Parasomnias during trans-meridian and long-distance travel: Critical literature review and clinical practice recommendations.

Parasomnias are undesirable events that occur during sleep. They can be classified into rapid eye movement parasomnias and non-rapid eye movement parasomnias. Those who experience parasomnias may be anxious about travel for many reasons, including the occurrence of unwanted events during the trip, increased exposure to environmental trigger factors, and the propensity for harm to occur due to unfamiliar surroundings while travelling. There is a paucity of literature examining this area. This review summarizes the relevant literature and the clinical experience of the authors to compile clinical practice recommendations. The clinical features of parasomnias and how they relate to trans-meridian and long-distance travel are described. Triggers for non-rapid eye movement parasomnias, particularly the use of sedative hypnotic drugs, alcohol, drug withdrawal, sleep deprivation, emotional stress and environmental stimulations, are described. Management of parasomnias whilst travelling is reviewed, with a particular focus on trigger minimalization. The role for clonazepam and melatonin is outlined. At the pre-travel health consultation, the physician is strongly advised to screen the traveller for co-morbid sleep conditions, which exacerbate parasomnias. Areas for further research are explored, including the extent to which these sleep disorders impact on the travel experience.

A radiomic model to classify response to neoadjuvant chemotherapy in breast cancer.

BACKGROUND: Medical image analysis has evolved to facilitate the development of methods for high-throughput extraction of quantitative features that can potentially contribute to the diagnostic and treatment paradigm of cancer. There is a need for further improvement in the accuracy of predictive markers of response to neo-adjuvant chemotherapy (NAC). The aim of this study was to develop a radiomic classifier to enhance current approaches to predicting the response to NAC breast cancer. METHODS: Data on patients treated for breast cancer with NAC prior to surgery who had a pre-NAC dynamic contrast enhanced breast MRI were included. Response to NAC was assessed using the Miller-Payne system on the excised tumor. Tumor segmentation was carried out manually under the supervision of a consultant breast radiologist. Features were selected using least absolute shrinkage selection operator regression. A support vector machine learning model was used to classify response to NAC. RESULTS: 74 patients were included. Patients were classified as having a poor response to NAC (reduction in cellularity < 90%, n = 44) and an excellent response (> 90% reduction in cellularity, n = 30). 4 radiomics features (discretized kurtosis, NGDLM contrast, GLZLM_SZE and GLZLM_ZP) were identified as pertinent predictors of response to NAC. A SVM model using these features stratified patients into poor and excellent response groups producing an AUC of 0.75. Addition of estrogen receptor status improved the accuracy of the model with an AUC of 0.811. CONCLUSION: This study identified a radiomic classifier incorporating 4 radiomics features to augment subtype based classification of response to NAC in breast cancer.

CXCR3A promotes the secretion of the antifibrotic decoy receptor sIL-13Rα2 by pulmonary fibroblasts.

CXC chemokine receptor 3 (CXCR3) A and its IFN-inducible ligands CXCL9 and CXCL10 regulate vascular remodeling and fibroblast motility. IL-13 is a profibrotic cytokine implicated in the pathogenesis of inflammatory and fibroproliferative conditions. Previous work from our laboratory has shown that CXCR3A is negatively regulated by IL-13 and is necessary for the basal regulation of the IL-13 receptor subunit IL-13Rα2. This study investigates the regulation of fibroblast phenotype, function, and downstream IL-13 signaling by CXCR3A in vitro. CXCR3A was overexpressed via transient transfection. CXCR3A-/- lung fibroblasts were isolated for functional analysis. Additionally, the contribution of CXCR3A to tissue remodeling following acute lung injury was assessed in vivo with wild-type (WT) and CXCR3-/- mice challenged with IL-13. CXCR3 and IL-13Rα2 displayed a reciprocal relationship after stimulation with either IL-13 or CXCR3 ligands. CXCR3A reduced expression of fibroblast activation makers, soluble collagen production, and proliferation. CXCR3A enhanced the basal expression of pERK1/2 while inducing IL-13-mediated downregulation of NF-κB-p65. CXCR3A-/- pulmonary fibroblasts were increasingly proliferative and displayed reduced contractility and α-smooth muscle actin expression. IL-13 challenge regulated expression of the CXCR3 ligands and soluble IL-13Rα2 levels in lungs and bronchoalveolar lavage fluid (BALF) of WT mice; this response was absent in CXCR3-/- mice. Alveolar macrophage accumulation and expression of genes involved in lung remodeling was increased in CXCR3-/- mice. We conclude that CXCR3A is a central antifibrotic factor in pulmonary fibroblasts, limiting fibroblast activation and reducing extracellular matrix (ECM) production. Therefore, targeting of CXCR3A may be a novel approach to regulating fibroblast activity in lung fibrosis and remodeling.

Novel differences in gene expression and functional capabilities of myofibroblast populations in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial pneumonia, is characterized by excessive fibroproliferation. Key effector cells in IPF are myofibroblasts that are recruited from three potential sources: resident fibroblasts, fibrocytes, and epithelial cells. We hypothesized that IPF myofibroblasts from different sources display unique gene expression differences and distinct functional characteristics. Primary human pulmonary fibroblasts (normal and IPF), fibrocytes, and epithelial cells were activated using the profibrotic factors TGF-ß and TNF-α. The resulting myofibroblasts were characterized using cell proliferation, soluble collagen, and contractility assays, ELISA, and human fibrosis PCR arrays. Genes of significance in human whole lung were validated by immunohistochemistry on human lung sections. Fibroblast-derived myofibroblasts exhibited the greatest increase in expression of profibrotic genes and genes involved in extracellular matrix remodeling and signal transduction. Functional studies demonstrated that myofibroblasts derived from fibrocytes expressed mostly soluble collagen and chemokine (C-C) motif ligand (CCL) 18 but were the least proliferative of the myofibroblast progeny. Activated IPF fibroblasts displayed the highest levels of contractility and CCL2 production. This study identified novel differences in gene expression and functional characteristics of different myofibroblast populations. Further investigation into the myofibroblast phenotype may lead to potential therapeutic targets in future IPF research.

Altered Expression of Bone Morphogenetic Protein Accessory Proteins in Murine and Human Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic disease with a poor prognosis. The balance between transforming growth factor ß1 and bone morphogenetic protein (BMP) signaling plays an important role in tissue homeostasis, and alterations can result in pulmonary fibrosis. We hypothesized that multiple BMP accessory proteins may be responsible for maintaining this balance in the lung. Using the bleomycin mouse model for fibrosis, we examined an array of BMP accessory proteins for changes in mRNA expression. We report significant increases in mRNA expression of gremlin 1, noggin, follistatin, and follistatin-like 1 (Fstl1), and significant decreases in mRNA expression of chordin, kielin/chordin-like protein, nephroblastoma overexpressed gene, and BMP and activin membrane-bound inhibitor (BAMBI). Protein expression studies demonstrated increased levels of noggin, BAMBI, and FSTL1 in the lungs of bleomycin-treated mice and in the lungs of idiopathic pulmonary fibrosis patients. Furthermore, we demonstrated that transforming growth factor ß stimulation resulted in increased expression of noggin, BAMBI, and FSTL1 in human small airway epithelial cells. These results provide the first evidence that multiple BMP accessory proteins are altered in fibrosis and may play a role in promoting fibrotic injury.

CXCL9 Regulates TGF-ß1-Induced Epithelial to Mesenchymal Transition in Human Alveolar Epithelial Cells.

Epithelial to mesenchymal cell transition (EMT), whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). CXCR3 and its ligands are recognized to play a protective role in pulmonary fibrosis. In this study, we investigated the presence and extent of EMT and CXCR3 expression in human IPF surgical lung biopsies and assessed whether CXCR3 and its ligand CXCL9 modulate EMT in alveolar epithelial cells. Coexpression of the epithelial marker thyroid transcription factor-1 and the mesenchymal marker α-smooth muscle actin and CXCR3 expression was examined by immunohistochemical staining of IPF surgical lung biopsies. Epithelial and mesenchymal marker expression was examined by quantitative real-time PCR, Western blotting, and immunofluorescence in human alveolar epithelial (A549) cells treated with TGF-ß1 and CXCL9, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting. We found that significantly more cells were undergoing EMT in fibrotic versus normal areas of lung in IPF surgical lung biopsy samples. CXCR3 was expressed by type II pneumocytes and fibroblasts in fibrotic areas in close proximity to cells undergoing EMT. In vitro, CXCL9 abrogated TGF-ß1-induced EMT. A decrease in TGF-ß1-induced phosphorylation of Smad2 and Smad3 occurred with CXCL9 treatment. This was associated with increased shuttling of Smad7 from the nucleus to the cytoplasm where it inhibits Smad phosphorylation. This suggests a role for EMT in the pathogenesis of IPF and provides a novel mechanism for the inhibitory effects of CXCL9 on TGF-ß1-induced EMT.

Modulation of pulmonary fibrosis by IL-13Rα2.

Pulmonary fibrosis is a progressive and fatal disease that involves the remodeling of the distal airspace and the lung parenchyma, which results in compromised gas exchange. The median survival time once diagnosed is less than three years. Interleukin (IL)-13 has been shown to play a role in a number of inflammatory and fibrotic diseases. IL-13 modulates its effector functions via a complex receptor system that includes the IL-4 receptor (R) α, IL-13Rα1, and the IL-13Rα2. IL-13Rα1 binds IL-13 with low affinity, yet, when it forms a complex with IL-4α, it binds with much higher affinity, inducing the effector functions of IL-13. IL-13Rα2 binds IL-13 with high affinity but has a short cytoplasmic tail and has been shown to act as a nonsignaling decoy receptor. Transfection of fibroblasts and epithelial cells with IL-13Rα2 inhibited the IL-13 induction of soluble collagen, TGF-ß, and CCL17. Adenoviral overexpression of IL-13Rα2 in the lung reduced bleomycin-induced fibrosis. Our work shows that overexpression of IL-13Rα2 inhibits the IL-13 induction of fibrotic markers in vitro and inhibits bleomycin-induced pulmonary fibrosis. In summary our study highlights the antifibrotic nature of IL-13Ra2.

Knockdown of interleukin-1 receptor 1 is not neuroprotective in the 6-hydroxydopamine striatal lesion rat model of Parkinson's disease.

It is well established that neuroinflammation is associated with the progression of many neurodegenerative diseases, including Parkinson's disease (PD). Activated microglia and elevated levels of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) have been found in the brain and cerebrospinal fluid of PD patients, suggesting that IL-1ß may be involved in the pathogenesis of this disease. This study aimed to knock down the expression of the interleukin-1 type 1 receptor (IL-1R1) to evaluate any potential therapeutic effect of limiting the action of IL-1ß in the substantia nigra following a unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion in rats. Adult Sprague-Dawley rats received intranigral injections of shRNA specific for IL-1R1, followed 2 weeks later by intrastriatal 6-OHDA. Injection of IL-1R1 shRNA did not prevent 6-OHDA-induced loss of motor function or loss of nigral dopamine neurons. IL-1R1 expression was increased in the midbrain following 6-OHDA injection; this effect was attenuated in 6-OHDA-treated animals that had received IL-1R1 shRNA. These data suggest that while IL-1R1 was increased in 6-OHDA-treated animals and reduced following shRNA injection, the neurodegeneration induced by 6-OHDA was not mediated through IL-1R1.

A multi-center prospective study of plant-based nutritional support in adult community-based patients at risk of disease-related malnutrition.

Introduction: There is an emerging need for plant-based, vegan options for patients requiring nutritional support. Methods: Twenty-four adults at risk of malnutrition (age: 59 years (SD 18); Sex: 18 female, 6 male; BMI: 19.0 kg/m2 (SD 3.3); multiple diagnoses) requiring plant-based nutritional support participated in a multi-center, prospective study of a (vegan suitable) multi-nutrient, ready-to-drink, oral nutritional supplement (ONS) [1.5 kcal/mL; 300 kcal, 12 g protein/200 mL bottle, mean prescription 275 mL/day (SD 115)] alongside dietary advice for 28 days. Compliance, anthropometry, malnutrition risk, dietary intake, appetite, acceptability, gastrointestinal (GI) tolerance, nutritional goal(s), and safety were assessed. Results: Patients required a plant-based ONS due to personal preference/variety (33%), religious/cultural reasons (28%), veganism/reduce animal-derived consumption (17%), environmental/sustainability reasons (17%), and health reasons (5%). Compliance was 94% (SD 16). High risk of malnutrition ('MUST' score ≥ 2) reduced from 20 to 16 patients (p = 0.046). Body weight (+0.6 kg (SD 1.2), p = 0.02), BMI (+0.2 kg/m2 (SD 0.5), p = 0.03), total mean energy (+387 kcal/day (SD 416), p < 0.0001) and protein intake (+14 g/day (SD 39), p = 0.03), and the number of micronutrients meeting the UK reference nutrient intake (RNI) (7 vs. 14, p = 0.008) significantly increased. Appetite (Simplified Nutritional Appetite Questionnaire (SNAQ) score; p = 0.13) was maintained. Most GI symptoms were stable throughout the study (p > 0.06) with no serious adverse events related. Discussion: This study highlights that plant-based nutrition support using a vegan-suitable plant-based ONS is highly complied with, improving the nutritional outcomes of patients at risk of malnutrition.

Experience-based learning: how a crisis solution informed fundamental change in a clinical education curriculum.

BACKGROUND: Clinical education represents the most important formative period in undergraduate medical education. It is often criticised as haphazard and inefficient. Experience-based learning (ExBL) is a novel clinical education design that utilises practices of support, learner participation and real patient learning to enhance students' development of vital professional capabilities. We introduced ExBL to address the challenges of a 50% reduction in clinical placement time that arose during the COVID-19 pandemic. APPROACH: Final year medical students were assimilated into clinical teams as co-workers to facilitate learning through participation rather than observation. Placement education was supported by an integrated case-based learning and high-fidelity simulation program. Real patient learning in workplace contexts was supported by a network of clinician mentors. EVALUATION: A qualitative evaluation revealed that granting students co-worker status strongly supported participatory learning and professional identity formation. Furthermore, the triangulation of placements with cognitive coaching and high-fidelity simulation greatly enhanced skills development and students' sense of readiness for practice. IMPLICATIONS: Utilisation of ExBL significantly enhanced the quality of informal learning on clinical placements despite the reduced clinical placement time. In addition, the integration of cognitive coaching with simulation opportunities meant students were better prepared for meaningful participation as members of clinical teams. The introduction of ExBL increased the workload of clinical teachers. Moreover, favouring learning through participatory experience reduced exposure to more traditional formal bedside teaching encounters. Despite these challenges, we have adopted an ExBL model created in a crisis as our core educational design for our final year clinical programme.

A Global Building Occupant Behavior Database.

This paper introduces a database of 34 field-measured building occupant behavior datasets collected from 15 countries and 39 institutions across 10 climatic zones covering various building types in both commercial and residential sectors. This is a comprehensive global database about building occupant behavior. The database includes occupancy patterns (i.e., presence and people count) and occupant behaviors (i.e., interactions with devices, equipment, and technical systems in buildings). Brick schema models were developed to represent sensor and room metadata information. The database is publicly available, and a website was created for the public to access, query, and download specific datasets or the whole database interactively. The database can help to advance the knowledge and understanding of realistic occupancy patterns and human-building interactions with building systems (e.g., light switching, set-point changes on thermostats, fans on/off, etc.) and envelopes (e.g., window opening/closing). With these more realistic inputs of occupants' schedules and their interactions with buildings and systems, building designers, energy modelers, and consultants can improve the accuracy of building energy simulation and building load forecasting.

Practical tips for introducing high-fidelity simulation to undergraduates at a large scale: learning from our experience.

The letter provides practical tips for developing, implementing and scaling an effective simulation­based education programme at a large scale for undergraduate medical students. Using time-lapsed scenarios and the pause-discuss method of debrief are some of the useful tips that are discussed further in the letter.

Defining clinicopathological and radiological features of breast cancer in women under the age of 35: an epidemiological study.

INTRODUCTION: Breast cancer is the most commonly diagnosed female cancer. Diagnosis in younger women (under 35 years) is different to their older counterparts, and mammography is not considered as sensitive in this cohort. Consequentially, younger patients may present later with more advanced disease. METHODS: This is a retrospective analysis of a prospectively updated database containing consecutive patients who presented to the symptomatic breast unit of Galway University Hospital between 2009 and 2015. Patient clinicopathologic factors, clinical examination features, diagnostic radiological modalities and Bi-RADS score were all assessed. Data was analysed using Statistical Package for the Social Sciences version 25. RESULTS: One thousand eight hundred thirty-six patients were diagnosed with breast cancer, and of these, 51 (2.8%) patients were < 35 years. Invasive ductal carcinoma made up 90% of diagnosis, and 42% had an associated ductal carcinoma in situ. Fifty-four percent were high-grade tumours and 52% presented with stage III disease or greater. The main radiological tool used was ultrasound, which had a sensitivity of 87.50% (95% confidence interval [CI] 74.75 to 95.27%). Mammogram sensitivity was 86.84% (95% CI 71.91 to 95.59%). Magnetic resonance imaging was used in 29% of cases, with a sensitivity of 100.00% (95% CI 78.20 to 100.00%). CONCLUSION: Females under 35 tend to be diagnosed with aggressive, advanced stage tumours. Ultrasound remains the radiological test of choice, although diagnosis using mammography demonstrated a relatively high sensitivity compared with previous reports. This study emphasises the varying epidemiology of breast cancer in younger patients and the potential role of mammography in making radiological diagnosis in those who are symptomatic.

The Impact of Preoperative Breast Magnetic Resonance Imaging on Surgical Management in Symptomatic Patients With Invasive Lobular Carcinoma.

OBJECTIVE: Due to an insidious proliferative pattern, invasive lobular breast cancer (ILC) often fails to form a defined radiological or palpable lesion and accurate diagnosis remains challenging. This study aimed to determine the value of preoperative magnetic resonance imaging (MRI) for ILC and its impact on surgical outcomes. METHODS: Consecutive symptomatic patients diagnosed with ILC in a tertiary centre over a 9-year period were reviewed. The time from diagnosis until surgery, initial type of surgery/index operation (breast-conserving surgery [BCS]/mastectomy) and the rates of reoperation (re-excision/completion mastectomy) were recorded. Patients were grouped into those who received conventional imaging and preoperative MRI (MR+) and those who received conventional imaging alone (MR-). RESULTS: There were 218 cases of ILC, and 32.1% (n = 70) had preoperative MRI. Time from diagnosis to surgery was longer in the MR+ than the MR- group (32.5 vs 21.1 days, P < .001) even when adjusting for age and breast density. Initial BCS was performed on 71.4% (n = 50) of MR+ patients and 72.3% (n = 107) of the MR- group. While the rate of completion mastectomy following initial BCS was higher in the MR+ group (30.0%, n = 15 vs 14.0%, n = 15; χ2 = 5.63; P = .018), this association was not maintained in multivariable analysis. No difference was recorded in overall (initial and completion) mastectomy rate between the MR+ and MR- group (50.0%, n = 35 vs 37.8%, n = 56; χ2 = 2.89; P = .089). Margin re-excision following BCS was comparable between groups (8.0%, n =4, vs 9.3%, n = 10; χ2 = 0.076, P = .783) despite the selection bias for borderline conservable cases in the MR+ group. The rate of usage of MRI for ILC cases declined over the study period. CONCLUSION: While MRI was associated with minor delays in treatment and did not reduce overall rates of margin re-excision or completion mastectomy, it altered the choice of surgical procedure in almost a quarter of MR+ cases. The benefit of preoperative breast MRI appears to be confined to select (younger, dense breast, borderline conservable) cases in symptomatic ILC.

Hypoxia increases normal prostate epithelial cell resistance to receptor-mediated apoptosis via AKT activation.

The aging prostate is associated with changes in its vascular structure, which could lead to changes in oxygen levels. Hypoxia is an important environmental change that leads to the progression of many cancers mediated through a number of cellular changes, which included resistance to apoptosis. The role of hypoxia in initiating tumour development has not been previously investigated. We demonstrate that normal prostate epithelial cells develop a resistance to receptor-mediated apoptosis following 24 hr of 1% hypoxia. This effect is associated with the altered expression of a number of pro- and anti-apoptotic proteins, which leads to inhibition of Cytochrome c release and downstream caspase activation. This is mediated via decreased Bax translocation and upstream Caspase 8 activity. Despite increased expression of cIAP-2, small interfering RNA (siRNA) knockdown does not restore susceptibility to TRAIL-induced apoptosis. Gene expression analysis indicated potential changes in AKT activation, which was confirmed by increased phosphorylation of AKT. Inhibition of this phosphorylation reversed the resistance to TRAIL-induced apoptosis. AKT activation is emerging as a key survival signal in prostate cancer. This study demonstrates that short exposure to low oxygen can increase resistance to immune surveillance mechanisms and might confer a survival advantage onto normal prostate epithelial cells so that they can survive subsequent genomic instability and other carcinogenetic insults leading to the early development of prostate cancer.

Injuries to the carpal bones revisited.

Falls on the outstretched hand, with resultant pain in the carpal region, account for a significant number of referrals to emergency rooms worldwide. Not only do they represent a significant proportion of the radiological workload arising from emergency rooms, interpretation of the images acquired is often difficult due to the complex anatomy of this region, compounded by an inability to obtain adequate views due to patient discomfort. Often, despite apparently normal radiological examinations, patient discomfort persists, prompting a need for further imaging. It is vital that the radiologist be entirely familiar with the bony and ligamentous anatomy of this body region, as well as possess an understanding of the frequent mechanisms of injury. Using a variety of imaging techniques, we illustrate a spectrum of carpal injuries, common and otherwise, explaining the mechanism and typical appearances of each.

Are respiratory specialist registrars trained to teach?

Respiratory SpRs are interested in medical education but rarely observed when teaching and receive little feedback http://ow.ly/Our0m.

Facilitating relational framing in children and individuals with developmental delay using the relational completion procedure.

The Relational Completion Procedure is effective for establishing same, opposite and comparative derived relations in verbally able adults, but to date it has not been used to establish relational frames in young children or those with developmental delay. In Experiment 1, the Relational Completion Procedure was used with the goal of establishing two 3-member sameness networks in nine individuals with Autism Spectrum Disorder (eight with language delay). A multiple exemplar intervention was employed to facilitate derived relational responding when required. Seven of nine participants in Experiment 1 passed tests for derived relations. In Experiment 2, eight participants (all of whom, except one, had a verbal repertoire) were given training with the aim of establishing two 4-member sameness networks. Three of these participants were typically developing young children aged between 5 and 6 years old, all of whom demonstrated derived relations, as did four of the five participants with developmental delay. These data demonstrate that it is possible to reliably establish derived relations in young children and those with developmental delay using an automated procedure.

6-Hydroxydopamine induces distinct alterations in GDF5 and GDNF mRNA expression in the rat nigrostriatal system in vivo.

Growth/differentiation factor (GDF)5 and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors that promote the survival of midbrain dopaminergic neurons in vitro and in vivo. Both factors have potent neurotrophic and neuroprotective effects in rat models of Parkinson's disease (PD) and represent promising new therapies for PD. The aim of this study was to investigate the expression of GDF5, GDNF and their receptors in the nigrostriatal dopaminergic system in rat models of PD. It found that endogenous GDF5, GDNF and their receptors are differentially expressed in two 6-hydroxydopamine lesion models of PD. In both striatal and medial forebrain bundle (MFB) lesion models, striatal levels of GDF5 mRNA increased at 10 days post-lesion, while GDNF mRNA levels in the nigrostriatal system decreased after 10 and 28 days. Midbrain mRNA levels for both GDF5 receptors transiently increased after striatal lesion, whereas those of two GDNF receptors decreased at later time-points in both models. Despite the fact that exogenous GDF5 and GDNF have comparable effects on dopaminergic neurons in vitro and in vivo, their endogenous responses to neurotoxic injury are different. This highlights the importance of studying neurotrophic factor expression at distinct disease stages and in various animal models of PD.