Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function.

Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. Here, we describe a therapeutic strategy called "RING-Bait," which employs an aggregating protein sequence combined with an E3 ubiquitin ligase. RING-Bait is recruited into aggregates, whereupon clustering dimerizes the RING domain and activates its E3 function, resulting in the degradation of the aggregate complex. We exemplify this concept by demonstrating the specific degradation of tau aggregates while sparing soluble tau. Unlike immunotherapy, RING-Bait is effective against both seeded and cell-autonomous aggregation. RING-Bait removed tau aggregates seeded from Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) brain extracts and was also effective in primary neurons. We used a brain-penetrant adeno-associated virus (AAV) to treat P301S tau transgenic mice, reducing tau pathology and improving motor function. A RING-Bait strategy could be applied to other neurodegenerative proteinopathies by replacing the Bait sequence to match the target aggregate.

Performance evaluation of image co-registration methods in photoacoustic mesoscopy of the vasculature.

Objective:The formation of functional vasculature in solid tumours enables delivery of oxygen and nutrients, and is vital for effective treatment with chemotherapeutic agents. Longitudinal characterisation of vascular networks can be enabled using mesoscopic photoacoustic imaging, but requires accurate image co-registration to precisely assess local changes across disease development or in response to therapy. Co-registration in photoacoustic imaging is challenging due to the complex nature of the generated signal, including the sparsity of data, artefacts related to the illumination/detection geometry, scan-to-scan technical variability, and biological variability, such as transient changes in perfusion. To better inform the choice of co-registration algorithms, we compared five open-source methods, in physiological and pathological tissues, with the aim of aligning evolving vascular networks in tumours imaged over growth at different time-points.Approach:Co-registration techniques were applied to 3D vascular images acquired with photoacoustic mesoscopy from murine ears and breast cancer patient-derived xenografts, at a fixed time-point and longitudinally. Images were pre-processed and segmented using an unsupervised generative adversarial network. To compare co-registration quality in different settings, pairs of fixed and moving intensity images and/or segmentations were fed into five methods split into the following categories: affine intensity-based using 1)mutual information (MI) or 2)normalised cross-correlation (NCC) as optimisation metrics, affine shape-based using 3)NCC applied to distance-transformed segmentations or 4)iterative closest point algorithm, and deformable weakly supervised deep learning-based using 5)LocalNet co-registration. Percent-changes in Dice coefficients, surface distances, MI, structural similarity index measure and target registration errors were evaluated.Main results:Co-registration using MI or NCC provided similar alignment performance, better than shape-based methods. LocalNet provided accurate co-registration of substructures by optimising subfield deformation throughout the volumes, outperforming other methods, especially in the longitudinal breast cancer xenograft dataset by minimising target registration errors.Significance:We showed the feasibility of co-registering repeatedly or longitudinally imaged vascular networks in photoacoustic mesoscopy, taking a step towards longitudinal quantitative characterisation of these complex structures. These tools open new outlooks for monitoring tumour angiogenesis at the meso-scale and for quantifying treatment-induced co-localised alterations in the vasculature.

Anaplastic Lymphoma Kinase (ALK)-Rearranged Renal Cell Carcinoma: A Case Report Highlighting Diagnostic Challenges and Therapeutic Opportunities.

A 57-year-old male underwent an open right radical nephrectomy in 2015 for a 3-cm kidney tumor which was classified at the time as a combined tubulocystic and collecting duct carcinoma. One of six nodes was positive for metastatic carcinoma and the patient received adjuvant carboplatin/gemcitabine chemotherapy. In 2020, he developed enlarging retroperitoneal adenopathy and underwent a retroperitoneal lymph node dissection with 11 of 13 nodes in the resected specimen positive for the previously described renal carcinoma, followed by adjuvant radiotherapy. In November 2022, he again underwent surgery for further locoregional recurrence with resection of a right psoas mass lesion and right hemicolectomy. Pathology on this occasion was reclassified as anaplastic lymphoma kinase-rearranged renal cell carcinoma (ALK-RCC). Shortly afterward, a restaging CT revealed multiple liver metastases and evidence of further disease recurrence in the right renal bed. He commenced alectinib with a complete radiological response and has continued on it for 12 months at the time of writing this report. To our knowledge, there are only five prior reports of ALK-RCC treated with targeted ALK inhibitor therapy in the literature. We report this case to highlight the importance of recognizing and diagnosing this rare RCC subtype since it has significant therapeutic implications. Furthermore, to our knowledge, this patient has had the longest follow-up reported to date in the literature so far. A concerted effort by the histopathology and oncology community is needed to gather more data on the incidence and treatment outcomes of these tumors so that progress can be made in optimizing their management. It is important to consider novel and emerging entities from the most recent WHO 2022 classification, many of which are defined by molecular characteristics with associated therapeutic implications.

Physics-informed deep generative learning for quantitative assessment of the retina.

Disruption of retinal vasculature is linked to various diseases, including diabetic retinopathy and macular degeneration, leading to vision loss. We present here a novel algorithmic approach that generates highly realistic digital models of human retinal blood vessels, based on established biophysical principles, including fully-connected arterial and venous trees with a single inlet and outlet. This approach, using physics-informed generative adversarial networks (PI-GAN), enables the segmentation and reconstruction of blood vessel networks with no human input and which out-performs human labelling. Segmentation of DRIVE and STARE retina photograph datasets provided near state-of-the-art vessel segmentation, with training on only a small (n = 100) simulated dataset. Our findings highlight the potential of PI-GAN for accurate retinal vasculature characterization, with implications for improving early disease detection, monitoring disease progression, and improving patient care.

The in vitro dynamics of pseudo-vascular network formation.

BACKGROUND/OBJECTIVES: Pseudo-vascular network formation in vitro is considered a key characteristic of vasculogenic mimicry. While many cancer cell lines form pseudo-vascular networks, little is known about the spatiotemporal dynamics of these formations. METHODS: Here, we present a framework for monitoring and characterising the dynamic formation and dissolution of pseudo-vascular networks in vitro. The framework combines time-resolved optical microscopy with open-source image analysis for network feature extraction and statistical modelling. The framework is demonstrated by comparing diverse cancer cell lines associated with vasculogenic mimicry, then in detecting response to drug compounds proposed to affect formation of vasculogenic mimics. Dynamic datasets collected were analysed morphometrically and a descriptive statistical analysis model was developed in order to measure stability and dissimilarity characteristics of the pseudo-vascular networks formed. RESULTS: Melanoma cells formed the most stable pseudo-vascular networks and were selected to evaluate the response of their pseudo-vascular networks to treatment with axitinib, brucine and tivantinib. Tivantinib has been found to inhibit the formation of the pseudo-vascular networks more effectively, even in dose an order of magnitude less than the two other agents. CONCLUSIONS: Our framework is shown to enable quantitative analysis of both the capacity for network formation, linked vasculogenic mimicry, as well as dynamic responses to treatment.

Unsupervised Segmentation of 3D Microvascular Photoacoustic Images Using Deep Generative Learning.

Mesoscopic photoacoustic imaging (PAI) enables label-free visualization of vascular networks in tissues with high contrast and resolution. Segmenting these networks from 3D PAI data and interpreting their physiological and pathological significance is crucial yet challenging due to the time-consuming and error-prone nature of current methods. Deep learning offers a potential solution; however, supervised analysis frameworks typically require human-annotated ground-truth labels. To address this, an unsupervised image-to-image translation deep learning model is introduced, the Vessel Segmentation Generative Adversarial Network (VAN-GAN). VAN-GAN integrates synthetic blood vessel networks that closely resemble real-life anatomy into its training process and learns to replicate the underlying physics of the PAI system in order to learn how to segment vasculature from 3D photoacoustic images. Applied to a diverse range of in silico, in vitro, and in vivo data, including patient-derived breast cancer xenograft models and 3D clinical angiograms, VAN-GAN demonstrates its capability to facilitate accurate and unbiased segmentation of 3D vascular networks. By leveraging synthetic data, VAN-GAN reduces the reliance on manual labeling, thus lowering the barrier to entry for high-quality blood vessel segmentation (F1 score: VAN-GAN vs. U-Net = 0.84 vs. 0.87) and enhancing preclinical and clinical research into vascular structure and function.

A three-dimensional, discrete-continuum model of blood pressure in microvascular networks.

We present a 3D discrete-continuum model to simulate blood pressure in large microvascular tissues in the absence of known capillary network architecture. Our hybrid approach combines a 1D Poiseuille flow description for large, discrete arteriolar and venular networks coupled to a continuum-based Darcy model, point sources of flux, for transport in the capillary bed. We evaluate our hybrid approach using a vascular network imaged from the mouse brain medulla/pons using multi-fluorescence high-resolution episcopic microscopy (MF-HREM). We use the fully-resolved vascular network to predict the hydraulic conductivity of the capillary network and generate a fully-discrete pressure solution to benchmark against. Our results demonstrate that the discrete-continuum methodology is a computationally feasible and effective tool for predicting blood pressure in real-world microvascular tissues when capillary microvessels are poorly defined.

Moving Beyond Simulation: Data-Driven Quantitative Photoacoustic Imaging Using Tissue-Mimicking Phantoms.

Accurate measurement of optical absorption coefficients from photoacoustic imaging (PAI) data would enable direct mapping of molecular concentrations, providing vital clinical insight. The ill-posed nature of the problem of absorption coefficient recovery has prohibited PAI from achieving this goal in living systems due to the domain gap between simulation and experiment. To bridge this gap, we introduce a collection of experimentally well-characterised imaging phantoms and their digital twins. This first-of-a-kind phantom data set enables supervised training of a U-Net on experimental data for pixel-wise estimation of absorption coefficients. We show that training on simulated data results in artefacts and biases in the estimates, reinforcing the existence of a domain gap between simulation and experiment. Training on experimentally acquired data, however, yielded more accurate and robust estimates of optical absorption coefficients. We compare the results to fluence correction with a Monte Carlo model from reference optical properties of the materials, which yields a quantification error of approximately 20%. Application of the trained U-Nets to a blood flow phantom demonstrated spectral biases when training on simulated data, while application to a mouse model highlighted the ability of both learning-based approaches to recover the depth-dependent loss of signal intensity. We demonstrate that training on experimental phantoms can restore the correlation of signal amplitudes measured in depth. While the absolute quantification error remains high and further improvements are needed, our results highlight the promise of deep learning to advance quantitative PAI.

'I Had It. I Don't Think I Have It But I Do Feel It Will Come Back Somewhere': A Qualitative Investigation of the Experience of People With Non-Muscle Invasive Bladder Cancer.

Very little is known about the impact of living with non-muscle invasive bladder cancer (NMIBC). NMIBC patients' experiences of their illness-in terms of their perceptions, coping strategies and psychological wellbeing-were explored. This study describes an interpretative phenomenological analysis (IPA) of individuals' accounts of living with NMIBC while on routine surveillance for cancer recurrence. Ten individuals took part in face-to-face semi-structured interviews. Three superordinate themes were derived from the data. The first theme, Being Diagnosed and Treated for NMIBC, concerned the observation that participants considered the physical implications, timeline and practicalities of their illness of primary importance and focused less on its psychological aspects. The second theme, Grappling with the Illness, outlined the impact of the doctor-patient relationship. The final theme, 'I don't treat it as a problem. I treat it as an issue', delineated how participants managed difficult emotions in the context of the illness. Findings from this study demonstrated that participants generally found effective ways to cope with their illness and experience of ongoing surveillance, though delay of emotional responses was common. Clinical implications for healthcare professionals are outlined including the importance of high-quality communication with the urology team.

The decline in transurethral resection of the prostate gland in Irish public hospitals between 2005 and 2021.

BACKGROUND: Lower urinary tract symptoms due to an enlarged prostate is a common condition. Transurethral resection of the prostate gland (TURP) has been the gold standard treatment. The objective of this study was to assess the trends in the prevalence of TURP procedures in Irish public hospitals within the period of 2005-2021. In addition, we explore the attitudes and practices of urologist in Ireland on this topic. METHODS: An analysis using the Hospital In-Patient Enquiry (HIPE) system using code 37203-00 was undertaken. 16,176 discharges contained the code of interest and had undergone a TURP procedure. The data from this cohort was further analysed. In addition, members of the Irish Society of Urology undertook a bespoke questionnaire to understand the TURP surgery practices. RESULTS: There has been a substantial decline in the prevalence of TURP procedures in Irish public hospitals from 2005 to 2021. The number of patients discharged from Irish hospitals with a TURP procedure was 66% less in 2021 compared to 2005. 75% (n = 36) of urologist surveyed felt that the declining TURP numbers were due to lack of resources, access to theatre/inpatient beds and outsourcing. 91.5% (n = 43) felt that the declining TURP numbers would result in a lack of training opportunities for trainees, 83% (39) felt this has increased morbidity for patients. CONCLUSIONS: TURP procedures in Irish public hospitals has declined over the 16-year period studied. This decline is a concern for patient morbidity and urology training.

Performance evaluation of mesoscopic photoacoustic imaging.

Photoacoustic mesoscopy visualises vascular architecture at high-resolution up to ~3 mm depth. Despite promise in preclinical and clinical imaging studies, with applications in oncology and dermatology, the accuracy and precision of photoacoustic mesoscopy is not well established. Here, we evaluate a commercial photoacoustic mesoscopy system for imaging vascular structures. Typical artefact types are first highlighted and limitations due to non-isotropic illumination and detection are evaluated with respect to rotation, angularity, and depth of the target. Then, using tailored phantoms and mouse models, we investigate system precision, showing coefficients of variation (COV) between repeated scans [short term (1 h): COV= 1.2%; long term (25 days): COV= 9.6%], from target repositioning (without: COV=1.2%, with: COV=4.1%), or from varying in vivo user experience (experienced: COV=15.9%, unexperienced: COV=20.2%). Our findings show robustness of the technique, but also underscore general challenges of limited-view photoacoustic systems in accurately imaging vessel-like structures, thereby guiding users when interpreting biologically-relevant information.

Heterogeneity in biological assemblages and exposure in chemical risk assessment: Exploring capabilities and challenges in methodology with two landscape-scale case studies.

Chemical exposure concentrations and the composition of ecological receptors (e.g., species) vary in space and time, resulting in landscape-scale (e.g. catchment) heterogeneity. Current regulatory, prospective chemical risk assessment frameworks do not directly address this heterogeneity because they assume that reasonably worst-case chemical exposure concentrations co-occur (spatially and temporally) with biological species that are the most sensitive to the chemical's toxicity. Whilst current approaches may parameterise fate models with site-specific data and aim to be protective, a more precise understanding of when and where chemical exposure and species sensitivity co-occur enables risk assessments to be better tailored and applied mitigation more efficient. We use two aquatic case studies covering different spatial and temporal resolution to explore how geo-referenced data and spatial tools might be used to account for landscape heterogeneity of chemical exposure and ecological assemblages in prospective risk assessment. Each case study followed a stepwise approach: i) estimate and establish spatial chemical exposure distributions using local environmental information and environmental fate models; ii) derive toxicity thresholds for different taxonomic groups and determine geo-referenced distributions of exposure-toxicity ratios (i.e., potential risk); iii) overlay risk data with the ecological status of biomonitoring sites to determine if relationships exist. We focus on demonstrating whether the integration of relevant data and potential approaches is feasible rather than making comprehensive and refined risk assessments of specific chemicals. The case studies indicate that geo-referenced predicted environmental concentration estimations can be achieved with available data, models and tools but establishing the distribution of species assemblages is reliant on the availability of a few sources of biomonitoring data and tools. Linking large sets of geo-referenced exposure and biomonitoring data is feasible but assessment of risk will often be limited by the availability of ecotoxicity data. The studies highlight the important influence that choices for aggregating data and for the selection of statistical metrics have on assessing and interpreting risk at different spatial scales and patterns of distribution within the landscape. Finally, we discuss approaches and development needs that could help to address environmental heterogeneity in chemical risk assessment.

Quantification of vascular networks in photoacoustic mesoscopy.

Mesoscopic photoacoustic imaging (PAI) enables non-invasive visualisation of tumour vasculature. The visual or semi-quantitative 2D measurements typically applied to mesoscopic PAI data fail to capture the 3D vessel network complexity and lack robust ground truths for assessment of accuracy. Here, we developed a pipeline for quantifying 3D vascular networks captured using mesoscopic PAI and tested the preservation of blood volume and network structure with topological data analysis. Ground truth data of in silico synthetic vasculatures and a string phantom indicated that learning-based segmentation best preserves vessel diameter and blood volume at depth, while rule-based segmentation with vesselness image filtering accurately preserved network structure in superficial vessels. Segmentation of vessels in breast cancer patient-derived xenografts (PDXs) compared favourably to ex vivo immunohistochemistry. Furthermore, our findings underscore the importance of validating segmentation methods when applying mesoscopic PAI as a tool to evaluate vascular networks in vivo.

Assessment of intrinsic aquifer vulnerability at continental scale through a critical application of the drastic framework: The case of South America.

An assessment of the intrinsic aquifer vulnerability of South America is presented. The outcomes represent the potential sensitivity of natural aquifers to leaching of dissolved compounds from the land surface. The study, developed at continental scale but retaining regionally a high resolution, is based on a critical application of the DRASTIC method. The biggest challenge in performing such a study in South America was the scattered and irregular nature of environmental datasets. Accordingly, the most updated information on soil, land use, geology, hydrogeology, and climate at continental, national, and regional scale were selected from international and local databases. To avoid spatial discrepancy and inconsistency, data were integrated, harmonized, and accurately cross-checked, using local professional knowledge where information was missing. The method was applied in a GIS environment to allow spatial analysis of raw data along with the overlaying and rating of maps. The application of the DRASTIC method allows to classify South America into five vulnerability classes, from very low to very high, and shows an overall medium to low vulnerability at continental scale. The Amazon region, coastal aquifers, colluvial Andean valleys, and alluvial aquifers of main rivers were the areas classified as highly vulnerable. Moreover, countries with the largest areas with high aquifer vulnerability were those characterized by extended regions of rainforest. In addition, a single parameter sensitivity analysis showed depth to water table to be the most significant factor, while a cross-validation using existing vulnerability assessments and observed concentrations of compounds in groundwater confirmed the reliability of the proposed assessment, even at regional scale. Overall, although additional field surveys and detailed works at local level are needed to develop effective water management plans, the present DRASTIC map represents an essential common ground towards a more sustainable land-use and water management in the whole territory of South America.

Patient reported factors influencing the decision-making process of men with localised prostate cancer when considering Active Surveillance-A systematic review and thematic synthesis.

OBJECTIVES: Outcomes for men with localised prostate cancer managed with Active Surveillance (AS) are similar to outcomes for men who have received Active Treatment. This review explore men's perceptions of the factors that influence their decision-making process when considering AS. METHOD: A systematic review of studies was conducted up to May 2021, including qualitative studies which explored the decision making of men with localised prostate cancer when considering AS. Evidence was analysed using thematic synthesis. RESULTS: Thirteen papers, including 426 men, met inclusion criteria and were analysed in the review. Approximately half of the men had chosen AS and half had chosen Active Treatment. The choice of AS was not a one-off decision but rather an ongoing behaviour. Four themes were identified and considered within a temporal model: pre-diagnosis representations of cancer and treatment; experience of testing and diagnosis; patient decision making; and emotional adjustment to AS. Key barriers and facilitators to men choosing AS were identified. In deciding whether or not to choose AS, men balanced a desire for quality of life against fear of cancer progression. CONCLUSIONS: Both cognitive representations and emotional arousal influence how men decided whether or not to opt for AS. Interventions tailored to elicit and address emotional appraisals of risk, and increase trust in AS protocols, may be of value in helping men to make decisions around treatment for localised prostate cancer.

A mathematical investigation into the uptake kinetics of nanoparticles in vitro.

Nanoparticles have the potential to increase the efficacy of anticancer drugs whilst reducing off-target side effects. However, there remain uncertainties regarding the cellular uptake kinetics of nanoparticles which could have implications for nanoparticle design and delivery. Polymersomes are nanoparticle candidates for cancer therapy which encapsulate chemotherapy drugs. Here we develop a mathematical model to simulate the uptake of polymersomes via endocytosis, a process by which polymersomes bind to the cell surface before becoming internalised by the cell where they then break down, releasing their contents which could include chemotherapy drugs. We focus on two in vitro configurations relevant to the testing and development of cancer therapies: a well-mixed culture model and a tumour spheroid setup. Our mathematical model of the well-mixed culture model comprises a set of coupled ordinary differential equations for the unbound and bound polymersomes and associated binding dynamics. Using a singular perturbation analysis we identify an optimal number of ligands on the polymersome surface which maximises internalised polymersomes and thus intracellular chemotherapy drug concentration. In our mathematical model of the spheroid, a multiphase system of partial differential equations is developed to describe the spatial and temporal distribution of bound and unbound polymersomes via advection and diffusion, alongside oxygen, tumour growth, cell proliferation and viability. Consistent with experimental observations, the model predicts the evolution of oxygen gradients leading to a necrotic core. We investigate the impact of two different internalisation functions on spheroid growth, a constant and a bond dependent function. It was found that the constant function yields faster uptake and therefore chemotherapy delivery. We also show how various parameters, such as spheroid permeability, lead to travelling wave or steady-state solutions.

Screening for Obstructive Sleep Apnea in an Atrial Fibrillation Population: What's the Best Test?

BACKGROUND: Among individuals with nonvalvular atrial fibrillation (AF), the prevalence of obstructive sleep apnea (OSA) can be as high as 85%. Continuous positive airway pressure treatment for moderate or severe OSA might improve AF outcomes and quality of life, so early identification of OSA might be of value. However, screening questionnaires for OSA are suboptimal because they are weighted toward tiredness and loud snoring, which might be absent in AF patients. NoSAS (Neck, Obesity, Snoring, Age, Sex) is a new OSA questionnaire that excludes these parameters. Acoustic pharyngometry (AP) is a potential novel screening technique that measures pharyngeal cross-sectional area, which is reduced in patients with OSA. METHODS: We prospectively compared the accuracy of the NoSAS, the STOP-BANG questionnaire (Snoring, Tiredness, Observed apnea, blood Pressure, Body mass index, Age, Neck circumference and Gender), and AP with home sleep apnea testing (HSAT) in consecutive patients with nonvalvular AF. RESULTS: Of 188 participants, 86% had OSA and 49% had moderate or severe OSA. Mean Epworth Sleepiness Scale scores were low; 5.9 (SD, 3.9), indicating that most participants were not sleepy. Receiver operating characteristic curves for comparisons of screening tests with HSAT showed suboptimal accuracy. For moderate plus severe and severe only groups respectively, the area under the curve was 0.50 (95% confidence interval [CI], 0.42-0.58) and 0.42 (95% CI, 0.34-0.52) for AP, 0.65 (95% CI, 0.58-0.73) and 0.63 (95% CI, 0.52-0.74) for the STOP-BANG questionnaire, and 0.68 (95% CI, 0.60-0.75) and 0.69 (95% CI, 0.59-0.80) for the NoSAS. CONCLUSIONS: AP and NoSAS are not sufficiently accurate for screening AF patients for OSA. Because of the high rates of OSA in this cohort, the potential benefits of OSA treatment, and the suboptimal accuracy of current screening questionnaires, cardiologists should consider HSAT for AF patients.

CONTEXTE: Chez les sujets présentant une fibrillation auriculaire (FA) non valvulaire, la prévalence de l'apnée obstructive du sommeil (AOS) peut atteindre 85 %. En cas d'AOS modérée ou sévère, un traitement par ventilation spontanée en pression positive continue peut améliorer les résultats liés à la FA et la qualité de vie du patient; un diagnostic précoce d'AOS pourrait donc être utile. Les questionnaires de dépistage de l'AOS ne sont toutefois pas optimaux parce qu'ils accordent une grande importance à la fatigue et aux ronflements sonores, des symptômes qui ne se manifestent pas nécessairement en cas de FA. Le questionnaire NoSAS (de l'anglais Neck, Obesity, Snoring, Age, Sex) est un nouvel outil d'évaluation de l'AOS qui ne tient pas compte de ces paramètres. La pharyngométrie acoustique (PA) pourrait aussi constituer une nouvelle technique de dépistage; elle mesure l'aire de section transversale du pharynx, qui est réduite chez les patients souffrant d'AOS. MÉTHODOLOGIE: Nous avons comparé de façon prospective la précision du score au questionnaire NoSAS, du score au questionnaire STOP-BANG (de l'anglais Snoring, Tiredness, Observed apnea, blood Pressure, Body mass index, Age, Neck circumference and Gender) et des résultats de la PA à celle du test d'apnée du sommeil à domicile (TASD) chez des patients consécutifs présentant une FA non valvulaire. RÉSULTATS: Sur les 188 participants, 86 % présentaient une AOS et 49 % souffraient d'AOS modérée ou sévère. Le score moyen sur l'échelle de somnolence d'Epworth était faible et se situait à 5,9 (écart-type : 3,9), ce qui indique que la plupart des participants ne ressentaient pas de somnolence. La comparaison entre les questionnaires de dépistage et le TASD effectuée au moyen des courbes caractéristiques de la performance des tests a révélé une précision sous-optimale. Dans les groupes souffrant d'AOS modérée ou sévère et d'AOS sévère seulement, les aires sous la courbe étaient respectivement de 0,50 (intervalle de confiance [IC] à 95 % : de 0,42 à 0,58) et de 0,42 (IC à 95 % : de 0,34 à 0,52) pour la PA, de 0,65 (IC à 95 % : de 0,58 à 0,73) et de 0,63 (IC à 95 % : de 0,52 à 0,74) pour le questionnaire STOP-BANG, et de 0,68 (IC à 95 % : de 0,60 à 0,75) et de 0,69 (IC à 95 % : de 0,59 à 0,80) pour le questionnaire NoSAS. CONCLUSIONS: La PA et le questionnaire NoSAS ne sont pas suffisamment précis pour dépister l'AOS chez les patients présentant une FA. Compte tenu de la forte prévalence de l'AOS dans cette cohorte, des bienfaits potentiels d'un traitement de l'AOS et de la précision sous-optimale des questionnaires de dépistage actuels, il conviendrait d'envisager un TASD chez les patients présentant une FA.

Regulatory groundwater monitoring: Realistic residues of pinoxaden and metabolites at vulnerable locations.

A bespoke groundwater monitoring programme was designed to generate a database of pinoxaden and metabolite concentrations in shallow groundwater at agricultural locations across Europe. The data generated from this programme represent a higher tier refinement of modelled exposure estimates and provide realistic information on groundwater quality at vulnerable locations which will aid plant protection product (PPP) assessment in Europe in relation to Regulation (EC) No. 1107/2009. The Regulatory GeoPEARL_3.3.3 model developed by RIVM was used to estimate the vulnerability of cereal growing regions to leaching of two pinoxaden metabolites across the entire EU at a 1 km2 level using 20 years of daily weather data (MARS, EU JRC). Seventy sites located within the upper 50th percentile of leaching vulnerability from this modelling exercise, crop density and shallow groundwater were selected for monitoring groundwater. Retrospective and prospective pinoxaden product applications at candidate sites were recorded and these data used to place sites in the distribution for Europe. The 70 sites all fulfil the site assessment criteria and have no confining layers which may prevent or delay leaching. All sites equipped with groundwater wells had a minimum of two pinoxaden applications in the preceding four years to cereal crops. A total of 1326 samples were analysed from up to 90 down hydraulic gradient wells at 70 locations between June 2015 and July 2018. Results indicate that pinoxaden and pinoxaden metabolites are very unlikely to reach shallow groundwater at concentrations greater than 0.1 µg/L for relevant metabolites, or 10 µg/L for non-relevant metabolites, respectively (Sanco/221/2000-rev.10). Over 38 months of groundwater monitoring the annual average and 90th percentile for pinoxaden or its metabolites never exceeded 0.1 µg/L and it is proposed that these data infer that exposure to these metabolites is minimal.

"Picture this"- Patients' Drawings of Non-Muscle Invasive Bladder Cancer: A Novel Method to Help Understand How Patients Perceive Their Condition.

BACKGROUND: There is a paucity of data regarding patient experiences of living with non-muscle-invasive bladder cancer (NMIBC). OBJECTIVES: To investigate patients' beliefs about NMIBC utilising both a well-established verbal/linguistic method, the Brief Illness Perception Questionnaire (B-IPQ) in addition to a novel visual/perceptual method, that is, asking patients to draw their bladder as it is now and as they perceive it will be in the future. METHODS: Cross-sectional study of patients with NMIBC. Patients completed: (i) the B-IPQ, and (ii) 2 drawings of their bladder: as they perceived it currently and as they perceived it would look in 5 years' time. RESULTS: A total of 118 patients completed the B-IPQ, of which 96 produced 2 bladder drawings. Forty-seven per cent of patients depicted no change in their bladder across time, 35% depicted improvements, while 18% drew their NMIBC as deteriorating between the two time points. Patients who drew their NMIBC worsening over time reported significantly stronger beliefs in the severity of current consequences from their NMIBC (F(2,94) = 9.07, p < 0.001, m = 5.68, 95% CI 4.38-6.88) and greater current concerns about their NMIBC (F(2,94) = 6.17, p < 0.01, m = 7.06, 95% CI 5.47-8.66). This was unrelated to cancer grade, cancer stage, treatment or demographic variables. CONCLUSION: This is the first study to explore beliefs about NMIBC in a sample of patients with NMIBC attending routine clinics using both a well-established and a novel method of assessing patients' perceptions. Results highlight the usefulness of a simple non-verbal technique, in identifying patients' concerns about the condition. Almost one fifth of patients with NMIBC may experience significant concerns about the worsening of their condition, which appear to be independent of demographic, histopathological, and treatment related variables. Further exploration of the psychological concerns of individuals with NMIBC is required in order to appropriately plan for needs led multidisciplinary approach in their care.

A knowledge-based approach to designing control strategies for agricultural pests.

Chemical control of insect pests remains vital to agricultural productivity, but limited mechanistic understanding of the interactions between crop, pest and chemical control agent have restricted our capacity to respond to challenges such as the emergence of resistance and demands for tighter environmental regulation. Formulating effective control strategies that integrate chemical and non-chemical management for soil-dwelling pests is particularly problematic owing to the complexity of the soil-root-pest system and the variability that occurs between sites and between seasons. Here, we present a new concept, termed COMPASS, that integrates ecological knowledge on pest development and behaviour together with crop physiology and mechanistic understanding of chemical distribution and toxic action within the rhizosphere. The concept is tested using a two-dimensional systems model (COMPASS-Rootworm) that simulates root damage in maize from the corn rootworm Diabrotica spp. We evaluate COMPASS-Rootworm using 119 field trials that investigated the efficacy of insecticidal products and placement strategies at four sites in the USA over a period of ten years. Simulated root damage is consistent with measurements for 109 field trials. Moreover, we disentangle factors influencing root damage and pest control, including pest pressure, weather, insecticide distribution, and temporality between the emergence of crop roots and pests. The model can inform integrated pest management, optimize pest control strategies to reduce environmental burdens from pesticides, and improve the efficiency of insecticide development.