Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial
Contributors: Arzika, Ahmed M, Maliki, Ramatou, Boubacar, Nameywa, Kane, Salissou, Cotter, Sun Y, Lebas, Elodie, Cook, Catherine, Bailey, Robin, West, Sheila K, Rosenthal, Philip J
... Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malaria.
Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs
Contributors: Phelan, Jody, O’Sullivan, Denise M, Machado, Diana, Ramos, Jorge, Oppong, Yaa EA, Campino, Susana, O’Grady, Justin, McNerney, Ruth, Hibberd, Martin L, Viveiros, Miguel
... Mycobacterium tuberculosis resistance to anti-tuberculosis drugs is a major threat to global public health. Whole genome sequencing (WGS) is rapidly gaining traction as a diagnostic tool for clinical tuberculosis settings. To support this informatically, previous work led to the development of the widely used TBProfiler webtool, which predicts resistance to 14 drugs from WGS data. However, for accurate and rapid high throughput of samples in clinical or epidemiological settings, there is a need for a stand-alone tool and the ability to analyse data across multiple WGS platforms, including Oxford Nanopore MinION.
Contributors: Wick, Ryan R, Judd, Louise M, Holt, Kathryn E.
... Basecalling, the computational process of translating raw electrical signal to nucleotide sequence, is of critical importance to the sequencing platforms produced by Oxford Nanopore Technologies (ONT). Here, we examine the performance of different basecalling tools, looking at accuracy at the level of bases within individual reads and at majority-rule consensus basecalls in an assembly. We also investigate some additional aspects of basecalling: training using a taxon-specific dataset, using a larger neural network model and improving consensus basecalls in an assembly by additional signal-level analysis with Nanopolish.
Contributors: Smith, Catherine M, Allen, David J., Nawaz, Sameena, Kozlakidis, Zisis, Nastouli, Eleni, Hayward, Andrew, Ward, Katherine N.
... Background: Healthcare-associated infections represent a major threat to patient, staff and visitor safety. Identification of episodes that are likely to have resulted from nosocomial transmission has important implications for infection control. Routinely collected data on ward admissions and sample dates, combined with pathogen genomic information could provide useful insights. We describe a novel, open-source, application for visualising these data, and demonstrate its utility for investigating nosocomial transmission using a case study of a large outbreak of norovirus infection. Methods: We developed the application using Shiny, a web application framework for R. For the norovirus case study, cases were defined as patients who had a faecal sample collected at the hospital in a winter season that tested positive for norovirus. Patient demographics and ward admission dates were extracted from hospital systems. Detected norovirus strains were genotyped and further characterised through sequencing of the hypervariable P2 domain. The most commonly detected sub-strain was visualised using the interactive application. Results: There were 156 norovirus-positive specimens collected from 107 patients. The most commonly detected sub-strain affected 30 patients in five wards. We used the interactive application to produce three visualisations: a bar chart, a timeline, and a schematic ward plan highlighting plausible transmission links. Visualisations showed credible links between cases on the elderly care ward. Conclusions: Use of the interactive application provided insights into transmission in this large nosocomial outbreak of norovirus, highlighting where infection control practices worked well or could be improved. This is a flexible tool that could be used for investigation of any infection in any hospital by interactively changing parameters. Challenges include integration with hospital systems for extracting data. Prospective use of this application could inform better infection control in real time.
Modelling pathogen load dynamics to elucidate mechanistic determinants of host–Plasmodium falciparum interactions
Contributors: Georgiadou, Athina, Lee, Hyun Jae, Walther, Michael, van Beek, Anna E, Fitriani, Fadlila, Wouters, Diana, Kuijpers, Taco W, Nwakanma, Davis, Dalessandro, Umberto, Riley, Eleanor
... During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of the mechanisms of disease and protection. We sought to model the contributions of the parasite multiplication rate and host response to observed parasite load in individual subjects infected with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in cases of severe malaria, with severe anaemia being more insidious than cerebral malaria. We predicted that parasite-growth inhibition was associated with platelet consumption, lower expression of CXCL10 and type 1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. The parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host–pathogen interactions and identify mechanistic correlates of protection.
Methods to generate and validate a Pregnancy Register in the UK Clinical Practice Research Datalink primary care database
Contributors: Minassian, Caroline, Williams, Rachael, Meeraus, Wilhelmine H, Smeeth, Liam, Campbell, Oona MR, Thomas, Sara
... Primary care databases are increasingly used for researching pregnancy, eg, the effects of maternal drug exposures. However, ascertaining pregnancies, their timing, and outcomes in these data is challenging. While individual studies have adopted different methods, no systematic approach to characterise all pregnancies in a primary care database has yet been published. Therefore, we developed a new algorithm to establish a Pregnancy Register in the UK Clinical Practice Research Datalink (CPRD) GOLD primary care database.
Common Genetic Variations Associated with the Persistence of Immunity following Childhood Immunization
Contributors: O’Connor, Daniel, Png, Eileen, Khor, Chiea Chuen, Snape, Matthew D, Hill, Adrian VS, van der Klis, Fiona, Hoggart, Clive, Levin, Michael, Hibberd, Martin L., Pollard, Andrew J
... Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood. Yet, there is considerable variability in the magnitude and persistence of vaccine-induced immunity. Maintenance of specific antibody is essential for continuity of vaccine-induced serological protection. We conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT) vaccines. We detail associations between variants in a locus containing a family of signal-regulatory proteins and the persistence MenC immunity. We postulate a regulatory role for the lead SNP, with supporting epigenetic and expression quantitative trait loci data. Furthermore, we define associations between SNPs in the human leukocyte antigen (HLA) locus and the persistence of TT-specific immunity. Moreover, we describe four classical HLA alleles, HLA DRB1∗0301, HLA DQB1∗0201, HLA DQB1∗0602, and HLA DRB1∗1501, associated with TT-specific immunity, independent of the lead SNP association.
Contributors: Messina, Jane P, Brady, Oliver J, Golding, Nick, Kraemer, Moritz UG, Wint, G R William, Ray, Sarah E, Pigott, David M, Shearer, Freya M, Johnson, Kimberly, Earl, Lucas
... Dengue is a mosquito-borne viral infection that has spread throughout the tropical world over the past 60 years and now affects over half the world’s population. The geographical range of dengue is expected to further expand due to ongoing global phenomena including climate change and urbanization. We applied statistical mapping techniques to the most extensive database of case locations to date to predict global environmental suitability for the virus as of 2015. We then made use of climate, population and socioeconomic projections for the years 2020, 2050 and 2080 to project future changes in virus suitability and human population at risk. This study is the first to consider the spread of Aedes mosquito vectors to project dengue suitability. Our projections provide a key missing piece of evidence for the changing global threat of vector-borne disease and will help decision-makers worldwide to better prepare for and respond to future changes in dengue risk.
Genetic dissociation of three antigenic genes in Plasmodium ovale curtisi and Plasmodium ovale wallikeri
Contributors: Saralamba, Naowarat, Nosten, Francois, Sutherland, Colin J., Paula Arez, Ana, Snounou, Georges, White, Nicholas J, Day, Nicholas PJ, Dondorp, Arjen M, Imwong, Mallika
... Plasmodium ovale curtisi and Plasmodium ovale wallikeri are two sympatric human malaria species prevalent in Africa, Asia and Oceania. The reported prevalence of both P. ovale spp. was relatively low compared to other malaria species, but more sensitive molecular detection techniques have shown that asymptomatic low-density infections are more common than previously thought. Whole genome sequencing of both P. ovale spp. revealed genetic dissociation between P. ovale curtisi and P. ovale wallikeri suggesting a species barrier. In this study we further evaluate such a barrier by assessing polymorphisms in the genes of three vaccine candidate surface protein: circumsporozoite protein/ thrombospondin-related anonymous-related protein (ctrp), circumsporozoite surface protein (csp) and merozoite surface protein 1 (msp1). The complete coding sequence of ctrp and csp, and a partial fragment of msp1 were isolated from 25 P. ovale isolates and compared to previously reported reference sequences. A low level of nucleotide diversity (Pi = 0.02–0.10) was observed in all three genes. Various sizes of tandem repeats were observed in all ctrp, csp and msp1 genes. Both tandem repeat unit and nucleotide polymorphism in all three genes exhibited clear dimorphism between P. ovale curtisi and P. ovale wallikeri, supporting evidence of non-recombination between these two species.
Characterizing herpes simplex virus type 1 and type 2 seroprevalence declines and epidemiological association in the United States
Contributors: Chemaitelly, Hiam, Nagelkerke, Nico, Omori, Ryosuke, Abu-Raddad, Laith J
... Assessing the epidemiological association between herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections in the United States, and characterizing the trends in the standardized HSV-1 and HSV-2 antibody prevalences (seroprevalences), 1999–2016.