bluuebunny/crossref_metadata_2025 huggingface dataset:
46 Solubility and the Toxicity of Metal Oxide Nanoparticles: Looking Through the Lens of Toxicogenomics and DNA Damage
Authors: Boyadzhiev Andrey , Solorio-Rodriguez Silvia Aidee , Avramescu Mary-Luyza , Wu Dongmei , Williams Andrew , Rasmussen Pat , Halappanavar Sabina
Published: May 2023

Metal oxide nanoparticles (MONPs) are amongst the most widely utilized classes of nanomaterials worldwide. The mechanisms underlying their pulmonary toxicity are dependant on the physical-chemical properties of the particles. Solubility plays a critical role, as proportions of nanoparticles and dissolved metals change over time; however their relative contribution to the resulting toxicity has yet to be thoroughly investigated. The objective of this study was to mechanistically evaluate the impact of solubility on the toxic potential of MONPs. In this study, mouse lung epithelial cells were exposed for 2 – 48 Hrs to copper, zinc, nickel, aluminum and titanium oxides (CuO, ZnO, NiO, Al2O3, TiO2) as MONPs and microparticles, and corresponding metal chloride salts. Viability was assessed at each timepoint using Trypan Blue staining. DNA damage was measured after 2 and 4 Hrs exposure via the CometChip assay, while transcriptomic changes were measured using microarrays after 2, 24, and 48 Hrs of exposure. Benchmark dose modelling of viability and transcriptomics data indicates that ZnO and CuO MONPs induced more pronounced cytotoxicity and gene expression, earlier, than NiO, Al2O3, and TiO2 MONPs. With respect to DNA damage potential, NiO, CuO and ZnO MONPs showed the highest potency, with ZnCl2 being the only chloride to induce DNA damage at either timepoint. The metal chlorides induced similar pathway perturbations as their respective MONPs, while corresponding microparticle oxides  (except ZnO microparticles) exhibited muted responses. This presentation will further explore these findings, with an emphasis on the effect of solubility on toxicity.
65 The Adverse Health Effects of Exposure to PM2.5 on the London Underground
Authors: Mak Justie , Cullinan Paul , Feary Johanna , Marczylo Emma , Amaral André F S , Green David
Published: May 2023

Transport for London (TfL) employed 36,506 staff between 2014 and 2019, 22,202 worked within the London Underground (LU). Employees were regularly exposed to PM2.5 concentrations 15-fold higher than those found above ground in London. However, PM2.5 in the LU differs in physical and chemical characteristics relative to outdoor air, and the health impacts are largely unquantified. This project aims to quantify LU PM exposure of staff and measure its impact on cardiorespiratory sickness absence. A job exposure matrix was developed to model TfL employee PM2.5 exposure based on their jobs. Measurement campaigns were deployed across the LU network to validate and revise staff PM2.5 exposure, which was then linked to sickness absence records. Poisson models were developed to explore the relationship with cardiorespiratory sickness absence. PM2.5 exposure of customer service staff varied depending on their grade and tasks they undertake. Concentrations ranged from 2 to 138 µg/m3 in the offices and 3 to 1,036 µg/m3 on the platforms. Drivers’ PM2.5 exposure was dependent on the line they worked on and the amount of time the train spent underground. Drivers have the highest PM2.5 exposure (median: 130 µg/m3) among all TfL staff and the highest mean number of all-cause (6.7) and respiratory (1.5) sickness absence episodes. This is the largest study to quantify LU PM exposure and the associated health effects within a London occupational cohort. It will contribute to a safer working environment for staff and to a better understanding of the potential health impact on the commuting population.
71 Metabolomics Study of a Lung Model Exposed to Different Ultrafine Particles (UFP) Aerosols
Authors: Alsaleh Rasha , Kersch Christian , Pantzke Jana , Das Anusmita , Delaval Mathilde N , Sklorz Martin , Bucchianico Sebastiano Di , Zimmermann Ralf , Schmitz-Spanke Simone
Published: May 2023

Ultrafine particles (UFP), diameter of <0.1 µm, contribute to urban particulate air pollution. There is still not much evidence on their effects on humans. Our study aims to address their possible effects on lung metabolome. 

Alveolar epithelial cells (A549) together with macrophages (THP-1) were seeded on the apical side of the insert membrane, and fibroblasts (MRC-5) on the downside, respectively. Triple cell cultures were exposed at the air liquid interface to different aerosols generated by a combustion aerosol standard (CAST) soot generator. Applied aerosols consisted of UFP with either high or low content of semi-volatile organic compounds (SVOC). Herein, apical cell lysates were extracted for metabolites. Data acquisition was performed by GC-MS and processed with R and then analyzed by MetaboAnalyst. Statistical analysis showed that top features differentiating the high SVOC from clean air controls were amino acids (L-tryptophan and L-lysine), whereas for low SVOC, 5-methylthioadenosine and 5-methoxyindoleacetate. Tryptophan and its metabolite 5-hydroxy- tryptophan were significantly upregulated in high SVOC. However, in low SVOC, 5-methoxyindoleacetate was substantially upregulated. Pathway analysis revealed that purine metabolism was between the top significant enriched pathways in both high and low SVOC groups. Moreover, tryptophan metabolism which modulates immunity and inflammation was enriched similarly in both groups. These findings suggest that lung cell metabolome is modulated distinctively based on the chemical identity of UFP, which could give more understanding about the lung response mechanism to inhaled UFP.

This work was funded by Bayerische Staatsministeriums für Umwelt und Verbraucherschutz (BayUFP).
72 Endotoxin Exacerbates the NLRP3-Dependent Inflammatory Potency of Saharan Dust
Authors: Bredeck Gerrit , Busch Mathias , Rossi Andrea , Stahlmecke Burkhard , Fomba Khanneh Wadinga , Herrmann Hartmut , Schins Roel P F
Published: May 2023

Epidemiological studies have shown that desert dust exposure affects respiratory health. We aimed to investigate the NLRP3 inflammasome-caspase-1 pathway-dependent inflammatory properties of Saharan dust (SD) in a macrophage model and an air-liquid interface (ALI) co-culture model of the alveolar epithelium. Under submerged conditions wild-type (WT) and NLRP3-/- THP-1 cells were exposed to SD at 50 µg/cm². Using a Vitrocell® Cloud, A549/THP-1 WT ALI co-cultures were exposed to SD or DQ12 quartz at non-cytotoxic concentrations of 10, 20, and 30 µg/cm². Additionally, ALI co-cultures containing NLRP3-/- or CASPASE1/- THP-1 cells were exposed to SD. SD was found to contain endotoxin, and caused manifold higher interleukin (IL)-1β secretion in WT than in NLRP3/- THP-1 cells. Baked SD (220°C, overnight) induced IL-1β secretion to a ~4-fold lower extent. Co-exposure to baked SD and endotoxin synergistically restored the IL-1β secretion. In ALI co-cultures SD but not DQ12 upregulated the expression and secretion of IL-1β, IL-6, IL-8, and tumor necrosis factor α. The secretion of these cytokines was strongly decreased in co-cultures with CASPASE1/- or NLRP3/- THP-1 cells. The screening of multiple SD samples on WT THP-1 cells revealed that their inflammatory potencies strongly depended on the sampling day and location. The surprisingly strong SD-mediated activation of the NLRP3 inflammasome emphasizes its hazardousness and the need for risk mitigation strategies. Therefore, the connection between the toxicity of SD and its composition, especially its microbial components, needs to be further unraveled.

Supported by the Leibniz Collaborative Excellence Programme project DUSTRISK.
88 Microplastic References for Inhalation Studies
Authors: Santizo Katherine , Mangold Hannah , Wohlleben Wendel , Illies Sarah , Sarau George , Kraus Annelena , Christiansen Silke , Hansen Tanja
Published: May 2023

Microplastic research has been increasing due to the uncertainty of potential effects on the environment and human health. However, microplastic references are currently missing. Not only is there a lack of references there is also a lack of diversity in polymer type for references, especially in toxicological studies. In specific, inhalation studies must rely on microplastics that are respirable and/or inhalable (< 10 µm) to result in toxicological outcomes.  Therefore, in this project, we focus on using solvent precipitation to produce microplastic references from TPU, PA-6, PET, and LDPE for microplastic inhalation toxicity studies. Particle size distribution of the dispersion is used to verify that the desired size range is achieved. To demonstrate that the produced microplastic references are representative from its original material, molecular and particle descriptors are characterized. Chemical composition, molecular weight, crystallinity, solidity, density, are among the descriptors tested for both the produced microplastic references and its corresponding commercial counterpart. Preliminary results have shown that quantities needed for in-vitro testing and particle size range desired is achieved with successful production of sub-100 nm constituent particle counts and all-respirable mass-based diameters. SEM images confirm the size distribution and show distribution of particle shapes. Chemical composition via spontaneous Raman Scattering illustrates clear polymer spectra signals from the microplastic dispersions. These microplastic reference materials are complemented by toxicology controls. In addition, the in-vitro screening uses both submersed and air-liquid interface cultures to expose cells. This study will thus provide information on microplastic material descriptors relevant for inhalation toxicity.
99 The Relative Toxicity and Bioreactivity of Ambient Microplastic Pollution to Human Alveolar Lung Epithelial Cells with and Without Urban PM2.5
Authors: Laskowska Julia , Alzahabi Khaled , Auyang Eric , Mudway Ian , Wright Stephanie , Tetley Teresa
Published: May 2023

Plastic has unique properties with multiple applications. Microsized plastic fragments (0.1−1000µm; secondary microplastics) are generated throughout the lifespan of plastic materials; primary microplastics are manufactured. Microplastics are present in PM2.5. With increased use of electric cars and reduction in tail pipe emissions, the amount and proportion of microplastics in airborne PM2.5 could increase. We know little about the effects of microplastic inhalation on human health. Hypothesis: Inhaled plastic microparticles will have adverse effects on the respiratory epithelium, both independently and in combination with PM2.5.  Two atmospheric plastics, polypropylene (PP) and polyamide (PA), were generated and characterized prior to study. They had a similar size distribution (1-3µm), polydispersity (PA: 0.9002; PP: 0.9037) and charge (PA: -9.66; PP: -5.79) in culture medium.  Human alveolar epithelial type 1-like cells (TT1) were exposed for 24h to 1.25-80µg/ml of PP, PA, and PM2.5; viability fell after PA exposure to 10µg/ml (~10%), reaching ~30% at 80µg/ml (p<0.0001); only 40 and 80µg/ml of PP caused a 15 and 20% drop in viability, respectively (p<0.01). PM2.5 had no effect on viability. Although plastics had no effect on IL-6 or IL-8 release, PM2.5 stimulated release at 20-80µg/ml, reaching 10-fold (p<0.001) and 2.5-fold (p<0.05) for IL6 and IL8 respectively. Exposure to plastic/PM2.5 ratios from 0.0001:1 to 1:1 had no consistent effect. TEM suggests internalization of PA, PP and PM2.5 by TT1 cells.  Thus, microplastics exhibit different responses (increased cell death) to PM2.5 (increased mediator production). The inconsistent response to  particle mixtures is likely dependent upon the proportion of microplastics.
135 Downregulation of ABCG1 and ABCG4 Transporters by rare Earth Oxide Nanoparticles Induces the Pulmonary Alveolar Proteinosis
Authors: Jeon Soyeon , Cho Wan-Seob
Published: May 2023

Pulmonary alveolar proteinosis (PAP) is rare disease that accumulates alveolar surfactant. PAP can be induced by nanoparticles (NPs), but there is little information about PAP-producing NPs and their mechanism. Here, we evaluated PAP-producing NPs including 6 of rare earth oxide (REO) NPs and NiO NPs and investigated the magnitude and related gene expression (ATP-binding cassette, ATP) of PAP at 1 and 6 months after single intratracheal instillation to Wistar rats. Furthermore, we evaluated morphological change of REO NPs because biotransformation is critical to understand the toxicity. The 6 REO NPs (Dy2O3, Eu2O3, In2O3, Pr6O11, Sm2O3, and Tb4O7) and NiO NPs caused PAP at 1 month, while only In2O3 NPs showed a persistent PAP at 6 months. All the REO NPs transformed sea urchin-shaped within the alveolar macrophage up to 6 months. The levels of phospholipids, indicators of PAP, showed good correlation with gene expression of five ABC transporters (ABCA1, ABCB4, ABCB8, ABCG1, and ABCG4), which effluxing phospholipids in PAP. Among them, ABCG1 and ABCG4 might be key transporters involved in PAP development because both showed negative correlation with the magnitude of PAP, while others might be compensatory transporters for PAP recovery, as they showed a positive correlation. In conclusion, the identification of seven PAP-producing NPs implies that PAP may be an emerging occupational disease and that ABCG1 and ABCG4 may be therapeutic targets for PAP. In this regard, we are studying therapeutic agent for PAP induced by NPs using medicine related PPAR-gamma, which is upstream mechanism of ABCG1 and ABCG4.
18 Can the Indoor Environment Influence the Toxicity of Indoor and Outdoor Air Pollution Particulates?
Authors: Meldrum Kirsty , Bateman Joshua W P , Doak Shareen H , Clift Martin J D
Published: May 2023

When considering air pollution particles (AP), they are often assessed in isolation, when this is not how the population is exposed to them. Within the indoor environment, there are bioaerosols present, which contain various allergens including house dust mite (HDM) and lipopolysaccharides (LPS). This RESPIRE study aims to apply a well-characterised in vitro model of the alveolar barrier (type I and II epithelial cells (NCI-H441 and hAELVi at relevant in vivo ratios) and macrophage-like cells) to determine the effects of these bioaerosols on the toxicological and immunological responses to AP. To achieve this, we will investigate cytotoxicity, inflammatory responses, morphology, oxidative stress, membrane integrity and genetic toxicology of these models with specific focus on responses from human allergic responses and airway diseases (i.e., bronchiolitis-interstitial lung disease and sarcoidosis) to determine the additional health considerations the addition of bioaerosols to AP has on our models. We will utilise a physiologically relevant aerosolization exposure method) and a standardised indoor (NIST2583) particulate at an environmentally relevant concentration to mimic air pollution along with HDM and LPS to determine if the addition of these environmentally appropriate bioaerosols influence the responses to IAP. 

This project is funded by the recently initiated RESPIRE project (NE/W002264/1), as part of the SPF Clean Air Programme.
69 Activation of the Aryl Hydrocarbon Receptor - a Major mode of Combustion Particle Toxicity?
Authors: Øvrevik Johan , Grytting Vegard S , Brinchmann Bendik C , Skuland Tonje S , Chand Prem , Refsnes Magne , Låg Marit , Holme Jørn A
Published: May 2023

Combustion-derived particles constitute an important part of the fine fraction of particulate matter with aerodynamic diameter less than 2.5 microns (PM2.5) and are considered central for the adverse effects of air pollution. Understanding the mechanisms of combustion particle toxicity may shed light on the components and characteristics of outdoor air PM driving adverse health effects. This may also enable more targeted and efficient policies to improve air quality and promote health and wellbeing. The aryl hydrocarbon receptor (AhR) is a ligand dependent transcription factor, originally discovered for its ability to bind polycyclic aromatic hydrocarbons (PAHs) and dioxin-like compounds and regulate PAH metabolism. It is now clear that AhR regulates a variety of biological and toxicological responses, overlapping to a considerable degree with the effects of combustion PM and ambient PM2.5. Studies from our lab and others also suggest that AhR activation is among the most sensitive responses to combustion PM exposure, induced at orders of magnitude lower concentrations than many other endpoints. This talk will discuss the potential role of the AhR and PAHs in combustion PM toxicity based on previous and ongoing work, with a main focus on intracellular signalling and regulation of inflammatory reactions in lung epithelial cells and vascular endothelial cells.
100 Co-Culture of Human type I and type II Pneumocyte Cell Lines as a Model of Alveolar Epithelium for Toxicity Testing
Authors: Boland Sonja , Brookes Oliver , Miremont Dorian , Kuen René Lai , Eon-Bertho Alice , Baeza-Squiban Armelle
Published: May 2023

The epithelial tissues of the distal lung are continuously exposed to inhaled air, and are thus of research interest in studying respiratory exposure to therapeutic and hazardous materials such as plastic particles which represent a new threat for human health. There is a need therefore to develop sophisticated models of the human alveolar epithelium, which better represent the different cell types present in the native lung. Our aim was to develop an air-liquid interface model of the alveolar epithelium by incorporating human cell-lines which bear features of type I (hAELVi) and type II (NCI-H441) epithelial cells. Working both in monotypic cultures and cocultures, we compared the morphology of single cells and the structure of cell layers of the two cell-lines using light and electron microscopy. We measured barrier function by trans-epithelial electrical resistance (TEER). We assessed expression of a panel of relevant genes that play important roles in barrier function and differentiation. We demonstrated that barrier properties can be maintained for 30 days. The coculture model was observed to form a stable barrier akin to that seen in hAELVi, while expressing surfactant protein C, and having a profile of expression of claudins and aquaporins appropriate for the distal lung (Brookes (2021) PLoSONE 16(9):e0248798). In summary, our results support the coculture of these two cell-lines to produce a model which better represents the breadth of functions seen in native alveolar epithelium.

Funding: From the European Union’s Horizon 2020 research and innovation programme under grant agreement No965367 (PlasticsFate)
3 An Introduction to the SbD4Nano Project
Authors: Hunt Neil
Published: May 2023

A major challenge for the global nanotechnology sector is the development of safe and functional engineered nanomaterials (ENMs) and nano-enabled products (NEPs). In order to minimise the risks to human and environmental health during the engineering of NEPs the goal of the Safe-by-Design for Nano (SbD4Nano) project is to create a novel e-infrastructure for the definition, performance testing and implementation of Safe-by-Design (SbD) approaches in the nanotechnology supply chains. The project aims to demonstrate how selecting appropriate surface modification of nanomaterials can reduce the hazard and risk to workers, consumers and the environment whilst maintaining its functionality.  The presentation will give an introduction to the project and outline the results generated thus far.

This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 862195
36 An Investigation into Mechanisms Responsible for (geno)Toxicity Induced by Exposure to Industrially-Relevant Multi-Component Nanomaterials and high Aspect Ratio Nanomaterials
Authors: Brooks Sian , Saccardo Angela , Vogel Ulla , Wohlleben Wendel , Doak Shareen , Clift Martin
Published: May 2023

Production and application of multi-component nanomaterials (MCNMs) and high aspect ratio nanomaterials (HARN) has raised questions as to their inhalation risk. A PRISMA-orientated systematic literature review indicated a key knowledge gap related to the (geno)toxicity of metal oxide MCNMs and HARN. The aim of this study was to conduct a mechanistic-based toxicology assessment of a number of industrially-relevant MCNMs and HARN materials, in order to fill this knowledge gap and provide vital hazard assessment towards these materials’ safe and sustainable design. A549 monocultures (2.5x105), and A549/dTHP-1 co-cultures (1:10) were seeded in 12-well transwell-membranes at the air-liquid interface. Cell cultures were exposed, via aerosol, to Printex90, LaCo0.5Ni0.05O3, LaCo0.475Ni0.475Pt0.05O3, LaCo0.475Ni0.475Pd0.05O3, LaCo0.25Ni0.75O3, LaNiO3, NiZnFe4O8, ZnFe2O4, and NiFe2O4 to human exposure-relevant concentrations of 390, 780, 3100 ng/cm2 (24hrs). Aerosolised MCNM and HARN were characterised following acellular deposition via electron microscopy. Cellular cytotoxicity, barrier integrity, (pro)inflammatory/fibrotic response, oxidative stress and mutagenicity/DNA damage was assessed. Results indicate barrier integrity and IL-8 production were unaffected by Printex90, LaCo0.5Ni0.05O3, and ZnFe2O4 exposure. A dose-dependent increase in micronucleus frequency was observed for these four materials. Investigations are continuing to determine the mechanisms associated with this noted genotoxic effect, as well as upon further MCNMs/HARN (i.e. Fe2CoO4(Fe1/Co3), Silica-Ref-Std). Emphasis is being placed upon elucidating specific structure-activity relationships for each MCNM/HARN by testing specific key events of inhalation-based adverse outcome pathways relevant to the in vitro models used. This project was funded by EU H2020 research and innovation programme, grant agreement No. 953183 (HARMLESS).
74 Impact of Air Pollution on Lung Immune Responses in a Mouse Model of Influenza Infection
Authors: Martín-Faivre Lydie , Prince Lisa , Chivé Chloé , Sallenave Jean-Michel , Baeza-Squiban Armelle , Garcia-Verdugo Ignacio
Published: May 2023

During air pollution peaks, influenza infections are more severe, and the number of hospitalizations associated to flu increases. This project aims to study if air pollution contributes to the severity of influenza infection. To this end, mice were intratracheally exposed once to well-characterized particulate matter collected from Paris atmosphere (PM2.5) and inflammation was determined in the broncho-alveolar lavages (BALs) of mice at different time points post-exposure.  We observed that 2 mg/kg PM2.5 induced the recruitment of neutrophils in the BALs at 1-day post-exposure.  Neutrophils recruitment decreased since the 3rd day post-exposure while the recruitment of eosinophils, monocytes, and lymphocytes appeared. CD4+ T lymphocyte recruitment was sustained at least until 5-7 days post-exposure. Concomitantly, the levels of proinflammatory cytokines and chemokines were evaluated in the BALs of PM-treated mice. Ongoing experiments of co-infection at different time points after PM2.5 exposure will elucidate if severity of influenza infection is exacerbated after PM exposure.

This work is support by the la Fondation pour la Recherche Médicale (Foundation for Medical Research).
93 Linking the Molecular Mechanisms of Alveolar Macrophage Cell Death Induced by Inhaled Nanoparticles with the Subsequent Pathological Outcome
Authors: Ren Hongyu , Han Lianyong , Stoeger Tobias , Rehberg Markus
Published: May 2023

Background

Carbon Nanomaterials (CNM) get released into the environment as combustion by-products and engineered materials. Our previous work has shown that inhalation of CNMs differing in shape, such as spherical carbon nanoparticles (CNPs) or fiber-shaped nanotubes (CNTs) triggers different response pattern ranging from acute and resolving to persistent and chronic lung inflammation. Furthermore, our cell and mouse data showed that, particularly rigid, multi-walled nanotubes (MWCNTs) can cell-specifically and persistently kill alveolar macrophages (AM). Here we hypothesize that the AM death pathway determines the fate of lung inflammation, as acute or chronic. 

Results

Exposure of the murine AM cell line MH-S to MWCNT led to significant decrease of cell viability in a dose-dependent manner (IC50: 10±5 μg/ml). In comparison, CNPs showed relatively low toxicity (IC50: >200 ug/ml) to MH-S cells. Also in contrast to hardly detectable apoptosis (cleaved-Caspase3), immunoblot and -fluorescence analysis demonstrated significant induction of LC3II, a central protein in the autophagy pathway, 12h after MWCNT treatment. The MWCNT triggered cell death response from BMDM-derived AM-like cells however, did not differ between LC3B-/- and wt mice, indicating the autophagy pathway as dispensable. In contrast, inhibition of lysosomal Cathepsins via K777, rescued MWCNT induced cell death of either MH-S or AM-like cells suggesting lysosomal Cathepsins as key player in AM cell death.

Conclusion

Lysosomal damage with subsequent Cathepsin activity seem a central key event in MWCNT triggered AM cell death. Current studies investigate the relevance of Cathepsins for the inflammatory consequences of CNT triggered AM cell death.
Development of a quantitative North and Central European job exposure matrix for wood dust
Authors: Basinas Ioannis , Liukkonen Tuula , Sigsgaard Torben , Andersen Nils T , Vestergaard Jesper M , Galea Karen S , van Tongeren Martie , Wiggans Ruth , Savary Barbara , Eduard Wijnand , Kolstad Henrik A , Vested Anne , Kromhout Hans , Schlünssen Vivi
Published: May 2023

Wood dust is an established carcinogen also linked to several non malignant respiratory disorders. A major limitation in research on wood dust and its health effects is the lack of (historical) quantitative estimates of occupational exposure for use in general population-based case-control or cohort studies. The present study aimed to develop a multinational quantitative Job Exposure Matrix (JEM) for wood dust exposure using exposure data from several Northern and Central European countries. For this, an occupational exposure database containing 12653 personal wood dust measurements collected between 1978 and 2007 in Denmark, Finland, France, The Netherlands, Norway, and the United Kingdom (UK) was established. Measurement data were adjusted for differences in inhalable dust sampling efficiency resulting from the use of different dust samplers and analysed using linear mixed effect regression with job codes (ISCO-88) and country treated as random effects. Fixed effects were the year of measurement, the expert assessment of exposure intensity (no, low, and high exposure) for every ISCO-88 job code from an existing wood dust JEM and sampling duration. The results of the models suggest that wood dust exposure has declined annually by approximately 8%. Substantial differences in exposure levels between countries were observed with the highest levels in the United Kingdom and the lowest in Denmark and Norway, albeit with similar job rankings across countries. The jobs with the highest predicted exposure are floor layers and tile setters, wood-products machine operators, and building construction labourers with geometric mean levels for the year 1997 between 1.7 and 1.9 mg/m3. The predicted exposure estimates by the model are compared with the results of wood dust measurement data reported in the literature. The model predicted estimates for full-shift exposures were used to develop a time-dependent quantitative JEM for exposure to wood dust that can be used to estimate exposure for participants of general population studies in Northern European countries on the health effects from occupational exposure to wood dust.
Juvenile leg autotomy predicts adult male morph in a New Zealand harvestman with weapon polymorphism
Authors: Powell Erin C , Painting Christina J , Machado Glauco , Holwell Gregory I
Published: May 2023

Intraspecific weapon polymorphisms that arise via conditional thresholds may be affected by juvenile experience such as predator encounters, yet this idea has rarely been tested. The New Zealand harvestman Forsteropsalis pureora has three male morphs: majors (alphas and betas) are large-bodied with large chelicerae used in male–male contests, while minors (gammas) are small-bodied with small chelicerae and scramble to find mates. Individuals use leg autotomy to escape predators and there is no regeneration of the missing leg. Here, we tested whether juvenile experience affects adult morph using leg autotomy scars as a proxy of predator encounters. Juvenile males that lost at least one leg (with either locomotory or sensory function) had a 45 times higher probability of becoming a minor morph at adulthood than intact juvenile males. Leg loss during development may affect foraging, locomotion, and/or physiology, potentially linking a juvenile’s predator encounters to their final adult morph and future reproductive tactic.
Universal robust regression via maximum mean discrepancy
Authors: Alquier P , Gerber M
Published: May 2023

Many modern datasets are collected automatically and are thus easily contaminated by outliers. This has led to a renewed interest in robust estimation, including new notions of robustness such as robustness to adversarial contamination of the data. However, most robust estimation methods are designed for a specific model. Notably, many methods were proposed recently to obtain robust estimators in linear models, or generalized linear models, and a few were developed for very specific settings, for example beta regression or sample selection models. In this paper we develop a new approach for robust estimation in arbitrary regression models, based on maximum mean discrepancy minimization. We build two estimators that are both proven to be robust to Huber-type contamination. For one of them, we obtain a non-asymptotic error bound and show that it is also robust to adversarial contamination, but this estimator is computationally more expensive to use in practice than the other one. As a by-product of our theoretical analysis of the proposed estimators, we derive new results on kernel conditional mean embedding of distributions that are of independent interest.
Bayesian learning of network structures from interventional experimental data
Authors: Castelletti F , Peluso S
Published: May 2023

Directed acyclic graphs provide an effective framework for learning causal relationships among variables given multivariate observations. Under pure observational data, directed acyclic graphs encoding the same conditional independencies cannot be distinguished and are collected into Markov equivalence classes. In many contexts, however, observational measurements are supplemented by interventional data that improve directed acyclic graph identifiability and enhance causal effect estimation. We propose a Bayesian framework for multivariate data partially generated after stochastic interventions. To this end, we introduce an effective prior elicitation procedure leading to a closed-form expression for the directed acyclic graph marginal likelihood and guaranteeing score equivalence among directed acyclic graphs that are Markov equivalent post intervention. Under the Gaussian setting, we show, in terms of posterior ratio consistency, that the true network will be asymptotically recovered, regardless of the specific distribution of the intervened variables and of the relative asymptotic dominance between observational and interventional measurements. We validate our theoretical results via simulation and we implement a Markov chain Monte Carlo sampler for posterior inference on the space of directed acyclic graphs on both synthetic and biological protein expression data.
Ghosts of the Gulag: Negotiating Spectres of the Penal Past in Northern Russia
Authors: Slade Gavin , Piacentini Laura , Kravtsova Alena
Published: May 2023

The paper develops the concept of penal spectrality—a sense of the presence of those who endured past penal suffering within environments and among objects related to the practice of punishment. The residents of Ukhta, a Gulag town in Northern Russia, engage uncomfortably with penal spectrality and employ two forms of distancing—pragmatic and cultural—to deal with its melancholic affects. Pragmatically, residents repurpose and reincorporate the things of the penal past into the social order, finding a use-value in them for the present day. Culturally, residents engage in the museumification and commodification of Gulag things. The paper advances two directions for research in ghost criminology. First, we show how uneasy spectral feelings are not passively observed but actively negotiated. Second, in this interaction, we show the immediacy of engaged practical interaction with material objects that points to modes of encountering and misrecognizing penal suffering beyond cultural commodification and penal spectatorship.
O002 Expression of MLN64 (lymph node metastasis 64) gene transcript in clinical gastric cancer and relationship with the ERBB4
Authors: Li A , Ji E , Martin T , Jia S , Ji J , Jiang W
Published: May 2023

Introduction

MLN64 (Lymph Node Metastasis 64, or STARD3 (StAR Related Lipid Transfer Domain Containing 3)) has a role in the progression of certain cancers including breast and prostate cancers and connected to the pattern of ERBB2 (Her2). The present study explored the expression of MLN64 in clinical gastric cancer in connection with the ERBB family.

Methods

A gastric cancer cohort (n=322) was tested for the expression profile of MLN64 along with the ERBB family members. Comparisons were made between clinical, pathological subgroups and the clinical outcome together with ERBB expression status.

Results

Gastric tumours expressed significantly raised levels of MLN64 than normal tissues (p=0.0012) and showed a stepwise increase with increased tumour grade and TNM staging. However, there was no significant difference between node negative and node positive tumours. MLN64 alone had a weak value in evaluating the overall (OS) and disease free (DFS) survival. Amongst the four ERBB family members, MLN64 had a significant correlation with ERBB4 (Her4) (p=0.004). Stratification of patients by ERBB4 expression status indicates that in patients with low ERBB4 tumours, MLN64 presents a significant factor in assessing both disease free (DFS) p=0.027) and overall survival (OS) (p=0.048). Similarly, MLN64 expression identified a subpopulation of node positive patients with a most adverse clinical outcome (p=0.009 for DFS and p=0.048 for OS).

Conclusion

MLN64 expression is an indicator for the disease progression and clinical outcome in gastric cancer. Together with the expression pattern of ERBB4, it makes a prognostic factor for the patients.
O023 Effectiveness of augmented reality for surgical training of medical students: a systematic review and meta-analysis
Authors: Shah A , Kaka A , Kumar N S , Patel A , Yunus A , Patel A
Published: May 2023

Introduction

Interest in augmented reality (AR) technologies within an educational setting have surged in recent years. However, few studies evaluate the use of AR in a primarily medical student population. This systematic review with meta-analysis intended to evaluate the existing literature on this topic.

Methods

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using relevant synonyms for the terms augmented reality, surgery and medical students, the databases Medline, Embase, and Scopus were searched. Data was extracted for outcome measures such as time for task completion, errors/fails, attempts/retries, motion sickness/nausea and focus shifts.

Results

Some 826 records were initially retrieved; 19 studies were included in our review, with a total of 485 participants. The AR group performed better than the comparator group in 84% of the statistically significant main outcomes. The AR groups were less likely to fail assessment, with a pooled odds ratio of 1.76 (95% CI:0.06-51.71, p=0.74, I2=81%). One study reported 57% fewer critical errors than the comparator group. Only two studies reported nausea/motion sickness as an outcome (12% (n=3) and mean Likert-scale score of 3 (of 10) in the AR groups).

Conclusion

AR can be an effective surgical teaching and training tool for medical students. However, the limitations of AR, including visually-induced motion sickness, have not yet been explored extensively by primary studies with a medical student population. Therefore, gradual integration of AR is proposed until further studies elucidating benefits and risks can be undertaken.
O038 Positive impact of an ERAS programme on living and deceased donor renal transplant recipients’ recovery during COVID pandemic
Authors: Simpson-Dent E , Webb M , Meredith H , Winn L , Pestrin O , Balfour A , Sutherland A , Usher H , Wakelin S , Oniscu G C , Thomas R
Published: May 2023

Introduction

An ERAS (Enhanced Recovery After Surgery) programme was created to reduce length of stay (LoS) and improve outcomes following renal transplant surgery. This aimed to reduce post-operative hospital-acquired infection, especially COVID-19.

Methods

The ERAS protocol was finalised following a literature review and MDT discussion. ERAS information, with post-operative exercise advice, was distributed to patients on the renal transplant waitlist. LOS was evaluated, comparing ERAS with pre-ERAS recipients and, to remove pandemic bias, pre-pandemic (December 2019) recipients. Secondary outcomes were opiate use, mobilisation, bowel function and patient-reported outcomes. ERAS protocol compliance was monitored. Data analysis was with student t-test and Chi-2 test in GraphPad Prism.

Results

Some 35 consecutive recipients completed ERAS protocol (March 2021). Baseline characteristics were comparable between live-donor recipients 9/35 vs 13/35 pre-ERAS and 12/35 pre-COVID. BMI>30 was higher in ERAS group (19vs. 11vs. 8). Median LoS was significantly reduced: ERAS - 5 days, pre-ERAS - 7 days, pre-COVID - 8 days (p=0.01). 51% of ERAS discharges were within 5 days vs. 17% pre-ERAS vs. none pre-COVID (X2 12.59, p<0.001). For overstayers (>5 days), potential preventable reasons were identified. 79.2% of ERAS recipients mobilised on day 1 post-op. ERAS indicated no significant reduced opiate use. Two ERAS recipients were readmitted within 30 days (vs.9/70 pre-ERAS) and one returned to theatre (vs.5/70 pre-ERAS).

Conclusion

This ERAS programme successfully reduced the LoS by 2 days in comparative population with minimal adverse events. Patient and staff feedback was positive. It's hypothesised that assigning a specialist ERAS nurse will improve compliance.
O041 Recipient outcomes after simultaneous pancreas and kidney transplant delineated by donor EGFR
Authors: Owen R , Fitzpatrick N , Counter C , Malik A , Mahendran B , Tingle S , Wilson C , Manas D , Sheerin N , White S
Published: May 2023

Introduction

This study aimed to assess if the use of kidneys from donors with a decreased eGFR had an adverse effect on patient and graft survival.

Methods

Data on all UK SPKT's from 2001-2021 were obtained from the NHSBT UK Transplant Registry (n=2,631). Cases with missing information were removed, leaving a final cohort of 1,819 (69.1%). eGFR was calculated using the CKD-EPI equation. Pancreas Graft (PGS), Kidney Graft (KGS) and patient survival analyses were conducted using Kaplan-Meier plots and Cox-regression models.

Results

71% (n=1,292) of grafts were from donors with an eGFR>90 and 29%(n=530) were from donors with an eGFR<90. Donors with an eGFR<90 were statistically significantly more likely to be older (p<0.0001), a DBD donor (p=0.0086**) and have a higher BMI(p<0.0001). Recipients who received a graft from a donor with an eGFR<90 were well matched with those who received a graft from a donor with an eGFR>90. Univariate analysis showed a statistically significant decreased KGS(p=0.007**) when the donor had an eGFR<90. This trend was not seen when comparing patient or pancreas survival.

Conclusion

We accept a lower GFR could be indicative of either an AKI or a sign of early chronic kidney disease. In this current data analysis, we have been unable to successfully distinguish between the two however we have shown poorer KGS in those with a lower eGFR (<90). This had no impact on pancreas or patient survival. Further analysis is needed to explain the precise reasons for the lower eGFRs at the time of organ donation.
O046 Reduction of surgical complications via 3D printed/virtual models available during (robotic-assisted) radical prostatectomy
Authors: Sarhan K , MacAskil F , Raison N , Byrne N , Heath M , Antonelli M , Prezzi D , Hyde E , Ourselin S , Dasgupta P , Granados A
Published: May 2023

Introduction

Prostate cancer is the leading cancer in males in the UK and mostly treated via robotic-assisted radical prostatectomy (RARP). The prognosis of prostate cancer is promising especially if detected early. Studies have shown that the use of 3D patient-specific models has positive effects on surgical outcomes in other fields. This systematic review aims to assess whether 3D printed and virtual models reduce surgical complications for patients undergoing RARP.

Methods

This study was a systematic review conducted using PRISMA guidelines from comprehensive databases - PubMed and Medline. These were then screened using an inclusion and exclusion criteria, to remove papers that were not relevant to the research question. Last, each abstract was screened for relevancy and duplicates were removed.

Results

A total of 201 patients had the use of 3D patient-specific modelling of the prostate to aid in surgery. Across all studies, a decrease in positive surgical margin rates was reported, indicating better outcomes for patients. However, no statistically significant difference was found between intervention and control groups, in nerve sparing, bladder neck sparing and postoperative SHIM score. A decrease in detectable PSA was found in intervention groups. Furthermore, the use of 3D models did lead to more surgeons changing the pre-operative plan, suggesting that 3D modelling enhances surgical planning – leading to potentially improved outcomes.

Conclusion

The use of 3D modelling has positive outcomes for patients undergoing RARP, however, the extent is still unclear as research in this area remains limited.
O053 Are rectus sheath catheters being placed accurately into optimum position during NELA laparotomies?
Authors: Waddell K , Nevins E , McCallum I
Published: May 2023

Introduction

Rectus sheath catheters (RSC) are a method of delivering local anaesthetic to post-operative laparotomy wounds. Ideal standard positioning for RSC's is in the retro-rectus space. They aim to reduce post-operative pain, and show less side effects than epidural analgesia. This audit reviews positioning of RSC in post-operative laparotomy patients at a centre in North East England.

Methods

All NELA (National Emergency Laparotomy Audit) patients who had open laparotomy or laparoscopic converted to open procedures between 1st December 2021 to September 2022 were identified and included. Patients who had both RSC inserted and had a CT scan within the first 3 post-operative days were identified.

Results

105 patients (68%) had RSC inserted. 11 (10.5%) patients with RSC placed had post-operative imaging within 3 days. CT images were reviewed assessing the position of RSC's. One patient had bilateral RSC correctly placed. Of the total individual RSC's (22) on imaging, 9 were correctly positioned, 9 incorrectly positioned, and 4 not identified when reviewing CT images. All of those incorrectly positioned were identified in the subcutaneous fat.

Conclusion

At this hospital in North East England, surgeons insert RSC and do not use ultrasound guidance. This audit highlighted that they are mostly placed in the incorrect position. Ultrasound guided insertion could be considered as a method of inserting RSC more accurately. Further research is needed to assess if correctly placed RSC
O058 Association and one-year trends of frailty, cognition, disability, and quality of life in individuals with chronic limb-threatening ischaemia
Authors: Houghton J , Essop-Adam A , Nduwayo S , Nickinson A , Black I , Bryant N , Meffen A , Gray L , Conroy S , Payne T , Rayt H , Sayers R , Haunton V
Published: May 2023

Introduction

This study aimed to describe the associations of frailty with cognition, disability, and quality of life (QoL) among individuals with chronic limb-threatening ischaemia (CLTI) over one-year following intervention.

Methods

Single-centre prospective cohort study. Patients aged ≥65 with CLTI and a planned intervention between May 2019 and May 2021 were eligible for inclusion. Patients underwent frailty, cognitive function, disability and QoL assessments before their procedure. Delirium screening was performed at 24- and 72-hours post-operatively. Frailty, disability and QoL assessments were repeated at three- and 12-months.

Results

Ninety-nine patients completed baseline assessments, of whom 45 (45%) were classified as frail by the Edmonton frail scale. Frailty was strongly associated with higher prevalence of cognitive impairment (52% vs 17%; p<.001).

Eighty-seven patients underwent a procedure. Ten (11%) developed POD, of whom 8 had frailty (p=.003). Cognitive impairment (OR 8.52; 95%CI 1.12, 64.67; p=.038) was independently associated with POD. Frailty was associated with worse vascular quality of life questionnaire (VascuQoL) (p=.001) and EQ-5D-5L scores (p<.001) at all timepoints, however both those with and without frailty had modest improvement in VascuQoL and EQ-5D-5L scores at 12-months (p=.001). Barthel index (disability) scores were lower for those with frailty (p<.001) and decreased slightly over 12-months for both groups (p=.007). Five patients (12%) transitioned from frailty to non-frailty at 12-months (clinical frailty scale), however 10 patients (23%) transitioned from non-frailty to frailty.

Conclusion

CLTI patients with frailty have worse cognition, QoL and disability. Overall, individuals with CLTI demonstrate progression in frailty and disability at one-year post-intervention.
O066 Outcomes following fenestrated and branched endovascular repair (F/BEVAR) of complex aneurysms in octogenarians: a time to event meta-analysis
Authors: Hanna L , Lam K , Jha R , Abdullah A , Sounderajah V , Antoniou G , Gibbs R
Published: May 2023

Introduction

Objective: To evaluate the clinical outcomes of F/BEVAR among octogenarians.

Methods

Databases were systematically searched for studies that compared outcomes following F/BEVAR between octogenarians and non-octogenarians. The primary outcome measures were peri-operative mortality, survival, re-intervention, aortic rupture, and aneurysm-related deaths. Secondary outcomes were peri-operative outcomes.

Results

Seven studies published between 2017 and 2022 were included reporting on a total of 7,552 patients (>80yrs, 1536; <80yrs, 6016). More males (OR [95% CI] 0.83 [0.73-0.94], p.003), smokers (OR 0.50 [0.43-0.58], p<.001) patients with ASA >3 (OR 0.72 [0.52-0.98], p=.04), hypercholesterolaemia (OR 0.56, [0.42-0.73], p<.001), and pulmonary disease (OR 0.75, [0.66-0.86], p<.001) were observed in non-octogenarians. There was no significant difference in the peri-operative mortality between the two groups, but the hazard of overall mortality during follow-up was significantly higher in the octogenarian group (HR 1.67 [1.27–2.20], p<.001). There was no statistically significant difference in re-intervention (HR 0.96, [0.85-1.09], p=.057) or aneurysm-related deaths (OR 0.02, [-0.02-0.07], p=.31) between the two groups, but older patients were at greater risk of aortic rupture during follow-up (OR 4.71, [1.73–12.85], p=.002). Octogenarians were at a greater risk of intra-operative blood loss (WMD 54.73 [17.89-91.58], p=.004), endoleaks on completion angiogram (ORs 1.42, [1.20-1.67], p<.001), cardiac events (1.34 [1.12-1.62], p=.002) and endoleaks during follow-up (OR 1.40[1.03-1.91], p=.03). The body of evidence for most primary outcomes was judged to be low.

Conclusion

Survival is lower in octogenarians but there was no significant difference in aneurysm-related deaths or re-interventions, despite the increased incidence of aortic rupture and endoleaks during follow-up.