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Abstract Gene set enrichment analysis (GSEA) tools can identify biological insights within gene expression-based studies. Although their statistical performance has been compared, the downstream biological implications that arise when choosing between the range of pairwise or single sample forms of GSEA methods remain understudied. We compare the statistical and biological results obtained from various pre-ranking methods/options for pairwise GSEA, followed by a stand-alone comparison of GSEA, single sample GSEA (ssGSEA) and gene set variation analysis (GSVA). Pairwise GSEA and fGSEA provide similar results when deployed using a range of gene pre-ranking methods. However, pairwise GSEA can overgeneralise biological enrichment, as when the most statistically significant signatures were assessed using single sample approaches, there was a complete absence of biological distinction between these groups. To avoid these issues, we developed a new dualGSEA tool, which provides users with multiple statistics and visuals to aid interpretation of results. This new tool removes the possibility of users inadvertently interpreting statistical findings as equating to biological distinction between samples within groups-of-interest. dualGSEA provides a more robust basis for discovery research, one which allows user to compare both statistical significance alongside biological distinctions in their data.

Abstract SETANTA (Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland) study aimed to investigate symptom burden and incidence of cardiac abnormalities after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 and to correlate these results with biomarkers of immunological response and coagulation. SETANTA was a prospective, single-arm observational cross-sectional study condcuted in a primary practice setting, and prospectively registered with ClinicalTrials.gov (identifier: NCT04823182). Patients with recent COVID-19 infection (≥ 6 weeks and ≤ 12 months) were prospectively enrolled. Primary outcomes of interest were markers of cardiac injury detected by cardiac magnetic resonance imaging (CMR), which included left ventricular ejection fraction, late gadolinium enhancement and pericardial abnormalities, as well as relevant biomarkers testing immunological response and coagulopathy. 100 patients (n = 129 approached) were included, amongst which 64% were female. Mean age of the total cohort was 45.2 years. The median (interquartile range) time interval between COVID-19 infection and enrolment was 189 [125, 246] days. 83% of participants had at least one persistent symptom, while 96% had positive serology for prior SARS-CoV-2 infection. Late gadolinium enhancement, pericardial effusion, was present in 2.2% and 8.3% respectively, while left ventricular ejection fraction was below the normal reference limit in 17.4% of patients. Von Willebrand factor antigen was elevated in 32.7% of patients and Fibrinogen and D-Dimer levels were found to be elevated in 10.2% and 11.1% of patients, respectively. In a cohort of primary practice patients recently recovered from SARS-CoV-2 infection, prevalence of persistent symptoms and markers of abnormal coagulation were high, despite a lower frequency of abnormalities on CMR compared with prior reports of patients assessed in a hospital setting. Trial Registration: Clinicaltrials.gov, NCT04823182 (prospectively registered on 30th March 2021).

Abstract Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron levels on disease risk. We meta-analyzed genome-wide association study summary statistics for serum iron levels from two cohorts and two previous meta-analyses. We then obtained summary statistics from 11 neurodegenerative, cerebrovascular, cardiovascular or lipid traits to assess global and regional genetic correlation between iron levels and these traits. We used two-sample Mendelian randomization (MR) to estimate causal effects. Sex-stratified analyses were also carried out to identify effects potentially differing by sex. Overall, we identified three significant global correlations between iron levels and (i) coronary heart disease, (ii) triglycerides, and (iii) high-density lipoprotein (HDL) cholesterol levels. A total of 194 genomic regions had significant (after correction for multiple testing) local correlations between iron levels and the 11 tested traits. MR analysis revealed two potential causal relationships, between genetically predicted iron levels and (i) total cholesterol or (ii) non-HDL cholesterol. Sex-stratified analyses suggested a potential protective effect of iron levels on Parkinson’s disease risk in females, but not in males. Our results will contribute to a better understanding of the genetic basis underlying iron in cardiovascular and neurological health in aging, and to the eventual identification of new preventive interventions or therapeutic avenues for diseases which affect women and men worldwide.

Abstract Climate change is causing ocean warming (OW) and increasing the frequency, intensity, and duration of extreme weather events, including Marine Heat Waves (MHWs). Both OW and MHWs pose a significant threat to marine ecosystems and marine organisms, including oysters, oyster reefs and farmed oysters. We investigated the survival and growth of juveniles of two commercial species of oyster, the Sydney rock oyster, Saccostrea glomerata, and the Pacific oyster, Crassostrea gigas, to elevated seawater temperatures reflecting a moderate and an extreme MHW in context with recent MHWs and beyond. The survival and size of Pacific oysters to moderate MHWs (22–32 °C; 14 days) was greater than that for Sydney rock oysters (24–32 °C; 15 days). While survival and growth of both species was significantly impacted by extreme MHWs (29–38 °C; 5–6 days), Sydney rock oysters were found to survive greater temperatures compared to the Pacific oyster. Overall, this study found that Pacific oyster juveniles were more tolerant of a moderate MHW, while Sydney rock oyster juveniles were more resilient to extreme MHWs. These differences in thermal tolerance may have consequences for aquaculture and coexistence of both species in their intertidal and latitudinal distributions along the south-eastern Australian coastline.

Abstract Dust samples were collected from Irish homes. House Dust Mite and storage mites were separated from the dust. The microbiome and resistome of mites and originating dust were assessed using a culture-independent approach. The bacterial microbiome of mites and dust were predominantly populated by Staphylococci. There was a highly significant (P = 0.005; Spearman’s rank test) correlation between the bacterial microbiome of mites and the dust. One-hundred and eighteen antimicrobial resistance genes (ARGs) were associated with mites and 176 with dust. Both contained ARGs encoding resistance for multi drug resistances, macrolide-lincosamide-streptogramin B, mobile genetic elements, Beta-lactam, Tetracycline and Aminoglycosides. By contrast, 15 ARGs were found for a laboratory-grown strain of Dermatophagoides pteronyssinus. A significant difference (P = 0.03; t test) was found in means between the resistome of mites and the household dust from which they emanated. No significant correlations (P = 0.23 and P = 0.22; Mantel test) were observed between the microbiome and resistome of mite and dust samples. There was not a significant difference (P = 0.54; t-test) between the means of ARGs for homes with and without a history of antibiotic use.

Abstract We report the first cryoEM structure of the Hendra henipavirus nucleoprotein in complex with RNA, at 3.5 Å resolution, derived from single particle analysis of a double homotetradecameric RNA-bound N protein ring assembly exhibiting D14 symmetry. The structure of the HeV N protein adopts the common bi-lobed paramyxoviral N protein fold; the N-terminal and C-terminal globular domains are bisected by an RNA binding cleft containing six RNA nucleotides and are flanked by the N-terminal and C-terminal arms, respectively. In common with other paramyxoviral nucleocapsids, the lateral interface between adjacent Ni and Ni+1 protomers involves electrostatic and hydrophobic interactions mediated primarily through the N-terminal arm and globular domains with minor contribution from the C-terminal arm. However, the HeV N multimeric assembly uniquely identifies an additional protomer-protomer contact between the Ni+1 N-terminus and Ni−1 C-terminal arm linker. The model presented here broadens the understanding of RNA-bound paramyxoviral nucleocapsid architectures and provides a platform for further insight into the molecular biology of HeV, as well as the development of antiviral interventions.

Abstract Despite progress towards malaria reduction in Peru, measuring exposure in low transmission areas is crucial for achieving elimination. This study focuses on two very low transmission areas in Loreto (Peruvian Amazon) and aims to determine the relationship between malaria exposure and proximity to health facilities. Individual data was collected from 38 villages in Indiana and Belen, including geo-referenced households and blood samples for microscopy, PCR and serological analysis. A segmented linear regression model identified significant changes in seropositivity trends among different age groups. Local Getis-Ord Gi* statistic revealed clusters of households with high (hotspots) or low (coldspots) seropositivity rates. Findings from 4000 individuals showed a seropositivity level of 2.5% (95%CI: 2.0%-3.0%) for P. falciparum and 7.8% (95%CI: 7.0%-8.7%) for P. vivax, indicating recent or historical exposure. The segmented regression showed exposure reductions in the 40–50 age group (β1 = 0.043, p = 0.003) for P. vivax and the 50–60 age group (β1 = 0.005, p = 0.010) for P. falciparum. Long and extreme distance villages from Regional Hospital of Loreto exhibited higher malaria exposure compared to proximate and medium distance villages (p

Abstract Here, we establish a CT-radiomics based method for application in invasive, orthotopic rodent brain tumour models. Twenty four NOD/SCID mice were implanted with U87R-Luc2 GBM cells and longitudinally imaged via contrast enhanced (CE-CT) imaging. Pyradiomics was employed to extract CT-radiomic features from the tumour-implanted hemisphere and non-tumour-implanted hemisphere of acquired CT-scans. Inter-correlated features were removed (Spearman correlation > 0.85) and remaining features underwent predictive analysis (recursive feature elimination or Boruta algorithm). An area under the curve of the receiver operating characteristic curve was implemented to evaluate radiomic features for their capacity to predict defined outcomes. Firstly, we identified a subset of radiomic features which distinguish the tumour-implanted hemisphere and non- tumour-implanted hemisphere (i.e, tumour presence from normal tissue). Secondly, we successfully translate preclinical CT-radiomic pipelines to GBM patient CT scans (n = 10), identifying similar trends in tumour-specific feature intensities (E.g. ‘glszm Zone Entropy’), thereby suggesting a mouse-to-human species conservation (a conservation of radiomic features across species). Thirdly, comparison of features across timepoints identify features which support preclinical tumour detection earlier than is possible by visual assessment of CT scans. This work establishes robust, preclinical CT-radiomic pipelines and describes the application of CE-CT for in-depth orthotopic brain tumour monitoring. Overall we provide evidence for the role of pre-clinical ‘discovery’ radiomics in the neuro-oncology space.

The goals of this study were to evaluate factors affecting recovery and antimicrobial resistance (AMR) in intrauterine E. coli in post-partum dairy cows with and without metritis from commercial California dairy farms. Using a cross-sectional study design, a total of 307 cows were sampled from 25 farms throughout California, from which a total of 162 intrauterine E. coli isolates were recovered. During farm visits, cows within 21 days post-partum were categorized in one of three clinical presentation groups before enrollment: metritis (MET, n = 86), defined as a cow with watery, red or brown colored, and fetid vaginal discharge; cows with purulent discharge (PUS, n = 106), defined as a non-fetid purulent or mucopurulent vaginal discharge; and control cows, (CTL, n = 115) defined as cows with either no vaginal discharge or a clear, non-purulent mucus vaginal discharge. Cows diagnosed as MET had significantly higher odds for recovery of E. coli compared to cows diagnosed as CTL (OR = 2.16, 95% CI: 1.17-3.96), with no significant difference observed between PUS and CTL, and PUS and MET. An increase in days in milk (DIM) at the time of sampling was significantly associated with a decrease in the odds ratio for E. coli recovery from intrauterine swabs (OR = 0.94, 95% CI: 0.89-0.98). All intrauterine E. coli were resistant to ampicillin (AMP), with an AMR prevalence of 30.2% and 33.9% observed for chlortetracycline and oxytetracycline, respectively. Only 8.6% of isolates were resistant to ceftiofur (CEFT), one of the most common drugs used to treat cows on farms sampled. No significant difference in the prevalence of AMR was observed among clinical groups at the individual cow level. At the farm level, a significantly higher odds for isolating intrauterine E. coli resistant to chlortetracycline (OR: 2.6; 95% CI: 3.7-58.0) or oxytetracycline (OR: 1.9; 95% CI: 1.4-33.8) was observed at farms that used an intrauterine infusion of oxytetracycline as a treatment for metritis when compared to those farms that did not use this practice. Findings from this study indicate the need for further research supporting a broader understanding of farm practices driving AMR in cows with metritis, as well as data to increase the accuracy of breakpoints for AMR classification of intrauterine E. coli from cattle.

Abstract Genomic regions associated with ripening time (RPT) and soluble solids concentration (SSC) were mapped using a pedigreed population including multiple F1 and F2 families from the Clemson University peach breeding program (CUPBP). RPT and SSC QTLs were consistently identified in two seasons (2011 and 2012) and the average datasets (average of two seasons). A target region spanning 10,981,971–11,298,736 bp on chromosome 4 of peach reference genome used for haplotype analysis revealed four haplotypes with significant differences in trait values among different diplotype combinations. Favorable alleles at the target region for both RPT and SSC were determined and a DNA test for predicting RPT and SSC was developed. Two Kompetitive Allele Specific PCR (KASP) assays were validated on 84 peach cultivars and 163 seedlings from the CUPBP, with only one assay (Ppe.RPT/SSC-1) needed to predict between early and late-season ripening cultivars and low and high SSC. These results advance our understanding of the genetic basis of RPT and SSC and facilitate selection of new peach cultivars with the desired RPT and SSC.

Abstract Surveillance of endemic pathogens is essential for disease control, providing an evidence base for policy and advice. Bovine Herpes Virus Type 1 (BoHV-1), the causative agent of Infectious Bovine Rhinotracheitis (IBR), has been found to have high seroprevalence within the Irish cattle population. The aim of the present study was to establish seroprevalence levels for culled cattle in Ireland aged

Abstract Multiple sclerosis (MS), a chronic neurodegenerative disease driven by damage to the protective myelin sheath, is currently incurable. Today, all clinically available treatments modulate the immune-mediated symptoms of the disease but they fail to stop neurodegeneration in many patients. Remyelination, the regenerative process of myelin repair by oligodendrocytes, which is considered a necessary step to protect demyelinated axons and stop neuronal death, is impaired in MS patients. One of the major obstacles to finding effective remyelinating drugs is the lack of biomimetic drug screening platforms that enable quantification of compounds’ potential to stimulate 3D myelination in the physiologically relevant axon-like environment. To address this need, we built a unique myelination drug discovery platform, by expanding our previously developed technology, artificial axons (AAs), which enables 3D-printing of synthetic axon mimics with the geometry and mechanical properties closely resembling those of biological axons. This platform allows for high-throughput phenotypic myelination assay based on quantification of 3D wrapping of myelin membrane around axons in response to compounds. Here, we demonstrate quantification of 3D myelin wrapping by rat oligodendrocytes around the axon mimics in response to a small library of known pro-myelinating compounds. This assay shows pro-myelinating activity for all tested compounds consistent with the published in vitro and in vivo data, demonstrating predictive power of AA platform. We find that stimulation of myelin wrapping by these compounds is dose-dependent, providing a facile means to quantify the compounds’ potency and efficacy in promoting myelin wrapping. Further, the ranking of relative efficacy among these compounds differs in this 3D axon-like environment as compared to a traditional oligodendrocyte 2D differentiation assay quantifying area of deposited myelin membrane. Together, we demonstrate that the artificial axons platform and associated phenotypic myelin wrapping assay afford direct evaluation of myelin wrapping by oligodendrocytes in response to soluble compounds in an axon-like environment, providing a predictive tool for the discovery of remyelinating therapies.

Abstract Malaysia has reported no indigenous cases of P. falciparum and P. vivax for over 3 years. When transmission reaches such low levels, it is important to understand the individuals and locations where exposure risks are high, as they may be at greater risk in the case of a resurgence of transmission. Serology is a useful tool in low transmission settings, providing insight into exposure over longer durations than PCR or RDT. We ran blood samples from a 2015 population-based survey in northern Sabah, Malaysian Borneo on a multiplex bead assay. Using supervised machine learning methods, we characterised recent and historic exposure to Plasmodium falciparum and P. vivax and found recent exposure to P. falciparum to be very low, with exposure to both species increasing with age. We performed a risk-factor assessment on environmental, behavioural, demographic and household factors, and identified forest activity and longer travel times to healthcare as common risk-factors for exposure to P. falciparum and P. vivax. In addition, we used remote-sensing derived data and geostatistical models to assess environmental and spatial associations with exposure. We created predictive maps of exposure to recent P. falciparum in the study area and showed 3 clear foci of exposure. This study provides useful insight into the environmental, spatial and demographic risk factors for P. falciparum and P. vivax at a period of low transmission in Malaysian Borneo. The findings would be valuable in the case of resurgence of human malarias in the region.

Abstract Respiratory viruses that were suppressed through previous lockdowns during the COVID-19 pandemic have recently started to co-circulate with SARS-CoV-2. Understanding the clinical characteristics and symptomatology of different respiratory viral infections can help address the challenges related to the identification of cases and the understanding of SARS-CoV-2 variants' evolutionary patterns. Flu Watch (2006–2011) and Virus Watch (2020–2022) are household community cohort studies monitoring the epidemiology of influenza, respiratory syncytial virus, rhinovirus, seasonal coronavirus, and SARS-CoV-2, in England and Wales. This study describes and compares the proportion of symptoms reported during illnesses infected by common respiratory viruses. The SARS-CoV-2 symptom profile increasingly resembles that of other respiratory viruses as new strains emerge. Increased cough, sore throat, runny nose, and sneezing are associated with the emergence of the Omicron strains. As SARS-CoV-2 becomes endemic, monitoring the evolution of its symptomatology associated with new variants will be critical for clinical surveillance.

Abstract There is tremendous variation in life-history strategies among anadromous salmonids. Species that enter the ocean environment at small sizes ( 90% of all parasites lost by 16 days post-infection (dpi). Rejection was concomitant with host epithelial granulomatous infiltrations that initially targeted the embedded frontal filament (4 dpi) and the entire parasite by 10 dpi. Illumina sequencing, followed by functional enrichment analysis, revealed a concerted defense response in the fin within 1 dpi that included multiple innate and adaptive immunity components. Strikingly, early indications of an allergic-type inflammatory response were associated with chitin sensing pathways orchestrated by early overexpression of the IgE-receptor, fcer1g. Additionally, there was profound overexpression of several classes of c-type lectin receptors, including dectin-2, mincle, and dc-sign at 1 dpi onward. These profiles and upregulation of cellular effector markers were corroborated by histopathological evaluation, revealing the simultaneous presence of mast cell/eosinophilic granular cells, sacciform cells, macrophages/histiocytes, and granulocytes in fin. At 10 dpi and concurrent with parasite expulsion, there was evidence of immunoregulation in addition to tissue remodelling pathways. At 16 dpi, the response was effectively abrogated. Simultaneous profiling of the parasite transcriptome revealed early induction of chitin metabolism and immunomodulation, toxin production and ECM degradation; however, after 7 dpi, these were replaced with overexpression of stress and immune defense genes. These data present the first evidence for Coho salmon demonstrating chitin- and sugar moiety-sensing as key drivers of salmon louse rejection.

Abstract Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.

Abstract Glioblastoma (GBM) is the most frequent malignant primary tumor of the CNS in adults, with a median survival of 14.6 months after diagnosis. The effectiveness of GBM therapies remains poor, highlighting the need for new therapeutic alternatives. In this work, we evaluated the effect of 4-methylumbelliferone (4MU), a coumarin derivative without adverse effects reported, in combination with temozolomide (TMZ) or vincristine (VCR) on U251, LN229, U251-TMZ resistant (U251-R) and LN229-TMZ resistant (LN229-R) human GBM cells. We determined cell proliferation by BrdU incorporation, migration through wound healing assay, metabolic and MMP activity by XTT and zymography assays, respectively, and cell death by PI staining and flow cytometry. 4MU sensitizes GBM cell lines to the effect of TMZ and VCR and inhibits metabolic activity and cell proliferation on U251-R cells. Interestingly, the lowest doses of TMZ enhance U251-R and LN229-R cell proliferation, while 4MU reverts this and even sensitizes both cell lines to TMZ and VCR effects. We showed a marked antitumor effect of 4MU on GBM cells alone and in combination with chemotherapy and proved, for the first time, the effect of 4MU on TMZ-resistant models, demonstrating that 4MU would be a potential therapeutic alternative for improving GBM therapy even on TMZ-refractory patients.

Abstract We have developed a high-throughput computational method to predict the superconducting transition temperature in stable hexagonal M $$_2$$ 2 AX phases, and applied it to all the known possible choices for M (M: Sc, Ti, V, Cr, Mn, Fe, Y, Zr, Nb, Mo, Lu, Hf and Ta). We combine this with the best candidates for A (A: Al, Cu, Ge and Sn ) and X (X: C and N) from our previous work, and predict T $$_c$$ c for 60 M $$_2$$ 2 AX-phase materials, 53 of which have never been studied before. From all of these, we identify Cr $$_2$$ 2 AlN as the best candidate for the highest T $$_c$$ c , and confirm its high T $$_c$$ c with more detailed density functional theory electron-phonon coupling calculations. Our detailed calculations predict $$T_c$$ T c = 14.8 K for Cr $$_2$$ 2 AlN, which is significantly higher than any $$T_c$$ T c value known or predicted for any material in the M $$_2$$ 2 AX family to date.

Abstract Eye movement data has been extensively utilized by researchers interested in studying decision-making within the strategic setting of economic games. In this paper, we demonstrate that both deep learning and support vector machine classification methods are able to accurately identify participants’ decision strategies before they commit to action while playing games. Our approach focuses on creating scanpath images that best capture the dynamics of a participant’s gaze behaviour in a way that is meaningful for predictions to the machine learning models. Our results demonstrate a higher classification accuracy by 18% points compared to a baseline logistic regression model, which is traditionally used to analyse gaze data recorded during economic games. In a broader context, we aim to illustrate the potential for eye-tracking data to create information asymmetries in strategic environments in favour of those who collect and process the data. These information asymmetries could become especially relevant as eye-tracking is expected to become more widespread in user applications, with the seemingly imminent mass adoption of virtual reality systems and the development of devices with the ability to record eye movement outside of a laboratory setting.

Abstract The nervous system of the Asteroidea (starfish or seastar) consists of radial nerve cords (RNCs) that interconnect with a ring nerve. Despite its relative simplicity, it facilitates the movement of multiple arms and numerous tube feet, as well as regeneration of damaged limbs. Here, we investigated the RNC ultrastructure and its molecular components within the of Pacific crown-of-thorns starfish (COTS; Acanthaster sp.), a well-known coral predator that in high-density outbreaks has major ecological impacts on coral reefs. We describe the presence of an array of unique small bulbous bulbs (40–100 μm diameter) that project from the ectoneural region of the adult RNC. Each comprise large secretory-like cells and prominent cilia. In contrast, juvenile COTS and its congener Acanthaster brevispinus lack these features, both of which are non-corallivorous. Proteomic analysis of the RNC (and isolated neural bulbs) provides the first comprehensive echinoderm protein database for neural tissue, including numerous secreted proteins associated with signalling, transport and defence. The neural bulbs contained several neuropeptides (e.g., bombyxin-type, starfish myorelaxant peptide, secretogranin 7B2-like, Ap15a-like, and ApNp35) and Deleted in Malignant Brain Tumor 1-like proteins. In summary, this study provides a new insight into the novel traits of COTS, a major pest on coral reefs, and a proteomics resource that can be used to develop (bio)control strategies and understand molecular mechanisms of regeneration.

Abstract Microbial growth within a wound often manifests as biofilms, which can prevent healing and is difficult to eradicate. Novel silver dressings claim to combat wound infection, but anti-biofilm efficacy and effects on healing independent of infection are often unclear. Using in vitro and in vivo S. aureus and P. aeruginosa biofilm models, we report the efficacy of a dressing which produces Ag1+ ions; an Ag1+ dressing containing ethylenediaminetetraacetic acid and benzethonium chloride (Ag1+/EDTA/BC), and a dressing containing silver oxynitrate (Ag Oxysalts) which produces Ag1+, Ag2+ and Ag3+ ions, against wound biofilms, and their effects on healing. Ag1+ dressings had minimal effect on in vitro and murine (C57BL/6j) wound biofilms. In contrast, Ag Oxysalts and Ag1+/EDTA/BC dressings significantly reduced viable bacteria within in vitro biofilms and demonstrated a visible reduction in bacteria and EPS components within murine wound biofilms. The dressings had different effects on the healing of biofilm-infected and uninfected wounds, with Ag Oxysalts dressings having a greater beneficial effect on re-epithelialisation, wound size and inflammation than the control treatment and the other silver dressings. The different physicochemical properties of the silver dressings result in varied effects on wound biofilms and healing which should be considered when selecting dressings to treat biofilm-infected wounds.

Abstract Here we present a comprehensive mass cytometry analysis of peripheral innate lymphoid cell (ILC) subsets in relapsing/remitting MS (RRMS) patients prior to and after onset of cladribine tablets (CladT). ILC analysis was conducted on CyTOF data from peripheral blood mononuclear cells (PBMC) of MS patients before, 2 and 6 months after onset of CladT, and non-MS controls. Dimensionality reduction was used for immunophenotyping ILC subsets. CladT reduced all ILC subsets, except for CD56bright NK cells and ILC2. Furthermore, CD38+ NK cell and CCR6+ ILC3 were excluded from CladT-induced immune cell reductions. Post-CladT replenishment by immature ILC was noted by increased CD5+ ILC1 proportions at 2 months, and boosted CD38−CD56bright NK cell numbers at 6 months. CladT induce immune cell depletion among ILC but exclude CD56bright NK cells and ILC2 subsets, as well as CD38+ NK cell and CCR6+ ILC3 immunophenotypes. Post-CladT ILC expansions indicate ILC reconstitution towards a more tolerant immune system phenotype.

Abstract Lumbar puncture (LP) has become increasingly common for people with Huntington’s disease (HD) both to administer intrathecal investigational medicinal products and to collect cerebrospinal fluid to develop biological markers to track disease stage and progression. We aimed to investigate the safety profile of LP in people with HD, building on a recently published work by increasing the sample size and more specifically, increasing the representation of the premanifest population and healthy controls. We conducted a multi-study cross-sectional analysis including eligible participants from the HDClarity (304 Huntington's disease gene expansion carriers and 91 controls) and HD-YAS studies (54 premanifest and 48 controls), enrolled between February 2016 and September 2019. We investigated the odds of any adverse events, headaches, and back pain independently. Intergroup comparisons and adjusted event odds were derived using hierarchical logistic regressions. A total of 669 LP procedures involving 497 participants were included in this analysis. There were 184 (27.5%) LP procedures associated with one or more adverse events. The two most common adverse events were: post LP headache and back pain. Younger age and female gender were found to be associated with a higher risk of developing adverse events. There was no difference in the rate of adverse events between the disease subgroups after adjusting for covariates such as age and gender. Our results suggest that the LP is safe and tolerable in premanifest and manifest HD subjects, providing useful reassurance about the procedure to the HD community.

Abstract Adults with congenital heart disease (CHD) face increased risk of various comorbid diseases. Previous work on lung dysfunction in this population has mainly focused on restrictive lung disease, in patients with severe CHD phenotypes. We examined the association of mild CHD with chronic obstructive pulmonary disease (COPD) in the UK Biobank (UKB). Electronic health records (EHR) were used to identify 3385 CHD cases and 479,765 healthy controls in UKB, before performing a case–control analysis over a 20-year study period for a total of > 9.5 M person-years of follow-up. Our analysis showed that UKB participants with CHD are at substantially greater risk of developing COPD than healthy controls (8.7% vs 3.1% prevalence, unadjusted OR 2.98, 95% CI 2.63, 3.36, P = 1.40e−53). Slightly increased rates of smoking were observed amongst CHD cases, however the association with COPD was shown to be robust to adjustment for smoking and other factors known to modulate COPD risk within a multivariable-adjusted Cox regression framework (fully adjusted HR 2.21, 95% CI 1.97, 2.48, P = 5.5e−41). Care for adults with CHD should aim to mitigate their increased risk of COPD, possibly via increased smoking cessation support.

Abstract While vitamin D deficiency is a public health concern in humans, comparatively little is known about vitamin D levels in non-human primates. Vitamin D plays a crucial role in overall health and its deficiency is associated with a range of disorders, including cardiovascular disease, which is a leading cause of death in great apes. Serum samples (n = 245) from chimpanzees (Pan troglodytes) housed at 32 European zoos were measured for 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and total 25-hydroxyvitamin D (25-OHD) using liquid chromatography and tandem mass spectrometry. Of these samples, 33.1% indicated inadequate vitamin D status, using the human reference interval (25-OHD

Abstract A high-throughput computational method is used to predict 39 new superconductors in the Ti-based M $$_2$$ 2 AX phases, and the best candidates are then studied in more detail using density functional theory electron–phonon coupling calculations. The detailed calculations agree with the simple predictions, and Ti $$_2$$ 2 AlX (X: B, C and N) materials are predicted to have higher values of $$T_c$$ T c than any currently known hexagonal M $$_2$$ 2 AX phases. The electronic states at the Fermi level are dominated by the Ti 3d states. The choice of X (X: B, C and N) has a significant impact on the electronic density of states but not on the phonon characteristics. The electron–phonon coupling parameter for Ti $$_2$$ 2 AlX (X: B, C and N) was determined to be 0.685, 0.743 and 0.775 with a predicted $$T_c$$ T c of 7.8 K, 10.8 K and 13.0 K, respectively.

Abstract The goals of this study were to evaluate factors affecting recovery and antimicrobial resistance (AMR) in intrauterine E. coli in post-partum dairy cows with and without metritis from commercial California dairy farms. Using a cross-sectional study design, a total of 307 cows were sampled from 25 farms throughout California, from which a total of 162 intrauterine E. coli isolates were recovered. During farm visits, cows within 21 days post-partum were categorized in one of three clinical presentation groups before enrollment: metritis (MET, n = 86), defined as a cow with watery, red or brown colored, and fetid vaginal discharge; cows with purulent discharge (PUS, n = 106), defined as a non-fetid purulent or mucopurulent vaginal discharge; and control cows, (CTL, n = 115) defined as cows with either no vaginal discharge or a clear, non-purulent mucus vaginal discharge. Cows diagnosed as MET had significantly higher odds for recovery of E. coli compared to cows diagnosed as CTL (OR = 2.16, 95% CI: 1.17–3.96), with no significant difference observed between PUS and CTL, and PUS and MET. An increase in days in milk (DIM) at the time of sampling was significantly associated with a decrease in the odds ratio for E. coli recovery from intrauterine swabs (OR = 0.94, 95% CI: 0.89–0.98). All intrauterine E. coli were resistant to ampicillin (AMP), with an AMR prevalence of 30.2% and 33.9% observed for chlortetracycline and oxytetracycline, respectively. Only 8.6% of isolates were resistant to ceftiofur (CEFT), one of the most common drugs used to treat cows on farms sampled. No significant difference in the prevalence of AMR was observed among clinical groups at the individual cow level. At the farm level, a significantly higher odds for isolating intrauterine E. coli resistant to chlortetracycline (OR: 2.6; 95% CI: 3.7–58.0) or oxytetracycline (OR: 1.9; 95% CI: 1.4–33.8) was observed at farms that used an intrauterine infusion of oxytetracycline as a treatment for metritis when compared to those farms that did not use this practice. Findings from this study indicate the need for further research supporting a broader understanding of farm practices driving AMR in cows with metritis, as well as data to increase the accuracy of breakpoints for AMR classification of intrauterine E. coli from cattle.

Abstract Bacteria in the Shigella genus remain a major cause of dysentery in sub-Saharan Africa, and annually cause an estimated 600,000 deaths worldwide. Being spread by contaminated food and water, this study highlights how wild caught food, in the form of freshwater catfish, can act as vectors for Shigella flexneri in Southern Kenya. A metatranscriptomic approach was used to identify the presence of Shigella flexneri in the catfish which had been caught for consumption from the Galana river. The use of nanopore sequencing was shown to be a simple and effective method to highlight the presence of Shigella flexneri and could represent a potential new tool in the detection and prevention of this deadly pathogen. Rather than the presence/absence results of more traditional testing methods, the use of metatranscriptomics highlighted how primarily one SOS response gene was being transcribed, suggesting the bacteria may be dormant in the catfish. Additionally, COI sequencing of the vector catfish revealed they likely represent a cryptic species. Morphological assignment suggested the fish were widehead catfish Clarotes laticeps, which range across Africa, but the COI sequences from the Kenyan fish are distinctly different from C. laticeps sequenced in West Africa.

Abstract This study investigated the distribution and the tree canopy cover (TCC) of the two most prominent street trees (Jacaranda mimosifolia and Platanus × acerifolia) in Johannesburg, using the multispectral SPOT 6 satellite data and field survey GPS points. The importance of the spectral bands (Blue, Green, Red and NIR) and the NDVI index in discriminating between the tree species was quantified using five separability indices (Divergence, Bhattacharyya, Transformed Divergence, Jeffries-Matusita and M-statistic). The visual comparison of the Blue band and the NDVI histograms between the two species and other vegetation type showed the lowest feature overlap, suggesting the highest separability between paired classes. This was further supported by the highest Divergence value for the Blue band (3.68) and NDVI index (2.48) followed by the M-statistic (0.8 and 0.73, respectively) indicating good to moderate separability between the two species, respectively. The results were also consistent with the RF classification where the Blue band and NDVI index were the most important variables for the discrimination between the two species with an overall accuracy of 88% (kappa = 8). The TCC of J. mimosifolia and P. × acerifolia constituted 38% of the total vegetation cover in the city. These findings not only would help prioritize the increase of targeted vegetation cover in low cover areas, but will also provide a valuable information for assessment and protection of vulnerable species such as P. × acerifolia from the threat of the polyphagous shot hole borer, Euwallacea fornicatus in Johannesburg.

Abstract The association between severe acute malnutrition (SAM) in early childhood and liver fat in adults is unknown. We hypothesized that exposure to SAM, especially severe wasting, is associated with fatty liver later in life. In this observational study, abdominal CT was used to quantify mean liver attenuation (MLA) and liver:spleen attenuation ratio (L/S). Birth weight (BW), serum lipids, insulin resistance (homeostatic model assessment), anthropometry and intrabdominal fat were collected. Mean differences between diagnostic groups were tested and hierarchical regression analysis determined the best predictors of liver fat. We studied 88 adult SAM survivors and 84 community participants (CPs); age 29.0 ± 8.4 years, BMI 23.5 ± 5.0 kg/m2 (mean ± SDs). SAM survivors had less liver fat than CPs (using L/S) (p = 0.025). Severe wasting survivors (SWs) had lower BW (-0.51 kg; p = 0.02), were younger, thinner and had smaller waist circumference than oedematous malnutrition survivors (OMs). In the final regression model adjusting for age, sex, birth weight and SAM phenotype (i.e., oedematous malnutrition or severe wasting), SWs had more liver fat than OMs (using MLA) (B = 2.6 ± 1.3; p = 0.04) but similar liver fat using L/S (p = 0.07) and lower BW infants had less liver fat (MLA) (B = -1.8 ± 0.8; p = 0.03). Greater liver fat in SWs than OMs, despite having less body fat, supports our hypothesis of greater cardiometabolic risk in SWs. Other postnatal factors might influence greater liver fat in survivors of severe wasting, suggesting the need to monitor infants exposed to SAM beyond the acute episode.

Abstract Exudate production is a natural part of the wound healing process, however levels of exudate need to be appropriately managed to maintain a moist wound environment which supports healing. An overly-exuding wound creates an environment favourable to bacterial growth. In recent years, a significant increase in commercially available superabsorbent dressings have become available which claim to absorb and retain excess exudate and its components. However, the effectiveness of these dressings in sequestering and retaining bacteria and host-derived proteins has not been compared. We have therefore investigated several superabsorbent dressings for their ability to absorb and retain bacteria (Staphylococcus aureus and Pseudomonas aeruginosa), their impact on bacterial viability, and their ability to sequester matrix metalloproteinases (MMP)-2 and 9 over 7 days. Whilst all dressings could sequester bacteria, some dressings internalised bacteria more effectively. There was considerable variation in bacterial viability within the dressings’ core, as well as differences in bacterial retention. Some dressings effectively internalised and retained bacteria over time, whereas other dressings retained significantly less. These differences were reflected visually using scanning electron microscopy. Most dressings fully sequestered MMP-2 and 9. These data illustrate differences in the ability of superabsorbent dressings to absorb and retain exudate and its components.