriansen et al. examine the serum levels of macrophage activators (sCD40L and neopterin) in such patients, and confirm that they are reduced in those with active VL, and increased in those with asymptomatic Leishmania infection. These markers could be useful when trying to predict the progress of disease in such patients. In contrast, van Griesvan et al. focus on the identification of biomarkers of therapeutic failure for VL and disease relapse in coinfected persons. This research paper shows that coinfected patients with high levels of Leishmania antigens in their urine at the moment of diagnosis of VL are at greater risk of therapeutic failure. In addition, those with high levels at the end of treatment are more likely suffer a relapse within 12 months. These results highlight the importance of antigenuria in monitoring the response to treatment and the risk of relapse in immunodepressed patients. The present collection of articles underscores the main problems faced in identifying biomarkers of leishmaniasis, and show that much work is needed to validate those already found. It is important that the knowledge we have be used in innovative ways resulting in novel clinical applications and rapid, sensitive and simple diagnostic tests. EC and JM have participated equally in the writing of this editorial. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors wish to thank all the authors who have sent their manuscripts to this Research Topic. We also want to thank all the reviewers who have participated in the revision of the manuscripts and have helped to improve the final result. Akuffo, H., Costa, C., van Griensven, J., Burza, S., Moreno, J., and Herrero, M. (2018). New insights into leishmaniasis in the immunosuppressed. PLoS Negl. Trop. Dis. 12:e0006375. doi: 10.1371/journal.pntd.0006375 PubMed Abstract | CrossRef Full Text | Google Scholar Alvar, J., Cañavate, C., Molina, R., Moreno, J., and Nieto, J. (2004). Canine leishmaniasis. Adv. Parasitol. 57, 1–88. doi: 10.1016/S0065-308X(04)57001-X PubMed Abstract | CrossRef Full Text | Google Scholar Alvar, J., Vélez, I. D., Bern, C., Herrero, M., Desjeux, P., Cano, J., et al. (2012). Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7:e35671. doi: 10.1371/journal.pone.0035671 PubMed Abstract | CrossRef Full Text | Google Scholar Alves, F., Bilbe, G., Blesson, S., Goyal, V., Monnerat, S., Mowbray, C., et al. (2018). Recent development of visceral leishmaniasis treatments: successes, pitfalls, and perspectives. Clin. Microbiol. Rev. 31:e00048–18. doi: 10.1128/CMR.00048-18 PubMed Abstract | CrossRef Full Text | Google Scholar Burza, S., Croft, S. L., and Boelaert, M. (2018). Leishmaniasis. Lancet392, 951–970. doi: 10.1016/S0140-6736(18)31204-2 PubMed Abstract | CrossRef Full Text | Google Scholar Christensen, S. M., Dillon, L. A., Carvalho, L. P., Passos, S., Novais, F. O., Hughitt, V. K., et al. (2016). Meta-transcriptome profiling of the human-leishmania braziliensis cutaneous lesion. PLoS Negl. Trop. Dis. 10:e0004992. doi: 10.1371/journal.pntd.0004992 PubMed Abstract | CrossRef Full Text | Google Scholar Jean Beltran, P. M., Federspiel, J. D., Sheng, X., and Cristea, I. M. (2017). Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases. Mol. Syst. Biol. 13:922. doi: 10.15252/msb.20167062 PubMed Abstract | CrossRef Full Text | Google Scholar Kip, A. E., Balasegaram, M., Beijnen, J. H., Schellens, J. H., de Vries, P. J., and Dorlo, T. P. (2015). Systematic review of biomarkers to monitor therapeutic response in leishmaniasis. Antimicrob. Agents Chemother. 59, 1–14. doi: 10.1128/AAC.04298-14 PubMed Abstract | CrossRef Full Text | Google Scholar Masoudzadeh, N., Mizbani, A., Taslimi, Y., Mashayekhi, V., Mortazavi, H., Sadeghipour, P., et al. (2017). Leishmania tropica infected human lesions: whole genome transcription profiling. Acta Trop. 176, 236–241. doi: 10.1016/j.actatropica.2017.08.016 PubMed Abstract | CrossRef Full Text | Google Scholar Matlashewski, G., Arana, B., Kroeger, A., Be-Nazir, A., Mondal, D., Nabi, S. G., et al. (2014). Research priorities for elimination of visceral leishmaniasis. Lancet Glob. Health 2, e683–e684. doi: 10.1016/S2214-109X(14)70318-3 PubMed Abstract | CrossRef Full Text | Google Scholar Moreno, J. (2019). Assessment of vaccine-induced immunity against canine visceral leishmaniasis. Front Vet Sci. 6:168. doi: 10.3389/fvets.2019.00168 PubMed Abstract | CrossRef Full Text | Google Scholar Moreno, J., and Alvar, J. (2002). Canine leishmaniasis: epidemiological risk and the experimental model. Trends Parasitol. 18, 399–405. doi: 10.1016/S1471-4922(02)02347-4 PubMed Abstract | CrossRef Full Text | Google Scholar Patino, L. H., and Ramírez, J. D. (2017). RNA-seq in kinetoplastids: a powerful tool for the understanding of the biology and host-pathogen interactions. Infect Genet. Evol. 49:273–82. doi: 10.1016/j.meegid.2017.02.003 PubMed Abstract | CrossRef Full Text | Google Scholar Reis, A. B., Giunchetti, R. C., Carrillo, E., Martins-Filho, O. A., and Moreno, J. (2010). Immunity to Leishmania and the rational search for vaccines against canine leishmaniasis. Trends Parasitol. 26:341–349. doi: 10.1016/j.pt.2010.04.005 PubMed Abstract | CrossRef Full Text | Google Scholar Rijal, S., Sundar, S., Mondal, D., Das, P., Alvar, J., and Boelaert, M. (2019). Eliminating visceral leishmaniasis in South Asia: the road ahead. BMJ 364:k5224. doi: 10.1136/bmj.k5224 PubMed Abstract | CrossRef Full Text | Google Scholar van Griensven, J., Carrillo, E., López-Vélez, R., Lynen, L., and Moreno, J. (2014). Leishmaniasis in immunosuppressed individuals. Clin. Microbiol. Infect. 20:286–99. doi: 10.1111/1469-0691.12556 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: biomarkers, leishmaniasis, diagnostic, vaccine, cure Citation: Carrillo E and Moreno J (2019) Editorial: Biomarkers in Leishmaniasis. Front. Cell. Infect. Microbiol. 9:388. doi: 10.3389/fcimb.2019.00388 Received: 09 October 2019; Accepted: 29 October 2019; Published: 12 November 2019. Edited and reviewed by: Jeroen P. J. Saeij, University of California, Davis, United States Copyright © 2019 Carrillo and Moreno. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Javier Moreno, [email protected]; Eugenia Carrillo, [email protected]
Neil Cowie, Keiko Sakui
Pacific Journal of Technology Enhanced Learning, Volume 2, pp 25-26; https://doi.org/10.24135/pjtel.v2i1.26

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Open non-formal online courses (Rha, 2018) are becoming increasingly popular as a self-paced option for learners. These courses are often hosted by commercial platforms where teachers and course creators develop and market courses to students across the globe. The numbers of students enrolled on these kinds of courses is hard to estimate but figures from providers do indicate the numbers are significant. For example, the Udemy course provider (https://www.udemy.com) states that as of October 2019 it has over 30 million students learning on 50,000 courses. However, the attrition rates for such courses, similar to other online options such as MOOCs, can be high (Sánchez-Elvira Paniagua & Simpson, 2018). In this presentation two teacher-researchers reflect on and analyse their experience of creating open non-formal online courses for English language learners, and go on to suggest several practical techniques to decrease the number of students that may drop out. The theoretical framework for this paper is that of exploratory practice (Allwright, 2003). This is an approach to teacher development in which teachers collect information on their courses and then try to use that data to reflect on their practice and improve conditions for learning. The two sources of data are the meta analytics supplied by Udemy for every course and surveys from university students who were asked to evaluate different types of video. These two sources of data were analysed using a two-step coding approach (Miles, Huberman & Saldana, 2014) in which codes are assigned and then grouped together based on emergent themes. In the presentation, firstly, the wider reasons why online students drop out, such as insufficient support (Simpson, 2017) or the impact of cognitive overload (Sweller, Ayres & Kalyuga, 2011), are discussed and several ways are suggested to get around these issues. Secondly, various principles of instructional design such as keeping lessons consistent but variable, relevant, and divided into manageable chunks are recommended (Lehman & Conceição, 2014). Finally, a number of ways that videos can be made more engaging are shown (Mayer, 2017), especially focusing on how a talking head can be best portrayed in order to give the clearest information and develop a more personalised teacher presence (Garrison, 2011). Although the data and analysis are focused on open non-formal online courses the findings and discussion are of relevance to other forms of online instruction and multimedia learning. References Allwright, D. (2003). Exploratory practice: Rethinking practitioner research in language teaching. Language Teaching Research, 7(2),113-141. https//doi.org/10.1191/1362168803lr118oa Garrison, D. R. (2011). E-learning in the 21st century: A framework for research and practice. (2nd ed.). New York, NY: Routledge. http://dx.doi.org/10.4324/9780203166093 Lehman, R., & Conceição, C. (2014). Motivating and retaining online students. San Francisco, CA: Jossey- Bass. Mayer, R. E. (2017). Using multimedia for e-learning. Journal of Computer Assisted Learning, 33, 403- https//doi.org/10.1111/jcal/12197 Miles, M.B., Huberman, A.M., & Saldana, J. (2014). Qualitative Data Analysis: A Methods Sourcebook. London: Sage. Rha, H.M. (2018). A study on the classification of online education types and development of quality management indicators for lifelong vocational skills development. In T. Bastiaens et al. (Eds.). Proceedings of EdMedia: World Conference on Educational Media and Technology (pp. 759- 763). Amsterdam, Netherlands: Association for the Advancement of Computing in Education (AACE). Retrieved from https://www.learntechlib.org/p/184274. Sánchez-Elvira Paniagua, A., & Simpson, O. (2018). Developing student support for open and distance learning: The EMPOWER project. Journal of Interactive Media in Education, 1(9), 1–10, https://doi.org/10.5334/jime.470 Simpson, O. (2017). Innovations in distance education student support: What are the chances? In: G. Ubachs, L., Konings, & M. Brown (Eds.). The Envisioning Report for Empowering Universities (pp. 52-55). Available from: https://empower. eadtu.eu/images/report/The_Envisioning_Report_ for_ Empowering_ Universities _ 1st_ edition_2017.pdf Sweller, J., Ayres, P., & Kalyuga, S. (2011). Cognitive load theory. New York, NY: Springer.
, Laurence Rahme, You-Hee Cho
Frontiers in Cellular and Infection Microbiology, Volume 9; https://doi.org/10.3389/fcimb.2019.00343

Abstract:
Editorial on the Research TopicBeyond Antimicrobials: Non-traditional Approaches to Combating Multidrug-Resistant Bacteria Since the time of Galen and Hippocrates, medicine has had a slow progression, with each new advance improving the length and quality of patients' lives. By the nineteenth century, medical science had even begun to understand the concept of vaccinations and had started to make substantial inroads into the prevention of communicable diseases. Despite this, diagnosis with a bacterial infection frequently remained tantamount to a death sentence. With treatment essentially limited to supportive care, patients were left to either recover or die. But in the twentieth century, the discovery of antimicrobials changed this. It is not an overstatement to say that medical science changed forever, because this allowed the development of countless medical advances that fall under the classification of internal medicine. Ranging from simple surgeries like the removal of an inflamed appendix to the complete replacement of whole organs and organ systems, not to mention the placement of various medical devices that have improved the lives of countless patients. Despite this, infectious diseases, including those caused by bacteria, remain the leading cause of premature death worldwide. Problematically, this trend looks as though it will worsen, as both the number and the proportion of clinically relevant bacterial strains and species exhibiting antimicrobial resistance is on the rise. For the ESKAPE pathogens (i.e., Enterococcus faecium, Staphylcoccus aureus, Klebsiella pneumonia, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter spp.), not only are single and multidrug resistance common, but pandrug resistance has begun to be clinically observed (Mulani et al., 2019). Overall, for the first time in nearly a century, the spread of antimicrobial resistance has begun to lead to regressions in treatment options and the re-emergence of formerly treatable infections as real threats to community health. While the public remains largely complacent to the threat, experts in healthcare warn of the “galloping hoofbeats of the horsemen of the apocalypse” and the very real possibility that voluntary medical procedures will become a historical phenomenon within the next century, even in the developed world (Projan, 2003). Further complicating matters, antimicrobial drug discovery has dramatically slowed over the last 20 years, with a paucity of new treatments on the market or in development pipelines. The most obvious problem is scientific. Using the same methods to screen the same libraries leads to the same treatments, which are now ineffective. Finding new methods and new libraries is one option, but it is laborious and requires a leap of faith that the new method will be effective. A more serious problem is economic (Ventola, 2015; Renwick and Mossialos, 2018). For large pharmaceutical companies, the return on investment for antimicrobials tends to be much lower than for lifestyle medicines, which are intended for disease maintenance rather than a cure. For antimicrobials, maintenance is often impractical or impossible. Moreover, identification, development, design, regulatory approval, and marketing are necessary steps for a large pharmaceutical corporation to get a new treatment into clinics for patients. These steps can take from 5 to 20 years. Meanwhile, antimicrobial resistance frequently arises in less than five, particularly when antimicrobial stewardship (i.e., limiting antimicrobial use to last-ditch cases, preventing agricultural or household cleaner use, etc.) is not stringently maintained (Rice, 2018). Worse yet, pricing for antibiotics tends to be lower than for other drugs that have such outsized impacts on morbidity and mortality (e.g., cancer drugs). Finally, the same stewardship programs limit antibacterial use to prolong clinical utility, also artificially curtailing the market size. Cumulatively, these effects result in a monetary loss for the company. A final obstacle is the incredible regulatory hurdles, particularly in the US, that stand in the way of companies and organizations willing to take on the burden (Metlay et al., 2006). For example, due to the transience of bacterial infections, it is often difficult to find enough patients for large-scale human trials. Another difficulty is the approval process (particularly the US FDA, the EMA has been generally more tractable) that places an undue burden of proof on pharmaceutical companies (e.g., patients only qualify as having been successfully treated if the causative bacterium is identified in complex infections like bacterial pneumonia, difficulty in demonstrating superiority of new treatments to existing therapy instead of non-inferiority to current treatments, etc.). Regulatory and legislative efforts have been initiated in the past 15 years to combat these trends, but rectification has occurred at a glacial pace (Humphries et al., 2018; Sfeir, 2018). Clearly, it behooves us to seek out alternative mechanisms of treatment to address this growing gap. Therefore, currently there is an increased interest in alternative approaches to the treatment of drug-resistant bacteria. A number of these strategies are presented in this Research Topic. To mitigate the resistance emergence, one increasingly viable option is the discovery and development of the therapeutic chemicals that target bacterial virulence, rather than bacterial growth. In most cases (with the notable exception of immune-related pathology activated by structural components), the mere presence of bacterial cells is insufficient to trigger disease. Instead, pathogenic microorganisms produce various virulence factors that are responsible for the damage inflicted on the host. There is mounting evidence that these pathogenic determinants are viable pharmaceutical targets; treatments that compromising one or more of these factors (i.e., anti-virulence or antipathogenic) can often largely, or even completely, mitigate disease. Anti-virulence drugs should reduce antibiotic use and, ultimately, decrease the development of antibiotic resistance, as they should not impose strong selective pressure on bacteria that favors the evolution of mechanisms of resistance and persistence. Additionally, because they do not affect bacterial cell viability, they should not disrupt beneficial microbiota. Anti-virulence compounds could serve as alternatives or adjuncts to traditional antibiotics and to potentiate their efficacy, generating even more effective treatment options in particular against multi-drug resistant pathogens and potentially viable options against pan-drug resistant bacteria. A number of articles utilizing this approach are reported in this Research Topic. One promising virulence-associated target is the quorum-sensing (QS) systems utilized by several clinically relevant pathogens (Rutherford and Bassler, 2012; Schuster et al., 2013; Castillo-Juarez et al., 2015). Singh et al. report on the inhibitory activity of 3-benzyl-hexahydro-pyrrolo[1,2-a]pyrazine-1,4-dione on QS in Pseudomonas aeruginosa. Interestingly, treatment also altered biofilm architecture, compromising bacterial adherence and biofilm development. Fong et al., report on itaconimide, another novel inhibitor of Pseudomonal QS and biofilm. Perhaps unsurprisingly, inhibition of biofilm formation is another common target for the development of anti-virulent compounds (Maura et al., 2016; Francois et al., 2017; Defoirdt, 2018; Salam and Quave, 2018). This approach can also be used against opportunistic fungi. For example, Lee et al. describe antibiofilm activity for 6-gingerol and 6-shogaol against Candida albicans. These two molecules prevented cell aggregation and inhibited the expression of several biofilm-related genes. Both QS signaling and biofilm contribute to chronic infections. They are associated with complex regulatory switches that control large numbers of genes whose activity alters the lifestyle of the pathogen to support long-term microbial presence within a host. This is in contrast to more stereotypically acute virulence determinants (e.g., the Type 3 Secretion System, proteases, lipases, toxins, etc.) that cause consequences for which microbial presence is less relevant. Dong et al. found that the flavonoid morin inhibits the hemolytic activity of aerolysin, protecting catfish from infection with Aeromonas hydrophila. Generally, drug discovery attempts have targeted chronic virulence factors. A notable exception to this is the Pseudomonal siderophore pyoverdine. Unlike many acute virulence determinants, pyoverdine plays a diverse and multifactorial role in pathogenesis, including iron acquisition (necessary for production of other virulence factors, including biofilm, and for bacterial growth) and is a transcriptional regulator of several other virulence factors and toxins (Ochsner et al., 1996; Wilderman et al., 2001; Lamont et al., 2002). In addition, it is directly cytotoxic (Kang et al., 2018). Previously, preventing pyoverdine biosynthesis has been shown to attenuate virulence in a variety of hosts, including invertebrates and mice (Meyer et al., 1996; Takase et al., 2000; Minandri et al., 2016). Here, Imperi et al. examined the limitations of this approach by selecting for P. aeruginosa mutants resistant to one class of these inhibitors, fluoropyrimidines (Imperi et al., 2013; Kirienko et al., 2016). To circumvent this form of resistance, Kirienko et al. identified small molecules that directly inhibit pyoverdine function, rather than its production. Interestingly, these molecules are also effective against multidrug-resistant isolates of P. aeruginosa collected from patients with cystic fibrosis (Kang et al., 2019). Frequently the strongest effects for anti-virulence molecule are in combination with other treatments. For example, Tharmalingam et al. demonstrated that 4-(1,3-dimethyl-2,3-dihydro-1H-S-benzimidazol-2-yl)phenol (BIP) inhibited several virulence factors of methicillin-resistant Staphylococcus aureus (MRSA). BIP treatment decreased MRSA virulence and sensitized bacteria to macrophage-dependent killing. Marini et al. showed that Cannabis sativa extracts reduced motility and biofilm formation in the food-borne pathogen Listeria monocytogenes. Martínez et al. reviewed a number of promising anti-virulence strategies, including disassembly of functional microdomains in bacterial membranes and toxin neutralization. Regulatory hurdles are another stumbling block in drug discovery. Researchers have begun to propose and implement innovative strategies to practically reduce time and costs for the drug development processes. Repositioning or repurposing already approved drugs is an approach that has recently gained momentum, with the hypothesis being that the compounds may have new modes of action for which the resistance has yet to develop. Similarly, combining two or more compounds with different or synergistic mechanisms is another alternative approach to improve the efficacy of the currently available antibiotic regimens and may increase the success rate of drug repositioning as well. In this collection, Miró-Canturri et al. reviewed the current state of knowledge regarding drug repurposing strategies for the treatment of bacterial and fungal infections. They focus on several successfully repurposed drugs, including former antihelminthic, anticancer, anti-inflammatory, immunomodulatory, and even psychopharmaceutical compounds. They have summarized their mechanisms and the status of on-going clinical trials for repurposed drugs like meloxicam, a widely available non-steroid anti-inflammatory drug. A different strategy, called drug redirecting, has been proposed by Jang et al. This strategy involves modifying a previously established chemical moiety to change its selectivity. Their example used an apoptotic inhibitor, YM155, that generates reactive-oxygen species upon entry into the target cells. By changing the substituents at the N3 position, they have optimized the antibacterial efficacy, possibly by selectively targeting the drug to Gram-positive bacterial cells, including MRSA. Drug combination can improve treatment efficacy and reduce drug dosages to minimize side effects, as exemplified in the combination of β-lactams (e.g., clavulanic acid and amoxicillin or ticarcillin; Salerno and Cazzaniga, 2010). In this Research Topic, Na et al. investigated the inhibitory activity of a cellular metabolite, NADPH on the class C β-lactamases such as AmpC BER. Based on their previous study (Na et al., 2017), they presented a molecular docking model indicating that this dinucleotide could bind AmpC BER. Combination of NADPH with ceftazidime successfully restored sensitivity to ceftazidime-resistant bacteria in an experimental murine infection. Strengths of this approach include that it may not require new chemical discovery and may be combined with repurposing or repositioning efforts as well. del Carmen Parquet et al. showed that an iron-chelating polymer (DIBI) suppressed a wound infection caused by MRSA. This makes intuitive sense, as iron is essential for microbial growth and survival. DIBI also increased the bactericidal activity of several antibiotics. DIBI also inhibits the growth of Candida albicans and increases its sensitivity to azole drugs in vitro and in vivo (Savage et al., 2018). Another transition metal discussed here is zinc. Interestingly, Crane et al. report a surprising role for zinc in preventing the SOS response, which is required for the hypermutation-mediated generation of antibiotic resistance and the horizontal transfer of resistance genes. Both zinc acetate and zinc pyrithione were effective, with the latter being more active. This suggests another approach to mitigate bacterial resistance may be to compromise the pathways that generate it. Recent advances in biotechnology have begun to allow the design, development, and production of new biologics with several advantages over chemical therapies. These include greater safety, potency, and specificity, potentially leading to fewer side effects. One “bioantibacterial” approach increasingly drawing favor is to revive the exploration of bacteriophages (phages) (Kim et al., 2019). The ability of phages to amplify at the site of infection and to cause the death and lysis of their bacterial targets makes it so that they can specifically eliminate an infectious bacterial strain or species without affecting the host microbiota (Abedon and Thomas-Abedon, 2010). In addition, as hosts develop resistance, phages may be able to evolve in concert to maintain their efficacy. Phages show substantial promise in a number of ways (Gorski et al., 2019; Hansen et al., 2019). One strategy practically at hand is to harness the endolysins produced by phages to degrade bacterial cell walls. For example, Wu et al. showed that the novel phage PD-6A3, and its purified endolysin Ply6A3, mitigated murine sepsis in approximately one-third of cases where clinical multi-drug resistant strains of Acinetobacter baumannii were tested. Seijsing et al. showed that extending serum retention time, such as by fusing an albumin-binding domain to the LysK endolysin from S. aureus phage improved efficiency. In addition to the phage-based therapies mentioned above, efforts to harness naïve or engineered antimicrobial peptides (AMPs) for clinical use have been accelerating. AMPs are generally short, positively-charged peptides that contribute to the innate immune systems of a wide variety of life forms. AMPs are conventionally thought to kill microbial pathogens directly by targeting membrane functions. Unfortunately, they are also toxic toward host cells, limiting their clinical use. Research teams are currently evaluating AMPs in clinical trials as novel anti-infectives and as immunomodulators and promoters of wound healing. Here, Zharkova et al. reported that mammalian AMPs can synergize with a variety of conventional antibiotics, including fluoroquinolines, polyketides, aminogylcosides, and β-lactams. This limits the amount of AMP needed for effective treatment, and may reduce off-target effects. Díaz-Roa et al. report identification and characterization of an AMP isolated from a necrophagous larvae, Sarconesiopsis magellanica. Sarconesin, as they dubbed it, showed no sign of cytotoxicity to mammalian cells and appears to increase permeability of the target membranes and bind to DNA. Moussouni et al. present a proof-of-concept study that leverages a rationally-designed synthetic version of MgtR that targets MgtC, a virulence factor required for intracellular survival of Salmonella and Mycobacterium species (Belon et al., 2015). They showed that synthetic MgtR (based on the Salmonella version of the protein) compromises the function of MgtC in P. aeruginosa, suppressing intracellular survival and biofilm formation. Bacteriocins are another natural product produced by bacteria to limit competition in their natural environment. These peptides are often used in a form of chemical warfare against closely related species, giving them substantial potential for development as a therapy. Ghequire et al. reviewed the therapeutic potential of one class of these proteins, lectin-like bacteriocins, or Llps, which are produced by Gram-negative proteobacteria. Unlike most bacteriocins, Llps appear to catalyze killing from the cell surface instead of requiring internalization. This trait will be useful if they are leveraged as a treatment for Pseudomonads, which have active export pumps that may limit the efficacy of an imported toxin. Corre et al. used a similar approach to identify effective natural products for limiting the growth of Legionella pnuemophila. By testing over 250 culturable bacterial isolates, they found a surprising variety of organisms that effectively limited L. pneumophila growth. Although this approach, which harnesses the natural competition in the bacterial microenvironment, is not unknown, it is very effective when looking for new treatments that are more specific than have been sought in the past. Finally, Równicki et al., describe the design and study of a peptide nucleic acid (PNA)-based treatment that exploits the MazEF-HipBA toxin-antitoxin systems in E. coli. They show that antisense PNAs could effectively repress translation of the anti-toxin, causing bacterial death. They also showed that antisense PNAs could be used to stimulate the expression of the toxin-antitoxin system in the first place, improving the utility of the treatment. Promisingly, antisense PNAs did not seem to activate strong cytotoxicity in mammalian cells, although the effect of PNA-mRNA hybrids on the activation of the interferon response, the difficulties in delivery of PNAs into cells, and the ease of antimicrobial resistance emergence against a nucleotide-hybridization-based treatment remain concerns. Although the threat of antimicrobial resistance is substantial, myriad approaches to circumvent it are currently being researched. These include classical approaches, such as searching for natural products in the environment of the pathogen and more synthetic attempts, like the discovery of new compounds with previously unknown mechanisms, rationally-mutated bacterial toxins, or even small molecules designed ab initio based on virtual docking screens. 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(2001). Characterization of an endoprotease (PrpL) encoded by a PvdS-regulated gene in Pseudomonas aeruginosa. Infect. Immun. 69, 5385–5394. doi: 10.1128/IAI.69.9.5385-5394.2001 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: antivirulence, phage (bacteriophage), antimicrobial peptide (AMP), quorum sensing (QS), antimicrobial resistance (AMR), novel therapeutic agents, drug repurposing and repositioning Citation: Kirienko NV, Rahme L and Cho Y-H (2019) Editorial: Beyond Antimicrobials: Non-traditional Approaches to Combating Multidrug-Resistant Bacteria. Front. Cell. Infect. Microbiol. 9:343. doi: 10.3389/fcimb.2019.00343 Received: 06 September 2019; Accepted: 24 September 2019; Published: 11 October 2019. Edited and reviewed by: Nahed Ismail, University of Illinois at Chicago, United States Copyright © 2019 Kirienko, Rahme and Cho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Natalia V. Kirienko, [email protected]; You-Hee Cho, [email protected]
Frontiers in Cellular and Infection Microbiology, Volume 9; https://doi.org/10.3389/fcimb.2019.00331

Abstract:
Editorial on the Research TopicCellular and Molecular Mechanisms of Mycobacterium tuberculosis VirulenceMycobacterium tuberculosis (Mtb) is the bacterial pathogen that causes the majority of human tuberculosis (TB), the leading infectious disease in the world (Glaziou et al., 2018). Mtb invades the human host by aerosol and establishes infection in the lung by using virulence factors to combat host immunity. Over the past several decades, significant progress has been made in our understanding of Mtb pathogenesis. However, the mechanisms of Mtb virulence remain largely unknown. Moreover, the emergence of multidrug-resistant Mtb strains and co-infection of Mtb with HIV have posed new challenges in TB control. There is an urgent need to enhance our understanding of Mtb pathogenesis and to develop effective countermeasures against TB. This Frontiers Research Topic reports recent new findings that cover diverse aspects of cellular and molecular mechanisms of Mtb virulence. ESAT-6 (6-kDa early secreted antigenic target), a well-documented Mtb virulence factor, is essential for Mtb pathogenesis, including phagosomal rupture, mycobacterial cytosolic translocation and cell-to-cell spreading (Hsu et al., 2003; Stanley et al., 2003; Abdallah et al., 2007; van der Wel et al., 2007; Houben et al., 2012; Manzanillo et al., 2012; Simeone et al., 2012, 2015; Zhang et al., 2016). ESAT-6 appears to function as an important modulator of host inflammatory responses by manipulating several intracellular signaling pathways in macrophages, T cells, and epithelial cells (Tsao et al., 1999; Giacomini et al., 2001; Junqueira-Kipnis et al., 2006; Pathak et al., 2007; Koo et al., 2008; Kurenuma et al., 2009; Mishra et al., 2010; Samten et al., 2011; Wong and Jacobs, 2011; Wu et al., 2019). Here, Refai et al. report a new role of ESAT-6 in macrophage differentiation and polarization. They found that during early infection, ESAT-6 induced differentiation of M0 and M2 macrophages toward the pro-inflammatory M1 phenotype to promote granuloma formation. Subsequently, ESAT-6 drove the phenotype switch from M1 to anti-inflammatory M2 macrophages to maintain the infection during the later persistent phases. A number of regions of difference (RD) among mycobacterial species have been identified by comparative genomic studies (Mahairas et al., 1996; Behr et al., 1999; Gordon et al., 1999; Brodin et al., 2002; Lewis et al., 2003). RD1, which is present in the Mtb complex and in a related species Mycobacterium marinum, but absent from the Mycobacterium bovis Bacille Calmette–Guérin (BCG) genome, encodes an ESX-1 type VII secretion system that has been extensively investigated as a major virulence factor (Simeone et al., 2009; Tiwari et al., 2019). However, other regions of difference between mycobacterial pathogens and attenuated BCG strain have been characterized to a lesser extent. Ru et al. investigated the potential role of RD4 in virulence. RD4 is larger in M. marinum than in Mtb, but absent in M. bovis, including BCG, suggesting a gradual decay of RD4 in mycobacterial genomes in the order of M. marinum, Mtb, and M. bovis. The knock-in strains of BCG and M. marinum containing the entire or partial RD4 regions exhibited alterations of wild-type virulence in both mouse and zebrafish models of infection. Thus, RD4 appears to be a new locus contributing to the mycobacterial virulence. Bacterial citrate lyase, which is important for both metabolism and virulence, is composed of three subunits, CitD (γ), CitF (α), and CitE (β) (Griffiths et al., 2012; Torres et al., 2012). The Mtb genome encodes 2 paralogous CitE subunits (CitE1 and CitE2), but their role in Mtb virulence has not been explored. Arora et al. biochemically and functionally characterized the CitE enzymatic subunits. The purified CitE1 and CitE2 proteins degraded acetyl-CoA and propionyl-CoA in vitro and the genes encoding both enzymes were up-regulated when Mtb was exposed to oxidative stress. Moreover, deletion of the citE genes from the Mtb genome reduced the resistance to oxidative stress, intracellular replication in macrophages, and growth in a guinea pig infection model. This study suggests that CitE may be a potential target for TB drug development. Rajwani et al. analyzed the phylogenetic relatedness of a hypervirulent Mtb strain (H112) with a global collection of Mtb genomes and identified a novel phylogenetic clade that share single-nucleotide polymorphisms (SNPs) in key virulence-associated loci, including the mce1 locus and the phoP gene. This clade includes four hypervirulent strains isolated from geographically diverse regions. The common SNPs and structural variations within the clade may be considered as potential genetic determinants of hypervirulence for future studies. While Mtb is the most common cause of human TB, M. bovis can cause TB in both humans and cattle, making it a zoonotic threat to both food safety and public health (Cosivi et al., 1998; Renwick et al., 2007; Michel et al., 2010). Moreover, the knowledge obtained in the studies of M. bovis infection is valuable for understanding of Mtb infection due to their close relationship. In the comparative proteomic study done by Li et al., they identified proteins that were differentially regulated in human macrophages following infection with M. bovis, including proteins in several pathways that are similar to Mtb infections, such as the phagosome maturation pathway and the TNF signaling pathway. In addition, in a number of proteins and enzymes that are mainly involved in metabolic pathways, endocytosis and endosome trafficking events were found to be uniquely affected by M. bovis infection. Drug resistance is mainly caused by mutations in the Mtb genome, particularly by single-nucleotide polymorphisms in genes whose protein products are directly targeted by anti-TB drugs (Coculescu, 2009; Stucki and Gagneux, 2013). Hameed et al. provided a comprehensive review on the major molecular targets that are related to drug resistance mechanisms of Mtb. The mutations in the thyA (encoding thymidylate synthase A) and folC (encoding FolC-dihydrofolate synthase) genes have been associated with resistance to para-aminosalicylic acid (PAS; Rengarajan et al., 2004; Zhao et al., 2014; Meumann et al., 2015), a second-line anti-TB drug. Methionine is structurally related to anti-folate drugs and is shown to antagonize PAS. However, the mechanism for methionine-based antagonism remains undefined. Using both targeted and untargeted approaches, Howe et al. found that MetM, a putative amino acid transporter, plays a crucial role in the synthesis of folate precursors, which antagonizes PAS activity. Drug induced reversion of antibiotic resistance has drawn recent attention as a prospective approach to combat drug resistance (Baym et al., 2016). FS-1, a new anti-TB drug, induces antibiotic resistance reversion in Mtb. In the report done by Ilin et al., FS-1 was used in combination with standard anti-TB antibiotics on guinea pigs infected with an XDR-Mtb strain. The genetic changes in Mtb genomes following infection were analyzed and FS-1 was found to cause a counter-selection of drug-resistant variants that sped up the recovery of the infected animals from XDR-TB. While the drug resistance mutations remained intact in more sensitive isolates, reversion of drug resistance was associated with a general increase in genetic heterogeneity of the Mtb population. The articles in this Research Topic present new findings regarding the cellular and molecular mechanisms of Mtb virulence, including characterization of new roles for known virulence factors, identification of new virulence factors, and the elucidation of drug-resistance mechanisms and reversion. This Research Topic, together with many recent publications, enhances our understanding of the mechanism of Mtb virulence and pathogenesis. JS, PC, and FB have made a substantial, direct and intellectual contribution to the work, and approved it for publication. JS was supported by a grant from the National Institute of General Medical Sciences (SC1GM095475). PC was supported by grants from the National Institute of Allergy and Infectious Diseases (AI106872 and AI142127). 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Agents Chemother. 58, 1479–87. doi: 10.1128/AAC.01775-13 CrossRef Full Text | Google Scholar Keywords: Mycobacterium tuberculosis, drug resistance, virulence, pathogenesis, host-pathogen interaction Citation: Sun J, Champion PA and Bigi F (2019) Editorial: Cellular and Molecular Mechanisms of Mycobacterium tuberculosis Virulence. Front. Cell. Infect. Microbiol. 9:331. doi: 10.3389/fcimb.2019.00331 Received: 28 August 2019; Accepted: 06 September 2019; Published: 09 October 2019. Edited and reviewed by: John S. Gunn, The Research Institute at Nationwide Children's Hospital, United States Copyright © 2019 Sun, Champion and Bigi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Jianjun Sun, [email protected]; Patricia A. Champion, [email protected]; Fabiana Bigi, [email protected]
Published: 19 September 2019
Frontiers in Microbiology, Volume 10; https://doi.org/10.3389/fmicb.2019.02173

Abstract:
Editorial on the Research TopicAlternative Therapeutics Against Antimicrobial-Resistant Pathogens Antimicrobial resistance (AMR) has emerged as one of the greatest global challenge to public health in the twenty-first century. The use of antibiotics is associated with the serendipitous discovery of Penicillin by Sir Alexander Fleming in 1928 (Fleming, 1929). However, Emmerich and Löw had demonstrated the first application of the antibiotic “Pyocyanase” in hospital in 1899. The golden era of antibiotic was ushered between 1950s and 1970s which was marked by rapid developments in discoveries of many classes and types of antibiotics (Emmerich and Löw, 1899). The increased use and abuse of antibiotics caused the emergence of multidrug resistant bacteria that caused hard-to-treat infections (Aminov, 2010). It is imperative to search alternative therapeutics and strategies to combat AMR and diminish the exacerbated use of antibiotics. In this special issue, we present 26 articles that highlight the use of novel peptides, phage-based therapies, nanomedicine, contemporary and alternative medicines, plant (herbal), and bacteria based antimicrobials as potential alternatives to combat multidrug resistant (MDR) bacteria. The articles are categorized in different groups, including (i) Antimicrobial nanoparticles against drug resistant bacteria, (ii) Bacteriophages: A promising approach to fight MDR, (iii) Anti biofilm agents, (iv) Antimicrobial peptides, (v) Efflux pump inhibitors, and (vi) Host /Pathogen directed therapies. A variety of repurposing FDA-approved drugs (Sharma et al.) that are employed in the management of pathological conditions of non-infectious etiology have been shown to exhibit broad spectrum antimicrobial activity in vitro and in vivo. Such compounds including marine eukaryotes like seaweeds (Karthick and Mohanraju), phytochemicals (Kim et al.; Lu et al.), antimicrobial peptides and proteins (Kumar et al.), termed “non-antibiotics” (Dutta et al., 2007; Mazumdar et al., 2009, 2010), possess antibacterial properties, acting through mechanisms different from those of existing drugs, by enhancement of combination-therapy effective (Pachon-Ibanez et al.; Shriram et al.), reversal of drug resistance (Guo et al.; Patwardhan et al.) or re-sensitizing activities (Dutta et al., 2014; Shriram et al.), inhibition of biofilm formation (Guo et al.; Karumathil et al.; Kaur et al.; Khalifa et al.; Kim et al.; Lu et al.; Punjabi et al.), as well as by induction and control of efflux pumps (Dutta et al., 2010; Baptista et al.; Karumathil et al.; Lu et al.; Shriram et al.). This broad group of antimicrobial agents has two sub-groups, each with distinctly different adjunct activities, either pathogen-directed or host directed. The first group is that of the antimicrobial non-antibiotics—drugs that have direct antimicrobial activity and the proposed path for compounds targeting microbial factors. The second group can generally be classified into two categories: those that enhance the antimicrobial activity of the host immune system, and those which dampen the inflammatory response preventing tissue damage (Karumathil et al.; Singh and Subbian). Host-directed therapies are attractive options as they are not prone to the resistance associated with antibiotics (Dutta et al., 2016; Frank et al., 2019). Currently, the following HDT agents are being evaluated in phase 2 clinical trials as adjuncts to rifabutin-modified standard therapy in adults with drug-sensitive, smear-positive pulmonary TB: (1) the mammalian target of rapamycin (mTOR) inhibitor, everolimus (0.5 mg), (2) auranofin (6 mg), (3) vitamin D3, and (4) the phosphodiesterase-4 (PDE4) inhibitor, CC-11050 (ClinicalTrials.gov Identifier: NCT02968927). A randomized clinical trial, Statins as Adjunctive Therapy for TB (StAT-TB), is currently underway to determine if pravastatin adjunctive therapy shortens the median time to sputum-culture negativity and improves lung function outcomes among HIV-infected and uninfected patients with drug-susceptible pulmonary TB (NCT03456102). In summary, these articles cover a vast expanse of research findings based on emerging trends in combatting antimicrobial resistance using traditional and natural antimicrobials, plant and microbial derivatives and nanomaterials. Currently, AMR is a constantly growing global threat to public health worldwide and has been declared as a thrust area by World Health Organization (WHO). AMR is mediated via various mechanisms such as enzymatic degradation of drugs, alteration of antimicrobial targets, efflux of drugs, alteration of microbial membrane permeability, formation of biofilms, and persister cell states. Most of the AMR resistance genes (ARG) are disseminated via horizontal gene transfer mediated by genetic elements like plasmids, transposons, bacteriophages, and other genetic elements (Thombre et al., 2016). One of the challenges of AMR is annihilating the spread and prevalence of ARGs in the environmental resistome via plasmids. Future strategies and new lines of research need to be undertaken using conjugation inhibitors, plasmid incompatibility systems, and CRISPR/Cas-based approaches to tackle the incredibly profound multidrug resistant bacteria (Buckner et al., 2018). All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank the contributing authors for submission of their papers and reviewers for their valuable time. The Editorial guidance and suggestions of Dr. Rustam Aminov for handling this special issue is highly appreciated. RT thanks the Principal, Modern College, Shivajinagar, Pune, for providing necessary facilities. Aminov, R. I. (2010). A brief history of the antibiotic era: lessons learned and challenges for the future. Front. Microbiol. 1:134. doi: 10.3389/fmicb.2010.00134 PubMed Abstract | CrossRef Full Text | Google Scholar Buckner, M., Ciusa, M. L., and Piddock, L. (2018). Strategies to combat antimicrobial resistance: anti-plasmid and plasmid curing. FEMS Microbiol. Rev. 42, 781–804. doi: 10.1093/femsre/fuy031 PubMed Abstract | CrossRef Full Text | Google Scholar Dutta, N.K., Pinn, M.L., and Karakousis, P.C. (2014). Reduced emergence of isoniazid resistance with concurrent use of thioridazine against acute murine tuberculosis. Antimicrob. Agents Chemother. 58 4048–4053. doi: 10.1128/AAC.02981-14 PubMed Abstract | CrossRef Full Text | Google Scholar Dutta, N. K., Annadurai, S., Mazumdar, K., Dastidar, S. G., Kristiansen, J. E., Molnar, J., et al. (2007). Potential management of resistant microbial infections with a novel non-antibiotic: the anti-inflammatory drug diclofenac sodium. Int. J. Antimicrob. Agents 30, 242–249. doi: 10.1016/j.ijantimicag.2007.04.018 PubMed Abstract | CrossRef Full Text | Google Scholar Dutta, N. K., Bruiners, N., Pinn, M. L., Zimmerman, M. D., Prideaux, B., Dartois, V., et al. (2016). Statin adjunctive therapy shortens the duration of TB treatment in mice. J. Antimicrob. Chemother. 71, 1570–1577. doi: 10.1093/jac/dkw014 PubMed Abstract | CrossRef Full Text | Google Scholar Dutta, N. K., Mehra, S., and Kaushal, D. (2010). A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine. PLoS ONE 5:e10069. doi: 10.1371/journal.pone.0010069 PubMed Abstract | CrossRef Full Text | Google Scholar Emmerich, R., and Löw, O. (1899). Bakteriolytische enzyme als Ursache der erworbenen Immunität und die Heilung von Infectionskrankheiten durch dieselben. Z. Hyg. 31, 1–6510. doi: 10.1007/BF02206499 CrossRef Full Text Fleming, A. (1929). On antibacterial action of culture of Penicillium, with special reference to their use in isolation of B. influenzae. Br. J. Exp. Pathol. 10, 226–236. Google Scholar Frank, D. J., Horne, D. J., Dutta, N. K., Shaku, M. T., Madensein, R., Hawn, T.R., et al. (2019). Remembering the host in tuberculosis drug development. J. Infect. Dis. 219, 1518–1524. doi: 10.1093/infdis/jiy712 PubMed Abstract | CrossRef Full Text | Google Scholar Mazumdar, K., Asok Kumar, K., and Dutta, N. K. (2010). Potential role of the cardiovascular non-antibiotic (helper compound) amlodipine in the treatment of microbial infections: scope and hope for the future. Int. J. Antimicrob. Agents 36, 295–302. doi: 10.1016/j.ijantimicag.2010.05.003 PubMed Abstract | CrossRef Full Text | Google Scholar Mazumdar, K., Dastidar, S. G., Park, J. H., and Dutta, N. K. (2009). The anti-inflammatory non-antibiotic helper compound diclofenac: an antibacterial drug target. Eur. J. Clin. Microbiol. Infect. Dis. 28, 881–891. doi: 10.1007/s10096-009-0739-z PubMed Abstract | CrossRef Full Text | Google Scholar Thombre, R. S., Shinde, V., Thaiparambil, E., Zende, S., and Mehta, S. (2016) Antimicrobial activity mechanism of inhibition of silver nanoparticles against extreme halophilic archaea. Front. Microbiol. 7:1424. doi: 10.3389/fmicb.2016.01424 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: antimicrobial resistance (AMR), multidrug-resistance (MDR), nanomaterials, nanoparticles, plant based compounds, antimicrobial agents, alternative therapy, novel compounds Citation: Thombre R, Jangid K, Shukla R and Dutta NK (2019) Editorial: Alternative Therapeutics Against Antimicrobial-Resistant Pathogens. Front. Microbiol. 10:2173. doi: 10.3389/fmicb.2019.02173 Received: 26 July 2019; Accepted: 05 September 2019; Published: 19 September 2019. Edited by: Reviewed by: Copyright © 2019 Thombre, Jangid, Shukla and Dutta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Rebecca Thombre, [email protected]
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