Search

ABSTRACT: A total of 960 male Ross 308 chicks (day-old) were used to investigate the effect of age on the relationship between metabolizable energy (ME) and digestible energy (DE) for broiler chickens. Bird growth variables, nitrogen retention (NR), nitrogen digestibility (ND), as well as the relative weight of liver, pancreas, and the gastrointestinal tract were determined. Practical diets that compared 2 cereals (corn and wheat) and exogenous xylanase (0 or 16,000 BXU/kg) were evaluated at 5 ages (7, 14, 21, 28, and 35 D) in a 2 × 2 × 5 factorial arrangement of treatments with 8 replicates per treatment and started with 30 birds per replicate. A randomized block ANOVA analysis of repeated measures was performed, and a 2 × 2 × 5 factorial structure was used to investigate the 2 dietary treatment factors (cereal type and the presence of xylanase) within the 5 bird ages (7, 14, 21, 28, and 35 D), and their interactions. Apparent metabolizable energy (AME) increased linearly from 7 until 28 D of age, but (P < 0.05) decreased at 35 D of age. Digestible energy was high at 7 D of age, then dropped and remained similar (P > 0.05) from 14 to 35 D of age. The AME: DE ratio was lowest (P < 0.05) at 7 D of age but there were no (P > 0.05) differences thereafter. Cereal type and xylanase supplementation did not (P > 0.05) change the ME: DE ratio. The results indicate that determining ME before 14 D of age may give absolute values that are lower than would be obtained with older birds. ME values that are determined on older broiler chickens may overestimate the energy availability of practical feeds used in broiler starter feeds.

Duchenne muscular dystrophy is an X-linked monogenic disease caused by mutations in the dystrophin gene (DMD) characterized by progressive muscle weakness, leading to loss of ambulation and decreased life expectancy. Since the current standard of care for Duchenne muscular dystrophy is to merely treat symptoms, there is a dire need for treatment modalities that can correct the underlying genetic mutations. While several gene replacement therapies are being explored in clinical trials, one emerging approach that can directly correct mutations in genomic DNA is base editing. We have recently developed CRISPR-SKIP, a base editing strategy to induce permanent exon skipping by introducing C > T or A > G mutations at splice acceptors in genomic DNA, which can be used therapeutically to recover dystrophin expression when a genomic deletion leads to an out-of-frame DMD transcript. We now demonstrate that CRISPR-SKIP can be adapted to correct some forms of Duchenne muscular dystrophy by disrupting the splice acceptor in human DMD exon 45 with high efficiency, which enables open reading frame recovery and restoration of dystrophin expression. We also demonstrate that AAV-delivered split-intein base editors edit the splice acceptor of DMD exon 45 in cultured human cells and in vivo, highlighting the therapeutic potential of this strategy.

Summary: Secondary human lymphoid tissue immune reactions take place in a highly coordinated environment with compartmentalization representing a fundamental feature of this organization. In situ profiling methodologies are indispensable for the understanding of this compartmentalization. Here, we propose a complementary experimental approach aiming to reveal different aspects of this process. The analysis of human tonsils, using a combination of single cell phenotypic analysis based on flow cytometry and multiplex imaging and mass spectrometry-based methodologies, revealed a compartmentalized organization at the cellular and molecular levels. More specifically, the skewed distribution of highly specialized immune cell subsets and relevant soluble mediators was accompanied by a compartmentalized localization of several lipids across different anatomical areas of the tonsillar tissue. The performance of such combinatorial experimental approaches could lead to the identification of novel in situ interactions and molecular targets for the in vivo manipulation of lymphoid organ, particularly the germinal center, immune reactions.

Although the fear of fat is considered central to the transdiagnostic conceptualization and treatment of eating disorders, the origin of this fear is unclear. Self-disgust, the profound revulsion at one's own character or actions, has been linked with various eating disorder symptoms, including drive for thinness, and may be a mechanism that partially explains the fear of fat observed among those with eating disorders. The present study examines the extent to which self-disgust explains the association between an eating disorder diagnosis and fear of fat. The sample consisted of community adult females diagnosed with an eating disorder (n = 30) and healthy comparisons (n = 30). Participants completed validated measures of fear of fat, self-disgust, and depression. Compared to healthy participants, individuals with an eating disorder reported significantly more fear of fat (t(58) = 9.51, p < .001, d = -2.45), self-disgust (t(46.58) = 8.87, p < .001, d = -2.29, and depression (t(41.17) = 8.30, p < .001, d = -2.14). Mediation analyses revealed self-disgust significantly mediated the relationship between an eating disorder diagnosis and fear of fat after controlling for depression (Effect = 6.10, SE = 1.41). Findings suggest that individuals with an eating disorder may employ various maladaptive strategies to prevent gaining weight (i.e., purging) that partially originate from a profound revulsion of the self. The implications for a transdiagnostic conceptualization and treatment of self-disgust in eating disorders as well as limitations and suggestions for future research directions are discussed.

Marine animals have been known to interact with and become entangled in plastic debris for decades. Despite increasing annual input volumes of plastic waste to the natural environment and the threat this constitutes to marine biodiversity, impacts of mismanaged plastic waste generally remain unquantified in environmental impact assessments. In this paper, we develop a Species Sensitivity Distribution (SSD) approach for estimating a spatially differentiated indicator of potential macroplastic entanglement impacts with global coverage of the world’s oceans. This constitutes a key modelling step that contributes towards the inclusion of plastic litter effects in impact assessments. We gathered entanglement incidence data for 20 species of marine mammals, turtles and birds from different populations and marine regions. To capture species-specific sensitivities to entanglement and spatially varying concentrations of plastic debris, concentration–response modelling of field data was used to develop the SSD-based model. This was achieved by linking population specific entanglement records to corresponding regional areas of exposure and an existing global model of plastic debris concentrations. The SSD was further applied to derive an estimate of the Potentially Affected Fraction (PAF) of species on a global scale, highlighting regional hotspots of potential entanglement impacts at current levels of marine plastic pollution. This indicator can be adapted and applied in impact assessments in order to account for potential impacts of mismanaged plastic waste ending up in marine ecosystems.

Purpose: Marine litter, mostly plastics, is a growing environmental problem. Environmental decision makers are beginning to take actions and implement regulations that aim to reduce plastic use and waste mismanagement. Nevertheless, life cycle assessment (LCA), a tool commonly used to assist environmental decision making, does not yet allow for considering the consequences of plastic waste leaked into the environment. This limits the application of LCA as a tool for highlighting potential tradeoffs between impact categories and the relative significance of their contribution on a specific Areas of Protection (AoP). A coordinated research effort to cover various parts of the marine litter impact pathway is required to ultimately produce characterisation factors that can cover this research gap. Here, we design a consistent and comprehensive framework for modelling plastic litter impact pathways in LCIA models. This framework is to support such coordinated research progress towards the development of harmonized pathways to account for impacts of plastic litter, specifically to the marine environment. The framework includes an overview of life cycle inventory requirements (leakage to the environment; a focus of other research efforts), and a detailed description of possible marine litter impact pathways, modelling approaches and data(-type) requirements. We focus on marine plastic litter and consider the potential contribution of different impact pathways to overall damage in the main operational AoPs, as well as recently proposed ones. Results and conclusions: The proposed framework links inventory data in terms of kg plastic leaked to a specified environmental compartment (air, terrestrial, freshwater, marine) to six AoPs: ecosystem quality, human health, socio-economic assets, ecosystem services, natural heritage and cultural heritage. The fate modelling step, which includes transportation, fragmentation and degradation processes, is common to all included impact pathways. Exposure and effect modelling steps differentiate between at least six exposure pathways, e.g. inhalation, ingestion, entanglement, invasive species rafting, accumulation, and smothering, that potentially compromise sensitive receptors, such as ecosystems, humans, and manmade structures. The framework includes both existing, e.g. human toxicity and ecotoxicity, and proposed new impact categories, e.g. physical effect on biota, and can be used as a basis for coordinating harmonized research efforts.

Long-chain PUFAs (LC-PUFAs; C20–C22; e.g., DHA and arachidonic acid) are highly enriched in vertebrate retina, where they are elongated to very-long-chain PUFAs (VLC-PUFAs; C ≥28) by the elongation of very-long-chain fatty acids-4 (ELOVL4) enzyme. These fatty acids play essential roles in modulating neuronal function and health. The relevance of different lipid requirements in rods and cones to disease processes, such as age-related macular degeneration, however, remains unclear. To better understand the role of LC-PUFAs and VLC-PUFAs in the retina, we investigated the lipid compositions of whole retinas or photoreceptor outer segment (OS) membranes in rodents with rod- or cone-dominant retinas. We analyzed fatty acid methyl esters and the molecular species of glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine) by GC-MS/GC-flame ionization detection and ESI-MS/MS, respectively. We found that whole retinas and OS membranes in rod-dominant animals compared with cone-dominant animals had higher amounts of LC-PUFAs and VLC-PUFAs. Compared with those of rod-dominant animals, retinas and OS membranes from cone-dominant animals also had about 2-fold lower levels of di-DHA (22:6/22:6) molecular species of glycerophospholipids. Because PUFAs are necessary for optimal G protein-coupled receptor signaling in rods, these findings suggest that cones may not have the same lipid requirements as rods.

The mechanisms of psychotic symptoms like hallucinations and delusions are often investigated in fully-formed illness, well after symptoms emerge. These investigations have yielded key insights, but are not well-positioned to reveal the dynamic forces underlying symptom formation itself. Understanding symptom development over time would allow us to identify steps in the pathophysiological process leading to psychosis, shifting the focus of psychiatric intervention from symptom alleviation to prevention. We propose a model for understanding the emergence of psychotic symptoms within the context of an adaptive, developing neural system. We will make the case for a pathophysiological process that begins with cortical hyperexcitability and bottom-up noise transmission, which engenders inappropriate belief formation via aberrant prediction error signaling. We will argue that this bottom-up noise drives learning about the (im)precision of new incoming sensory information because of diminished signal-to-noise ratio, causing a compensatory relative over-reliance on prior beliefs. This over-reliance on priors predisposes to hallucinations and covaries with hallucination severity. An over-reliance on priors may also lead to increased conviction in the beliefs generated by bottom-up noise and drive movement toward conversion to psychosis. We will identify predictions of our model at each stage, examine evidence to support or refute those predictions, and propose experiments that could falsify or help select between alternative elements of the overall model. Nesting computational abnormalities within longitudinal development allows us to account for hidden dynamics among the mechanisms driving symptom formation and to view established symptomatology as a point of equilibrium among competing biological forces., (Copyright © 2024. Published by Elsevier Inc.)

Background: Neurocognitive impairment is a well-known phenomenon in schizophrenia that begins prior to psychosis onset. Connectome-wide association studies have inconsistently linked cognitive performance to resting-state fMRI. We hypothesized a carefully selected cognitive instrument and refined population would allow identification of reliable brain-behavior associations with connectome-wide association studies. To test this hypothesis, we first identified brain-cognition correlations via a connectome-wide association study in early psychosis. We then asked, in an independent dataset, if these brain-cognition relationships would generalize to individuals who develop psychosis in the future., Methods: The Seidman Auditory Continuous Performance Task (ACPT) effectively differentiates healthy participants from those with psychosis. Our connectome-wide association study used the Human Connectome Project for Early Psychosis (n=183) to identify links between connectivity and ACPT performance. We then analyzed the North American Prodrome Longitudinal Study 2 (n=345), a multi-site prospective study of individuals at risk for psychosis. We tested the connectome-wide association study-identified cognition-connectivity relationship in both individuals at risk for psychosis and controls., Results: Our connectome-wide association study in early-course psychosis identified robust associations between better ACPT performance and higher prefrontal-somatomotor connectivity (p<.005). Prefrontal-somatomotor connectivity was also related to ACPT performance in at-risk individuals who would develop psychosis (n=17). This finding was not observed in nonconverters (n=196) or controls (n=132)., Conclusions: This connectome-wide association study identified reproducible links between connectivity and cognition in separate samples of psychosis and at-risk individuals who would later develop psychosis. A carefully selected task and population improves the ability of connectome-wide association studies to identify reliable brain-phenotype relationships., (Copyright © 2024. Published by Elsevier Inc.)

Background: Fentanyl test strips (FTS) are used to detect the presence of fentanyl in other substances, but Alabama pharmacists' opinions regarding FTS provision are unknown., Objective: The purpose of this study was to assess the knowledge and perceptions of Alabama pharmacists regarding FTS and factors influencing pharmacists' FTS provision intentions across community pharmacy locations and types., Methods: An anonymous cross-sectional survey was distributed via email to Alabama pharmacists employed in community (retail) pharmacies. The survey consisted of multiple-choice questions and 5-point Likert-type scales (1 = strongly disagree, 5 = strongly agree) informed by the Theory of Planned Behavior. Primary outcome measures included: knowledge; general attitudes; perceived benefits; perceived barriers; self-efficacy; subjective norms; perceived behavioral control (PBC); and intention regarding FTS provision. Outcomes were characterized using descriptive statistics and differences in scales scores across pharmacy locations (rural vs. urban) and types (corporately-vs. independently-owned) were assessed using Mann-Whitney U tests. Predictors of FTS provision intentions were evaluated using multiple linear regression (alpha=0.05)., Results: Respondents (N = 131; 3.82% response rate) were mostly female (64%) and Caucasian (92%). No respondents stocked FTS at their pharmacy and knowledge about FTS was low (mean[SD] knowledge score: 58.7% [15.1]). Despite the existence of perceived barriers (mean [SD] scale score: 3.2 [0.6]), pharmacists' general attitudes (3.4 [0.5]), perceived benefits (3.7 [0.6]), self-efficacy (3.1 [0.8]), and intentions (3.2[0.7]) were positive. While subjective norms were positive (3.5[0.6]), PBC over FTS decision-making was negative (2.7[0.8]). Subjective norms were higher (P = 0.040) and PBC was lower (P < 0.001) amongst corporately-versus independently-owned pharmacies, but no differences existed between rural and urban locations for any measures. Additionally, perceived benefits (β=0.342, P = 0.002), PBC (β = 0.133, P = 0.045), and self-efficacy (β = 0.142, P = 0.034) were positive predictors and perceived barriers (β = -0.211, P = 0.029) was a negative predictor of intention., Conclusion: Alabama community pharmacists have positive attitudes regarding FTS, but future research should focus on strategies to increase PBC and overcome perceived barriers., Competing Interests: Disclosure Abstracts describing portions of this study were presented as posters at the 2023 Alabama Society of Health System Pharmacists Annual Clinical Meeting, the 2023 American Society of Health-System Pharmacists (ASHP) Mid-Year Meeting, and the 2024 Auburn University Student Research Symposium., (Copyright © 2024 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Cardiac angiosarcoma (CAS) is the most prevalent malignant primary cardiac tumor in adults, often affecting young males. We present a case of this rare entity in a young female, highlighting the multidisciplinary team's role and multimodality imaging in the diagnosis and management., Competing Interests: Declaration of competing interest The authors report that they have no relationships relevant to the contents of this article to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Antagonist coactivation is the simultaneous activation of agonist and antagonist muscles during a motor task. Age-related changes in coactivation may contribute to observed differences in muscle performance between children and adults. Our aim was to systematically summarize age-related differences in antagonist muscle coactivation during multi-joint dynamic and single-joint isometric and isokinetic contractions. Electronic databases were searched for peer-reviewed studies comparing coactivation in upper or lower extremity muscles between healthy children and adolescents/young adults. Of the 1083 studies initially identified, 25 met eligibility criteria. Thirteen studies examined multi-joint dynamic movements, 10 single-joint isometric contractions, and 2 single-joint isokinetic contractions. Of the studies investigating multi-joint dynamic contractions, 83% (11/13 studies) reported at least one significant age-related difference: In 84% (9/11 studies) coactivation was higher in children, whereas 16% (2/11 studies) reported higher coactivation in adults. Among single-joint contractions, only 25% (3/12 studies) reported significantly higher coactivation in children. Fifty six percent of studies examined females, with no clear sex-related differences. Child-adult differences in coactivation appear to be more prevalent during multi-joint dynamic contractions, where generally, coactivation is higher in children. When examining child-adult differences in muscle function, it is important to consider potential age-related differences in coactivation, specifically during multi-joint dynamic contractions., 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 © 2022 Elsevier Ltd. All rights reserved.)

The ADAMTS superfamily is composed of secreted metalloproteases and structurally related non-catalytic ADAMTS-like proteins. A subset of this superfamily, including ADAMTS6, ADAMTS10 and ADAMTSL2, are involved in elastic fiber assembly and bind to fibrillin and other matrix molecules that regulate the extracellular bioavailability of the potent growth factor TGFβ. Fibrillinopathies, that can also result from mutation of these ADAMTS/L proteins, have been linked to disrupted TGFβ homeostasis. ADAMTS6 and ADAMTS10 are homologous metalloproteases with poorly characterized substrates where ADAMTS10 is thought to process fibrillin-2 and ADAMTS6 latent TGFβ-binding protein (LTBP)-1. In order to understand the contribution of ADAMTS6, and these other members of the ADAMTS/L family, to TGFβ homeostasis, we have analyzed the effects of ADAMTS6, ADAMTS10 and ADAMTSL2 expression on TGFβ activation. We found that their expression increases TGFβ activation in a dose dependent manner, following stimulation with mature TGFβ1. For ADAMTS6, the catalytically active protease is required for effective TGFβ activation, where ADAMTS6 cleaves LTBP3 as well as LTBP1, and binds to the large latent TGFβ complexes of LTBP1 and LTBP3. Furthermore, ADAMTS6 expression increases the mechanotension of cells which results in inactivation of the Hippo Pathway, resulting in an increased translocation of YAP/TAZ complex to the nucleus. Together these findings suggest that when the balance of TGFβ is perturbed ADAMTS6 can influence TGFβ activation via two mechanisms. It directly cleaves the latent TGFβ complexes and also acts indirectly, along with ADAMTS10 and ADAMTSL2, by altering the mechanotension of cells. Together this increases activation of TGFβ from large latent complexes which may contribute to disease pathogenesis., Competing Interests: Declaration of Competing Interest Authors declare that they have no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The COVID-19 pandemic resulted in social-distancing measures and the suspension of organised sport globally, and has been shown to have negatively impacted mental health. However, athletes may have experienced reprieve from sport demands, which have previously been linked with maladaptive responses such as burnout and stress. The aims of this study were (1) compare levels of burnout and stress reported by Gaelic games athletes pre- and post-COVID-19 suspension period, (2) explore how athletes utilised and perceived this period and the return to sport, and (3) examine the implications of this for burnout. Participants completed an online questionnaire, which included the athlete burnout questionnaire, perceived stress scale , sport emotion questionnaire , demographic questions, weekly training hours , and other hours for sport (e.g. travel) before Covid-19 (BC-19) and after the Covid-19-induced suspension (AC-19&#95;S). Questions relating to how athletes utilised (e.g. training focus) and perceived (positive/negative impact) the period were included AC-19 S. Data was compared across time-points and we explored predictors of burnout AC-19&#95;S. Ninety-two athletes completed the questionnaire at both time-points. No significant differences in burnout or stress were identified, suggesting the suspension period did not significantly impact these variables. Burnout BC-19, stress AC-19&#95;S, unpleasant emotions about returning to sport and using the period to rest/recover positively predicted burnout AC-19&#95;S. Reduction in other hours across time-points and pleasant emotions about returning predicted lower burnout. Results suggest an athletes' response to a suspension period and subsequent return to sport can impact feelings of burnout, and may have implications for future unanticipated change events., Competing Interests: 5The authors declare they have no conflict of interest. The first author (SW) was the recipient of a University studentship which served as funding for the project., (© 2022 The Authors.)

Competing Interests: Declaration of Competing Interest None to declare.

Purpose: The purpose of this study is to determine the effect of Cytoglobin (Cygb) deficiency on Crb1-related retinopathy. The Crb1 cell polarity complex is required for photoreceptor function and survival. Crb1-related retinopathies encompass a broad range of phenotypes which are not completely explained by the variability of Crb1 mutations. Genes thought to modify Crb1 function are therefore important targets of research. The biological function of Cygb involves oxygen delivery, scavenging of reactive oxygen species, and nitric oxide metabolism. However, the relationship of Cygb to diseases involving the Crb1 cell polarity complex is unknown., Methods: Cygb knockout mice homozygous for the rd8 mutation (Cygb -/-rd8/rd8 ) were screened for ocular abnormalities and imaged using optical coherence tomography and fundus photography. Electroretinography was performed, as was histology and immunohistochemistry. Quantitative PCR was used to determine the effect of Cygb deficiency on transcription of Crb1 related cell polarity genes., Results: Cygb -/-rd8/rd8 mice develop an abnormal retina with severe lamination abnormalities. The retina undergoes progressive degeneration with the ventral retina more severely affected than the dorsal retina. Cygb expression is in neurons of the retinal ganglion cell layer and inner nuclear layer. Immunohistochemical studies suggest that cell death predominates in the photoreceptors. Electroretinography amplitudes show reduced a- and b-waves, consistent with photoreceptor disease. Cygb deficient retinas had only modest transcriptional perturbations of Crb1-related cell polarity genes. Cygb -/- mice without the rd8 mutation did not exhibit obvious retinal abnormalities., Conclusions: Cygb is necessary for retinal lamination, maintenance of cell polarity, and photoreceptor survival in rd8 mice. These results are consistent with Cygb as a disease modifying gene in Crb1-related retinopathy. Further studies are necessary to investigate the role of Cygb in the human retina., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A total of 960 male Ross 308 chicks (day-old) were used to investigate the effect of age on the relationship between metabolizable energy (ME) and digestible energy (DE) for broiler chickens. Bird growth variables, nitrogen retention (NR), nitrogen digestibility (ND), as well as the relative weight of liver, pancreas, and the gastrointestinal tract were determined. Practical diets that compared 2 cereals (corn and wheat) and exogenous xylanase (0 or 16,000 BXU/kg) were evaluated at 5 ages (7, 14, 21, 28, and 35 D) in a 2 × 2 × 5 factorial arrangement of treatments with 8 replicates per treatment and started with 30 birds per replicate. A randomized block ANOVA analysis of repeated measures was performed, and a 2 × 2 × 5 factorial structure was used to investigate the 2 dietary treatment factors (cereal type and the presence of xylanase) within the 5 bird ages (7, 14, 21, 28, and 35 D), and their interactions. Apparent metabolizable energy (AME) increased linearly from 7 until 28 D of age, but (P < 0.05) decreased at 35 D of age. Digestible energy was high at 7 D of age, then dropped and remained similar (P > 0.05) from 14 to 35 D of age. The AME: DE ratio was lowest (P < 0.05) at 7 D of age but there were no (P > 0.05) differences thereafter. Cereal type and xylanase supplementation did not (P > 0.05) change the ME: DE ratio. The results indicate that determining ME before 14 D of age may give absolute values that are lower than would be obtained with older birds. ME values that are determined on older broiler chickens may overestimate the energy availability of practical feeds used in broiler starter feeds., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: We used phase-3 CONVERT trial data to investigate the impact of fludeoxyglucose F 18 ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) in SCLC., Methods: CONVERT randomized patients with limited-stage SCLC to twice-daily (45 Gy in 30 fractions) or once-daily (66 Gy in 33 fractions) chemoradiotherapy. Patients were divided into two groups in this unplanned analysis: those staged with conventional imaging (contrast-enhanced thorax and abdomen CT and brain imaging with or without bone scintigraphy) and those staged with 18 F-FDG PET/CT in addition., Results: Data on a total of 540 patients were analyzed. Compared with patients who underwent conventional imaging (n = 231), patients also staged with 18 F-FDG PET/CT (n = 309) had a smaller gross tumor volume (p = 0.003), were less likely to have an increased pretreatment serum lactate dehydrogenase level (p = 0.035), and received more chemotherapy (p = 0.026). There were no significant differences in overall (hazard ratio = 0.87, 95% confidence interval: 0.70-1.08, p = 0.192) and progression-free survival (hazard ratio = 0.87, 95% confidence interval: 0.71-1.07], p = 0.198) between patients staged with or without 18 F-FDG PET/CT. In the conventional imaging group, we found no survival difference between patients staged with or without bone scintigraphy. Although there were no differences in delivered radiotherapy dose, 18 F-FDG PET/CT-staged patients received lower normal tissue (lung, heart, and esophagus) radiation doses. Apart from a higher incidence of late esophagitis in patients staged with conventional imaging (for grade ≥1, 19% versus 11%; [p = 0.012]), the incidence of acute and late radiotherapy-related toxicities was not different between the two groups., Conclusion: In CONVERT, survival outcomes were not significantly different in patients staged with or without 18 F-FDG PET/CT. However, this analysis cannot support the use or omission of 18 F-FDG PET/CT owing to study limitations., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The Hedgehog (Hh) signalling pathway plays important roles during embryonic development and in adult tissue homeostasis, for example cartilage, where its deregulation can lead to osteoarthritis (OA). microRNAs (miRNAs) are important regulators of gene expression, and have been implicated in the regulation of signalling pathways, including Hh, thereby impacting upon development and disease. Our aim was to identify the function of miRNAs whose expression is altered in OA cartilage. Here we identified an increase in miR-324-5p expression in OA cartilage and hypothesised that, as in glioma, miR-324-5p would regulate Hh signalling. We determined that miR-324-5p regulates osteogenesis in human mesenchymal stem cells (MSCs) and in mouse C3H10T1/2 cells. Luciferase reporter assays demonstrated that miR-324-5p directly regulated established targets GLI1 and SMO in human but not in mouse, suggesting species-dependent mechanism of Hh pathway regulation. Stable Isotope Labelling with Amino acids in Cell culture (SILAC), mass spectrometry and whole genome transcriptome analysis identified Glypican 1 (Gpc1) as a novel miR-324-5p target in mouse, which was confirmed by real-time RT-PCR, immunoblotting and 3'UTR-luciferase reporters. Knockdown of Gpc1 reduced Hh pathway activity, and phenocopied the effect of miR-324-5p on osteogenesis, indicating that miR-324-5p regulates Hh signalling in mouse via direct targeting of Gpc1. Finally, we showed that human GPC1 is not a direct target of miR-324-5p. Importantly, as well as identifying novel regulation of Indian Hedgehog (Ihh) signalling, this study demonstrates how a miRNA can show conserved pathway regulation in two species but by distinct mechanisms and highlights important differences between human diseases and mouse models., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The MALT1 (Mucosa associated lymphoid tissue lymphoma translocation protein 1) paracaspase couples antigen receptors on lymphocytes to downstream signaling events. Activation of MALT1 is known to involve stimulus-dependent CBM complex formation, that is, the recruitment of BCL10-bound MALT1 to a CARD-Coiled Coil protein. Beyond this canonical, CBM-dependent mechanism of MALT1 activation, recent studies suggest that MALT1 protease activity may be triggered by alternative mechanisms. For instance, the E3-ligase TRAF6 can activate MALT1 proteolytic function and induce MALT1 auto-cleavage. However, the interplay between CBM and TRAF6 with regard to MALT1 activation has remained incompletely elucidated. Here, by generating CRISPR/Cas9-derived knock-out Jurkat T-cells, we show that TRAF6 was dispensable for CARD11/BCL10-dependent MALT1 activation upon T-cell stimulation. However, ectopically-expressed TRAF6 could induce MALT1 activity in Jurkat T-cells devoid of either CARD11 or BCL10. These data provide unequivocal evidence that TRAF6-mediated MALT1 activation does not require the upstream scaffold CARD11 or the interaction between MALT1 and BCL10. Thus, TRAF6 may be part of a previously unidentified non-canonical pathway that triggers MALT1 protease activity independently of canonical CBM signalosomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A 20-month-old male miniature dachshund was evaluated for a 10-week history of intermittent stranguria, pollakiuria, haematuria and obstructive urolithiasis. Retrograde urethrocystography revealed a subcutaneous saccular structure in the perineal area connected to the intrapelvic urethra associated with urolithiasis. After excision of the perineal saccular structure, microscopical examination confirmed the presence of transitional epithelium lining the diverticulum, with isolated submucosal smooth muscle bundles. This structure was attached to another saccular structure lined by stratified squamous keratinizing epithelium with hair follicles, sebaceous glands and apocrine glands. An incomplete urethral duplication with dermoid cyst was diagnosed. The dog recovered uneventfully from surgery and was still urinary continent and free from clinical signs 5 months after surgery. To the authors' knowledge this is the first report of an incomplete urethral duplication with a dermoid cyst and concurrent obstructive urolithiasis in a dog., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A growing body of research suggests that the interpretation of fingerprint evidence is open to contextual bias. While there has been suggestion in the literature that the same might apply to bitemarks - a form of identification evidence in which a degree of contextual information during the comparison phase is generally unavoidable - there have so far been no empirical studies to test this assertion. We explored dental and non-dental students' ability to state whether two bitemarks matched, while manipulating task ambiguity and the presence and emotional intensity of additional contextual information. Provision of the contextual information influenced participants' decisions on the ambiguous bitemarks. Interestingly, when participants were presented with highly emotional images and subliminally primed with the words 'same' and 'guilty', they made fewer matches relative to our control condition. Dental experience also played a role in decision-making, with dental students making more matches as the experiment progressed, regardless of context or task ambiguity. We discuss ways that this exploratory research can be extended in future studies., (Copyright © 2013 Forensic Science Society. Published by Elsevier Ireland Ltd. All rights reserved.)

We show that the strength of T-cell stimulation determines the capability of human CD4(+) T cells to become interleukin-17 (IL-17) producers. CD4(+) T cells received either high- (THi) or low (TLo)-strength stimulation via anti-CD3/CD28 beads or dendritic cells pulsed with superantigen in the presence of pro-Th17 cytokines IL-1β, transforming growth factor β, and IL-23. We found that TLo, but not THi, stimulation profoundly promoted Th17 responses by enhancing both the relative proportion and total number of Th17 cells. Titration of anti-CD3 revealed that low TCR signaling promoted Th17 cells, but only in the presence of anti-CD28. Impaired IL-17 production in THi cells could not be explained by high levels of Foxp3 or transforming growth factor β-latency-associated peptide expressed by THi cells. Nuclear factor of activated T cells was translocated to the nucleus in both THi and TLo cells, but only bound to the proximal region of the IL-17 promoter in TLo cells. The addition of a Ca(2+) ionophore under TLo conditions reversed the pro-Th17 effect, suggesting that high Ca(2+) signaling impairs Th17 development. Although our data do not distinguish between priming of naive T cells versus expansion/differentiation of memory T cells, our results clearly establish an important role for the strength of T-cell activation in regulating Th17 responses.

A cross-sectional study is reported in which loneliness and emotional problems are explored in adolescent victims of direct or relational bullying, together with the potentially moderating influence of friendship quality. Adolescents (N=401, mean age 13.5) completed the School Relationships Questionnaire, to identify bullying and victimisation roles, the Friendship Activity Questionnaire (FAQ), the Strengths and Difficulties Questionnaire (SDQ) to assess emotional problems, and the Loneliness and Social Dissatisfaction Questionnaire (LSDQ). Relational victims, but not direct victims reported significantly elevated feelings of loneliness and emotional problems compared to non-victims. Direct victims reported a significantly higher quality of friendship, compared to non-victims. Poor quality of friendship was also associated with high levels of loneliness, and vice versa for direct victims, but not for relational victims. This indicates that the higher quality of friendship found in direct victims is associated with the reduced levels of loneliness found in this group. Given the cross-sectional nature of this study, it is not possible to ascertain whether this association truly reflects the role of friendship quality as a moderator, and hence protective factor against adverse influences of victimisation. The different mechanisms underlying direct and relational victimisation are important for future research and intervention programmes.

Objectives: To evaluate the clinical efficacy and safety of zolpidem extended release for the treatment of primary insomnia in elderly patients., Methods: A randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 205 (117 women, 88 men; mean age 70.2 +/- 4.5 years) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined primary insomnia patients were randomized to 3 weeks of nightly treatment with either zolpidem extended release 6.25 mg or placebo; 198 patients completed the study., Results: Relative to placebo, zolpidem extended release 6.25 mg significantly decreased wake time after sleep onset during the first six hours of the night, as measured by polysomnogram (PSG). PSG latency to persistent sleep was reduced and PSG total sleep time was increased, both at nights 1/2 and 15/16. Patient self-report measures were significantly better with zolpidem extended-release 6.25 mg than with placebo throughout treatment. Some PSG measures indicated a worsening of sleep for a single night after abrupt discontinuation of zolpidem extended release. No next-morning residual effects were observed. The overall incidence and nature of adverse events was comparable between the two groups., Conclusions: Zolpidem extended release 6.25 mg improved both sleep maintenance and sleep induction in elderly primary insomnia patients during three weeks of administration.

Research into bullying behaviour has identified two main categories of bullying behaviour, direct bullying and relational bullying, within which different profiles are evident, namely 'pure' bullies, 'pure' victims, bully/victims and neutral children. The current study examined the relationship between direct and relational bullying profiles, arousal levels, and behaviour problems. 242 (males: 121, females: 121) Secondary school pupils (mean age 13.5 years) completed three questionnaires; the Arousal Predisposition Scale (APS) (Behav. Res. Therapy 26 (1988) 415); the School Relationships Questionnaire (SRQ) (detailed in J. Child Psychol. Psychiatry 41(8) (2000) 989; Br. J. Psychol. 92 (2001) 673); the Strengths and Difficulties Questionnaire (SDQ) (J. Child Psychol. Psychiatry 38(5) (1997) 581). Results revealed that the bully/victim profile for direct and relational bullying had the highest levels of arousal compared to other bullying profiles. Conversely, direct 'pure' bullies had low levels of arousal. Clinical behaviour problems as measured by the SDQ were associated with high levels of arousal. Clinically low arousal was not related to either bullying profiles, or behaviour problems. These findings were largely consistent with the arousal theory of behaviour (Crime and personality, 1964), which indicates that arousal levels are differentially associated with distinct behaviour patterns. The results provide implications for bullying intervention strategies, and methods to manage the school environment in relation to arousal levels.

Background and Aims: In the UK, cerebrovascular accident (CVA) is the third commonest cause of death and the commonest diagnosis in patients receiving home enteral feeding (HETF). This study aimed to use data from the British Artificial Nutrition Survey (BANS) collected between 1996 and 1999 to assess the outcome of patients on HETF, including mortality, return to oral feeding, level of physical activity, and level of dependency, which has resource implications., Results: it is estimated that about 1.7% of all patients suffering a CVA in the UK between 1996 and 1999 received HETF. At one year, 29.6% died while receiving HETF and another 13% returned to oral feeding. Mortality increased with age and was twice as high in those managed in nursing homes compared to those in their own homes. The patients receiving tube feeding spent only 0.6% of their time in hospital. A total of 43.9% of patients were bed-bound at home (1.9% unconscious) and an additional 30.3% were house-bound. Only 21.2% were independent, and the majority were totally dependent on their carers. In CVA patients on HETF the level of dependency was greater than for those with all types of diagnoses (n=12,997)., Conclusion: This study has described the outcome of a large number of patients receiving HETF in the UK. Since patients spent less than 1% of their time in hospital, HETF relieves pressure on the expensive hospital environment, but places more demands on the carers, who have to deal with severely disabled patients. Recovery of swallowing function should be assessed intermittently to prevent unnecessary HETF., (Copyright 2001 Harcourt Publishers Ltd.)

Because clozapine may be prescribed to cocaine abusing patients with schizophrenia, we studied cocaine-clozapine interactions in a controlled setting. Eight male cocaine addicts underwent four oral challenges with ascending doses of clozapine (12.5, 25 and 50 mg) and placebo followed 2 h later by a 2-mg/kg dose of intranasal cocaine. Subjective and physiological responses, and serum cocaine levels were measured over a total 4-h period. Clozapine pretreatment increased cocaine levels during the study and significantly increased the peak serum cocaine levels in a dose dependent manner. In spite of this elevation in blood levels, clozapine pretreatment had a significant diminishing effect upon subjective responses to cocaine, including 'expected high', 'high' and 'rush', notably at the 50 mg dose. There was also a significant effect upon 'sleepiness', 'paranoia' and 'nervous'. Clozapine caused a significant near-syncopal episode in one subject in the study, requiring his removal from the study. Clozapine had no significant effect on baseline pulse rate and systolic blood pressure, but it attenuated the significant pressor effects of the single dose of intranasal cocaine. These data suggested a possible therapeutic role for clozapine in the treatment of cocaine addiction in humans, but also suggests caution due to the near-syncopal event and the increase in serum cocaine levels.

Background: Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects., Methods: A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96)., Results: A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex., Conclusions: Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.

Thirty-six parents were videotaped during visits with their preterm infants in a neonatal intensive care unit in order to describe some characteristics of parental touch. Parents most often touched infants' hands, backs, and heads, using stroke, hold, or contact actions of moderate intensity. Mothers and grandmothers provided more touch than fathers, and parents provided less touch to infants at or below a gestational age of 28 weeks. The results can be used as a basis for more controlled experimental studies evaluating preterm infants' physiologic responses to early parental touch.