Latest publications

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

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

ABSTRACT

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

EMBO Rep. 2023 Dec 15. doi: 10.1038/s44319-023-00008-2. Online ahead of print.

ABSTRACT

Mechano-immunity, the intersection between cellular or tissue mechanics and immune cell function, is emerging as an important factor in many inflammatory diseases. Mechano-sensing defines how cells detect mechanical changes in their environment. Mechano-response defines how cells adapt to such changes, e.g. form synapses, signal or migrate. Inflammasomes are intracellular immune sensors that detect changes in tissue and cell homoeostasis during infection or injury. We and others recently found that mechano-sensing of tissue topology (swollen tissue), topography (presence and distribution of foreign solid implant) or biomechanics (stiffness), alters inflammasome activity. Once activated, inflammasomes induce the secretion of inflammatory cytokines, but also change cellular mechanical properties, which influence how cells move, change their shape, and interact with other cells. When overactive, inflammasomes lead to chronic inflammation. This clearly places inflammasomes as important players in mechano-immunity. Here, we discuss a model whereby inflammasomes integrate pathogen- and tissue-injury signals, with changes in tissue mechanics, to shape the downstream inflammatory responses and allow cell and tissue mechano-adaptation. We will review the emerging evidence that supports this model.

PMID:38177903 | DOI:10.1038/s44319-023-00008-2

Lancet Reg Health Eur. 2023 Dec 11;37:100812. doi: 10.1016/j.lanepe.2023.100812. eCollection 2024 Feb.

ABSTRACT

BACKGROUND: Higher-valency pneumococcal vaccines are anticipated. We aimed to describe serotype distribution and risk factors for vaccine-serotype community-acquired pneumonia (CAP) in the two years pre-SARS-CoV-2 pandemic.

METHODS: We conducted a prospective cohort study of adults hospitalised with CAP at three UK sites between 2018 and 2020. Pneumococcal serotypes were identified using a 24-valent urinary-antigen assay and blood cultures. Risk factors associated with vaccine-type pneumonia caused by serotypes in the 13-, 15- and 20-valent pneumococcal conjugate vaccines (PCV13, PCV15, PCV20) and 23-valent pneumococcal polysaccharide vaccine (PPV23) were determined from multivariable analysis.

FINDINGS: Of 1921 adults hospitalised with CAP, 781 (40.7%, 95% confidence intervals (CI) 38.5-42.9%) had pneumococcal pneumonia. A single PCV13-serotype was detected in 242 (31.0%, 95% CI 27.8-34.3%) pneumococcal CAP patients, mostly serotype 3 (171/242, 70.7%, 95% CI 64.5-76.0%). The additional two PCV15-serotypes were detected in 31 patients (4%, 95% CI 2.8-5.6%), and PCV20-non13-serotypes in 192 (24.6%), with serotype 8 most prevalent (123/192, 64.1%, 95% CI 57.1-70.5%). Compared to PCV13-serotype CAP, people with PCV20-non13 CAP were younger (median age 62 versus 72 years, p < 0.001) and less likely to be male (44% versus 61%, p = 0.01). PPV23-non13-serotypes were found in 252 (32.3%, 95% CI 29.1-35.6%) pneumococcal CAP patients.

INTERPRETATION: Despite mature infant pneumococcal programmes, the burden of PCV13-serotype pneumonia remains high in older adults, mainly due to serotype 3. PCV20-non13-serotype pneumonia is more likely in younger people with fewer pneumococcal risk factors.

FUNDING: Unrestricted investigator-initiated research grant from Pfizer, United Kingdom; support from National Institute for Health Research (NIHR) Biomedical Research Centre, Nottingham.

PMID:38170136 | PMC:PMC10758948 | DOI:10.1016/j.lanepe.2023.100812