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Department of Veterinary Medicine

Cambridge Veterinary School

The mobility of the brachycephalic canine nostril in relation to the degree of nostril stenosis

Latest publications - Sat, 24/02/2024 - 11:00

Vet J. 2024 Feb 22:106085. doi: 10.1016/j.tvjl.2024.106085. Online ahead of print.


Previous studies have shown that the most reliable external conformational risk factor of whether a brachycephalic dog will develop Brachycephalic Obstructive Airway Syndrome (BOAS) is the status of nostril stenosis, assessed as a static observation using the brachycephalic nostril grading scheme. The nostrils however are a dynamic structure, opening further when the dog is exercising, sniffing or panting. The hypothesis of this study was that brachycephalic dogs with open or mildly stenotic nostrils are more likely to have nostril mobility whilst dogs with moderately or severely stenotic nostrils are more likely to have immobile nostrils. A retrospective study of dogs presented for BOAS assessment at two UK referral centres between 2012-2020 was performed. Data extracted included nares stenosis status and nares mobility. A mesocephalic pilot control group was recruited from a third referral centre. Statistical analysis was performed with χ2, Cochran-Armitage, spearman's rho and linear-by-linear tests as appropriate. Of the 974 brachycephalic dogs included in the study: 124 had open nostrils (68.5% mobile); 212 mildly stenotic nostrils (58.5% mobile); 379 moderately stenotic nostrils (35% mobile) and 259 severely stenotic nostrils (19.3% mobile). The nostril stenotic status was significantly associated with nostril wing mobility (χ2 =135.55; P<0.0001). When considering open and mildly stenotic (considered acceptable) nostrils versus moderate and severely stenotic nostrils, mobility was 62% versus 25.5% (χ2= 135.88; P = <0.0001). All 27 mesocephalic dogs had nostril mobility. Brachycephalic dogs with moderate and severely stenotic nares have reduced nasal mobility compared to brachycephalic dogs with mildly stenotic and open nares. Data is further evidence that dogs with moderately and severely stenotic nares should not be bred.

PMID:38401643 | DOI:10.1016/j.tvjl.2024.106085

A Practical Guide to Full Value of Vaccine Assessments

Latest publications - Sat, 24/02/2024 - 11:00

Vaccines (Basel). 2024 Feb 16;12(2):201. doi: 10.3390/vaccines12020201.


Articulating the wide range of health, social and economic benefits that vaccines offer may help to overcome obstacles in the vaccine development pipeline. A framework to guide the assessment and communication of the value of a vaccine-the Full Value of Vaccine Assessment (FVVA)-has been developed by the WHO. The FVVA framework offers a holistic assessment of the value of vaccines, providing a synthesis of evidence to inform the public health need of a vaccine, describing the supply and demand aspects, its market and its impact from a health, financial and economic perspective. This paper provides a practical guide to how FVVAs are developed and used to support investment in vaccines, ultimately leading to sustained implementation in countries. The FVVA includes a range of elements that can be broadly categorised as synthesis, vaccine development narrative and defining vaccine impact and value. Depending on the features of the disease/vaccine in question, different elements may be emphasised; however, a standardised set of elements is recommended for each FVVA. The FVVA should be developed by an expert group who represent a range of stakeholders, perspectives and geographies and ensure a fair, coherent and evidence-based assessment of vaccine value.

PMID:38400184 | DOI:10.3390/vaccines12020201

Comparative analysis of tuberculin and defined antigen skin tests for detection of bovine tuberculosis in buffaloes (Bubalus bubalis) in Haryana state, India

Latest publications - Fri, 23/02/2024 - 11:00

BMC Vet Res. 2024 Feb 23;20(1):65. doi: 10.1186/s12917-024-03913-3.


BACKGROUND: Bovine tuberculosis (bTB) is a chronic disease that results from infection with any member of the Mycobacterium tuberculosis complex. Infected animals are typically diagnosed with tuberculin-based intradermal skin tests according to World Organization of Animal Health which are presently in use. However, tuberculin is not suitable for use in BCG-vaccinated animals due to a high rate of false-positive reactions. Peptide-based defined skin test (DST) antigens have been identified using antigens (ESAT-6, CFP-10 and Rv3615c) which are absent from BCG, but their performance in buffaloes remains unknown. To assess the comparative performance of DST with the tuberculin-based single intradermal test (SIT) and the single intradermal comparative cervical test (SICCT), we screened 543 female buffaloes from 49 organized dairy farms in two districts of Haryana state in India.

RESULTS: We found that 37 (7%), 4 (1%) and 18 (3%) buffaloes were reactors with the SIT, SICCT and DST tests, respectively. Of the 37 SIT reactors, four were positive with SICCT and 12 were positive with the DST. The results show that none of the animals tested positive with all three tests, and 6 DST positive animals were SIT negative. Together, a total of 43 animals were reactors with SIT, DST, or both, and the two assays showed moderate agreement (Cohen's Kappa 0.41; 95% Confidence Interval (CI): 0.23, 0.59). In contrast, only slight agreement (Cohen's Kappa 0.18; 95% CI: 0.02, 0.34) was observed between SIT and SICCT. Using a Bayesian latent class model, we estimated test specificities of 96.5% (95% CI, 92-99%), 99.7% (95% CI: 98-100%) and 99.0% (95% CI: 97-100%) for SIT, SICCT and DST, respectively, but considerably lower sensitivities of 58% (95% CI: 35-87%), 9% (95% CI: 3-21%), and 34% (95% CI: 18-55%) albeit with broad and overlapping credible intervals.

CONCLUSION: Taken together, our investigation suggests that DST has a test specificity comparable with SICCT, and sensitivity intermediate between SIT and SICCT for the identification of buffaloes suspected of tuberculosis. Our study highlights an urgent need for future well-powered trials with detailed necropsy, with immunological and microbiological profiling of reactor and non-reactor animals to better define the underlying factors for the large observed discrepancies in assay performance, particularly between SIT and SICCT.

PMID:38395846 | DOI:10.1186/s12917-024-03913-3

Transdisciplinary approaches to addressing factors that influence antimicrobial use in dairy cattle: A scoping review

Latest publications - Wed, 21/02/2024 - 11:00

Heliyon. 2024 Feb 8;10(4):e25550. doi: 10.1016/j.heliyon.2024.e25550. eCollection 2024 Feb 29.


Interest in antimicrobial resistance (AMR) associated with livestock farming is increasing. During the 1990s, 30-40 academic papers a year on the use of antibiotics in dairy farming were indexed on the scientific database PubMed, but this has grown to more than 200 a year in the 2020s. Most (85%) of these papers are published in veterinary or livestock science journals. There has been a corresponding increase in social science interest in why responsible antibiotic stewardship in the livestock sector is so challenging. However, most social science insights are published in journals specific to the lead authors' field(s), missing opportunities for knowledge translation to veterinary and animal science. This threatens to inhibit the transdisciplinary One Health approaches required to tackle the problem. Between 1 June and 31 December 2021, we undertook a scoping review of papers on the use of antibiotics in dairy farming indexed in PubMed, Scopus and Web of Science. Our aim was to identify studies that incorporate social science approaches and methodologies, and to note the main field of the journal in which these studies are published. Papers were most likely to be published in veterinary science, dairy science and/or livestock science journals (61, 29 and 18 respectively out of 127 papers) and were most likely to be concerned with antibiotic use, prescribing practice, and/or diagnosis (94%, 39% and 33% of included papers respectively). Only 27% of papers meeting our inclusion criteria included a qualitative approach to understanding reasons for antibiotic use. Even fewer acknowledged underlying drivers of behaviour, whereas such reasons are frequently highlighted in social science literature. Thus, to address the global health threat from antibiotic resistance, more work is needed to bring together the disparate but equally valid disciplines, methodologies and researchers working on antibiotic use in the livestock sector.

PMID:38379999 | PMC:PMC10877173 | DOI:10.1016/j.heliyon.2024.e25550

Development of an indirect ELISA for the serodiagnosis of canine infection by Onchocerca lupi

Latest publications - Fri, 09/02/2024 - 11:00

Sci Rep. 2024 Feb 9;14(1):3348. doi: 10.1038/s41598-024-53759-w.


Onchocerca lupi is a zoonotic filarioid parasite of dogs and cats with widespread distribution. A specific non-invasive diagnostic assay for the detection of O. lupi infections remains unavailable. This study aimed to assess the accuracy, specificity, and sensitivity of an ELISA test designed using nine peptides from two O. lupi proteins. Sera (n = 54) collected from O. lupi infected dogs from endemic areas (Portugal and USA), alongside sera from dogs positive for Dirofilaria immitis, D. repens, Cercopithifilaria bainae, and Acanthocheilonema reconditum (n = 53) from a non-endemic area for O. lupi, as well as from helminth-free dogs (n = 60), were tested. The checkerboard titration method was applied for the optimization of peptide concentrations and conjugate anti-dog dilutions. Sensitivity, specificity, and optimal cut-off values were calculated using ROC curve analysis. All peptides reacted against sera of O. lupi, with no correlation between optic density (OD) values and microfilariae (mfs) loads. Sensitivity and specificity values ranging from 85.45 to 100%, and 88.89% to 100%, respectively, were recorded for all peptides examined, with 100% specificity and sensitivity observed for peptides 40_3, 40_5, 130_3, 120_3 and 40_1, 130_5, respectively. The maximum cut-off value was observed for peptides 40_5 (0.765) and 40_3 (0.708). Testing of sera from dogs positive for other filarioids resulted in lower OD values (up to 1.565) for peptides 40_3 and 40_5 when compared with O. lupi (up to 2.929). The availability of this assay will be of value in epidemiological studies of canine O. lupi infection in both endemic and non-endemic areas, and in assessing the risk for zoonotic transmission.

PMID:38336818 | DOI:10.1038/s41598-024-53759-w

Seroepidemiological and biomolecular survey on <em>Toxoplasma gondii</em> in Sardinian wild boar (<em>Sus scrofa</em>)

Latest publications - Wed, 07/02/2024 - 11:00

Food Waterborne Parasitol. 2024 Jan 26;34:e00222. doi: 10.1016/j.fawpar.2024.e00222. eCollection 2024 Mar.


Toxoplasma gondii is a zoonotic parasite able of infecting all warm-blooded animals. Toxoplasmosis is one of the major foodborne diseases globally. The consumption of wild boar (Sus scrofa) meat from recreational hunting has been linked to outbreaks of human toxoplasmosis. The island of Sardinia (Italy) contains a large wild boar population, thus providing an opportunity to assess the distribution of Toxoplasma in this species and the associated risks of transmission to humans. A total of 562 wild boars were screened: heart and meat juice samples were tested for T. gondii DNA via nested-PCR and IgG anti-Toxoplasma by commercial ELISA. Anti-Toxoplasma IgG were detected in 24.6% (138/562) of animals, while 37.2% (209/562) of the heart samples were PCR positive. The prevalence of T. gondii antibodies and DNA highlights the potential role of wild boar as an important reservoir for this parasite. The study suggests that wild boar could play a significant role in spreading the parasite to humans. As wild boar numbers are increasing throughout their range, their potential role in transmitting toxoplasmosis should be communicated to stakeholders, and the impact of different population control methods on disease transmission should be thoroughly assessed to mitigate potential threats effectively.

PMID:38323095 | PMC:PMC10844814 | DOI:10.1016/j.fawpar.2024.e00222

Immunological insights into COVID-19 in Southern Nigeria

Latest publications - Wed, 07/02/2024 - 11:00

Front Immunol. 2024 Jan 23;15:1305586. doi: 10.3389/fimmu.2024.1305586. eCollection 2024.


INTRODUCTION: One of the unexpected outcomes of the COVID-19 pandemic was the relatively low levels of morbidity and mortality in Africa compared to the rest of the world. Nigeria, Africa's most populous nation, accounted for less than 0.01% of the global COVID-19 fatalities. The factors responsible for Nigeria's relatively low loss of life due to COVID-19 are unknown. Also, the correlates of protective immunity to SARS-CoV-2 and the impact of pre-existing immunity on the outcome of the COVID-19 pandemic in Africa are yet to be elucidated. Here, we evaluated the natural and vaccine-induced immune responses from vaccinated, non-vaccinated and convalescent individuals in Southern Nigeria throughout the three waves of the COVID-19 pandemic in Nigeria. We also examined the pre-existing immune responses to SARS-CoV-2 from samples collected prior to the COVID-19 pandemic.

METHODS: We used spike RBD and N- IgG antibody ELISA to measure binding antibody responses, SARS-CoV-2 pseudotype assay protocol expressing the spike protein of different variants (D614G, Delta, Beta, Omicron BA1) to measure neutralizing antibody responses and nucleoprotein (N) and spike (S1, S2) direct ex vivo interferon gamma (IFNγ) T cell ELISpot to measure T cell responses.

RESULT: Our study demonstrated a similar magnitude of both binding (N-IgG (74% and 62%), S-RBD IgG (70% and 53%) and neutralizing (D614G (49% and 29%), Delta (56% and 47%), Beta (48% and 24%), Omicron BA1 (41% and 21%)) antibody responses from symptomatic and asymptomatic survivors in Nigeria. A similar magnitude was also seen among vaccinated participants. Interestingly, we revealed the presence of preexisting binding antibodies (N-IgG (60%) and S-RBD IgG (44%)) but no neutralizing antibodies from samples collected prior to the pandemic.

DISCUSSION: These findings revealed that both vaccinated, non-vaccinated and convalescent individuals in Southern Nigeria make similar magnitude of both binding and cross-reactive neutralizing antibody responses. It supported the presence of preexisting binding antibody responses among some Nigerians prior to the COVID-19 pandemic. Lastly, hybrid immunity and heterologous vaccine boosting induced the strongest binding and broadly neutralizing antibody responses compared to vaccine or infection-acquired immunity alone.

PMID:38322252 | PMC:PMC10844438 | DOI:10.3389/fimmu.2024.1305586

Identification of Campylobacter jejuni and Campylobacter coli genes contributing to oxidative stress response using TraDIS analysis

Latest publications - Fri, 02/02/2024 - 11:00

BMC Microbiol. 2024 Feb 1;24(1):46. doi: 10.1186/s12866-024-03201-y.


BACKGROUND: Campylobacter jejuni and Campylobacter coli are the major causative agents of bacterial gastroenteritis worldwide and are known obligate microaerophiles. Despite being sensitive to oxygen and its reduction products, both species are readily isolated from animal food products kept under atmospheric conditions where they face high oxygen tension levels.

RESULTS: In this study, Transposon Directed Insertion-site Sequencing (TraDIS) was used to investigate the ability of one C. jejuni strain and two C. coli strains to overcome oxidative stress, using H2O2 to mimic oxidative stress. Genes were identified that were required for oxidative stress resistance for each individual strain but also allowed a comparison across the three strains. Mutations in the perR and ahpC genes were found to increase Campylobacter tolerance to H2O2. The roles of these proteins in oxidative stress were previously known in C. jejuni, but this data indicates that they most likely play a similar role in C. coli. Mutation of czcD decreased Campylobacter tolerance to H2O2. The role of CzcD, which functions as a zinc exporter, has not previously been linked to oxidative stress. The TraDIS data was confirmed using defined deletions of perR and czcD in C. coli 15-537360.

CONCLUSIONS: This is the first study to investigate gene fitness in both C. jejuni and C. coli under oxidative stress conditions and highlights both similar roles for certain genes for both species and highlights other genes that have a role under oxidative stress.

PMID:38302896 | DOI:10.1186/s12866-024-03201-y

Temporal dynamics of the early immune response following Mycobacterium bovis infection of cattle

Latest publications - Wed, 31/01/2024 - 11:00

Sci Rep. 2024 Jan 31;14(1):2600. doi: 10.1038/s41598-024-52314-x.


Bovine tuberculosis is an infectious disease of global significance that remains endemic in many countries. Mycobacterium bovis infection in cattle is characterized by a cell-mediated immune response (CMI) that precedes humoral responses, however the timing and trajectories of CMI and antibody responses determined by newer generation assays remain undefined. Here we used defined-antigen interferon-gamma release assays (IGRA) and an eleven-antigen multiplex ELISA (Enferplex TB test) alongside traditional tuberculin-based IGRA and IDEXX M. bovis antibody tests to assess immune trajectories following experimental M. bovis infection of cattle. The results show CMI responses developed as early as two-weeks post-infection, with all infected cattle testing positive three weeks post-infection. Interestingly, 6 of 8 infected animals were serologically positive with the Enferplex TB assay as early as 4 weeks post-infection. As expected, application of the tuberculin skin test enhanced subsequent serological reactivity. Infrequent M. bovis faecal shedding was observed but was uncorrelated with observed immune trajectories. Together, the results show that early antibody responses to M. bovis infection are detectable in some individuals and highlight an urgent need to identify biomarkers that better predict infection outcomes, particularly for application in low-and-middle income countries where test-and-slaughter based control methods are largely unfeasible.

PMID:38297023 | DOI:10.1038/s41598-024-52314-x

Segmental aplasia of the paramesonephric duct in a New Zealand white rabbit and a review of the literature

Latest publications - Mon, 29/01/2024 - 11:00

J Vet Diagn Invest. 2024 Jan 28:10406387231220884. doi: 10.1177/10406387231220884. Online ahead of print.


In females, the paramesonephric (syn: Müllerian) duct gives rise to the uterine tubes, uterus, cervix, and part of the vagina. Segmental uterine aplasia resulting from a paramesonephric duct abnormality has been reported in a range of species including bovids, canids, felids, equids, camelids, and lagomorphs. Here we document segmental aplasia of the left paramesonephric duct in a New Zealand white rabbit. The proximal 70 mm of the left uterine tube was present and terminated in adipose tissue. A 10 × 2 × 1-mm tag of cream tissue was present and was composed of sheets of adipose tissue and streams of smooth muscle, but otherwise, there was no evidence of the left uterine horn, supporting a diagnosis of unilateral uterine aplasia (uterus unicornis) analogous to a human class II (unicornuate uterus) lesion of the "no horn" subtype. In addition, our case had a concurrent uterine tube fimbrial cyst, minor cysts in the left kidney, and mammary gland hyperplasia with secretory activity. We suggest the adoption of a uniform classification system specifically for lagomorph uterine anomalies. Large-scale multi-center studies documenting prevalence of such lesions would facilitate identification of trends in laterality and other factors.

PMID:38282435 | DOI:10.1177/10406387231220884

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting

Latest publications - Wed, 24/01/2024 - 11:00

Cell Rep. 2024 Jan 23;43(2):113700. doi: 10.1016/j.celrep.2024.113700. Online ahead of print.


Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

PMID:38265935 | DOI:10.1016/j.celrep.2024.113700

Plasma protein signatures of adult asthma

Latest publications - Wed, 24/01/2024 - 11:00

Allergy. 2024 Jan 23. doi: 10.1111/all.16000. Online ahead of print.


BACKGROUND: Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma.

METHODS: Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non-case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non-case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta-analyzed using inverse-variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)).

RESULTS: Meta-analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75-0.79 in training set; AUC = 0.72, 95% CI = 0.69-0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma-atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis.

CONCLUSION: This first large-scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management.

PMID:38263798 | DOI:10.1111/all.16000

Assessing the microbiota of the snail intermediate host of trematodes, Galba truncatula

Latest publications - Tue, 23/01/2024 - 11:00

Parasit Vectors. 2024 Jan 23;17(1):31. doi: 10.1186/s13071-024-06118-7.


BACKGROUND: The microbiome is known to play key roles in health and disease, including host susceptibility to parasite infections. The freshwater snail Galba truncatula is the intermediate host for many trematode species, including the liver and rumen flukes Fasciola hepatica and Calicophoron daubneyi, respectively. The snail-parasite system has previously been investigated. However, the specific interaction between the snail-associated microbiota and intra-snail developmental stages of trematodes has yet to be explored.

METHODS: Galba truncatula snails were collected from farms in Northern Ireland and trematode infection was diagnosed using PCR. High-throughput sequencing analysis of the bacterial 16S ribosomal DNA V3-V4 hypervariable regions was subsequently applied to characterise the microbiota of both uninfected and infected snails.

RESULTS: We first showed that the snail harboured microbiota that was distinct for its environment. The microbiota of infected snails was found to differ significantly from that of uninfected snails. In particular, the bacterial genera Mycoplasma and Methylotenera were significantly more abundant in infected snails, while genera Sphingomonas and Nocardioides were predominantly associated with uninfected snails.

CONCLUSION: These findings pave the way to future studies on the functional roles of bacteria in host-parasite relationships.

PMID:38263069 | DOI:10.1186/s13071-024-06118-7

Short-duration selective decontamination of the digestive tract infection control does not contribute to increased antimicrobial resistance burden in a pilot cluster randomised trial (the ARCTIC Study)

Latest publications - Mon, 22/01/2024 - 11:00

Gut. 2024 Jan 22:gutjnl-2023-330851. doi: 10.1136/gutjnl-2023-330851. Online ahead of print.


OBJECTIVE: Selective decontamination of the digestive tract (SDD) is a well-studied but hotly contested medical intervention of enhanced infection control. Here, we aim to characterise the changes to the microbiome and antimicrobial resistance (AMR) gene profiles in critically ill children treated with SDD-enhanced infection control compared with conventional infection control.

DESIGN: We conducted shotgun metagenomic microbiome and resistome analysis on serial oropharyngeal and faecal samples collected from critically ill, mechanically ventilated patients in a pilot multicentre cluster randomised trial of SDD. The microbiome and AMR profiles were compared for longitudinal and intergroup changes. Of consented patients, faecal microbiome baseline samples were obtained in 89 critically ill children. Additionally, samples collected during and after critical illness were collected in 17 children treated with SDD-enhanced infection control and 19 children who received standard care.

RESULTS: SDD affected the alpha and beta diversity of critically ill children to a greater degree than standard care. At cessation of treatment, the microbiome of SDD patients was dominated by Actinomycetota, specifically Bifidobacterium, at the end of mechanical ventilation. Altered gut microbiota was evident in a subset of SDD-treated children who returned late longitudinal samples compared with children receiving standard care. Clinically relevant AMR gene burden was unaffected by the administration of SDD-enhanced infection control compared with standard care. SDD did not affect the composition of the oral microbiome compared with standard treatment.

CONCLUSION: Short interventions of SDD caused a shift in the microbiome but not of the AMR gene pool in critically ill children at the end mechanical ventilation, compared with standard antimicrobial therapy.

PMID:38253478 | DOI:10.1136/gutjnl-2023-330851

Fri 19 Jan 12:00: Modelling optimal intervention strategies for animal diseases in data poor settings This talk will be streamed and will be accessible remotely once it has started, with raven login here:

Departmental Seminars - Mon, 15/01/2024 - 09:21
Modelling optimal intervention strategies for animal diseases in data poor settings

Abstract: Emerging diseases of livestock can devastate the agricultural industry and have a severe impact upon livestock exports. It is therefore vital to provide tools to assess the risk associated with infectious diseases and establish surveillance and intervention protocols that will reduce the cost of such outbreaks in the future. In this presentation, I will discuss the role of infectious disease models in supporting contingency planning for livestock disease outbreaks. These models typically require data on locations, sizes and species compositions of farms, as well as detailed information on any animals that are infected with the disease. However, in many settings such data are not available. I will therefore demonstrate how models can support infectious disease control in settings where such detailed data are not accessible and how surveillance resources should be targeted to reduce model uncertainty and provide accurate predictions regarding the future spread of disease.

Bio: Prof. Mike Tildesley is a Professor of Infectious Disease Modelling at the University of Warwick. He has an interest in the predictive power of models in the early stages of emerging disease outbreaks and in communicating modelling results to policy advisors. He has extensive experience of modelling livestock disease systems, including Foot-and-Mouth Disease (FMD) and Highly Pathogenic Avian Influenza (HPAI). Prof. Tildesley has advised the UK Government’s Department for the Environment, Food and Rural Affairs, the US Department of Agriculture and the Food and Agriculture Organisation of the United Nations about strategies for control of livestock diseases including FMD and HPAI . From March 2020 to March 2022, He was a member of the Scientific Pandemic Influenza Modelling Operational group (SPI-M-O), and worked extensively on COVID -19, providing policy advice to the UK government.

This talk will be streamed and will be accessible remotely once it has started, with raven login here:

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Antibiotic resistance determination using Enterococcus faecium whole-genome sequences: a diagnostic accuracy study using genotypic and phenotypic data

Latest publications - Sun, 14/01/2024 - 11:00

Lancet Microbe. 2024 Jan 11:S2666-5247(23)00297-5. doi: 10.1016/S2666-5247(23)00297-5. Online ahead of print.


BACKGROUND: DNA sequencing could become an alternative to in vitro antibiotic susceptibility testing (AST) methods for determining antibiotic resistance by detecting genetic determinants associated with decreased antibiotic susceptibility. Here, we aimed to assess and improve the accuracy of antibiotic resistance determination from Enterococcus faecium genomes for diagnosis and surveillance purposes.

METHODS: In this retrospective diagnostic accuracy study, we first conducted a literature search in PubMed on Jan 14, 2021, to compile a catalogue of genes and mutations predictive of antibiotic resistance in E faecium. We then evaluated the diagnostic accuracy of this database to determine susceptibility to 12 different, clinically relevant antibiotics using a diverse population of 4382 E faecium isolates with available whole-genome sequences and in vitro culture-based AST phenotypes. Isolates were obtained from various sources in 11 countries worldwide between 2000 and 2018. We included isolates tested with broth microdilution, Vitek 2, and disc diffusion, and antibiotics with at least 50 susceptible and 50 resistant isolates. Phenotypic resistance was derived from raw minimum inhibitory concentrations and measured inhibition diameters, and harmonised primarily using the breakpoints set by the European Committee on Antimicrobial Susceptibility Testing. A bioinformatics pipeline was developed to process raw sequencing reads, identify antibiotic resistance genetic determinants, and report genotypic resistance. We used our curated database, as well as ResFinder, AMRFinderPlus, and LRE-Finder, to assess the accuracy of genotypic predictions against phenotypic resistance.

FINDINGS: We curated a catalogue of 228 genetic markers involved in resistance to 12 antibiotics in E faecium. Very accurate genotypic predictions were obtained for ampicillin (sensitivity 99·7% [95% CI 99·5-99·9] and specificity 97·9% [95·8-99·0]), ciprofloxacin (98·0% [96·4-98·9] and 98·8% [95·9-99·7]), vancomycin (98·8% [98·3-99·2] and 98·8% [98·0-99·3]), and linezolid resistance (after re-testing false negatives: 100·0% [90·8-100·0] and 98·3% [97·8-98·7]). High sensitivity was obtained for tetracycline (99·5% [99·1-99·7]), teicoplanin (98·9% [98·4-99·3]), and high-level resistance to aminoglycosides (97·7% [96·6-98·4] for streptomycin and 96·8% [95·8-97·5] for gentamicin), although at lower specificity (60-90%). Sensitivity was expectedly low for daptomycin (73·6% [65·1-80·6]) and tigecycline (38·3% [27·1-51·0]), for which the genetic basis of resistance is not fully characterised. Compared with other antibiotic resistance databases and bioinformatic tools, our curated database was similarly accurate at detecting resistance to ciprofloxacin and linezolid and high-level resistance to streptomycin and gentamicin, but had better sensitivity for detecting resistance to ampicillin, tigecycline, daptomycin, and quinupristin-dalfopristin, and better specificity for ampicillin, vancomycin, teicoplanin, and tetracycline resistance. In a validation dataset of 382 isolates, similar or improved diagnostic accuracies were also achieved.

INTERPRETATION: To our knowledge, this work represents the largest published evaluation to date of the accuracy of antibiotic susceptibility predictions from E faecium genomes. The results and resources will facilitate the adoption of whole-genome sequencing as a tool for the diagnosis and surveillance of antimicrobial resistance in E faecium. A complete characterisation of the genetic basis of resistance to last-line antibiotics, and the mechanisms mediating antibiotic resistance silencing, are needed to close the remaining sensitivity and specificity gaps in genotypic predictions.

FUNDING: Wellcome Trust, UK Department of Health, British Society for Antimicrobial Chemotherapy, Academy of Medical Sciences and the Health Foundation, Medical Research Council Newton Fund, Vietnamese Ministry of Science and Technology, and European Society of Clinical Microbiology and Infectious Disease.

PMID:38219758 | DOI:10.1016/S2666-5247(23)00297-5

Modulation of multidrug-resistant clone success in Escherichia coli populations: a longitudinal, multi-country, genomic and antibiotic usage cohort study

Latest publications - Sun, 14/01/2024 - 11:00

Lancet Microbe. 2024 Jan 4:S2666-5247(23)00292-6. doi: 10.1016/S2666-5247(23)00292-6. Online ahead of print.


BACKGROUND: The effect of antibiotic usage on the success of multidrug-resistant (MDR) clones in a population remains unclear. With this genomics-based molecular epidemiology study, we aimed to investigate the contribution of antibiotic use to Escherichia coli clone success, relative to intra-strain competition for colonisation and infection.

METHODS: We sequenced all the available E coli bloodstream infection isolates provided by the British Society for Antimicrobial Chemotherapy (BSAC) from 2012 to 2017 (n=718) and combined these with published data from the UK (2001-11; n=1090) and Norway (2002-17; n=3254). Defined daily dose (DDD) data from the European Centre for Disease Prevention and Control (retrieved on Sept 21, 2021) for major antibiotic classes (β-lactam, tetracycline, macrolide, sulfonamide, quinolone, and non-penicillin β-lactam) were used together with sequence typing, resistance profiling, regression analysis, and non-neutral Wright-Fisher simulation-based modelling to enable systematic comparison of resistance levels, clone success, and antibiotic usage between the UK and Norway.

FINDINGS: Sequence type (ST)73, ST131, ST95, and ST69 accounted for 892 (49·3%) of 1808 isolates in the BSAC collection. In the UK, the proportion of ST69 increased between 2001-10 and 2011-17 (p=0·0004), whereas the proportions of ST73 and ST95 did not vary between periods. ST131 expanded quickly after its emergence in 2003 and its prevalence remained consistent throughout the study period (apart from a brief decrease in 2009-10). The extended-spectrum β-lactamase (ESBL)-carrying, globally disseminated MDR clone ST131-C2 showed overall greater success in the UK (154 [56·8%] of 271 isolates in 2003-17) compared with Norway (51 [18·3%] of 278 isolates in 2002-17; p<0·0001). DDD data indicated higher total use of antimicrobials in the UK, driven mainly by the class of non-penicillin β-lactams, which were used between 2·7-times and 5·1-times more in the UK per annum (ratio mean 3·7 [SD 0·8]). This difference was associated with the higher success of the MDR clone ST131-C2 (pseudo-R2 69·1%). A non-neutral Wright-Fisher model replicated the observed expansion of non-MDR and MDR sequence types under higher DDD regimes.

INTERPRETATION: Our study indicates that resistance profiles of contemporaneously successful clones can vary substantially, warranting caution in the interpretation of correlations between aggregate measures of resistance and antibiotic usage. Our study further suggests that in countries with low-to-moderate use of antibiotics, such as the UK and Norway, the extent of non-penicillin β-lactam use modulates rather than determines the success of widely disseminated MDR ESBL-carrying E coli clones. Detailed understanding of underlying causal drivers of success is important for improved control of resistant pathogens.

FUNDING: Trond Mohn Foundation, Marie Skłodowska-Curie Actions, European Research Council, Royal Society, and Wellcome Trust.

PMID:38219757 | DOI:10.1016/S2666-5247(23)00292-6

Global emergence of a hypervirulent carbapenem-resistant Escherichia coli ST410 clone

Latest publications - Fri, 12/01/2024 - 11:00

Nat Commun. 2024 Jan 12;15(1):494. doi: 10.1038/s41467-023-43854-3.


Carbapenem-resistant Escherichia coli (CREC) ST410 has recently emerged as a major global health problem. Here, we report a shift in CREC prevalence in Chinese hospitals between 2017 and 2021 with ST410 becoming the most commonly isolated sequence type. Genomic analysis identifies a hypervirulent CREC ST410 clone, B5/H24RxC, which caused two separate outbreaks in a children's hospital. It may have emerged from the previously characterised B4/H24RxC in 2006 and has been isolated in ten other countries from 2015 to 2021. Compared with B4/H24RxC, B5/H24RxC lacks the blaOXA-181-bearing X3 plasmid, but carries a F-type plasmid containing blaNDM-5. Most of B5/H24RxC also carry a high pathogenicity island and a novel O-antigen gene cluster. We find that B5/H24RxC grew faster in vitro and is more virulent in vivo. The identification of this newly emerged but already globally disseminated hypervirulent CREC clone, highlights the ongoing evolution of ST410 towards increased resistance and virulence.

PMID:38216585 | DOI:10.1038/s41467-023-43854-3

Replicative fitness and pathogenicity of primate lentiviruses in lymphoid tissue, primary human and chimpanzee cells: relation to possible jumps to humans

Latest publications - Fri, 12/01/2024 - 11:00

EBioMedicine. 2024 Jan 11;100:104965. doi: 10.1016/j.ebiom.2023.104965. Online ahead of print.


BACKGROUND: Simian immunodeficiency viruses (SIV) have been jumping between non-human primates in West/Central Africa for thousands of years and yet, the HIV-1 epidemic only originated from a primate lentivirus over 100 years ago.

METHODS: This study examined the replicative fitness, transmission, restriction, and cytopathogenicity of 22 primate lentiviruses in primary human lymphoid tissue and both primary human and chimpanzee peripheral blood mononuclear cells.

FINDINGS: Pairwise competitions revealed that SIV from chimpanzees (cpz) had the highest replicative fitness in human or chimpanzee peripheral blood mononuclear cells, even higher fitness than HIV-1 group M strains responsible for worldwide epidemic. The SIV strains belonging to the "HIV-2 lineage" (including SIVsmm, SIVmac, SIVagm) had the lowest replicative fitness. SIVcpz strains were less inhibited by human restriction factors than the "HIV-2 lineage" strains. SIVcpz efficiently replicated in human tonsillar tissue but did not deplete CD4+ T-cells, consistent with the slow or nonpathogenic disease observed in most chimpanzees. In contrast, HIV-1 isolates and SIV of the HIV-2 lineage were pathogenic to the human tonsillar tissue, almost independent of the level of virus replication.

INTERPRETATION: Of all primate lentiviruses, SIV from chimpanzees appears most capable of infecting and replicating in humans, establishing HIV-1. SIV from other Old World monkeys, e.g. the progenitor of HIV-2, replicate slowly in humans due in part to restriction factors. Nonetheless, many of these SIV strains were more pathogenic than SIVcpz. Either SIVcpz evolved into a more pathogenic virus while in humans or a rare SIVcpz, possibly extinct in chimpanzees, was pathogenic immediately following the jump into human.

FUNDING: Support for this study to E.J.A. was provided by the NIH/NIAID R01 AI49170 and CIHR project grant 385787. Infrastructure support was provided by the NIH CFAR AI36219 and Canadian CFI/Ontario ORF 36287. Efforts of J.A.B. and N.J.H. was provided by NIH AI099473 and for D.H.C., by VA and NIH AI AI080313.

PMID:38215691 | DOI:10.1016/j.ebiom.2023.104965

A Bayesian approach to Mendelian randomization using summary statistics in the univariable and multivariable settings with correlated pleiotropy

Latest publications - Fri, 05/01/2024 - 11:00

Am J Hum Genet. 2024 Jan 4;111(1):165-180. doi: 10.1016/j.ajhg.2023.12.002.


Mendelian randomization uses genetic variants as instrumental variables to make causal inferences on the effect of an exposure on an outcome. Due to the recent abundance of high-powered genome-wide association studies, many putative causal exposures of interest have large numbers of independent genetic variants with which they associate, each representing a potential instrument for use in a Mendelian randomization analysis. Such polygenic analyses increase the power of the study design to detect causal effects; however, they also increase the potential for bias due to instrument invalidity. Recent attention has been given to dealing with bias caused by correlated pleiotropy, which results from violation of the "instrument strength independent of direct effect" assumption. Although methods have been proposed that can account for this bias, a number of restrictive conditions remain in many commonly used techniques. In this paper, we propose a Bayesian framework for Mendelian randomization that provides valid causal inference under very general settings. We propose the methods MR-Horse and MVMR-Horse, which can be performed without access to individual-level data, using only summary statistics of the type commonly published by genome-wide association studies, and can account for both correlated and uncorrelated pleiotropy. In simulation studies, we show that the approach retains type I error rates below nominal levels even in high-pleiotropy scenarios. We demonstrate the proposed approaches in applied examples in both univariable and multivariable settings, some with very weak instruments.

PMID:38181732 | DOI:10.1016/j.ajhg.2023.12.002