Publications by authors named "Taane G Clark"

209 Publications

Characterization of rifampicin-resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa, Pakistan.

Sci Rep 2021 Jul 9;11(1):14194. Epub 2021 Jul 9.

Institute of Basic Medical Science, Khyber Medical University, Peshawar, KP, Pakistan.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is endemic in Pakistan. Resistance to both firstline rifampicin and isoniazid drugs (multidrug-resistant TB; MDR-TB) is hampering disease control. Rifampicin resistance is attributed to rpoB gene mutations, but rpoA and rpoC loci may also be involved. To characterise underlying rifampicin resistance mutations in the TB endemic province of Khyber Pakhtunkhwa, we sequenced 51 M. tuberculosis isolates collected between 2016 and 2019; predominantly, MDR-TB (n = 44; 86.3%) and lineage 3 (n = 30, 58.8%) strains. We found that known mutations in rpoB (e.g. S405L), katG (e.g. S315T), or inhA promoter loci explain the MDR-TB. There were 24 unique mutations in rpoA, rpoB, and rpoC genes, including four previously unreported. Five instances of within-host resistance diversity were observed, where two were a mixture of MDR-TB strains containing mutations in rpoB, katG, and the inhA promoter region, as well as compensatory mutations in rpoC. Heteroresistance was observed in two isolates with a single lineage. Such complexity may reflect the high transmission nature of the Khyber Pakhtunkhwa setting. Our study reinforces the need to apply sequencing approaches to capture the full-extent of MDR-TB genetic diversity, to understand transmission, and to inform TB control activities in the highly endemic setting of Pakistan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-93501-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270973PMC
July 2021

Artemether-lumefantrine treatment failure of uncomplicated Plasmodium falciparum malaria in travellers coming from Angola and Mozambique.

Int J Infect Dis 2021 Jul 6. Epub 2021 Jul 6.

Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, Portugal. Electronic address:

The failure of artemisinin combination therapy (ACT) in malaria patients returning from endemic regions may be driven by parasite resistance to this treatment. ACT is used globally as the first-line treatment for Plasmodium falciparum malaria. However, artemisinin-resistant strains of P. falciparum have emerged and spread across Southeast Asia, with the risk of reaching high malaria burden regions in Africa and elsewhere. Here, we report on two malaria imported cases from Africa with possible parasite resistance to the ACT artemether-lumefantrine (AL). Case presentation: Two middle-aged males returning from Angola and Mozambique developed malaria symptoms in Portugal, where they were diagnosed and received treatment with AL as hospital inpatients. After apparent cure and discharge from hospital, these individuals returned to hospital showing signs of late clinical failure. Molecular analysis was performed across a number of drug resistance associated genes. No evidence of pfk13-mediated artemisinin resistance was found. Both subjects had complete parasite clearance after treatment with a non-ACT antimalarials. Conclusion: Our case-studies highlight the need for close monitoring of signs of unsatisfactory antimalarial efficacy among AL treated patients and the possible implication of other genes or mutations in the parasite response to ACTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.07.008DOI Listing
July 2021

Practices and Challenges of Veterinary Paraprofessionals in Regards to Antimicrobial Use and Resistance in Animals in Dar Es Salaam, Tanzania.

Antibiotics (Basel) 2021 Jun 17;10(6). Epub 2021 Jun 17.

SACIDS Foundation for One Health, Sokoine University of Agriculture, Morogoro 3019, Tanzania.

We conducted a qualitative study to explore the practices and challenges of veterinary paraprofessionals (paravets) on antimicrobial use and resistance in domestic animals.

Methods: This was a qualitative study, which involved semi-structured interviews with paravets from the Ilala, Ubungo, Kigamboni, Kinondoni, and Temeke districts in Dar es Salaam, Tanzania.

Results: A total of 40 paravets participated in this study. The majority (72.5%) admitted to having not undergone any formal training on antimicrobial use and/or resistance. Paravets face several challenges, including poor working conditions and having no access to laboratory services to advise on antimicrobial choice and selection. They also face challenges from livestock farmers such as the inability to afford the recommended medicines, the self-prescription of antimicrobials, and poor record keeping. The presence of sub-standard medicine and the lack of guidelines on the appropriate disposal of medicines were also identified as affecting their services.

Conclusion: Paravets should be trained in the judicious use of antimicrobials, and the same training should be used to refresh their knowledge on the diagnosis and prevention of infections. The Veterinary Council of Tanzania and other regulatory agencies should assist in addressing the challenges facing paravets that are related to animal health services and the quality of medicines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antibiotics10060733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234030PMC
June 2021

Flavivirus integrations in Aedes aegypti are limited and highly conserved across samples from different geographic regions unlike integrations in Aedes albopictus.

Parasit Vectors 2021 Jun 26;14(1):332. Epub 2021 Jun 26.

Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.

Mosquitoes of the genus Aedes are the main vectors of many viruses, e.g. dengue and Zika, which affect millions of people each year and for which there are limited treatment options. Understanding how Aedes mosquitoes tolerate high viral loads may lead to better disease control strategies. Elucidating endogenous viral elements (EVEs) within vector genomes may give exploitable biological insights. Previous studies have reported the presence of a large number of EVEs in Aedes genomes. Here we investigated if flavivirus EVEs are conserved across populations and different Aedes species by using ~ 500 whole genome sequence libraries from Aedes aegypti and Aedes albopictus, sourced from colonies and field mosquitoes across continents. We found that nearly all flavivirus EVEs in the Ae. aegypti reference genome originate from four separate putative viral integration events, and that they are highly conserved across geographically diverse samples. By contrast, flavivirus EVEs in the Ae. albopictus reference genome originate from up to nine distinct integration events and show low levels of conservation, even within samples from narrow geographical ranges. Our analysis suggests that flaviviruses integrated as long sequences and were subsequently fragmented and shuffled by transposable elements. Given that EVEs of Ae. aegypti and Ae. albopictus belong to different phylogenetic clades and have very differing levels of conservation, they may have different evolutionary origins and potentially different functional roles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13071-021-04828-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235865PMC
June 2021

Using deep learning to identify recent positive selection in malaria parasite sequence data.

Malar J 2021 Jun 14;20(1):270. Epub 2021 Jun 14.

London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Background: Malaria, caused by Plasmodium parasites, is a major global public health problem. To assist an understanding of malaria pathogenesis, including drug resistance, there is a need for the timely detection of underlying genetic mutations and their spread. With the increasing use of whole-genome sequencing (WGS) of Plasmodium DNA, the potential of deep learning models to detect loci under recent positive selection, historically signals of drug resistance, was evaluated.

Methods: A deep learning-based approach (called "DeepSweep") was developed, which can be trained on haplotypic images from genetic regions with known sweeps, to identify loci under positive selection. DeepSweep software is available from https://github.com/WDee/Deepsweep .

Results: Using simulated genomic data, DeepSweep could detect recent sweeps with high predictive accuracy (areas under ROC curve > 0.95). DeepSweep was applied to Plasmodium falciparum (n = 1125; genome size 23 Mbp) and Plasmodium vivax (n = 368; genome size 29 Mbp) WGS data, and the genes identified overlapped with two established extended haplotype homozygosity methods (within-population iHS, across-population Rsb) (~ 60-75% overlap of hits at P < 0.0001). DeepSweep hits included regions proximal to known drug resistance loci for both P. falciparum (e.g. pfcrt, pfdhps and pfmdr1) and P. vivax (e.g. pvmrp1).

Conclusion: The deep learning approach can detect positive selection signatures in malaria parasite WGS data. Further, as the approach is generalizable, it may be trained to detect other types of selection. With the ability to rapidly generate WGS data at low cost, machine learning approaches (e.g. DeepSweep) have the potential to assist parasite genome-based surveillance and inform malaria control decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12936-021-03788-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201710PMC
June 2021

Distinctive genetic structure and selection patterns in Plasmodium vivax from South Asia and East Africa.

Nat Commun 2021 05 26;12(1):3160. Epub 2021 May 26.

Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.

Despite the high burden of Plasmodium vivax malaria in South Asian countries, the genetic diversity of circulating parasite populations is not well described. Determinants of antimalarial drug susceptibility for P. vivax in the region have not been characterised. Our genomic analysis of global P. vivax (n = 558) establishes South Asian isolates (n = 92) as a distinct subpopulation, which shares ancestry with some East African and South East Asian parasites. Signals of positive selection are linked to drug resistance-associated loci including pvkelch10, pvmrp1, pvdhfr and pvdhps, and two loci linked to P. vivax invasion of reticulocytes, pvrbp1a and pvrbp1b. Significant identity-by-descent was found in extended chromosome regions common to P. vivax from India and Ethiopia, including the pvdbp gene associated with Duffy blood group binding. Our investigation provides new understanding of global P. vivax population structure and genomic diversity, and genetic evidence of recent directional selection in this important human pathogen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23422-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154914PMC
May 2021

An inter-laboratory study to investigate the impact of the bioinformatics component on microbiome analysis using mock communities.

Sci Rep 2021 May 19;11(1):10590. Epub 2021 May 19.

Molecular Biology, National Measurement Laboratory, LGC, Queens Road, Teddington, TW11 0LY, Middlesex, UK.

Despite the advent of whole genome metagenomics, targeted approaches (such as 16S rRNA gene amplicon sequencing) continue to be valuable for determining the microbial composition of samples. Amplicon microbiome sequencing can be performed on clinical samples from a normally sterile site to determine the aetiology of an infection (usually single pathogen identification) or samples from more complex niches such as human mucosa or environmental samples where multiple microorganisms need to be identified. The methodologies are frequently applied to determine both presence of micro-organisms and their quantity or relative abundance. There are a number of technical steps required to perform microbial community profiling, many of which may have appreciable precision and bias that impacts final results. In order for these methods to be applied with the greatest accuracy, comparative studies across different laboratories are warranted. In this study we explored the impact of the bioinformatic approaches taken in different laboratories on microbiome assessment using 16S rRNA gene amplicon sequencing results. Data were generated from two mock microbial community samples which were amplified using primer sets spanning five different variable regions of 16S rRNA genes. The PCR-sequencing analysis included three technical repeats of the process to determine the repeatability of their methods. Thirteen laboratories participated in the study, and each analysed the same FASTQ files using their choice of pipeline. This study captured the methods used and the resulting sequence annotation and relative abundance output from bioinformatic analyses. Results were compared to digital PCR assessment of the absolute abundance of each target representing each organism in the mock microbial community samples and also to analyses of shotgun metagenome sequence data. This ring trial demonstrates that the choice of bioinformatic analysis pipeline alone can result in different estimations of the composition of the microbiome when using 16S rRNA gene amplicon sequencing data. The study observed differences in terms of both presence and abundance of organisms and provides a resource for ensuring reproducible pipeline development and application. The observed differences were especially prevalent when using custom databases and applying high stringency operational taxonomic unit (OTU) cut-off limits. In order to apply sequencing approaches with greater accuracy, the impact of different analytical steps needs to be clearly delineated and solutions devised to harmonise microbiome analysis results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-89881-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134577PMC
May 2021

G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials.

Front Genet 2021 9;12:645688. Epub 2021 Apr 9.

Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Primaquine (PQ) is an antimalarial drug with the potential to reduce malaria transmission due to its capacity to clear mature gametocytes in the human host. However, the large-scale roll-out of PQ has to be counterbalanced by the additional risk of drug-induced hemolysis in individuals suffering from Glucose-6-phospate dehydrogenase (G6PD) deficiency, a genetic condition determined by polymorphisms on the X-linked gene. Most studies on G6PD deficiency and PQ-associated hemolysis focused on the G6PD A- variant, a combination of the two single nucleotide changes G202A (rs1050828) and A376G (rs1050829), although other polymorphisms may play a role. In this study, we tested the association of 20 G6PD single nucleotide polymorphisms (SNPs) with hemolysis measured seven days after low single dose of PQ given at the dose of 0.1 mg/kg to 0.75 mg/kg in 957 individuals from 6 previously published clinical trials investigating the safety and efficacy of this drug spanning five African countries. After adjusting for inter-study effects, age, gender, baseline hemoglobin level, PQ dose, and parasitemia at screening, our analysis showed putative association signals from the common G6PD mutation, A376G [-log(-value) = 2.44] and two less-known SNPs, rs2230037 [-log(-value] = 2.60), and rs28470352 [-log(-value) = 2.15]; A376G and rs2230037 were in very strong linkage disequilibrium with each other ( = 0.978). However, when the effects of these SNPs were included in the same regression model, the subsequent associations were in the borderline of statistical significance. In conclusion, whilst a role for the A- variant is well established, we did not observe an important additional role for other G6PD polymorphisms in determining post-treatment hemolysis in individuals treated with low single-dose PQ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.645688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062977PMC
April 2021

The Governance and Implementation of the National Action Plan on Antimicrobial Resistance in Tanzania: A Qualitative Study.

Antibiotics (Basel) 2021 Mar 9;10(3). Epub 2021 Mar 9.

Muhimbili University of Health and Allied Sciences, Dar es Salaam 65001, Tanzania.

Tanzania launched its first National Action Plan (NAP) on antimicrobial resistance (AMR) in 2017 to reduce the burden of AMR in the country and contribute to the global response. We aimed to analyze the implementation of the NAP on AMR in Tanzania using the governance framework. In-depth interviews were conducted with human and animal health practitioners and national-level policy actors. We adapted Chua's AMR governance framework to analyze the development and implementation of the NAP in Tanzania. Implementation of the NAP has realized several achievements, including: (i) the establishment of a functioning Multi-Sectoral Coordinating Committee for coordinating the implementation of AMR activities; (ii) existence of governance structure; (iii) establishment of human and animal surveillance sites; (iv) creation of AMR awareness in the community and (v) availability of guidelines at the health facility level to ensure AMR stewardship. However, some dimensions of the governance areas, including reporting and feedback mechanisms, accountability, transparency and sustainability of AMR plans, are not effectively implemented. Addressing these challenges should involve strengthening the collaboration of the different sectors involved at different NAP implementation levels by careful planning and coordination, and provision of adequate resources to ensure sustainability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antibiotics10030273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998560PMC
March 2021

Drug resistance profile and clonality of Plasmodium falciparum parasites in Cape Verde: the 2017 malaria outbreak.

Malar J 2021 Mar 31;20(1):172. Epub 2021 Mar 31.

Global Health and Tropical Medicine, GHTM, Instituto de Higiene E Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, Rua da Junqueira 100, 1349-008, Lisbon, Portugal.

Background: Cape Verde is an archipelago located off the West African coast and is in a pre-elimination phase of malaria control. Since 2010, fewer than 20 Plasmodium falciparum malaria cases have been reported annually, except in 2017, when an outbreak in Praia before the rainy season led to 423 autochthonous cases. It is important to understand the genetic diversity of circulating P. falciparum to inform on drug resistance, potential transmission networks and sources of infection, including parasite importation.

Methods: Enrolled subjects involved malaria patients admitted to Dr Agostinho Neto Hospital at Praia city, Santiago island, Cape Verde, between July and October 2017. Neighbours and family members of enrolled cases were assessed for the presence of anti-P. falciparum antibodies. Sanger sequencing and real-time PCR was used to identify SNPs in genes associated with drug resistance (e.g., pfdhfr, pfdhps, pfmdr1, pfk13, pfcrt), and whole genome sequencing data were generated to investigate the population structure of P. falciparum parasites.

Results: The study analysed 190 parasite samples, 187 indigenous and 3 from imported infections. Malaria cases were distributed throughout Praia city. There were no cases of severe malaria and all patients had an adequate clinical and parasitological response after treatment. Anti-P. falciparum antibodies were not detected in the 137 neighbours and family members tested. No mutations were detected in pfdhps. The triple mutation S108N/N51I/C59R in pfdhfr and the chloroquine-resistant CVIET haplotype in the pfcrt gene were detected in almost all samples. Variations in pfk13 were identified in only one sample (R645T, E668K). The haplotype NFD for pfmdr1 was detected in the majority of samples (89.7%).

Conclusions: Polymorphisms in pfk13 associated with artemisinin-based combination therapy (ACT) tolerance in Southeast Asia were not detected, but the majority of the tested samples carried the pfmdr1 haplotype NFD and anti-malarial-associated mutations in the the pfcrt and pfdhfr genes. The first whole genome sequencing (WGS) was performed for Cape Verdean parasites that showed that the samples cluster together, have a very high level of similarity and are close to other parasites populations from West Africa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12936-021-03708-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011132PMC
March 2021

Methylation analysis of Klebsiella pneumoniae from Portuguese hospitals.

Sci Rep 2021 Mar 22;11(1):6491. Epub 2021 Mar 22.

Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Klebsiella pneumoniae is an important nosocomial infectious agent with a high antimicrobial resistance (AMR) burden. The application of long read sequencing technologies is providing insights into bacterial chromosomal and putative extra-chromosomal genetic elements (PEGEs) associated with AMR, but also epigenetic DNA methylation, which is thought to play a role in cleavage of foreign DNA and expression regulation. Here, we apply the PacBio sequencing platform to eight Portuguese hospital isolates, including one carbapenemase producing isolate, to identify methylation motifs. The resulting assembled chromosomes were between 5.2 and 5.5Mbp in length, and twenty-six PEGEs were found. Four of our eight samples carry bla, a dominant Extended Spectrum Beta Lactamase in Europe. We identified methylation motifs that control Restriction-Modification systems, including GATC of the DNA adenine methylase (Dam), which methylates N6-methyladenine (m6A) across all our K. pneumoniae assemblies. There was a consistent lack of methylation by Dam of the GATC motif downstream of two genes: fosA, a locus associated with low level fosfomycin resistance, and tnpB transposase on IncFIB(K) plasmids. Overall, we have constructed eight high quality reference genomes of K. pneumoniae, with insights into horizontal gene transfer and methylation m6A motifs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85724-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985491PMC
March 2021

Policy actors and human and animal health practitioners' perceptions of antimicrobial use and resistance in Tanzania: A qualitative study.

J Glob Antimicrob Resist 2021 06 1;25:40-47. Epub 2021 Mar 1.

Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; Eastern and Southern Africa Centers of Excellence for Infectious Diseases of Humans and Animals (SACIDS-ACE), 3019 Morogoro, Tanzania.

Objective: To explore and describe the perceptions of policy actors and practitioners on antimicrobial use and resistance in human and animal health in Tanzania.

Methods: This was an exploratory qualitative study, which involved semi-structured interviews with nine policy makers and 102 practitioners.

Results: Improved multisectoral collaboration and coordination among experts from the animal and human sectors, government will, improved infrastructures, existence of public awareness campaigns on appropriate use of antimicrobials and existence of antimicrobial stewardship were identified as strengths for the implementation of National Action Plan on Antimicrobial Resistance (NAP-AMR) in Tanzania. Despite these strengths, insufficient public awareness of AMR, limited community engagement and inadequate human resources were among the reported weaknesses. A number of opportunities for the implementation of NAP-AMR were also reported including the presence of integrated disease surveillance and response strategy in health sector and development of a coordinated surveillance system. Furthermore, the inadequate laboratory capacity and poor resource mobilization were identified as challenges facing the implementation of NAP-AMR.

Conclusion: The future policies of AMR need to capitalize on the identified strengths and opportunities as well as design interventions to improve public awareness of AMR and community engagement, deployment of adequate human resources and ensure adequate resource mobilization to meet AMR needs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgar.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213539PMC
June 2021

Clusters of Drug-Resistant Mycobacterium tuberculosis Detected by Whole-Genome Sequence Analysis of Nationwide Sample, Thailand, 2014-2017.

Emerg Infect Dis 2021 03;27(3):813-822

Multidrug-resistant tuberculosis (MDR TB), pre-extensively drug-resistant tuberculosis (pre-XDR TB), and extensively drug-resistant tuberculosis (XDR TB) complicate disease control. We analyzed whole-genome sequence data for 579 phenotypically drug-resistant M. tuberculosis isolates (28% of available MDR/pre-XDR and all culturable XDR TB isolates collected in Thailand during 2014-2017). Most isolates were from lineage 2 (n = 482; 83.2%). Cluster analysis revealed that 281/579 isolates (48.5%) formed 89 clusters, including 205 MDR TB, 46 pre-XDR TB, 19 XDR TB, and 11 poly-drug-resistant TB isolates based on genotypic drug resistance. Members of most clusters had the same subset of drug resistance-associated mutations, supporting potential primary resistance in MDR TB (n = 176/205; 85.9%), pre-XDR TB (n = 29/46; 63.0%), and XDR TB (n = 14/19; 73.7%). Thirteen major clades were significantly associated with geography (p<0.001). Clusters of clonal origin contribute greatly to the high prevalence of drug-resistant TB in Thailand.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3201/eid2703.204364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920678PMC
March 2021

A snapshot of translation in Mycobacterium tuberculosis during exponential growth and nutrient starvation revealed by ribosome profiling.

Cell Rep 2021 Feb;34(5):108695

TB Centre and Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Electronic address:

Mycobacterium tuberculosis, which causes tuberculosis, can undergo prolonged periods of non-replicating persistence in the host. The mechanisms underlying this are not fully understood, but translational regulation is thought to play a role. A large proportion of mRNA transcripts expressed in M. tuberculosis lack canonical bacterial translation initiation signals, but little is known about the implications of this for fine-tuning of translation. Here, we perform ribosome profiling to characterize the translational landscape of M. tuberculosis under conditions of exponential growth and nutrient starvation. Our data reveal robust, widespread translation of non-canonical transcripts and point toward different translation initiation mechanisms compared to canonical Shine-Dalgarno transcripts. During nutrient starvation, patterns of ribosome recruitment vary, suggesting that regulation of translation in this pathogen is more complex than originally thought. Our data represent a rich resource for others seeking to understand translational regulation in bacterial pathogens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.108695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856553PMC
February 2021

The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957.

Sci Rep 2021 Jan 21;11(1):1888. Epub 2021 Jan 21.

Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.

New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957-a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-81343-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820608PMC
January 2021

An integrated in silico immuno-genetic analytical platform provides insights into COVID-19 serological and vaccine targets.

Genome Med 2021 01 7;13(1). Epub 2021 Jan 7.

Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

During COVID-19, diagnostic serological tools and vaccines have been developed. To inform control activities in a post-vaccine surveillance setting, we have developed an online "immuno-analytics" resource that combines epitope, sequence, protein and SARS-CoV-2 mutation analysis. SARS-CoV-2 spike and nucleocapsid proteins are both vaccine and serological diagnostic targets. Using the tool, the nucleocapsid protein appears to be a sub-optimal target for use in serological platforms. Spike D614G (and nsp12 L314P) mutations were most frequent (> 86%), whilst spike A222V/L18F have recently increased. Also, Orf3a proteins may be a suitable target for serology. The tool can accessed from: http://genomics.lshtm.ac.uk/immuno (online); https://github.com/dan-ward-bio/COVID-immunoanalytics (source code).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00822-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790334PMC
January 2021

External validation of a deep learning electrocardiogram algorithm to detect ventricular dysfunction.

Int J Cardiol 2021 04 2;329:130-135. Epub 2021 Jan 2.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address:

Objective: To validate a novel artificial-intelligence electrocardiogram algorithm (AI-ECG) to detect left ventricular systolic dysfunction (LVSD) in an external population.

Background: LVSD, even when asymptomatic, confers increased morbidity and mortality. We recently derived AI-ECG to detect LVSD using ECGs based on a large sample of patients treated at the Mayo Clinic.

Methods: We performed an external validation study with subjects from the Know Your Heart Study, a cross-sectional study of adults aged 35-69 years residing in two cities in Russia, who had undergone both ECG and transthoracic echocardiography. LVSD was defined as left ventricular ejection fraction ≤ 35%. We assessed the performance of the AI-ECG to identify LVSD in this distinct patient population.

Results: Among 4277 subjects in this external population-based validation study, 0.6% had LVSD (compared to 7.8% of the original clinical derivation study). The overall performance of the AI-ECG to detect LVSD was robust with an area under the receiver operating curve of 0.82. When using the LVSD probability cut-off of 0.256 from the original derivation study, the sensitivity, specificity, and accuracy in this population were 26.9%, 97.4%, 97.0%, respectively. Other probability cut-offs were analysed for different sensitivity values.

Conclusions: The AI-ECG detected LVSD with robust test performance in a population that was very different from that used to develop the algorithm. Population-specific cut-offs may be necessary for clinical implementation. Differences in population characteristics, ECG and echocardiographic data quality may affect test performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.12.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955278PMC
April 2021

Genetic diversity of the Plasmodium falciparum GTP-cyclohydrolase 1, dihydrofolate reductase and dihydropteroate synthetase genes reveals new insights into sulfadoxine-pyrimethamine antimalarial drug resistance.

PLoS Genet 2020 12 31;16(12):e1009268. Epub 2020 Dec 31.

Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Plasmodium falciparum parasites resistant to antimalarial treatments have hindered malaria disease control. Sulfadoxine-pyrimethamine (SP) was used globally as a first-line treatment for malaria after wide-spread resistance to chloroquine emerged and, although replaced by artemisinin combinations, is currently used as intermittent preventive treatment of malaria in pregnancy and in young children as part of seasonal malaria chemoprophylaxis in sub-Saharan Africa. The emergence of SP-resistant parasites has been predominantly driven by cumulative build-up of mutations in the dihydrofolate reductase (pfdhfr) and dihydropteroate synthetase (pfdhps) genes, but additional amplifications in the folate pathway rate-limiting pfgch1 gene and promoter, have recently been described. However, the genetic make-up and prevalence of those amplifications is not fully understood. We analyse the whole genome sequence data of 4,134 P. falciparum isolates across 29 malaria endemic countries, and reveal that the pfgch1 gene and promoter amplifications have at least ten different forms, occurring collectively in 23% and 34% in Southeast Asian and African isolates, respectively. Amplifications are more likely to be present in isolates with a greater accumulation of pfdhfr and pfdhps substitutions (median of 1 additional mutations; P<0.00001), and there was evidence that the frequency of pfgch1 variants may be increasing in some African populations, presumably under the pressure of SP for chemoprophylaxis and anti-folate containing antibiotics used for the treatment of bacterial infections. The selection of P. falciparum with pfgch1 amplifications may enhance the fitness of parasites with pfdhfr and pfdhps substitutions, potentially threatening the efficacy of this regimen for prevention of malaria in vulnerable groups. Our work describes new pfgch1 amplifications that can be used to inform the surveillance of SP drug resistance, its prophylactic use, and future experimental work to understand functional mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1009268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774857PMC
December 2020

Robust detection of point mutations involved in multidrug-resistant Mycobacterium tuberculosis in the presence of co-occurrent resistance markers.

PLoS Comput Biol 2020 12 21;16(12):e1008518. Epub 2020 Dec 21.

Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Tuberculosis disease is a major global public health concern and the growing prevalence of drug-resistant Mycobacterium tuberculosis is making disease control more difficult. However, the increasing application of whole-genome sequencing as a diagnostic tool is leading to the profiling of drug resistance to inform clinical practice and treatment decision making. Computational approaches for identifying established and novel resistance-conferring mutations in genomic data include genome-wide association study (GWAS) methodologies, tests for convergent evolution and machine learning techniques. These methods may be confounded by extensive co-occurrent resistance, where statistical models for a drug include unrelated mutations known to be causing resistance to other drugs. Here, we introduce a novel 'cannibalistic' elimination algorithm ("Hungry, Hungry SNPos") that attempts to remove these co-occurrent resistant variants. Using an M. tuberculosis genomic dataset for the virulent Beijing strain-type (n = 3,574) with phenotypic resistance data across five drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin), we demonstrate that this new approach is considerably more robust than traditional methods and detects resistance-associated variants too rare to be likely picked up by correlation-based techniques like GWAS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1008518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785249PMC
December 2020

Genomic Epidemiology of Carbapenemase Producing Strains at a Northern Portuguese Hospital Enables the Detection of a Misidentified KPC-3 Producing Strain.

Microorganisms 2020 Dec 13;8(12). Epub 2020 Dec 13.

Department of Microbiology and Immunology, Faculty of Pharmacy, Universidade de Lisboa, 1649-033 Lisboa, Portugal.

The evolutionary epidemiology, resistome, virulome and mobilome of thirty-one multidrug resistant clinical isolates from the northern Vila Real region of Portugal were characterized using whole-genome sequencing and bioinformatic analysis. The genomic population structure was dominated by two main sequence types (STs): ST147 ( = 17; 54.8%) and ST15 ( = 6; 19.4%) comprising four distinct genomic clusters. Two main carbapenemase coding genes were detected ( and ) along with additional extended-spectrum β-lactamase coding loci (, , , and ). Moreover, whole genome sequencing enabled the identification of one KPC-3 producer isolate previously misidentified as , which in addition to the carbapenemase gene, bore the chromosomal broad spectrum β-lactamase coding gene, and resistance loci. The genes were located in a transposon = 1; = 2) and isoform ( = 28). Overall, our work describes the first report of a producing as well as the detection of this species during infection control measures in surveillance cultures from infected patients. It also highlights the importance of additional control measures to overcome the clonal dissemination of carbapenemase producing clones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/microorganisms8121986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763156PMC
December 2020

Robust barcoding and identification of Mycobacterium tuberculosis lineages for epidemiological and clinical studies.

Genome Med 2020 12 14;12(1):114. Epub 2020 Dec 14.

Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Background: Tuberculosis, caused by bacteria in the Mycobacterium tuberculosis complex (MTBC), is a major global public health burden. Strain-specific genomic diversity in the known lineages of MTBC is an important factor in pathogenesis that may affect virulence, transmissibility, host response and emergence of drug resistance. Fast and accurate tracking of MTBC strains is therefore crucial for infection control, and our previous work developed a 62-single nucleotide polymorphism (SNP) barcode to inform on the phylogenetic identity of 7 human lineages and 64 sub-lineages.

Methods: To update this barcode, we analysed whole genome sequencing data from 35,298 MTBC isolates (~ 1 million SNPs) covering 9 main lineages and 3 similar animal-related species (M. tuberculosis var. bovis, M. tuberculosis var. caprae and M. tuberculosis var. orygis). The data was partitioned into training (N = 17,903, 50.7%) and test (N = 17,395, 49.3%) sets and were analysed using an integrated phylogenetic tree and population differentiation (F) statistical approach.

Results: By constructing a phylogenetic tree on the training MTBC isolates, we characterised 90 lineages or sub-lineages or species, of which 30 are new, and identified 421 robust barcoding mutations, of which a minimal set of 90 was selected that included 20 markers from the 62-SNP barcode. The barcoding SNPs (90 and 421) discriminated perfectly the 86 MTBC isolate (sub-)lineages in the test set and could accurately reconstruct the clades across the combined 35k samples.

Conclusions: The validated 90 SNPs can be used for the rapid diagnosis and tracking of MTBC strains to assist public health surveillance and control. To facilitate this, the SNP markers have now been incorporated into the TB-Profiler informatics platform ( https://github.com/jodyphelan/TBProfiler ).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00817-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734807PMC
December 2020

Combining structure and genomics to understand antimicrobial resistance.

Comput Struct Biotechnol J 2020 29;18:3377-3394. Epub 2020 Oct 29.

Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

Antimicrobials against bacterial, viral and parasitic pathogens have transformed human and animal health. Nevertheless, their widespread use (and misuse) has led to the emergence of antimicrobial resistance (AMR) which poses a potentially catastrophic threat to public health and animal husbandry. There are several routes, both intrinsic and acquired, by which AMR can develop. One major route is through non-synonymous single nucleotide polymorphisms (nsSNPs) in coding regions. Large scale genomic studies using high-throughput sequencing data have provided powerful new ways to rapidly detect and respond to such genetic mutations linked to AMR. However, these studies are limited in their mechanistic insight. Computational tools can rapidly and inexpensively evaluate the effect of mutations on protein function and evolution. Subsequent insights can then inform experimental studies, and direct existing or new computational methods. Here we review a range of sequence and structure-based computational tools, focussing on tools successfully used to investigate mutational effect on drug targets in clinically important pathogens, particularly . Combining genomic results with the biophysical effects of mutations can help reveal the molecular basis and consequences of resistance development. Furthermore, we summarise how the application of such a mechanistic understanding of drug resistance can be applied to limit the impact of AMR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.csbj.2020.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683289PMC
October 2020

Knowledge, attitudes and practices regarding antimicrobial use and resistance among communities of Ilala, Kilosa and Kibaha districts of Tanzania.

Antimicrob Resist Infect Control 2020 12 7;9(1):194. Epub 2020 Dec 7.

SACIDS Foundation for One Health, Sokoine University of Agriculture, Morogoro, Tanzania.

Background: Antimicrobial resistance (AMR) represents one of the biggest threats to health globally. This cross-sectional study determined knowledge, attitudes and practices (KAP) regarding antimicrobial use (AMU) and AMR among communities of Ilala, Kilosa and Kibaha in Tanzania.

Method: A semi-structured questionnaire was used to collect socio-demographic and KAP data through face-to-face interviews. Responses related to the triad of KAP were assigned scores that were aggregated for each participant. Linear regression analysis was conducted to determine predictors of KAP scores.

Results: The study enrolled 828 participants from the three districts. A total of 816 (98.6%) were aware of antimicrobials, and 808 (99%, n = 816) reported to have used them. Antimicrobials were mainly used to treat cough (68.0%), urinary tract infections (53.4%), diarrhoea (48.5%) and wounds (45.2%). The most frequent sources of antimicrobials were health facility (65.0%, n = 820) and pharmacies/basic drug shops (53.7%). The median AMU knowledge score was 5 (IQR = 4, 7) and that of AMR was 26 (IQR=23, 29). The median AMU attitudes score was 32 (IQR: 29, 35) and that of AMR was 19 (IQR=17, 22). The median AMU practice score was 3 (IQR: 3, 3). The KAP scores were significantly influenced by increased participant's age (β=0.10; 95% CI: 0.05, 0.15) and level of education, being lower among those with primary education (β=5.32; 95% CI: 3.27, 7.37) and highest among those with college/university education (β=9.85; 95% CI: 6.04, 13.67).

Conclusion: The study documented a moderate level of KAP regarding AMU and AMR in the study districts. The participant's age and level of education were significantly associated with participant's KAP scores. The observed inadequate knowledge, inappropriate attitude, and practices of AMU and AMR should be considered as alarming problems that require immediate actions including policy formulation and planning of community-based mitigation measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13756-020-00862-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720393PMC
December 2020

Genomic evidence supporting the clonal expansion of extensively drug-resistant tuberculosis bacteria belonging to a rare protoBeijing genotype.

Emerg Microbes Infect 2020 Dec;9(1):2632-2641

Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Tuberculosis disease (TB), caused by , is a major public health issue in Thailand. The high prevalence of modern Beijing (Lineage 2.2.1) strains has been associated with multi- and extensively drug-resistant infections (MDR-, XDR-TB), complicating disease control. The impact of rarer proto-Beijing (L2.1) strains is less clear. In our study of thirty-seven L2.1 clinical isolates spanning thirteen years, we found a high prevalence of XDR-TB cases (32.4%). With ≤ 12 pairwise SNP distances, 43.2% of L2.1 patients belong to MDR-TB or XDR-TB transmission clusters suggesting a high level of clonal expansion across four Thai provinces. All XDR-TB (100%) were likely due to transmission rather than inadequate treatment. We found a 47 mutation signature and a partial deletion of the gene in the circulating XDR-TB cluster, which can be used for surveillance of this rare and resilient strain-type that is causing increasing health burden. We also detected three novel deletion positions, a deletion of 1285 bp within (Rv3230c) large deletions in the and gene which may play a role in the virulence, pathogenesis or evolution of the L2.1 strain-type.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/22221751.2020.1852891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738298PMC
December 2020

Surveillance of Aedes aegypti populations in the city of Praia, Cape Verde: Zika virus infection, insecticide resistance and genetic diversity.

Parasit Vectors 2020 Sep 21;13(1):481. Epub 2020 Sep 21.

Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Background: Aedes spp. are responsible for the transmission of many arboviruses, which contribute to rising human morbidity and mortality worldwide. The Aedes aegypti mosquito is a main vector for chikungunya, dengue and yellow fever infections, whose incidence have been increasing and distribution expanding. This vector has also driven the emergence of the Zika virus (ZIKV), first reported in Africa which spread rapidly to Asia and more recently across the Americas. During the outbreak in the Americas, Cape Verde became the first African country declaring a Zika epidemic, with confirmed cases of microcephaly. Here we investigate the prevalence of ZIKV and dengue (DENV) infected Ae. aegypti mosquitoes in the weeks following the outbreak in Cape Verde, and the presence of insecticide resistance in the circulating vector population. Genetic diversity in the mosquito population was also analysed.

Methods: From August to October 2016, 816 Ae. aegypti mosquitoes were collected in several locations across Praia, Cape Verde, the major hot spot of reported ZIKV cases in the country. All mosquitoes were screened by reverse transcription PCR for ZIKV and DENV, and a subset (n = 220) were screened for knockdown insecticide resistance associated mutations in the voltage gated sodium channel (VGSC) gene by capillary sequencing. The mitochondrial NADH dehydrogenase subunit 4 (nad4) gene was sequenced in 100 mosquitoes. These data were compared to 977 global sequences in a haplotype network and a phylogenetic tree analysis.

Results: Two Ae. aegypti mosquitoes were ZIKV positive (0.25%). There were no SNP mutations found in the VGSC gene associated with insecticide resistance. Analysis of the nad4 gene revealed 11 haplotypes in the Cape Verdean samples, with 5 being singletons. Seven haplotypes were exclusive to Cape Verde. Several of the remaining haplotypes were frequent in the global dataset, being present in several countries (including Cape Verde) across five different continents. The most common haplotype in Cape Verde (50.6 %) was also found in Africa and South America.

Conclusions: There was low-level Zika virus circulation in mosquitoes from Praia shortly after the outbreak. The Ae. aegypti population did not appear to have the kdr mutations associated with pyrethroid resistance. Furthermore, haplotype and phylogenetic analyses revealed that Cape Verde Ae. aegypti mosquitoes are most closely related to those from other countries in Africa and South America.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13071-020-04356-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507728PMC
September 2020

Reply to Collins et al.

Clin Infect Dis 2020 Sep 16. Epub 2020 Sep 16.

Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Tongji Shanxi Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1407DOI Listing
September 2020

How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS.

Front Neurol 2020 11;11:826. Epub 2020 Aug 11.

Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.

We propose a framework for understanding and interpreting the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease. As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to singular or repeated insults, and the nature of the host response. In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium. With time variation in disease presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular feature is currently representative of all patients at different disease stages. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may support future research design and health care interventions for people with ME/CFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431524PMC
August 2020

Genetic diversity and risk factors for the transmission of antimicrobial resistance across human, animals and environmental compartments in East Africa: a review.

Antimicrob Resist Infect Control 2020 08 6;9(1):127. Epub 2020 Aug 6.

Department of Microbiology and Immunology, School of Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.

Background: The emergence and spread of antimicrobial resistance (AMR) present a challenge to disease control in East Africa. Resistance to beta-lactams, which are by far the most used antibiotics worldwide and include the penicillins, cephalosporins, monobactams and carbapenems, is reducing options for effective control of both Gram-positive and Gram-negative bacteria. The World Health Organization, Food and Agricultural Organization and the World Organization for Animal Health have all advocated surveillance of AMR using an integrated One Health approach. Regional consortia also have strengthened collaboration to address the AMR problem through surveillance, training and research in a holistic and multisectoral approach. This review paper contains collective information on risk factors for transmission, clinical relevance and diversity of resistance genes relating to extended-spectrum beta-lactamase-producing (ESBL) and carbapenemase-producing Enterobacteriaceae, and Methicillin-resistant Staphylococcus aureus (MRSA) across the human, animal and environmental compartments in East Africa.

Main Body: The review of the AMR literature (years 2001 to 2019) was performed using search engines such as PubMed, Scopus, Science Direct, Google and Web of Science. The search terms included 'antimicrobial resistance and human-animal-environment', 'antimicrobial resistance, risk factors, genetic diversity, and human-animal-environment' combined with respective countries of East Africa. In general, the risk factors identified were associated with the transmission of AMR. The marked genetic diversity due to multiple sequence types among drug-resistant bacteria and their replicon plasmid types sourced from the animal, human and environment were reported. The main ESBL, MRSA and carbapenem related genes/plasmids were the CTX-Ms (45.7%), SCCmec type III (27.3%) and IMP types (23.8%), respectively.

Conclusion: The high diversity of the AMR genes suggests there may be multiple sources of resistance bacteria, or the possible exchange of strains or a flow of genes amongst different strains due to transfer by mobile genetic elements. Therefore, there should be harmonized One Health guidelines for the use of antibiotics, as well as regulations governing their importation and sale. Moreover, the trend of ESBLs, MRSA and carbapenem resistant (CAR) carriage rates is dynamic and are on rise over time period, posing a public health concern in East Africa. Collaborative surveillance of AMR in partnership with regional and external institutions using an integrated One Health approach is required for expert knowledge and technology transfer to facilitate information sharing for informed decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13756-020-00786-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409632PMC
August 2020

Development and Validation of a Nomogram for Assessing Survival in Patients With COVID-19 Pneumonia.

Clin Infect Dis 2021 02;72(4):652-660

Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University, Shanxi Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, China.

Background: The outbreak of coronavirus disease 2019 (COVID-19) has spread worldwide and continues to threaten peoples' health as well as put pressure on the accessibility of medical systems. Early prediction of survival of hospitalized patients will help in the clinical management of COVID-19, but a prediction model that is reliable and valid is still lacking.

Methods: We retrospectively enrolled 628 confirmed cases of COVID-19 using positive RT-PCR tests for SARS-CoV-2 in Tongji Hospital, Wuhan, China. These patients were randomly grouped into a training (60%) and a validation (40%) cohort. In the training cohort, LASSO regression analysis and multivariate Cox regression analysis were utilized to identify prognostic factors for in-hospital survival of patients with COVID-19. A nomogram based on the 3 variables was built for clinical use. AUCs, concordance indexes (C-index), and calibration curves were used to evaluate the efficiency of the nomogram in both training and validation cohorts.

Results: Hypertension, higher neutrophil-to-lymphocyte ratio, and increased NT-proBNP values were found to be significantly associated with poorer prognosis in hospitalized patients with COVID-19. The 3 predictors were further used to build a prediction nomogram. The C-indexes of the nomogram in the training and validation cohorts were 0.901 and 0.892, respectively. The AUC in the training cohort was 0.922 for 14-day and 0.919 for 21-day probability of in-hospital survival, while in the validation cohort this was 0.922 and 0.881, respectively. Moreover, the calibration curve for 14- and 21-day survival also showed high coherence between the predicted and actual probability of survival.

Conclusions: We built a predictive model and constructed a nomogram for predicting in-hospital survival of patients with COVID-19. This model has good performance and might be utilized clinically in management of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454485PMC
February 2021
-->