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bioRxiv2018

GLU: A tool for analysing continuously measured glucose in epidemiology

MotivationContinuous glucose monitors (CGM) record interstitial glucose continuously, producing a sequence of measurements for each participant (e.g. the average glucose every 5 minutes over several days, both day and night). To analyze these data, researchers tend to derive summary variables such as the Area Under the Curve (AUC), to then use in subsequent analyses. To date, a lack of consistency and transparency of precise definitions used for these summary variables has hindered interpretation, replication and comparison of results across studies. We present GLU, an open-source software package for deriving a consistent set of summary variables from CGM data.\n\nGeneral featuresGLU performs quality control of each CGM sample (e.g. addressing missing data), derives a diverse set of summary variables (e.g. AUC, and proportion of time spent in hypo-, normo- and hyper-glycaemic levels) covering six broad domains, and outputs these (with quality control information) to the user.\n\nImplementationGLU is implemented in R.\n\nAVAILABILITYGLU is available on GitHub at [https://github.com/MRCIEU/GLU]. Git tag v0.1 corresponds to the version presented here.

epidemiology↗

bioRxiv2019

Elevated serum aspartate aminotransferase levels concomitant with normal alanine aminotransferase levels in older low body weight people: Preliminary findings from a community-based epidemiological study

BackgroundSerum enzyme levels, including hepatic transaminase, are unknown in older people with low body weight (LBW), who can easily experience sarcopenia. Therefore, we addressed preliminarily this issue in a cross-sectional study of an apparently healthy population. MethodsWe investigated the relationship of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and total bilirubin levels with body mass index (BMI) and age in 79,623 subjects aged 20-80 years who underwent an annual checkup. ResultsSerum levels of AST, ALP, and LDH levels were significantly higher in older ([≥]50 years) non-obese subjects compared with younger (< 50 years) corresponding subjects. Serum AST levels were significantly higher in older LBW subjects (BMI[≤]18.9 kg/m2) than in those with a reference BMI of 20.9-22.9 kg/m2. Serum AST levels showed a J-shaped curve against BMI, whereas ALT and GGT levels showed a linear relationship, regardless of age. ConclusionElevated serum AST levels concomitant with normal ALT levels, which might reflect systemic damage of skeletal muscle, may be prevalent in older LBW people. Further studies need to determine whether such a condition is equivalent to the etiology of sarcopenia.

epidemiology↗

bioRxiv2019

Epidemiology of Childhood Blindness: a Community based study in Bangladesh

This study has aimed to detect the prevalence and causes of childhood blindness in rural area of Bangladesh. A cross sectional quantitative study design was adopted for this study which carried-out in three unions (sub-districts) of Raiganj upazila of Sirajganj district of Bangladesh. Using a validated tool a screening program was conducted at household level. After initial screening a team of ophthalmologists confirmed the diagnosis by clinical examinations. The prevalence of childhood blindness found was 6.3 per 10,000 children. The rate of uni-ocular blindness was 4.8 per 10,000 children. Congenital problems were the major cause of both uniocular and binocular blindness (UOB: 84% and BB: 92% &). For binocular blindness, whole globe was the responsible site (28.0%, CI: 13.1, 47.7) and cornea was for the uni-ocular blindness (57.8%, CI: 35.3, 78.1). Childhood blindness is a public health problem in Bangladesh. Childhood blindness is common irrespective of gender. Major causes of childhood blindness are congenital.

epidemiology↗

bioRxiv2019

Descriptive epidemiology of energy expenditure in the UK: Findings from the National Diet and Nutrition Survey 2008 to 2015

BackgroundLittle is known about population levels of energy expenditure as national surveillance systems typically employ only crude measures. The National Diet and Nutrition Survey (NDNS) in the UK measures energy expenditure in a 10% subsample by gold-standard doubly-labelled water (DLW). MethodsDLW-subsample participants from the NDNS (383 males, 387 females) aged 4-91yrs were recruited between 2008 and 2015. Height and weight were measured, and bodyfat percentage was estimated by deuterium dilution. ResultsAbsolute Total Energy Expenditure (TEE) increases steadily throughout childhood, ranging from 6.3 and 7.2 MJ/day in 4-7yr-old to 9.9 and 11.8 MJ/day for 14-16yr-old girls and boys, respectively. TEE peaked in 17-27yr-old women (10.9 MJ/day) and 28-43yr-old men (14.4 MJ/day), before decreasing gradually in old age. Physical Acitivty Energy Expenditure (PAEE) declines steadily with age from childhood (87.7 kJ/day/kg in 4-7yr olds) through to old age (38.9 kJ/day/kg in 71-91yr olds). Bodyfat percentage was strongly inversely associated with PAEE throughout life, irrespective of expressing PAEE relative to bodymass or fat-free mass. Compared to females with <30% bodyfat, females >40% recorded 28 kJ/day/kg and 17 kJ/day/kg fat-free mass less PAEE in analyses adjusted for age, geographical region, and time of assessment. Similarly, compared to males with <25% bodyfat, males >35% recorded 26 kJ/day/kg and 10 kJ/day/kg fat-free mass less PAEE. ConclusionsThis first nationally representative study reports levels of human energy expenditure as measured by gold-standard methodology; values may serve as reference for other population studies. Age, sex and body composition are main biological determinants of energy expenditure. Key messagesO_LIFirst nationally representative study of human energy expenditure, covering the UK in the period 2008-2015 C_LIO_LITotal Energy Expenditure (MJ/day) increases steadily with age thoughout childhood and adolescence, peaks in the 3rd decade of life in women and 4th decade of life in men, before decreasing gradually in old age C_LIO_LIPhysical Acitivty Energy Expenditure (kJ/day/kg or kJ/day/kg fat-free mass) declines steadily with age from childhood to old age, more steeply so in males C_LIO_LIBodyfat percentage is strongly inversely associated with physical activity energy expenditure C_LI

epidemiology↗

bioRxiv2019

Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance

Plasmodium vivax invasion of human erythrocytes depends on the Duffy Binding Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number varies between P. vivax isolates, but the prevalence of PvDBP multiplications in Sub-Saharan Africa and its impact are unknown. We determined the prevalence and type of PvDBP duplications, as well as PvDBP copy number variation among 178 Ethiopian P. vivax isolates using a PCR-based diagnostic method, a novel quantitative real-time PCR assay and whole genome sequencing. For the 145 symptomatic samples, PvDBP duplications were detected in 95 isolates, of which 81 had the Cambodian and 14 Malagasy-type PvDBP duplications. PvDBP varied from 1 to >4 copies. Isolates with multiple PvDBP copies were found to be higher in symptomatic than asymptomatic infections. For the 33 asymptomatic samples, PvDBP was detected with two copies in two of the isolates, and both were the Cambodian-type PvDBP duplication. PvDBP copy number in Duffy-negative heterozygotes was not significantly different from that in Duffy-positives, providing no support for the hypothesis that increased copy number is a specific association with Duffy-negativity, although the number of Duffy-negatives was small and further sampling is required to test this association thoroughly. Author summaryPlasmodium vivax invasion of human erythrocytes relies on interaction between the Duffy antigen and P. vivax Duffy Binding Protein (PvDBP). Whole genome sequences from P. vivax field isolates in Madagascar identified a duplication of the PvDBP gene and PvDBP duplication has also been detected in non-African P. vivax-endemic countries. Two types of PvDBP duplications have been reported, termed Cambodian and Malagasy-type duplications. Our study used a combination of PCR-based diagnostic method, a novel quantitative real-time PCR assay, and whole genome sequencing to determine the prevalence and type of PvDBP duplications, as well as PvDBP copy number on a broad number of P. vivax samples in Ethiopia. We found that over 65% of P. vivax isolated from the symptomatic infections were detected with PvDBP duplications and PvDBP varied from 1 to >4 copies. The majority of PvDBP duplications belongs to the Cambodian-type while the Malagasy-type duplications was also detected. For the asymptomatic infections, despite a small sample size, the majority of P. vivax were detected with a single-copy based on both PCR and qPCR assays. There was no significant difference in PvDBP copy number between Duffy-null heterozygote and Duffy-positive homozygote/heterozygote. Further investigation is needed with expanded Duffy-null homozygotes to examine the functional significance of PvDBP expansion.

epidemiology↗

bioRxiv2019

Multiple-serotype models of dengue virus transmission: simulation study and perspectives for the application of inference in epidemiological surveillance

With around 3 billion people at risk, dengue virus is endemic to many parts of the world. In the Brazilian city of Rio de Janeiro, surveillance measures require notification of new dengue virus cases, and are supplemented by serum collection from patients and sequencing of viral RNA. Phylogenetic analyses have been performed for all serotypes circulating in the country to identify viral genotypes, potentially identify new introductions, and compare viruses presently circulating in the country with those in the past, and of other countries. As a separate type of analysis, a number of mathematical models have been developed to describe dengue virus transmission - particularly qualitative incidence or prevalence patterns - although few have been tested. In this chapter, I show how different mathematical formulations could represent transmission of dengue virus by mosquitoes to humans, how the different model structures entail assumptions about the process, and how these affect outputs qualitatively. Inference from simulated data is used as proof of principle that the kind of data available could be used to accurately estimate all model parameters; however, it is shown that stochasticity may severely hamper efforts to test the models quantitatively. I further implement inference from sequence data for the different models, and compare the performance to that of time series. The methods are applied to the data available for the city of Rio de Janeiro.

epidemiology↗

bioRxiv2019

Epidemiology of drug-resistant tuberculosis in Chongqing, China: a retrospective observational study from 2010 to 2017

China is one of the top 30 countries with high multidrug-resistant tuberculosis (MDR-TB) and rifampin-resistant tuberculosis (RR-TB) burden. Chongqing is a southwest city of China with a large rural population. A retrospective observational study has been performed based on routine tuberculosis (TB) surveillance data in Chongqing from 2010 to 2017. The MDR/RR-TB notification rate increased from 0.03 cases per 100,000 population in 2010 to 2.09 cases per 100,000 population in 2017. The extensively drug-resistant TB (XDR-TB) notification rate has increased to 0.09 cases per 100,000 population in 2017. There was a decreasing detection gap between the number of notified MDR/RR-TB cases and the estimate number of MDR/RR-TB cases among all notified TB cases. The treatment success rate of MDR/RR-TB was 50.66% in this period. The rate of MDR/RR-TB in new TB cases was 6.23%, and this rate in previously treated TB cases was 32.7%. Despite the progress achieved, the prevalence of MDR/RR-TB was still high facing challenges including detection gaps, the regional disparity, and the high risk for MDR/RR-TB in elderly people and farmers. Sustained government financing and policy support should be guaranteed in the future.

epidemiology↗

bioRxiv2016

Declaring a tuberculosis outbreak over with genomic epidemiology

We report an updated method for inferring the time at which an infectious disease was transmitted between persons from a time-labelled pathogen genome phylogeny. We applied the method to 48 Mycobacterium tuberculosis genomes as part of a real-time public health outbreak investigation, demonstrating that although active tuberculosis (TB) cases were diagnosed through 2013, no transmission events took place beyond mid-2012. Subsequent cases were the result of progression from latent TB infection to active disease and not recent transmission. This evolutionary genomic approach was used to declare the outbreak over in January 2015.

Genomics↗

bioRxiv2016

Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim. We estimate that 30% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 7.6-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 151 AJ enriched protein-altering alleles that overlap with \"pathogenic\" ClinVar alleles, including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohns disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically evaluate whether strong acting rare alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohns disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are strongly enriched in AJ, including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10-16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC to pinpoint genetic variation that contributes to variable disease predisposition across populations.

Genetics↗

bioRxiv2016

Genetic,transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimers disease.

Multiple pathogens have been detected in Alzheimers disease (AD) brains. A bioinformatics approach was used to assess relationships between pathogens and AD genes (GWAS), the AD hippocampal transcriptome and plaque or tangle proteins. Host/pathogen interactomes (C.albicans, C.Neoformans, Bornavirus, B.Burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, C.Pneumoniae, P.Gingivalis, H.Pylori, T.Gondii, T.Cruzi) significantly overlap with misregulated AD hippocampal genes, with plaque and tangle proteins and, except Bornavirus, Ebola and HERV-W, with AD genes. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi or protozoa in immunocompetent blood cells. AD genes are enriched in bone marrow and immune locations and in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance. The age of AD patients implies resistance to infections afflicting the younger. APOE4 protects against malaria and hepatitis C, and immune/inflammatory gain of function applies to APOE4, CR1, TREM2 and presenilin variants. 30/78 AD genes are expressed in the blood brain barrier (BBB), which is disrupted by AD risk factors (ageing, alcohol, aluminium, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolaemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption and smoking). The BBB and AD benefit from statins, NSAIDs, oestrogen, melatonin and the Mediterranean diet. Polymicrobial involvement is supported by the upregulation of pathogen sensors/defenders (bacterial, fungal, viral) in the AD brain, blood or CSF. Cerebral pathogen invasion permitted by BBB inadequacy, activating a hyper-efficient immune/inflammatory system, betaamyloid and other antimicrobial defence may be responsible for AD which may respond to antibiotic, antifungal or antiviral therapy.

Neuroscience↗

bioRxiv2016

SNVPhyl: A Single Nucleotide Variant Phylogenomics pipeline for microbial genomic epidemiology

MotivationThe recent widespread application of whole-genome sequencing (WGS) for microbial disease investigations has spurred the development of new bioinformatics tools, including a notable proliferation of phylogenomics pipelines designed for infectious disease surveillance and outbreak investigation. Transitioning the use of WGS data out of the research lab and into the front lines of surveillance and outbreak response requires user-friendly, reproducible, and scalable pipelines that have been well validated.\n\nResultsSNVPhyl (Single Nucleotide Variant Phylogenomics) is a bioinformatics pipeline for identifying high-quality SNVs and constructing a whole genome phylogeny from a collection of WGS reads and a reference genome. Individual pipeline components are integrated into the Galaxy bioinformatics framework, enabling data analysis in a user-friendly, reproducible, and scalable environment. We show that SNVPhyl can detect SNVs with high sensitivity and specificity and identify and remove regions of high SNV density (indicative of recombination). SNVPhyl is able to correctly distinguish outbreak from non-outbreak isolates across a range of variant-calling settings, sequencing-coverage thresholds, or in the presence of contamination.\n\nAvailabilitySNVPhyl is available as a Galaxy workflow, Docker and virtual machine images, and a Unix-based command-line application. SNVPhyl is released under the Apache 2.0 license and available at http://snvphyl.readthedocs.io/ or at https://github.com/phac-nml/snvphyl-galaxy.

bioinformatics↗

bioRxiv2016

Creating a National Vector Surveillance System: Integrated mosquito trap data and digital epidemiology

According to the World Health Organization, every year more than a billion people are infected with vector-borne diseases worldwide. There are no vaccines for most vector-borne diseases. Vector control, therefore, is often the only way to prevent outbreaks. Despite the major impact of vectors on human health, knowledge gaps exist regarding their natural population dynamics. Even the most basic information--such as spatiotemporal abundance-- is not available. Mosquitoes transmit malaria and the viruses causing Yellow Fever, West Nile, Dengue, Chikungunya, and Zika in the Americas. The Americas have a long history of mosquito control efforts, including the unsustained but successful Aedes aegypti eradication initiative. In the US, municipalities have independently created agencies for mosquito control and monitoring. We propose that the ensemble of US mosquito control agencies can, and should, be used to develop a national--and potentially international--system for Cross-Scale Vector Monitoring and Control (CSVMaC), in which local level monitoring and control efforts are cross-linked by unified real-time data streaming to build the data capital needed to gain a mechanistic understanding of vector population dynamics. Vectors, and the pathogens they transmit, know no jurisdictions. The vision of CSVMaC is, therefore, to provide data for (i) the general study of mosquito ecology and (ii) to inform vector control during epidemics/outbreaks that impact multiple jurisdictions (i.e., counties, states, etc.). We reveal >1000 mosquito control agencies in the US with enormous troves of data that are hidden among many data silos. For CSVMaC, we propose the creation of a nationally-coordinated open-access database to collate mosquito data. The database would provide scientific and public health communities with highly resolved spatiotemporal data on arboviral disease vectors, empowering new interventions and insights while leveraging pre-existing human efforts, operational infrastructure, and investments already funded by taxpayers.

ecology↗

bioRxiv2017

Genomic epidemiology of global Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli

The dissemination of carbapenem resistance in Escherichia coli has major implications for the management of common human infections. blaKPC, encoding a transmissible carbapenemase (KPC), has historically largely been associated with Klebsiella pneumoniae, a predominant plasmid (pKpQIL), and a specific transposable element (Tn4401, ~10kb). Here we characterize the genetic features of the emergence of blaKPC in global E. coli, 2008-2013, using both long-and short-read whole genome sequencing.\n\nAmongst 43/45 successfully sequenced blaKPC-E. coli strains, we identified high strain (n=21 sequence types, 18% of annotated genes in the core genome); plasmid ([≥]9 replicon types); and blaKPC-associated, mobile genetic element (MGE) diversity (50% not within complete Tn4401 elements). We also found evidence of interspecies, regional and international plasmid spread. In several cases blaKPC was found on high copy number, small Col-like plasmids, previously associated with horizontal transmission of resistance genes in the absence of antimicrobial selection pressures.\n\nE. coli is a common human pathogen, but also a commensal in a multiple environmental and animal reservoirs, and easily transmissible. The association of blaKPC with a range of MGEs previously linked to the successful spread of widely endemic resistance mechanisms (e.g. blaTEM, blaCTX-M) suggests that it is likely to become similarly prevalent.

microbiology↗

bioRxiv2017

Genetic Epidemiology And Mendelian Randomization For Informing Disease Therapeutics: Conceptual And Methodological Challenges

The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets (1-4), but this has yet to be realised at a level reflecting expectation. One reason for this, we suggest, is that GWAS to date have generally not focused on phenotypes that directly relate to the progression of disease, and thus speak to disease treatment.

genetics↗

bioRxiv2017

The Genetic Epidemiology of Developmental Dysplasia of the Hip: A Genome-Wide Association Study Harnessing National Clinical Audit Data

BackgroundDevelopmental dysplasia of the hip (DDH) is a common, heritable condition characterised by abnormal formation of the hip joint, but has a poorly understood genetic architecture due to small sample sizes. We apply a novel case-ascertainment approach using national clinical audit (NCA) data to conduct the largest DDH genome-wide association study (GWAS) to date, and replicate our findings in independent cohorts.\n\nMethodsWe used the English National Joint Registry (NJR) dataset to collect DNA and conducted a GWAS in 770 DDH cases and 3364 controls. We tested the variant most strongly associated with DDH in independent replication cohorts comprising 1129 patients and 4652 controls.\n\nResultsThe heritable component of DDH attributable to common variants was 55% and distributed similarly across autosomal and the X-chromosomes. Variation within the GDF5 gene promoter was strongly and reproducibly associated with DDH (rs143384, OR 1.44 [95% CI 1.34-1.56], p=3.55x10-22). Two further replicating loci showed suggestive association with DDH near NFIB (rs4740554, OR 1.30 [95% CI 1.16-1.45], p=4.44x10-6) and LOXL4 (rs4919218, 1.19 [1.10-1.28] p=4.38x10-6). Through gene-based enrichment we identify GDF5, UQCC1, MMP24, RETSAT and PDRG1 association with DDH (p<1.2x10-7). Using the UK Biobank and arcOGEN cohorts to generate polygenic risk scores we find that risk alleles for hip osteoarthritis explain <0.5% of the variance in DDH susceptibility.\n\nConclusionUsing the NJR as a proof-of-principle, we describe the genetic architecture of DDH and identify several candidate intervention loci and demonstrate a scalable recruitment strategy for genetic studies that is transferrable to other complex diseases.\n\nKey MessagesO_LIWe report the first genome-wide scan for DDH in a European population, and the first to use national clinical audit data for case-ascertainment in complex disease.\nC_LIO_LIThe heritable component of DDH attributable to common variants is 55% and is distributed similarly across autosomal and the X-chromosomes.\nC_LIO_LIVariation within the GDF5 gene promoter is strongly and reproducibly associated with DDH, with fine-mapping indicating rs143384 as the likely casual variant.\nC_LIO_LIEnrichment analyses implicate GDF5, UQCC1, MMP24, RETSAT and PDRG1 as candidate targets for intervention in DDH.\nC_LIO_LIDDH shares little common genetic aetiology with idiopathic osteoarthritis of the hip, despite sharing variation within the GDF5 promoter as a common risk factor.\nC_LI

genetics↗

bioRxiv2017

Epidemiology of paediatric gastrointestinal colonisation by extended spectrum cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates in north-west Cambodia

Extended-spectrum cephalosporin resistance (ESC-R) in Escherichia coli and Klebsiella pneumoniae is a healthcare threat; high gastrointestinal carriage rates are reported from South-east Asia. Colonisation prevalence data in Cambodia are lacking. We determined gastrointestinal colonisation prevalence of ESC-resistant E. coli (ESC-R-EC) and K. pneumoniae (ESC-R-KP) in Cambodian children/adolescents and associated risk factors; characterised relevant resistance genes, their genetic contexts, and the genetic relatedness of ESC-R strains using whole genome sequencing (WGS). Faeces and questionnaire data were obtained from individuals <16 years in northwestern Cambodia, 2012. WGS of cultured ESC-R-EC/KP was performed (Illumina). Maximum likelihood phylogenies were used to characterise relatedness of isolates; ESC-R-associated resistance genes and their genetic contexts were identified from de novo assemblies using BLASTn and automated/manual annotation. 82/148 (55%) of children/adolescents were ESC-R-EC/KP colonised; 12/148 (8%) were co-colonised with both species. Independent risk factors for colonisation were hospitalisation (OR: 3.12, 95%, CI [1.52-6.38]) and intestinal parasites (OR: 3.11 [1.29-7.51]); school attendance conferred decreased risk (OR: 0.44 [0.21-0.92]. ESC-R strains were diverse; the commonest ESC-R mechanisms were blaCTX-M 1 and 9 sub-family variants. Structures flanking these genes were highly variable, and for blaCTX-M-15, -55 and -27, frequently involved IS26. Chromosomal blaCTX-M integration was common in E. coli. Gastrointestinal ESC-R-EC/KP colonisation is widespread in Cambodian children/adolescents; hospital admission and intestinal parasites are independent risk factors. The genetic contexts of blaCTX-M are highly mosaic, consistent with rapid horizontal exchange. Chromosomal integration of blaCTX-M may result in stable propagation in these community-associated pathogens.

microbiology↗

bioRxiv2020

A dynamic nomenclature proposal for SARS-CoV-2 to assist genomic epidemiology

The ongoing pandemic spread of a novel human coronavirus, SARS-COV-2, associated with severe pneumonia disease (COVID-19), has resulted in the generation of thousands of virus genome sequences. The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding phylogenetic diversity of SARS-CoV-2. We present a rational and dynamic virus nomenclature that uses a phylogenetic framework to identify those lineages that contribute most to active spread. Our system is made tractable by constraining the number and depth of hierarchical lineage labels and by flagging and declassifying virus lineages that become unobserved and hence are likely inactive. By focusing on active virus lineages and those spreading to new locations this nomenclature will assist in tracking and understanding the patterns and determinants of the global spread of SARS-CoV-2.

microbiology↗

bioRxiv2020

Population genomic molecular epidemiological study of macrolide resistant Streptococcus pyogenes in Iceland,1995-2016: Identification of a large clonal population with a pbp2x mutation conferring reduced in vitro beta-lactam susceptibility

Resistance to macrolide antibiotics is a global concern in the treatment of Streptococcus pyogenes (Group A Streptococcus, GAS) infections. In Iceland, since the detection of the first macrolide-resistant isolate in 1998, three epidemic waves of macrolide-resistant GAS infections have occurred with peaks in 1999, 2004, and 2008. We conducted whole genome sequencing of all 1,575 available GAS macrolide-resistant clinical isolates of all infection types collected at the national reference laboratory in Reykjavik from 1998 to 2016. Among 1,515 erythromycin-resistant isolates, 90.3% were of only three emm types: emm4 (n = 713), emm6 (n = 324), and emm12 (n = 332), with each being predominant in a distinct epidemic peak. The antibiotic efflux pump genes, mef(A) and msr(D), were present on chimeric mobile genetic elements in 99.3% of the macrolide-resistant isolates of these emm types. Of note, in addition to macrolide resistance, virtually all emm12 isolates had a single amino acid substitution in penicillin-binding protein PBP2X that conferred a two-fold increased penicillin G and ampicillin MIC among isolates tested. We conclude that each of the three large epidemic peaks of macrolide-resistant GAS infections occurring in Iceland since 1998 was caused by the emergence and clonal expansion of progenitor strains, with macrolide resistance being conferred predominantly by inducible Mef(A)-Msr(D) drug efflux pumps. The occurrence of emm12 strains with macrolide resistance and decreased beta-lactam susceptibility was unexpected and is of public health concern. RepositoriesGenomic sequencing data for all 1,515 macrolide/erythromycin-resistant isolates were deposited into the National Center for Biotechnology Information Sequence Read Archive under bioproject accession PRJNA614628 and assembled sequences for composite elements {Phi}29854, {Phi}29862 and {Phi}29661 were deposited in Genbank under accessions ###, ### and ### respectively.

genomics↗