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Background: The coronavirus (COVID-19) pandemic resulted in the rapid implementation of remote consultations to maintain musculoskeletal physiotherapy services. However, little is known about UK musculoskeletal physiotherapists' experiences of providing services during the COVID-19 pandemic., Objectives: To explore musculoskeletal physiotherapists' experiences of using remote consultations in one area of England during the COVID-19 pandemic., Design: Qualitative study using hermeneutic phenomenology based on the approach of Gadamer., Methods: Semi-structured interviews with twelve musculoskeletal physiotherapists were conducted online using Microsoft Teams. Data were analysed using frameworks based on the philosophical concepts of Gadamer's hermeneutics., Findings: Musculoskeletal physiotherapists' experience of using remote consultations during the COVID-19 pandemic was framed by three concepts: therapeutic relationship, transformational change, and uncertainty. These concepts are underpinned by four main themes capturing their experiences: (1) Disconnection: Difficulties building a rapport and reduced non-verbal communication affected building an effective therapeutic relationship, (2) Necessity: Transformation of services to remote consultations was positive, although technology and connectivity issues had a negative impact, (3) Loss of control: Diagnostic uncertainty, being unprepared, and experience affected physiotherapists' clinical practice, (4) Protection: Peer support and the use of technology facilitated a feeling of protection for physiotherapists., Conclusion: The findings of this study contribute to a better understanding of musculoskeletal physiotherapists' experience of using remote consultations during the COVID-19 pandemic. Implications for practice include the need to provide training for all musculoskeletal physiotherapists and undergraduates to enable the effective delivery of remote physiotherapy. Furthermore, digital infrastructure should be optimised to support future delivery of remote musculoskeletal physiotherapy services., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A factor constraining the elimination of dog-mediated human rabies is limited information on the size and spatial distribution of free-roaming dog populations (FRDPs). The aim of this study was to develop a statistical model to predict the size of free-roaming dog populations and the spatial distribution of free-roaming dogs in urban areas of Nepal, based on real-world dog census data from the Himalayan Animal Rescue Trust (HART) and Animal Nepal. Candidate explanatory variables included proximity to roads, building density, specific building types, human population density and normalised difference vegetation index (NDVI). A multivariable Poisson point process model was developed to estimate dog population size in four study locations in urban Nepal, with building density and distance from nearest retail food establishment or lodgings as explanatory variables. The proposed model accurately predicted, within a 95 % confidence interval, the surveyed FRDP size and spatial distribution for all four study locations. This model is proposed for further testing and refinement in other locations as a decision-support tool alongside observational dog population size estimates, to inform dog health and public health initiatives including rabies elimination efforts to support the 'zero by 30' global mission., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Former Associate Editor, Spatial and Spatio-temporal Epidemiology (Mark Stevenson), (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The inability to visualise was given the name aphantasia in 2015 by Zeman and colleagues. In 2018 we published research showing that fifteen individuals who self-identified as having aphantasia also demonstrated a lack of sensory visual imagery when undergoing the binocular rivalry imagery paradigm, suggesting more than just a metacognitive difference. Here we update these findings with over fifty participants with aphantasia and show that there is evidence for a lack of sensory imagery in aphantasia. How the binocular rivalry paradigm scores relate to the vividness of visual imagery questionnaire (VVIQ) and how aphantasia can be confirmed is discussed., (Copyright © 2024. Published by Elsevier B.V.)

Cognitive neuroscience research on mental imagery has largely focused on the visual imagery modality in unimodal task contexts. Recent studies have uncovered striking individual differences in visual imagery capacity, with some individuals reporting a subjective absence of conscious visual imagery ability altogether ("aphantasia"). However, naturalistic mental imagery is often multi-sensory, and preliminary findings suggest that many individuals with aphantasia also report a subjective lack of mental imagery in other sensory domains (such as auditory or olfactory imagery). In this paper, we perform a series of cluster analyses on the multi-sensory imagery questionnaire scores of two large groups of aphantasic subjects, defining latent sub-groups in this sample population. We demonstrate that aphantasia is a heterogenous phenomenon characterised by dominant sub-groups of individuals with visual aphantasia (those who report selective visual imagery absence) and multi-sensory aphantasia (those who report an inability to generate conscious mental imagery in any sensory modality). We replicate our findings in a second large sample and show that more unique aphantasia sub-types also exist, such as individuals with selectively preserved mental imagery in only one sensory modality (e.g. intact auditory imagery). We outline the implications of our findings for network theories of mental imagery, discussing how unique aphantasia aetiologies with distinct self-report patterns might reveal alterations to various levels of the sensory processing hierarchy implicated in mental imagery., Competing Interests: Declaration of Interests The author(s) declared that there were no conflicts of interest with respect to the authorship or the publication of this article., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

An experimental study was conducted on how polymer density affects the transport and fate of microplastics in aquatic flows. For the first time, polypropylene (PP), polyethylene (PE), polymethyl methacrylate (PMMA), polyetheretherketone (PEEK), and polyvinyl chloride (PVC) were chemically stained and tested using solute transport techniques and velocities found among rivers in the natural environment (0.016 - 0.361 m/s). The movement of 3D-polymers with densities ranging from 0.9 - 1.4 g/cm³ was quantified in a laboratory flume scaled to simulate open-channel flows in fluvial systems. Except for PP, in most conditions microplastics exhibited similar transport characteristics to solutes regardless of density and established solute transport models were successfully implemented to predict their transport and fate. Mass recoveries and ADE routing model demonstrated microplastic deposition and resuspension was associated with polymer density below critical velocity thresholds ≤ 0.1 m/s. When density becomes the dominant force at these slower velocities, concentrations of denser than water microplastics will be momentarily or permanently deposited in channel beds and microplastics follow the classical Shields sediment transport methodology. This data is the first to provide microplastic suspension and deposition thresholds based on river velocity and polymer density, making a key contribution to research predicting microplastic fate and organismal exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd., Patients and Methods: Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded., Results: Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred., Conclusion: In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration., Competing Interests: Disclosure CP reports grant funding support: Pfizer, Daiichi Sankyo, Exact Sciences, Gilead and Seagen. Honoraria for advisory boards: Pfizer, Roche, Daiichi Sankyo, Novartis, Exact Sciences, Gilead, SeaGen and Eli Lilly. Support for travel and conferences: Roche, Novartis and Gilead. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The transport of microplastics within urban water systems remains poorly understood, with little prior research on their behaviour within manhole configurations. This study represents the first to measure and model the transport dynamics of microplastics within circular and square manholes under different hydraulic scenarios. The transport and fate of polyethylene (PE) was quantified and compared to solutes (Rhodamine WT dye) using energy losses, residence time distributions (RTDs), and mixing models within surcharging and overflowing manholes. The bulk mass of solute and PE concentrations followed similar flow paths across all conditions except for 17.3 ± 7.9 % of PE mass that was immobilized in a dead zone above the inlet pipe for manholes with a surcharge to pipe diameter ratio ≥2. Consequently, these microplastics only exit after a significant change in hydraulic regime occurs, causing microplastics to be at risk of being contaminated over a prolonged duration. No significant mixing differences for PE and solutes were found between manhole geometries. The deconvolution method outperformed the ADZ model with goodness of fit (R t 2 ) values of 0.99 (0.60) and 1.00 (0.89) for PE and solute mixing, respectively. This establishes the deconvolution method as the most accurate and appropriate model to accurately predict microplastic mixing in manholes and urban drainage systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Monetary rewards and punishments enhance motor performance and are associated with corticospinal excitability (CSE) increases within the motor cortex (M1) during movement preparation. However, such CSE changes have unclear origins. Based on converging evidence, one possibility is that they stem from increased glutamatergic (GLUTergic) facilitation and/or decreased type A gamma-aminobutyric acid (GABA A )-mediated inhibition within M1. To investigate this, paired-pulse transcranial magnetic stimulation was used over the left M1 to evaluate intracortical facilitation (ICF) and short intracortical inhibition (SICI), indirect assays of GLUTergic activity and GABA A -mediated inhibition, in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. Behaviourally, rewards and punishments enhanced both reaction and movement time. During movement preparation, regardless of rewards or punishments, ICF increased when the index finger initiated sequences, whereas SICI decreased when both the index and little fingers initiated sequences. This finding suggests that GLUTergic activity increases in a finger-specific manner whilst GABA A -mediated inhibition decreases in a finger-unspecific manner during preparation. In parallel, both rewards and punishments non-specifically increased ICF, but only rewards non-specifically decreased SICI as compared to neutral. This suggests that to enhance performance rewards both increase GLUTergic activity and decrease GABA A -mediated inhibition, whereas punishments selectively increase GLUTergic activity. A control experiment revealed that such changes were not observed post-movement as participants processed reward and punishment feedback, indicating they were selective to movement preparation. Collectively, these results map the intracortical excitability changes in M1 by which incentives enhance motor performance., Competing Interests: Declaration of competing interest This work was funded by the Fonds de Recherche du Québec – Nature et Technologie (Québec, Canada), European Research Council Starting Grant (MotMotLearn 637,488) and Proof of Concept Grant (ImpHandRehab 872,082). We wish to declare to Brain Stimulation that there is no financial/personal interest or belief that could affect the objectivity of the results wherein submitted. All authors agreed on the content of the manuscript prior to its submission to Brain Stimulation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The SARS-CoV-2 coronavirus continues to evolve with scores of mutations of the spike, membrane, envelope, and nucleocapsid structural proteins that impact pathogenesis. Infection data from nasal swabs, nasal PCR assays, upper respiratory samples, ex vivo cell cultures and nasal epithelial organoids reveal extreme variabilities in SARS-CoV-2 RNA titers within and between the variants. Some variabilities are naturally prone to clinical testing protocols and experimental controls. Here we focus on nasal viral load sensitivity arising from the timing of sample collection relative to onset of infection and from heterogeneity in the kinetics of cellular infection, uptake, replication, and shedding of viral RNA copies. The sources of between-variant variability are likely due to SARS-CoV-2 structural protein mutations, whereas within-variant population variability is likely due to heterogeneity in cellular response to that particular variant. With the physiologically faithful, agent-based mechanistic model of inhaled exposure and infection from (Chen et al., 2022), we perform statistical sensitivity analyses of the progression of nasal viral titers in the first 0-48 h post infection, focusing on three kinetic mechanisms. Model simulations reveal shorter latency times of infected cells (including cellular uptake, viral RNA replication, until the onset of viral RNA shedding) exponentially accelerate nasal viral load. Further, the rate of infectious RNA copies shed per day has a proportional influence on nasal viral load. Finally, there is a very weak, negative correlation of viral load with the probability of infection per virus-cell encounter, the model proxy for spike-receptor binding affinity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The COVID-19 pandemic has provided stiff challenges for planning and resourcing in health services in the UK and worldwide. Epidemiological models can provide simulations of how infectious disease might progress in a population given certain parameters. We adapted an agent-based model of COVID-19 to inform planning and decision-making within a healthcare setting, and created a software framework that automates processes for calibrating the model parameters to health data and allows the model to be run at national population scale on National Health Service (NHS) infrastructure. We developed a method for calibrating the model to three daily data streams (hospital admissions, intensive care occupancy, and deaths), and demonstrate that on cross-validation the model fits acceptably to unseen data streams including official estimates of COVID-19 incidence. Once calibrated, we use the model to simulate future scenarios of the spread of COVID-19 in England and show that the simulations provide useful projections of future COVID-19 clinical demand. These simulations were used to support operational planning in the NHS in England, and we present the example of the use of these simulations in projecting future clinical demand during the rollout of the national COVID-19 vaccination programme. Being able to investigate uncertainty and test sensitivities was particularly important to the operational planning team. This epidemiological model operates within an ecosystem of data technologies, drawing on a range of NHS, government and academic data sources, and provides results to strategists, planners and downstream data systems. We discuss the data resources that enabled this work and the data challenges that were faced., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Our capacity to re-experience the past and simulate the future is thought to depend heavily on visual imagery, which allows us to construct complex sensory representations in the absence of sensory stimulation. There are large individual differences in visual imagery ability, but their impact on autobiographical memory and future prospection remains poorly understood. Research in this field assumes the normative use of visual imagery as a cognitive tool to simulate the past and future, however some individuals lack the ability to visualise altogether (a condition termed "aphantasia"). Aphantasia represents a rare and naturally occurring knock-out model for examining the role of visual imagery in episodic memory recall. Here, we assessed individuals with aphantasia on an adapted form of the Autobiographical Interview, a behavioural measure of the specificity and richness of episodic details underpinning the memory of events. Aphantasic participants generated significantly fewer episodic details than controls for both past and future events. This effect was most pronounced for novel future events, driven by selective reductions in visual detail retrieval, accompanied by comparatively reduced ratings of the phenomenological richness of simulated events, and paralleled by quantitative linguistic markers of reduced perceptual language use in aphantasic participants compared to those with visual imagery. Our findings represent the first systematic evidence (using combined objective and subjective data streams) that aphantasia is associated with a diminished ability to re-experience the past and simulate the future, indicating that visual imagery is an important cognitive tool for the dynamic retrieval and recombination of episodic details during mental simulation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance., Patients and Methods: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel., Results: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent., Conclusions: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy., Competing Interests: Disclosure OK has consulted for XING Technologies. JVP and NW are founders and shareholders of genomiQa Pty Ltd, and members of its board. GH is the clinical genomics lead at genomiQa Pty Ltd. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

When comparing the roles of the lightning strike and the dry climate in causing the forest fire, one might think that the lightning strike is more of a cause than the dry climate, or one might think that the lightning strike completely caused the fire while the dry conditions did not cause it at all. Psychologists and philosophers have long debated whether such causal judgments are graded; that is, whether people treat some causes as stronger than others. To address this debate, we first reanalyzed data from four recent studies. We found that causal judgments were actually multimodal: although most causal judgments made on a continuous scale were categorical, there was also some gradation. We then tested two competing explanations for this gradation: the confidence explanation, which states that people make graded causal judgments because they have varying degrees of belief in causal relations, and the strength explanation, which states that people make graded causal judgments because they believe that causation itself is graded. Experiment 1 tested the confidence explanation and showed that gradation in causal judgments was indeed moderated by confidence: people tended to make graded causal judgments when they were unconfident, but they tended to make more categorical causal judgments when they were confident. Experiment 2 tested the causal strength explanation and showed that although confidence still explained variation in causal judgments, it did not explain away the effects of normality, causal structure, or the number of candidate causes. Overall, we found that causal judgments were multimodal and that people make graded judgments both when they think a cause is weak and when they are uncertain about its causal role., (Published by Elsevier B.V.)

Visual imagery allows us to revisit the appearance of things in their absence and to test out virtual combinations of sensory experience. Visual imagery has been linked to many cognitive processes, such as autobiographical and visual working memory. Imagery also plays symptomatic and mechanistic roles in neurologic and mental disorders and is utilized in treatment. A large network of brain activity spanning frontal, parietal, temporal, and visual cortex is involved in generating and maintain images in mind. The ability to visualize has extreme variations, ranging from completely absent (aphantasia) to photo-like (hyperphantasia). The anatomy and functionality of visual cortex, including primary visual cortex, have been associated with individual differences in visual imagery ability, pointing to a potential correlate for both aphantasia and hyperphantasia. Preliminary evidence suggests that lifelong aphantasia is associated with prosopagnosia and reduction in autobiographical memory; hyperphantasia is associated with synesthesia. Aphantasic individuals can also be highly imaginative and are able to complete many tasks that were previously thought to rely on visual imagery, demonstrating that visualization is only one of many ways of representing things in their absence. The study of extreme imagination reminds us how easily invisible differences can escape detection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Germline genetic mutations occur in approximately 25% of women with epithelial ovarian cancers (EOC). We sought to determine whether newly initiated in-office oncologist-led germline testing improved time to testing and dissemination of results compared with historical controls. Patients with epithelial ovarian cancer seen between 4/1/2018 and 12/31/2019 were identified. Patients treated before genetic testing kits were made available in the gynecologic oncology clinics were compared to those treated after. Categorical variables were compared using Chi Squared and Fisher's Exact test. Cox proportional hazards model was used to compare elapsed time from testing to results. 73 patients were identified, and 502 clinic visits were analyzed. 56 (76.7%) patients were White Hispanic, 15 (20.5%) were Black, and 2 (2.7%) were White non-Hispanic. 55 (75.7%) underwent germline testing. Median time to genetic testing in the intervention group was shorter than in the control group (5, vs 24.3 weeks, 95% CI = 0-10.8 vs 14.9-33.7, p < 0.001). Among the 51 patients with genetic tests completed; results were recorded in a clinic note at 14 weeks (95% CI = 0-28.1) from first visit in the intervention group compared with 47 weeks (95% CI = 30.7-63.3) in the control group (p < 0.001). The majority of patients tested had county charity care insurance or were uninsured. Genetic testing in a safety net gynecologic oncology clinic is feasible. By initiating in-office testing, time to testing and receipt of results were meaningfully shortened. This allowed for timely identification of patients who would most benefit from PARP inhibitor maintenance therapy., (© 2020 The Authors. Published by Elsevier Inc.)

Solid-state 13 C and 19 F NMR spectroscopy offers a non-destructive, highly selective protocol for the identification of forensically relevant synthetic cannabinoids on herbal substrates. Using this technique, well resolved 13 C spectra were obtained that readily enabled structural identification; in some instances complemented by 19 F spectral data. The approach described has potential for related applications such as the direct detection of pesticides on plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The serrated neoplasia pathway gives rise to a distinct subgroup of colorectal cancers distinguished by the presence of mutant BRAF V600E and the CpG Island Methylator Phenotype (CIMP). BRAF mutant CRC are commonly associated with microsatellite instability, which have an excellent clinical outcome. However, a proportion of BRAF mutant CRC retain microsatellite stability and have a dismal prognosis. The molecular drivers responsible for the development of this cancer subgroup are unknown. To address this, we established a murine model of BRAF V600E mutant microsatellite stable CRC and comprehensively investigated the exome and transcriptome to identify molecular alterations in signaling pathways that drive malignancy. Exome sequencing of murine serrated lesions (mSL) and carcinomas identified frequent hot spot mutations within the gene encoding β-catenin (Ctnnb1). Immunohistochemical staining of β-catenin indicated that these mutations led to an increase in the presence of aberrant nuclear β-catenin that resulted in gene expression changes in targets of β-catenin transcription. Gene expression profiling identified a significant enrichment for transforming growth factor-β (TGF-β) signaling that was present in mSL and carcinomas. Early activation of TGF-β suggests that this pathway may be an early cue directing mSL to microsatellite stable carcinoma. These findings in the mouse model support the importance of alterations in WNT and TGF-β signaling during the transition of human sessile serrated lesions to malignancy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer., Patients and Methods: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30)., Results: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2., Conclusions: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

A pulsed light emitting diode, coupled with a properly configured spectrometer is implemented in open source analytical ultracentrifugation detection hardware, allowing for spectral acquisition spanning the visible to near infrared. Details of the challenges arising with the new hardware are described, along with the necessary solutions to overcome them. The system is successfully tested with polystyrene and gold nanoparticles, demonstrating effectiveness for different material and particle geometries. Sedimentation coefficient distributions and analytically extracted spectra are presented for the multiwavelength datasets extending into the near infrared. Additionally, deconvolution algorithms are applied as a further demonstration of tools applicable to these datasets and the resolving power possible. The results of gold nanoparticle analysis presented here show effective near infrared spectral acquisition is now possible for multiwavelength analytical ultracentrifugation, opening the door for analysis of many important samples with spectral properties in this range, including rich classes of metal and semiconductor nanoparticles., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Gastro-oesophageal reflux disease (GORD) is a common comorbidity in bronchiectasis, and is often associated with poorer outcomes. The cause and effect relationship between GORD and bronchiectasis has not yet been fully elucidated and a greater understanding of the pathophysiology of the interaction and potential therapies is required. This review explores the underlying pathophysiology of GORD, its clinical presentation, risk factors, commonly applied diagnostic tools, and a detailed synthesis of original articles evaluating the prevalence of GORD, its influence on disease severity and current management strategies within the context of bronchiectasis. The prevalence of GORD in bronchiectasis ranges from 26% to 75%. Patients with co-existing bronchiectasis and GORD were found to have an increased mortality and increased bronchiectasis severity, manifest by increased symptoms, exacerbations, hospitalisations, radiological extent and chronic infection, with reduced pulmonary function and quality of life. The pathogenic role of Helicobacter pylori infection in bronchiectasis, perhaps via aspiration of gastric contents, also warrants further investigation. Our index of suspicion for GORD should remain high across the spectrum of disease severity in bronchiectasis. Identifying GORD in bronchiectasis patients may have important therapeutic and prognostic implications, although clinical trial evidence that treatment targeted at GORD can improve outcomes in bronchiectasis is currently lacking., (Copyright © 2018. Published by Elsevier Ltd.)

Individuals with grapheme-colour synaesthesia experience anomalous colours when reading achromatic text. These unusual experiences have been said to resemble 'normal' colour perception or colour imagery, but studying the nature of synaesthesia remains difficult. In the present study, we report novel evidence that synaesthetic colour impacts conscious vision in a way that is different from both colour perception and imagery. Presenting 'normal' colour prior to binocular rivalry induces a location-dependent suppressive bias reflecting local habituation. By contrast, a grapheme that evokes synaesthetic colour induces a facilitatory bias reflecting priming that is not constrained to the inducing grapheme's location. This priming does not occur in non-synaesthetes and does not result from response bias. It is sensitive to diversion of visual attention away from the grapheme, but resistant to sensory perturbation, reflecting a reliance on cognitive rather than sensory mechanisms. Whereas colour imagery in non-synaesthetes causes local priming that relies on the locus of imagined colour, imagery in synaesthetes caused global priming not dependent on the locus of imagery. These data suggest a unique psychophysical profile of high-level colour processing in synaesthetes. Our novel findings and method will be critical to testing theories of synaesthesia and visual awareness., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The idea that unconscious input can result in long-term learning or task improvement has been debated for decades, yet there is still little evidence to suggest that learning outside of awareness can produce meaningful changes to decision-making. Here we trained participants using noisy motion stimuli, which require the gradual accumulation of information until a decision can be reached. These stimuli were suppressed from conscious awareness by simultaneously presenting a dynamic dichoptic mask. We show that a short period of training on either a partially or fully suppressed motion stimulus resulted in improved accuracy when tested on a partially suppressed motion stimulus traveling in the orthogonal direction. We found this improvement occurred even when performance on the training task was at chance. Performance gains generalized across motion directions, suggesting that the improvement was the result of changes to the decisional mechanisms rather than perceptual. Interestingly, unconscious learning had a stronger effect on unconscious, compared to conscious decisional accumulation. We further show that a conscious coherent percept is necessary to reap the benefits of unconscious learning. Together, these data suggest that unconscious decisional processing can be improved via training., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: With no established standard for assessing tobacco dependence (TD) across tobacco products in surveys, the Population Assessment of Tobacco and Health (PATH) Study provides a unique platform for examining the psychometric properties and validity of multiple indicators of tobacco dependence across a range of tobacco products., Participants: A U.S. nationally representative sample from the 32,320 adult Wave 1 interviews with analyses focused on 14,287 respondents who were current established users of tobacco products., Findings: This analysis confirms a single primary latent construct underlying responses to TD indicators for cigarettes, e-cigarettes, cigars, hookah, and smokeless tobacco products. Mutually exclusive past year tobacco-user groups included: cigarette only (n=8689), e-cigarette only (n=437), cigar only (traditional, cigarillo, or filtered) (n=706), hookah only (n=461), smokeless tobacco only (n=971), cigarette plus e-cigarette (n=709), and multiple tobacco product users (n=2314). Differential Item Functioning (DIF) analyses supported use of 16 of the 24 examined TD indicators for comparisons across tobacco users. With cigarette users as a reference (mean=0.0, SD=1.0), we observed a range of TD with hookah (mean=-1.71) and cigar (mean=-1.92) only users being the lowest, and cigarette plus e-cigarette product users being the highest (mean=0.35). Regression models including sociodemographic factors supported concurrent validity with increased product use frequency and TD among cigarette-only (p<0.001), e-cigarette only (p<0.002), cigar (p<0.001), hookah only (p<0.001), and smokeless tobacco users (p<0.001)., Conclusion: The PATH Study Adult Wave 1 Questionnaire provided psychometrically valid measures of TD that enables future regulatory investigations of nicotine dependence across tobacco products., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Despite the brain's immense processing power, it has finite resources. Where do these resource limits come from? Little research has examined possible low-level sensory contributions to these limitations. Mental imagery is a fundamental part of human cognition that bridges cognition with sensory representations. Hence, imagery serves as a good candidate sensory process for probing how low capacity limitations might extend down the processing hierarchy. Here we introduce a novel technique to measure the sensory capacity of mental imagery, while removing the need for memory and any direct subjective reports. Contrary to our dynamic phenomenological experience, we demonstrate that visual imagery is severely limited by the perceptual and phenomenal bottleneck of visual representation. These capacity limits appear to be independent of generation time, depend on visual feature heterogeneity, are attenuated by concurrent retinal stimulation and are endowed with good metacognition. Additionally, the precision of visual representation declines rapidly with the number of stimuli, which is governed by a simple power law. We anticipate that this assay will be important for mapping the limits of human information processing., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: A subset of presenting cutaneous squamous cell carcinomas (CSCC) is high risk with respect to their high rates of recurrence, metastasis and patient death. The identification of such high risk CSCC is problematic. Neutrophil and granulocytic myeloid derived suppressor cell (G-MDSC) numbers are elevated in a number of cancers, but their association with current markers of high risk tumors in the setting of CSCC is unknown., Objectives: To assess circulating and tumor-localised neutrophil and G-MDSC populations for associations with high-risk tumor characteristics and overall survival (OS) in CSCC patients., Methods: A retrospective clinical audit was performed of patients who had hospital operations for primary CSCC and did not have other malignancies or HIV. Therapeutically immuno-suppressed individuals (TII, n=129) and non-TII (n=29) were analysed separately with respect to the presence of high-risk tumor features and OS. In addition, 47 patients with prospectively collected blood and primary CSCC tumor samples were analysed to determine frequencies of circulating G-MDSC and tumor localised CD66b+ and CD8+ leukocytes., Results: In the clinical audit of non-TII, high circulating neutrophil counts were associated with tumor thickness≥5mm, Clark level V and high T-stage. Univariate analysis showed elevated neutrophil count was a significant marker of poor OS, whilst tumor thickness remained the only independent histological predictor of OS after adjusting for age and immuno-suppression. The prospective study demonstrated that tumors≥5mm thick had significantly increased total and peri-tumorally localised CD66b+ leukocytes (comprising neutrophils and/or G-MDSC) and that elevated circulating G-MDSC numbers were associated with high T-stage tumors., Conclusions: This study demonstrates that the presence of high risk CSCC is associated with increased numbers of both circulating and tumor resident populations of neutrophils and/or G-MDSC. These cell types therefore merit further investigation with respect to their functional and prognostic significance in CSCC., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

To compare the management and outcome of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in patients known to be MRSA-colonized/infected (C-patients) with the management and outcome in those not known to be colonized/infected (NC-patients), we conducted a 10-year retrospective review of MRSA bacteraemia in an adult tertiary hospital. Clinical data were obtained by chart review, and mortality data from linked databases. Prior MRSA colonization/infection status was available to treating clinicians at the time of the bacteraemia as a 'Micro-Alert' tag on the patient's labels, in medical charts, and in electronic information systems. C-patients accounted for 35.4% of all MRSA bacteraemia episodes. C-patients were more likely to be indigenous, to be diabetic, or to have a history of previous S. aureus infection. Markers of illness severity (Simplified Acute Physiology Score (SAPS)-II, need for admission to the intensive-care unit, length of stay, and metastatic seeding) were similar in both groups. Empirical therapy included a glycopeptide in 49.3% of C-patients vs. 18.9% of NC-patients (p <0.01), and contained an antibiotic to which the MRSA isolate tested susceptible in vitro in 56.7% of C-patients vs. 45.1% of NC-patients (p 0.13). All-cause 7-day and 30-day mortality were 7.5% vs. 18.9% (p 0.04), and 22.4% vs. 31.1% (p 0.20), in the C-patient and NC-patient groups, respectively. Knowing MRSA colonization status was significantly associated with lower 30-day mortality in Cox regression analysis (p <0.01). These data suggest that mortality from MRSA bacteraemia is lower in C-patients, which may reflect the earlier use of glycopeptides. The low use of empirical glycopeptides in septic patients known to be previously MRSA-colonized/infected may represent a missed opportunity for infection control to positively impact on clinical management., (© 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.)

Biopharmaceuticals administered to the human body have the potential to trigger the production of anti-drug (also called anti-therapeutic) antibodies (ADA) that can neutralize the therapeutic activity. For antibody therapeutics, cell-based neutralizing ADA assays are frequently used to evaluate ADA in clinical studies. We developed a method to detect neutralizing antibodies against MEDI-575, a fully human IgG2κ antagonistic antibody against PDGFR-α. We evaluated three assay formats, two of which measured late responses, cell proliferation and apoptosis, whereas the third assay detected an early signaling event, phosphorylation of PDGFR-α. Measuring phosphorylation provided a superior assay window and therefore was developed as a neutralizing ADA (NAb) assay. Matrix interference, however, was significant, and could be identified to be caused by PDGF-AA and PDGF-AB, apparently the two most abundant ligands of PDGFR-α present in human serum samples. A simple pre-treatment step, addition of an inhibitory antibody to PDGF-A, a subunit present in PDGF-AA and PDGF-AB, was found to eliminate matrix interference, increasing assay reliability and sensitivity. We integrated the pre-treatment step into assay development and qualified a robust NAb assay., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

The transcription factor octamer-binding protein 4 (Oct4; encoded by POU5F1) has a key role in maintaining embryonic stem cell pluripotency during early embryonic development and it is required for generation of induced pluripotent stem cells. Controversy exists concerning Oct4 expression in somatic tissues, with reports that Oct4 is expressed in normal and in neoplastic urothelium carrying implications for a bladder cancer stem cell phenotype. Here, we show that the pluripotency-associated Oct4A transcript was absent from cultures of highly regenerative normal human urothelial cells and from low-grade to high-grade urothelial carcinoma cell lines, whereas alternatively spliced variants and transcribed pseudogenes were expressed in abundance. Immunolabeling and immunoblotting studies confirmed the absence of Oct4A in normal and neoplastic urothelial cells and tissues, but indicated the presence of alternative isoforms or potentially translated pseudogenes. The stable forced expression of Oct4A in normal human urothelial cells in vitro profoundly inhibited growth and affected morphology, but protein expression was rapidly down-regulated. Our findings demonstrate that pluripotency-associated isoform Oct4A is not expressed by normal or malignant human urothelium and therefore is unlikely to play a role in a cancer stem cell phenotype. However, our findings also indicate that urothelium expresses a variety of other Oct4 splice-variant isoforms and transcribed pseudogenes that warrant further study., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Cytochrome P4501A1 (CYP1A1), an important drug metabolizing enzyme, is expressed in human placenta throughout gestation as well as in fetal liver. Obesity, a chronic inflammatory condition, is known to alter CYP enzyme expression in non-placental tissues. In the present study, we test the hypothesis that maternal obesity alters the distribution of CYP1A1 activity in feto-placental unit. Placentas were collected from non-obese (BMI < 30) and obese (BMI > 30) women at term. Livers were collected from gestation day 130 fetuses of non-human primates fed either control diet or high-fat diet (HFD). Cytosol and microsomes were collected using differential centrifugation, and incubated with 7-ethoxyresorufin. The CYP1A1 specific activity (pmoles of resorufin formed/min/mg of protein) was measured at excitation/emission wavelength of 530/590 nm. Placentas of obese women had significantly reduced microsomal CYP1A1 activity compared to non-obese women (0.046 vs. 0.082; p < 0.05); however no such effect was observed on cytosolic activity. Similarly, fetal liver from HFD fed mothers had significantly reduced microsomal CYP1A1 activity (0.44 ± 0.04 vs. 0.20 ± 0.10; p < 0.05), with no significant difference in cytosolic CYP1A1 activity (control, 1.23 ± 0.20; HFD, 0.80 ± 0.40). Interestingly, multiple linear regression analyses of placental efficiency indicate cytosolic CYP1A1 activity is a main effect (5.67 ± 2.32 (β ± SEM); p = 0.022) along with BMI (-0.57 ± 0.26; p = 0.037), fetal gender (1.07 ± 0.26; p < 0.001), and maternal age (0.07 ± 0.03; p = 0.011). In summary, while maternal obesity affects microsomal CYP1A1 activity alone, cytosolic activity along with maternal BMI is an important determinant of placental efficiency. Together, these data suggest that maternal lifestyle could have a significant impact on CYP1A1 activity, and hints at a possible role for CYP1A1 in feto-placental growth and thereby well-being of fetus., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Microaspiration is often considered a potential cause of cough. The aim of this study was to investigate the relationship between microaspiration, the degree and type of gastroesophageal reflux, and the frequency of coughing in patients with chronic cough., Methods: One hundred patients with chronic cough (mean [± SD] age, 55.8 years [± 11.0 years]; 65 women) and 32 healthy volunteers (median age, 43.5 years [interquartile range (IQR), 30-50.8 years]; 16 women) were recruited. Patients with chronic cough performed 24-h objective cough frequency with simultaneous esophageal impedance/pH monitoring and measurement of pepsin concentrations in sputum and BAL. Twelve healthy volunteers underwent bronchoscopy/BAL, and 20 underwent impedance/pH monitoring., Results: Patients with chronic cough had significantly more reflux episodes than healthy volunteers (median, 63.5 reflux episodes [IQR, 52.5-80.0] vs 59.0 [IQR, 41.8-66.0]; P = .03), although the absolute difference was small, and there was no difference in numbers of events extending into the proximal esophagus (median, 17.2% [IQR, 8.0%-26.0%] vs 20.3% [IQR, 5.1%-32.1%]; P = .36). BAL pepsin levels were also similar in chronic cough to control subjects (median, 18.2 ng/mL [range, 0-56.4 ng/mL] vs 9.25 ng/mL [range, 0-46.9 ng/mL]; P = .27). Sputum but not BAL pepsin weakly correlated with the number of proximally occurring reflux events (r = 0.33, P = .045) but was inversely related to cough frequency (r = −0.52, P = .04). Sputum pepsin was, therefore, best predicted by combining the opposing influences of cough and proximal reflux (r = 0.50, P = .004)., Conclusions: Proximal gastroesophageal reflux and microaspiration into the airways have limited roles in provoking chronic cough. Indeed, coughing appears to be protective, reducing pepsin concentration in the larger airways of patients with chronic cough.