Association between early life antibiotic use and childhood overweight and obesity: a narrative review.

Background: Recent research implicates antibiotic use as a potential contributor to child obesity risk. In this narrative review, we examine current observational evidence on the relation between antibiotic use in early childhood and subsequent measures of child body mass. Methods: We searched PubMed, Web of Science and the Cochrane Library to identify studies that assessed antibiotic exposure before 3 years of age and subsequent measures of body mass or risk of overweight or obesity in childhood. Results: We identified 13 studies published before October 2017, based on a total of 6 81 332 individuals, which examined the relation between early life antibiotic exposure and measures of child body mass. Most studies did not appropriately account for confounding by indication for antibiotic use. Overall, we found no consistent and conclusive evidence of associations between early life antibiotic use and later child body mass [minimum overall adjusted odds ratio (aOR) reported: 1.01, 95% confidence interval (95% CI) 0.98-1.04, N = 2 60 556; maximum overall aOR reported: 2.56, 95% CI 1.36-4.79, N = 616], with no clinically meaningful increases in weight reported (maximum increase: 1.50 kg at 15 years of age). Notable methodological differences between studies, including variable measures of association and inclusion of confounders, limited more comprehensive interpretations. Conclusions: Evidence to date is insufficient to indicate that antibiotic use is an important risk factor for child obesity, or leads to clinically important differences in weight. Further comparable studies using routine clinical data may help clarify this association.This work was supported by the Wellcome Trust (grant number 206194), the African Partnership for Chronic Disease Research (Medical Research Council UK partnership grant number MR/K013491/1) and the National Institute for Health Research Cambridge Biomedical Research Centre (UK). EP is supported by the Gates Cambridge Trust

Asynchrony between virus diversity and antibody selection limits influenza virus evolution.

Funder: H2020 European Research Council; FundRef: http://dx.doi.org/10.13039/100010663; Grant(s): Naviflu:818353Seasonal influenza viruses create a persistent global disease burden by evolving to escape immunity induced by prior infections and vaccinations. New antigenic variants have a substantial selective advantage at the population level, but these variants are rarely selected within-host, even in previously immune individuals. Using a mathematical model, we show that the temporal asynchrony between within-host virus exponential growth and antibody-mediated selection could limit within-host antigenic evolution. If selection for new antigenic variants acts principally at the point of initial virus inoculation, where small virus populations encounter well-matched mucosal antibodies in previously-infected individuals, there can exist protection against reinfection that does not regularly produce observable new antigenic variants within individual infected hosts. Our results provide a theoretical explanation for how virus antigenic evolution can be highly selective at the global level but nearly neutral within-host. They also suggest new avenues for improving influenza control

Genetic and antigenic characterization of influenza A/H5N1 viruses isolated from patients in Indonesia, 2008–2015

Since the initial detection in 2003, Indonesia has reported 200 human cases of highly pathogenic avian influenza H5N1 (HPAI H5N1), associated with an exceptionally high case fatality rate (84%) compared to other geographical regions affected by other genetic clades of the virus. However, there is limited information on the genetic diversity of HPAI H5N1 viruses, especially those isolated from humans in Indonesia. In this study, the genetic and antigenic characteristics of 35 HPAI H5N1 viruses isolated from humans were analyzed. Full genome sequences were analyzed for the presence of substitutions in the receptor binding site, and p

The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2

Understanding the circumstances that lead to pandemics is important for their prevention. Here, we analyze the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted A and B. Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October–8 December), while the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans prior to November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events

Emergence and spread of two SARS-CoV-2 variants of interest in Nigeria.

Identifying the dissemination patterns and impacts of a virus of economic or health importance during a pandemic is crucial, as it informs the public on policies for containment in order to reduce the spread of the virus. In this study, we integrated genomic and travel data to investigate the emergence and spread of the SARS-CoV-2 B.1.1.318 and B.1.525 (Eta) variants of interest in Nigeria and the wider Africa region. By integrating travel data and phylogeographic reconstructions, we find that these two variants that arose during the second wave in Nigeria emerged from within Africa, with the B.1.525 from Nigeria, and then spread to other parts of the world. Data from this study show how regional connectivity of Nigeria drove the spread of these variants of interest to surrounding countries and those connected by air-traffic. Our findings demonstrate the power of genomic analysis when combined with mobility and epidemiological data to identify the drivers of transmission, as bidirectional transmission within and between African nations are grossly underestimated as seen in our import risk index estimates

Phylogenetic approaches for quantifying the genotypic diversity of influenza viruses

Wild aquatic birds are thought to be the main reservoir for Influenza A viruses, hosting the largest burden of influenza diversity generated by high frequencies of co-infection and segment reassortment. The recently emerged avian influenza viruses that spilled-over into the human population were all produced by dynamic reassortment between wild bird viruses and poultryadapted H9N2 viruses. The recruitment of poultry-adapted internal gene cassettes (i.e. the polymerase, nucleoprotein, matrix and non-structural genes) has been shown to increase the fitness of wild-bird viruses in domestic poultry populations. It is unclear whether acquisition of poultry-adapted genes by wild-bird viruses increases the probability of human infection by increased fitness in domestic poultry and associated increased transmission risk at the humananimal interface or whether it mediates improved adaptation to mammalian hosts. It is also unclear whether the recent H9N2 genotype that emerged in human infections of H7N9, H10N8 and H5N6 is the only major set of internal genes prevalently facilitating the genesis of novel reassortants of pandemic concern, or whether there are similar internal genotypes circulating. There is therefore a need to characterize the observed and unobserved genotypic diversity of the internal genes of avian influenza viruses across the global influenza ecosystem. However, this effort has been limited by the lack of a pansubtypic nomenclature to partition and describe the complex lineage distribution of the internal genes across all HA/NA-defined subtypes resulting from dynamic reassortment. The ecological and evolutionary processes that structure reassortment dynamics have also been incompletely investigated across subtypes and reservoir and non-reservoir hosts, with questions remaining regarding constraints on reassortment frequency and co-segregation bias for segments in wild birds relative to domestic birds and swine populations. The current work set out to address these questions, centrally depending on the development of an internal gene genotyping framework based on phylogenetic clustering of the respective internal gene phylogenies. A new phylogenetic clustering algorithm, PhyCLIP, was developed and described in Chapter 2 to overcome current methods’ limiting reliance on arbitrary genetic distance thresholds for cluster definition. PhyCLIP operates on the distribution of all branch lengths in the phylogeny, using this global patristic distance distribution as a pseudo-null distribution to test the within-cluster distance distribution of putative clusters against. PhyCLIP was validated on the WHO H5Nx clade nomenclature to identify evolutionarily informative clusters in viral phylogenies. PhyCLIP was applied to develop a pansubtypic genotyping nomenclature for the internal genes of avian influenza in Chapter Three in a globally representative dataset of n=14 428 sequences and n=120 subtypes. The system designated 4763 genotypes, with their diversity quantified across spatiotemporal, host and subtype scales. Genotypic diversity was significantly unevenly distributed, with wild birds in North America accounting for 45% of all designated genotypes and subtypes H4N6 and H3N8 for 11% each. Approximately 69% of the genotypes were singletons, reflecting the high reassortment frequency in the natural reservoir. The evolutionary pathways generating genotypes infecting humans was also described using the lineage-assignment of the new system, allowing for more complete tracing of progenitor genotypes across subtypes and identification of lineage distinctions between human viruses. Chapter 4 quantified reassortment frequencies in the pansubtypic dataset of avian and swine influenza with a new algorithm, DeviantChild. DeviantChild quantifies phylogenetic incongruency as a measure of reassortment frequency based on PhyCLIP’s phylogenetic clustering and patristic distance distributional shift testing. DeviantChild detected extensive reassortment in the avian influenza dataset and no strong evidence of reassortment bias among segments on a population scale, supporting evidence of predominantly free reassortment of the internal genes. Reassortment was twice and three times as high in the natural reservoir Anseriformes hosts relative to shorebirds and domestic gallinaceous poultry, with the lowest reassortment frequencies reported for H5Nx, H7Nx and H9Nx viruses in gallinaceous poultry. There was evidence of segregated gene flow for the H13 and H16 subtypes in shorebird populations, supported by evidence from the genotypic diversity distribution of gull-restricted genotypes. Chapter five used the genotype distribution and a comprehensive suite of diversity measurements, accounting for sampling heterogeneity to characterise the patterns of unobserved diversity across HA-NA subtype, geographic region and host order. It identified a subset of low pathogenic viruses including H4N6, H3N8, H1N1, H6N1 and H6N2 estimated to have very high levels of undetected diversity in wild bird hosts. It also identified wild birds in China, Guatemala and Japan as major sources of undersampled diversity, as well as domestic poultry in Bangladesh, Pakistan and H5N2 in the USA

Phylogenetic Clustering by Linear Integer Programming (PhyCLIP)

Subspecies nomenclature systems of pathogens are increasingly based on sequence data. The use of phylogenetics to identify and differentiate between clusters of genetically similar pathogens is particularly prevalent in virology from the nomenclature of human papillomaviruses to highly pathogenic avian influenza (HPAI) H5Nx viruses. These nomenclature systems rely on absolute genetic distance thresholds to define the maximum genetic divergence tolerated between viruses designated as closely related. However, the phylogenetic clustering methods used in these nomenclature systems are limited by the arbitrariness of setting intra and intercluster diversity thresholds. The lack of a consensus ground truth to define well-delineated, meaningful phylogenetic subpopulations amplifies the difficulties in identifying an informative distance threshold. Consequently, phylogenetic clustering often becomes an exploratory, ad hoc exercise. Phylogenetic Clustering by Linear Integer Programming (PhyCLIP) was developed to provide a statistically principled phylogenetic clustering framework that negates the need for an arbitrarily defined distance threshold. Using the pairwise patristic distance distributions of an input phylogeny, PhyCLIP parameterizes the intra and intercluster divergence limits as statistical bounds in an integer linear programming model which is subsequently optimized to cluster as many sequences as possible. When applied to the hemagglutinin phylogeny of HPAI H5Nx viruses, PhyCLIP was not only able to recapitulate the current WHO/OIE/FAO H5 nomenclature system but also further delineated informative higher resolution clusters that capture geographically distinct subpopulations of viruses. PhyCLIP is pathogen-agnostic and can be generalized to a wide variety of research questions concerning the identification of biologically informative clusters in pathogen phylogenies. PhyCLIP is freely available at http://github.com/alvinxhan/PhyCLIP, last accessed March 15, 2019

Asynchrony between virus diversity and antibody selection limits influenza virus evolution

Seasonal influenza viruses create a persistent global disease burden by evolving to escape immunity induced by prior infections and vaccinations. New antigenic variants have a substantial selective advantage at the population level, but these variants are rarely selected within-host, even in previously immune individuals. We find that the temporal asynchrony between within-host virus exponential growth and antibody-mediated selection can limit within-host antigenic evolution. If selection for new antigenic variants acts principally at the point of initial virus inoculation, where small virus populations encounter well-matched mucosal antibodies in previously infected individuals, there can exist protection against reinfection that does not regularly produce observable new antigenic variants within individual infected hosts. Our results explain how virus antigenic evolution can be highly selective at the global level but nearly neutral within hosts. They also suggest new avenues for improving influenza control

Hepatitis C Virus Transmission Among Men Who Have Sex With Men in Amsterdam: External Introductions May Complicate Microelimination Efforts

BACKGROUND: It is unclear whether unrestricted access and high uptake of direct-acting antivirals (DAAs) is sufficient to eliminate hepatitis C virus (HCV) in high-risk populations such as men who have sex with men (MSM). This study presents historic trends and current dynamics of HCV transmission among MSM in Amsterdam based on sequence data collected between 1994 and 2019. METHODS: Hypervariable region 1 sequences of 232 primary HCV infections and 56 reinfections were obtained from 244 MSM in care in Amsterdam. Maximum-likelihood phylogenies were constructed for HCV genotypes separately, and time-scaled phylogenies were constructed using a Bayesian coalescent approach. Transmission clusters were determined by Phydelity and trends in the proportion of unclustered sequences over time were evaluated using logistic regression. RESULTS: Seventy-six percent (218/288) of sequences were part of 21 transmission clusters and 13 transmission pairs. Transmission cluster sizes ranged from 3 to 44 sequences. Most clusters were introduced between the late 1990s and early 2010s and no new clusters were introduced after 2012. The proportion of unclustered sequences of subtype 1a, the most prevalent subtype in this population, fluctuated between 0% and 20% in 2009-2012, after which an increase occurred from 0% in 2012 to 50% in 2018. CONCLUSIONS: The proportion of external introductions of HCV infections among MSM in Amsterdam has recently increased, coinciding with high DAA uptake. Frequent international transmission events will likely complicate local microelimination efforts. Therefore, international collaboration combined with international scale-up of prevention, testing, and treatment of HCV infections (including reinfections) is warranted, in particular for local microelimination efforts