Publications


Integrating the social sciences into the COVID-19 response in Alberta, Canada

Author: Myles LeslieRaad FadaakJan DaviesJohanna BlaakP G ForestLee GreenJohn Conly

Date: July 2020

Summary

This paper outlines the rapid integration of social scientists into a Canadian province's COVID-19 response. We describe the motivating theory, deployment and initial outcomes of our team of Organisational Sociologist ethnographers, Human Factors experts and Infection Prevention and Control clinicians focused on understanding and improving Alberta's responsiveness to the pandemic. Specifically, that interdisciplinary team is working alongside acute and primary care personnel, as well as public health leaders to deliver 'situated interventions' that flow from studying communications, interpretations and implementations across responding organisations. Acting in real time, the team is providing critical insights on policy communication and implementation to targeted members of the health system. Using our rapid and ongoing deployment as a case study of social science techniques applied to a pandemic, we describe how other health systems might leverage social science to improve their preparations and communications.

Keywords: epidemiology; health policy; health services research; health systems; public health.

Policy Brief No.1: The Use of Remdesivir to Treat Severe Cases of COVID-19

Author: AMR - One Health Consortium

Content Expert(s): Matthias Götte, PhD; John Conly, MD

Date: July 2020

The Issue: During the COVID-19 pandemic, treating hospitalized patients with severe diseaseh as been a primary concern of healthcare providers. Shortening the course of the illness, reducing length of hospital stay, and reducing mortality are crucial treatment goals. Successful treatment would alleviate patient suffering, decrease the burden on healthcare system costs, and increase the availability of resources for other acute care patients.

Remdesivir is an investigational antiviral drug that was shown to address this issue. However, neither remdesivir nor any other antiviral agent is currently approved for the treatment of COVID-19 in Canada.

Longitudinal blood transcriptomic analysis to identify molecular regulatory patterns of bovine respiratory disease in beef cattle

Authors: Hui-Zeng Sun; Vythegi Srithayakumar; Janelle Jiminez; Weiwu Jin; Afshin Hosseini; Mikolaj Raszek; Karin Orsel; Le Luo Guan; Graham Plastow

Date: July 2020

Summary

Bovine respiratory disease (BRD) is the most common disease in beef cattle and leads to considerable economic losses in both beef and dairy cattle. It is important to uncover the molecular mechanisms underlying BRD and to identify biomarkers for early identification of BRD cattle in order to address its impact on production and welfare. In this study, a longitudinal transcriptomic analysis was conducted using blood samples collected from 24 beef cattle at three production stages in the feedlot: 1) arrival (Entry group); 2) when identified as sick (diagnosed as BRD) and separated for treatment (Pulled); 3) prior to marketing (Close-out, representing healthy animals). Expressed genes were significantly different in the same animal among Entry, Pulled and Close-out stages (false discovery rate (FDR) < 0.01 & |Fold Change| > 2). Beef steers at both Entry and Pulled stages presented obvious difference in GO terms (FDR < 0.05) and affected biological functions (FDR < 0.05 & |Z-score| > 2) when compared with animals at Close-out. However, no significant functional difference was observed between Entry and Pulled animals. The interferon signaling pathway showed the most significant difference between animals at Entry/Pulled and Close-out stages (P < .001 & |Z-score| > 2), suggesting the animals initiated antiviral responses at an early stage of infection. Six key genes including IFI6, IFIT3, ISG15, MX1, and OAS2 were identified as biomarkers to predict and recognize sick cattle at Entry. A gene module with 169 co-expressed genes obtained from WGCNA analysis was most positively correlated (R = 0.59, P = 6E-08) with sickness, which was regulated by 11 transcription factors. Our findings provide an initial understanding of the BRD infection process in the field and suggests a subset of novel marker genes for identifying BRD in cattle at an early stage of infection.

Acknowledgment:

This research is also part of the AMR – One Health Consortium, funded by the Major Innovation Fund program of the Alberta Ministry of Economic Development, Trade and Tourism.

Characterization of Novel Broad-Host-Range Bacteriophage DLP3 Specific to Stenotrophomonas maltophilia as a Potential Therapeutic Agent

Authors: Danielle L. PetersJaclyn G. McCutcheon, and Jonathan J. Dennis*

Date: June 24, 2020

Abstract 

A novel Siphoviridae phage specific to the bacterial species Stenotrophomonas maltophilia was isolated from a pristine soil sample and characterized as a second member of the newly established Delepquintavirus genus. Phage DLP3 possesses one of the broadest host ranges of any S. maltophilia phage yet characterized, infecting 22 of 29 S. maltophilia strains. DLP3 has a genome size of 96,852 bp and a G+C content of 58.4%, which is significantly lower than S. maltophilia host strain D1571 (G+C content of 66.9%). The DLP3 genome encodes 153 coding domain sequences covering 95% of the genome, including five tRNA genes with different specificities. The DLP3 lysogen exhibits a growth rate increase during the exponential phase of growth as compared to the wild type strain. DLP3 also encodes a functional erythromycin resistance protein, causing lysogenic conversion of the host D1571 strain. Although a temperate phage, DLP3 demonstrates excellent therapeutic potential because it exhibits a broad host range, infects host cells through the S. maltophilia type IV pilus, and exhibits lytic activity in vivo. Undesirable traits, such as its temperate lifecycle, can be eliminated using genetic techniques to produce a modified phage useful in the treatment of S. maltophilia bacterial infections.

Keywords: Stenotrophomonas, bacteriophage, phage, phage therapy, antimicrobial resistance

A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae

Authors: Jinshui Zheng, Stijn Wittouck, Elisa Salvetti, Charles M.A.P. Franz​, Hugh M.B. Harris, Paola Mattarelli, Paul W. O’Toole5​, Bruno Pot, Peter Vandamme, Jens Walter, Koichi Watanabe, Sander Wuyts, Giovanna E. Felis, Michael G. Gänzle, Sarah Lebeer

Date: April 2020

Summary

The genus Lactobacillus comprises 261 species (at March 2020) that are extremely diverse at phenotypic, ecological and genotypic levels. This study evaluated the taxonomy of Lactobacillaceae and Leuconostocaceae on the basis of whole genome sequences. Parameters that were evaluated included core genome phylogeny, (conserved) pairwise average amino acid identity, clade-specific signature genes, physiological criteria and the ecology of the organisms. Based on this polyphasic approach, we propose reclassification of the genus Lactobacillus into 25 genera including the emended genus Lactobacillus , which includes host-adapted organisms that have been referred to as the Lactobacillus delbrueckii group, Paralactobacillus and 23 novel genera for which the names Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, Loigolactobacilus, Lacticaseibacillus, Latilactobacillus, Dellaglioa, Liquorilactobacillus, Ligilactobacillus, Lactiplantibacillus, Furfurilactobacillus, Paucilactobacillus, Limosilactobacillus, Fructilactobacillus, Acetilactobacillus, Apilactobacillus, Levilactobacillus, Secundilactobacillus and Lentilactobacillus are proposed. We also propose to emend the description of the family Lactobacillaceae to include all genera that were previously included in families Lactobacillaceae and Leuconostocaceae . The generic term ‘lactobacilli’ will remain useful to designate all organisms that were classified as Lactobacillaceae until 2020. This reclassification reflects the phylogenetic position of the micro-organisms, and groups lactobacilli into robust clades with shared ecological and metabolic properties, as exemplified for the emended genus Lactobacillus encompassing species adapted to vertebrates (such as Lactobacillus delbrueckii , Lactobacillus iners , Lactobacillus crispatus , Lactobacillus jensensii, Lactobacillus johnsonii and Lactobacillus acidophilus ) or invertebrates (such as Lactobacillus apis and Lactobacillus bombicola ).

Note: 

The significance to the ARM One Health Consortium is threefold:

  • All lactobacilli that are adapted to vertebrate hosts are not in three of the 23 (26) new genera, Lactobacillus, Ligilactobacillus and Limosilactobacillus. This also means that taxonomy can now be used to identify host adapted probiotic lactobacilli for use in animals. One example on how this concept was successful is Lactobacillus delbrueckii - this is the oldest Lactobacillus species but for 120 years after its first description has been recognized only with respect to its role in yoghurt fermentation. Very recently, it was identified as an organism that is specialized to suckling mammals including calved and pigs - we are currently exploring this concept to develop specific probiotic preparations for calved and piglets, also with the aim to minimize disease and the use of antibiotics.
  • Vertebrate animal adapted lactobacilli not only share the phylogenetic position but also metabolic and physiological traits. One example is tetW coding for tetracyclin resistance; this gene is exclusively found in intestinal lactobacilli (of the genera Lactobacillus, Ligilactobacillus and Limosilactobacillis) and very likely was acquired by horizontal gene transfer from other intestinal bacteria.
  • The paper will change Canadian regulations on probiotic bacteria. Health Canada announced that their regulations of probiotic food additives will be updated in the next years.

Despite COVID-19, the paper has received substantial social media and news coverage, and has ranked as the "top social media score" "top read this month" and "top cited this month" paper with IJSEM for more than two month now (July 2020).

Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Authors: Gordon, C., Tchesnokov, E., Woolner, E., Perry, J., Feng, J., Porter, D., and Gotte, M. 

Date: April, 2020

Summary 

Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain-termination is RDV’s plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the non-structural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2’-C–methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral (DAA).

 

Antimicrobial Resistance of Human Campylobacter Species Infections in Saskatchewan, Canada (1999–2006): A Historical Provincial Collection of All Reported Cases

Authors: Simon J.G. Otto, Paul N. Levett, Richard J. Reid-Smith, David L. Pearl, Dawn Daku, Evelyn Nagle, Greg B. Horsman, and Scott A. McEwen

Date: March, 2020

Summary

To describe a historical baseline of antimicrobial resistance (AMR) profiles for human clinical Campylobacter species isolates obtained by laboratory surveillance in the province of Saskatchewan from 1999 to 2006; to determine if there were differences in resistance between Campylobacter jejuni and Campylobacter coli; and to determine if there were changes in the annual resistance levels in the two species. One thousand three hundred seventy-eight Campylobacter isolates were subjected to antimicrobial susceptibility testing using the E-test method. Annual resistance levels in C. jejuni and C. coli were compared using logistic regression models. One thousand two hundred (87.1%) isolates were C. jejuni and 129 (9.4%) were C. coli. Resistance in C. jejuni isolates included ciprofloxacin (CIP: 9.4%), erythromycin (ERY: 0.5%), and tetracycline (33.3%). CIP resistance in C. jejuni was higher in 1999 (15.5%, odds ratio [OR] = 3.96, p = 0.01), 2000 (12.7%, OR = 3.10, p = 0.01), 2005 (10.2%, OR = 2.47, p = 0.05), and 2006 (13.0%, OR = 3.22, p = 0.01) compared with 2004 (4.4%). C. coli had significantly higher CIP resistance (15.5%, OR = 1.78, p = 0.03), ERY resistance (13.2%, OR = 60.12, p < 0.01), multidrug resistance (2.3%, OR = 36.29, p < 0.01), and CIP-ERY resistance (3.1%, OR = 50.23, p < 0.01) compared with C. jejuni. This represents the first and most current report of AMR of the collective human Campylobacter isolates from a province in Canada and provides a baseline against which current and future resistance patterns can be compared. Fluoroquinolone resistance in C. jejuni isolates fluctuated from 1999 to 2006, including an increased prevalence in 2005–2006, while macrolide/lincosamide resistance remained very low. Human clinical C. jejuni isolates from Saskatchewan demonstrated resistance to multiple antimicrobials but had significantly less fluoroquinolone and macrolide resistance than C. coli isolates.

Exploring Phenotypes for Disease Resilience in Pigs Using Complete Blood Count Data from a Natural Disease Challenge Model

Authors: Xuechun Bai, Austin M. Putz, Zhiquan Wang, Frédéric Fortin, John C. S. Harding, Michael K. Dyck, Jack C. M. Dekkers, Catherine J. Field, Graham S. Plastow, and PigGen Canada

Date: March 2020

Summary

Disease resilience is a valuable trait to help manage infectious diseases in livestock. It is anticipated that improved disease resilience will sustainably increase production efficiency, as resilient animals maintain their performance in the face of infection. The objective of this study was to identify phenotypes related to disease resilience using complete blood count (CBC) data from a wean-to-finish natural disease challenge model, established to mimic the disease pressure caused by many common pathogens at the commercial level of pig production. In total, 2433 F1 crossbred (Landrace × Yorkshire) barrows that went through the natural disease challenge model were classified into four groups (resilient, average, susceptible, and dead) based on their divergent responses in terms of growth and individual treatment. Three sets of blood samples for CBC analysis were drawn at 2-weeks before, and at 2- and 6-weeks after the challenge: Blood 1, Blood 3, and Blood 4 respectively. CBC of Blood 1 taken from healthy pigs before challenge did not show differences between groups. However, resilient animals were found to be primed to initiate a faster adaptive immune response and recover earlier following infection, with greater increases of lymphocyte concentration from Blood 1 to Blood 3 and for hemoglobin concentration and hematocrit from Blood 3 to Blood 4, but a lower neutrophil concentration from Blood 3 to Blood 4 than in susceptible and dead animals (FDR < 0.05). The CBC traits in response to the challenge were found to be heritable and genetically correlated with growth and treatment, which may indicate the potential for developing CBC under disease or commercial conditions as a phenotype in commercial systems as part of developing predictions for disease resilience.

Surveillance of Enterococcus spp. reveals distinct species and antimicrobial resistance diversity across a One-Health continuum

Authors: Rahat Zaheer, Shaun R. Cook, Ruth Barbieri, Noriko Goji, Andrew Cameron, Aaron Petkau, Rodrigo O rtega Polo, Lisa Tymensen, Courtney Stamm, Jiming Song, Sherry Hannon, Tineke Jones, Deirdre Church, Calvin W. Booker, Kingsley Amoako, Gary Van Domselaar, Ron R. Read & Tim A. McAllister

Date: March 2020

Summary

For a One-Health investigation of antimicrobial resistance (AMR) in Enterococcus spp., isolates from humans and beef cattle along with abattoirs, manured fields, natural streams, and wastewater from both urban and cattle feedlot sources were collected over two years. Species identification of Enterococcus revealed distinct associations across the continuum. Of the 8430 isolates collected, Enterococcus faecium and Enterococcus faecalis were the main species in urban wastewater (90%) and clinical human isolates (99%); Enterococcus hirae predominated in cattle (92%) and feedlot catch-basins (60%), whereas natural streams harbored environmental Enterococcus spp. Wholegenome sequencing of E. faecalis (n = 366 isolates) and E. faecium (n = 342 isolates), revealed source clustering of isolates, indicative of distinct adaptation to their respective environments. Phenotypic resistance to tetracyclines and macrolides encoded by tet(M) and erm(B) respectively, was prevalent among Enterococcus spp. regardless of source. For E. faecium from cattle, resistance to β-lactams and quinolones was observed among 3% and 8% of isolates respectively, compared to 76% and 70% of human clinical isolates. Clinical vancomycin-resistant E. faecium exhibited high rates of multi-drug resistance, with resistance to all β-lactam, macrolides, and quinolones tested. Differences in the AMR profiles among isolates reflected antimicrobial use practices in each sector of the One-Health continuum.

Industry incentives and antibiotic resistance: an introduction to the antibiotic susceptibility bonus

Authors: Chantal M. Morel, Olof Lindahl, Stephan Harbarth, Marlieke E. A. de Kraker, Suzanne Edwards & Aidan Hollis

Date: March 2020

Summary

The scarcity of novel antibiotic compounds in a time of increasing resistance rates has begun to ring alarm bells at the highest echelons of government. Large new financial incentives to accelerate antibiotic research and development, such as market entry rewards (MERs), are being considered. However, there is little focus on how to sustain the efficacy of new, promising antibiotics reaching the market. Currently, inappropriate use of antibiotics is commonplace, which has accelerated resistance development. In an attempt to halt this trend, antibiotic stewardship policies are being implemented in many resource-rich settings. Unfortunately, this has not yet had an impact on the amount of antibiotics being prescribed globally. One important hurdle is misalignment of incentives. While governments and health services are incentivized to promote prudent use of this common good, pharmaceutical companies are incentivized to increase volume of sales to maximize profits. This problem must be addressed or else the major efforts going into developing new antibiotics will be in vain. In this paper we outline an approach to realign the incentives of pharmaceutical companies with wider antibiotic conservation efforts by making a staged bonus a component of an MER for antibiotic developers when resistance to their drug remains low over time. This bonus could address the lack of stewardship focus in any innovation-geared incentive.


Impact of Isolation Precautions on Quality of Life: A Meta-Analysis Journal of Hospital Infection

Authors: A. Sharma, D.R. Pillai, M. Lua, C. Doolan, J. Leal, J. Kim, A. Hollis

Date: February 2020

Summary

Impact of isolation precautions on psychological wellbeing of patients has yet to be fully quantified. To assess the impact of isolation precautions on patients' health-related quality of life and depression or anxiety scales and estimate per day cost of anxiety and depression. Literature pertaining to impact of isolation precautions was searched on EMBASE and PubMed databases and Google Scholar. A two-step independent screening of the articles was performed. Articles that compared isolated and non-isolated patients using different quality of life and psychological burden scales were included. A meta-analysis was conducted using the Hospital Anxiety and Depression Scales (HADS-A and HADS-D). Psychological burden measures from selected literature were presented in a graph as effect sizes. Per day cost of anxiety and depression was estimated using pooled mean difference from meta-analysis. Out of 106 articles, 94 were excluded due to inclusion criteria, leaving 12 for full text review. After review of full text of the articles, seven articles were shortlisted for empirical analysis and four out of these seven for meta-analysis. The pooled mean difference estimates for HADS-A was Math Eq (P=0.15) and that for HADS-D was Math Eq (P=0.09). In the empirical analysis of psychological burden scales, the effect in all studies except one was negative. Results from meta-analysis and empirical analysis of psychological burden implied that isolated patients are worse off in general. The implied estimated per day cost of anxiety and depression in terms of quality-adjusted life years (QALYs) is approximately US$10.

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Authors: Calvin J. Gordon, Egor P. Tchesnokov, Joy Y. Feng, Danielle P. Porter, and Matthias Götte

Date: February 2020

Summary

Antiviral drugs for managing infections with human coronaviruses are not yet approved,

posing a serious challenge to current global efforts aimed at containing the outbreak of

severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including SARS-CoV and Middle East respiratory syndrome (MERSCoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We

initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogues. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i+3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3’–5’ exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cellbased  assays.

 


Phage Crusade

Check out a recent magazine article of a project from Jon Dennis lab, one of the AMR - One Health Co-Investigators

Author: Mark Czarneckljan

Date: January, 2020

Summary

A Canadian scientist once harnessed the power of viruses against bacterial infections. In dire times, a new generation of scientists is fighting to do the same.