Search

Introduction Central venous access devices (CVADs) are commonly used for the treatment of paediatric cancer patients. Catheter locking is a routine intervention that prevents CVAD-associated adverse events, such as infection, occlusion and thrombosis. While laboratory and clinical data are promising, tetra-EDTA (T-EDTA) has yet to be rigorously evaluated or introduced in cancer care as a catheter lock.Methods and analysis This is a protocol for a two-arm, superiority type 1 hybrid effectiveness-implementation randomised controlled trial conducted at seven hospitals across Australia and New Zealand. Randomisation will be in a 3:2 ratio between the saline (heparinised saline and normal saline) and T-EDTA groups, with randomly varied blocks of size 10 or 20 and stratification by (1) healthcare facility; (2) CVAD type and (3) duration of dwell since insertion. Within the saline group, there will be a random allocation between normal and heparin saline. Participants can be re-recruited and randomised on insertion of a new CVAD. Primary outcome for effectiveness will be a composite of CVAD-associated bloodstream infections (CABSI), CVAD-associated thrombosis or CVAD occlusion during CVAD dwell or at removal. Secondary outcomes will include CABSI, CVAD-associated-thrombosis, CVAD failure, incidental asymptomatic CVAD-associated-thrombosis, other adverse events, health-related quality of life, healthcare costs and mortality. To achieve 90% power (alpha=0.05) for the primary outcome, data from 720 recruitments are required. A mixed-methods approach will be employed to explore implementation contexts from the perspective of clinicians and healthcare purchasers.Ethics and dissemination Ethics approval has been provided by Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC) (HREC/22/QCHQ/81744) and the University of Queensland HREC (2022/HE000196) with subsequent governance approval at all sites. Informed consent is required from the substitute decision-maker or legal guardian prior to participation. In addition, consent may also be obtained from mature minors, depending on the legislative requirements of the study site. The primary trial and substudies will be written by the investigators and published in peer-reviewed journals. The findings will also be disseminated through local health and clinical trial networks by investigators and presented at conferences.Trial registration number ACTRN12622000499785.

Abstract Background Caring for people who are ill or injured in pre-hospital environments is emotionally draining and physically demanding. This article focuses on the Psychosocial and Mental Health Programme commissioned by the Faculty of Pre-Hospital Care (FPHC) at the Royal College of Surgeons of Edinburgh (RCSEd) in 2018 to investigate the experiences and needs of responders to pre-hospital emergencies and make recommendations. It summarises the report to FPHC published in 2022, and adds material from research published subsequently. Method FPHC appointed a team to undertake the work. Team members conducted a literature review, and a systematic review of the literature concerning the impacts on the mental health of pre-hospital practitioners. They conducted fieldwork, participated in training and had conversations with trainees and established practitioners, and took evidence from the Pre-hospital Emergency Medicine Trainees Association (PHEMTA). Results The Results summarise the evidence-based theoretical background derived from the programme and practical guidance for practitioners, professional organisations, and employers who deliver pre-hospital care on the implications of, preventing and intervening with pre-hospital providers who experience psychosocial and mental health problems. Conclusion This paper summarises the outputs from a multidisciplinary programme of scholarship, research, and fieldwork. The authors condense the findings and the guidance developed by the Programme Team to provide a summary of the report and guidance on implementation. They believe that the recommendations are applicable to all healthcare organisations and particularly those that employ responders to emergencies and provide pre-hospital care.

There is an ongoing need for antifungal agents to treat humans. Identification of new antifungal agents can be based on screening compounds using whole cell assays. Screening compounds that target a particular molecule is possible in budding yeast wherein sophisticated strain engineering allows for controlled expression of endogenous or heterologous genes. We have considered the yeast Mps1 protein kinase as a reasonable target for antifungal agents because mutant or druggable forms of the protein, upon inactivation, cause rapid loss of cell viability. Furthermore, extensive analysis of the Mps1 in budding yeast has offered potential tactics for identifying inhibitors of its enzymatic activity. One such tactic is based on the finding that overexpression of Mps1 leads to cell cycle arrest via activation of the spindle assembly checkpoint. We have endeavored to adapt this assay to be based on the overexpression of Mps1 orthologs from pathogenic yeast in hopes of having a whole-cell assay system to test the activity of these orthologs. Mps1 orthologous genes from seven pathogenic yeast or other pathogenic fungal species were isolated and expressed in budding yeast. Two orthologs clearly produced phenotypes similar to those produced by the overexpression of budding yeast Mps1, indicating that this system for heterologous Mps1 expression has potential as a platform for identifying prospective antifungal agents.

Background: Lung infection by Scedosporium apiospermum in immunocompetent individuals is very rare. Case Report: We present a unique case of mediastinal granulomatous inflammatory lymphadenopathy in a diabetic and cirrhotic individual with a history of significant exposure to airborne fungus. Results: The patient underwent a computed tomography pulmonary angiogram to investigate for pulmonary embolus, which showed multiple enlarged mediastinal and hilar lymph nodes with punctate calcification and small lung nodules in both lungs. The patient had mild symptoms of a cough productive of clear-green sputum. Endobronchial ultrasound bronchoscopy fluid from the subcarinal lymph node and fine needle aspiration tissue both isolated a mould identified as Scedosporium apiospermum. As the patient was stable, symptomatic and radiological monitoring was pursued in the first instance. Interval imaging showed no change in the lymphadenopathy or lung nodules at three months. Conclusion: The mediastinal granulomatous lymphadenopathy in this case could represent a successful attempt by the patient’s innate immune response to control the infection and prevent invasive spread. It could also represent sarcoidosis secondary to fungal exposure. This pattern of disease for Scedosporium apiospermum is previously unreported.

Background: Partial nephrectomy (PN) is preferred for a renal mass in a solitary kidney (RMSK), although tumors with high complexity can be challenging. Objective: To evaluate the evolution of RMSK management with a focus on achievement of PN. Design, setting, and participants: Patients with nonmetastatic RMSK (n = 499) were retrospectively reviewed; 133 had high tumor complexity, including 80 in the pre-tyrosine kinase inhibitor (TKI) era (1999–2008) and 53 in the TKI era (2009–2022). After 2009, 23/53 patients received neoadjuvant TKI and 30/53 had immediate-surgery. Outcome measurements and statistical analysis: Functional outcomes, adverse events and complications, dialysis-free survival, and recurrence-free survival (RFS) were the measures evaluated. Mann-Whitney and χ2 tests were used to compare cohorts, and the log-rank test was applied for survival analyses. Results and limitations: Overall, the median RENAL score was 10 and the median tumor diameter was 5.2 cm. Demographic characteristics, tumor diameter, and RENAL scores were similar between the pre-TKI-era and TKI-era groups. In the TKI era, 23/53 patients (43%) with clear-cell histology were selected for neoadjuvant TKI. These 23 patients had a greater median tumor diameter (7.1 vs 4.4 cm; p = 0.02) and RENAL score (11 vs 10; p = 0.07). After TKI treatment, the median tumor diameter decreased to 5.6 cm and the RENAL score to 9, and tumor volume was reduced by 59% (all p

Abstract Accurate prediction of new baseline GFR (NBGFR) after radical nephrectomy (RN) can inform clinical management and patient counseling whenever RN is a strong consideration. Preoperative global GFR, split renal function (SRF), and renal functional compensation (RFC) are fundamentally important for the accurate prediction of NBGFR post-RN. While SRF has traditionally been obtained from nuclear renal scans (NRS), differential parenchymal volume analysis (PVA) via software analysis may be more accurate. A simplified approach to estimate parenchymal volumes and SRF based on length/width/height measurements (LWH) has also been proposed. We compare the accuracies of these three methods for determining SRF, and, by extension, predicting NBGFR after RN. All 235 renal cancer patients managed with RN (2006–2021) with available preoperative CT/MRI and NRS, and relevant functional data were analyzed. PVA was performed on CT/MRI using semi-automated software, and LWH measurements were obtained from CT/MRI images. RFC was presumed to be 25%, and thus: Predicted NBGFR = 1.25 × Global GFRPre-RN × SRFContralateral. Predictive accuracies were assessed by mean squared error (MSE) and correlation coefficients (r). The r values for the LWH/NRS/software-derived PVA approaches were 0.72/0.71/0.86, respectively (p

Summary: Critics judge quality based upon subjective characteristics of wine. These judgments are converted by critics into quantitative scores, which allow for comparison of vintages. This paper uses high resolution discrete and continuous time-based weather estimates at both a local and regional level to determine the role of weather conditions on producing high quality Bordeaux vintages, as determined by critics scores. By using discrete-time weather variables across local AOCs, this study reveals climate-quality relationships across the whole year, including previously ignored season effects. By using continuous time weather variables, we reinforce the evidence for these local effects by finding higher quality wine is made in years with higher rainfall, warmer temperatures; and earlier, shorter seasons. We propose management impacts of our results and suggest that as the climate continues to change, the quality of Bordeaux wines may continue to improve.

Anarchist pedagogy has existed for well over 100 years, but little has been written on the subject within the counseling profession and the counselor education literature specifically. Anarchist pedagogy offers a direct relationship between education and social justice praxis that many counseling programs espouse, and thus the consideration of an explicitly political pedagogy may benefit the counselor education profession. This manuscript aims to provide a brief overview of anarchist pedagogy, how it fits into the work of counselor education, and how counselor educators can utilize anarchist pedagogy. Limitations for the infusion of anarchist pedagogy into counselor education and future areas of research are detailed.

As the fifth-generation (5G) network is introduced in the millimetre-wave (mmWave) spectrum, and the widespread deployment of 5G standalone (SA) is approaching, it becomes essential to establish scientifically grounded exposure limits in the mmWave frequency band. To achieve this, conducting experiments at specific frequencies is crucial for obtaining reliable evidence of potential biological impacts. However, there is a literature gap where experimental research either does not utilise the mmWave high band (e.g., the 26 Gigahertz (GHz) band) or most studies mainly rely on computational approaches. Moreover, some experimental studies do not establish reproducible test environment and exposure systems. Addressing these gaps is vital for a comprehensive exploration of the biological implications associated with mmWave exposure. This study was designed to develop and implement a mmWave exposure system operating at 26 GHz. The step-by-step design and development of the system are explained. This specialised system was designed and implemented within an anechoic chamber to minimise external electromagnetic (EM) interference, creating a controlled and reproducible environment for experiments involving high-frequency EM fields. The exposure system features a 1 cm radiation spot size, enabling highly localised exposure for various biological studies. This configuration facilitates numerous dosimetry studies related to mmWave frequencies.

The active global SARS-CoV-2 pandemic caused more than 426 million cases and 5.8 million deaths worldwide. The development of completely new drugs for such a novel disease is a challenging, time intensive process. Despite researchers around the world working on this task, no effective treatments have been developed yet. This emphasizes the importance of drug repurposing, where treatments are found among existing drugs that are meant for different diseases. A common approach to this is based on knowledge graphs, that condense relationships between entities like drugs, diseases and genes. Graph neural networks (GNNs) can then be used for the task at hand by predicting links in such knowledge graphs. Expanding on state-of-the-art GNN research, Doshi et al. recently developed the Dr-COVID model. We further extend their work using additional output interpretation strategies. The best aggregation strategy derives a top-100 ranking of 8,070 candidate drugs, 32 of which are currently being tested in COVID-19-related clinical trials. Moreover, we present an alternative application for the model, the generation of additional candidates based on a given pre-selection of drug candidates using collaborative filtering. In addition, we improved the implementation of the Dr-COVID model by significantly shortening the inference and pre-processing time by exploiting data-parallelism. As drug repurposing is a task that requires high computation and memory resources, we further accelerate the post-processing phase using a new emerging hardware-we propose a new approach to leverage the use of high-capacity Non-Volatile Memory for aggregate drug ranking.

It is established that non-white people experience worse health outcomes than white people within the same population. Equity addresses differences between patient subgroups, allowing needs-based distribution of resources. The use of quality-of-life (QoL) tools to assist clinical decision making such as the SNOT-22 for chronic rhinosinusitis promotes equality, not equity, as quality-of-life (QoL) tools provide the same criteria of symptom scoring across diverse populations. We considered the effects of ethnicity and race on SNOT-22 scores and whether these scores should be adjusted to improve equity. PubMed and MEDLINE provided papers for a scoping review. A combination of the following search terms was used: patient-reported outcome measures (PROM) (OR) quality of life; (AND) race (OR) ethnicity (OR) disparities; (AND) otolaryngology (OR) SNOT-22 (OR) sinusitis. The first study identified no evidence of ethnic variability in SNOT-22 scores. However, the study did not represent the local population, including 86% white people. Other studies identified baseline SNOT-22 disparities with respect to population demographics, gender, and age. Ethnic differences appear to exist in acute sinusitis symptomatology. In other fields both within and outside of otorhinolaryngology, ethnic differences exist with regard to QoL tools. This scoping review identified a paucity of data in rhinology. However, evidence implies some form of correction to QoL scores could help promote equity for non-white patients.

The concept of religious tolerance and toleration has been the subject of much scholarly discussion for centuries. In the wake of the Reformation, however, it became a much more practical concept, with Europeans living next door to people perceived as heretics. A certain level of tolerance had to be achieved or else the entire continent would fall into a state of mass violence and disarray. Religious tolerance as a social practice was tested to its limits in the principality of Transylvania during the mid-sixteenth century. The multiconfessional state was home to five competing denominations and somehow managed to establish and maintain a certain level of peace in the region during the age in which religious warfare was rife throughout the continent. This article analyzes the unique emergence of the Unitarian, or anti-Trinitarian, confession in the Transylvanian principality, in order to answer broader questions on the concept of religious tolerance in early modern Europe. After initially outlining current thinking on the concept of religious tolerance, it describes the unique emergence of Unitarianism in Transylvania, aided greatly by political rulers. Challenging the idea of Transylvania being a haven for religious freedom in this time period, the article addresses contemporary debates surrounding the emergence of Unitarianism, namely in the 1567 Debrecen Reformed Synod. It also analyzes legal actions taken to sanction multiconfessionalism in the region, before ultimately situating this study within the broader context of religious tolerance in early modern Europe.

Abstract Background Exposure to radiofrequency (RF) electromagnetic fields (EMF), particularly from telecommunications sources, is one of the most common and fastest growing anthropogenic factors on the environment. In many countries, humans are protected from excessive RF EMF exposure by safety standards that are based on guidelines by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). The ICNIRP guidelines are based on knowledge of how RF EMF affects the human body, however, there are currently no recognised international guidelines to specifically protect animals and plants. Whether the ICNIRP guidelines for humans is adequate to provide protection to the environment is a subject of active debate. This systematic map will collate all the available evidence on whether anthropogenic RF EMF has a negative effect on plants and animals in the environment. The map will also identify gaps in knowledge, recommend future research and inform environmental and radiation protection authorities. Methods The proposed systematic map will include peer-reviewed and grey literature published in English. The EMF—Portal, PubMed and Web of Science databases will be searched using a search string prepared by the review team and tested for comprehensiveness against a list of known relevant reviews. Once duplicates are removed, retrieved articles will be screened in three stages: title, abstract, and full text. Studies will be selected with a subject population of all plants and animals, with exposures to anthropogenic RF EMF (frequency range 100 kHz–300 GHz) compared to no or lower-level exposure, and for all outcomes related to the studied populations. Kappa statistic tests will be conducted at each stage to ensure consistency of decision-making regarding the predefined inclusion/exclusion criteria. Eligible studies will then proceed to the data extraction phase, which will extract meta-data such as bibliographic information, taxonomic information, RF EMF exposure data, outcome(s), sample size, etc. The extracted data will then be organised into a systematic map and the findings summarised by cross-tabulating key meta-data variables in heat maps, charts or other data visualization methods. The systematic map will identify gaps in knowledge, priorities for future research and potential subtopics for further analysis and/or systematic review.

Background: Early intraoperative hypotension is associated with acute kidney and myocardial injury in patients undergoing noncardiac surgery. Precise arterial blood pressure measurement before and during the induction of general anaesthesia may avert early intraoperative hypotension. However, rapid arterial cannulation in anxious, conscious patients can be challenging. We describe the protocol for a randomised controlled trial designed to test the hypothesis that readily available, handheld ultrasound-guided arterial cannulation is the optimal method in conscious patients undergoing noncardiac surgery. Methods: Participants >45 yr undergoing noncardiac surgery expected to last >120 min and requiring an overnight hospital stay will be eligible. We will randomly allocate participants to undergo cannulation of the radial artery in the non-dominant arm before the induction of general or regional anaesthesia using either handheld ultrasound-guided dynamic needle position technique or palpation. The primary outcome is first-pass successful arterial cannulation, analysed by intention-to-treat. Secondary outcomes include adequacy/characteristics of the arterial waveform and complications within 24 h of cannulation. We will require 118 patients to demonstrate a doubling of successful first-pass arterial cannulation, from ∼30% using the palpation approach (α=0.05; 1–β=0.1). Results: This study has been approved by the NHS Health Research Authority and Health Care Research Wales (21/WA/0403) and commenced recruitment in May 2022. Conclusions: This study will establish whether handheld ultrasound-guided arterial cannulation before the induction of anaesthesia should be the standard of care in patients at risk of developing perioperative organ injury after noncardiac surgery. Clinical trial registration: NCT05249036.

The importance of investigating the health effects of RF radiation on the cornea cannot be overstated. This study aimed to address this need by utilizing a mathematical simulation to examine the absorption of millimeter wave (mmW) and terahertz (THz) waves by the cornea, considering both normal and pathological conditions. The simulation incorporated variations in tear film thickness and hydration levels, as these factors play a crucial role in corneal health. To assess the impact of RF radiation on the cornea, the study calculated temperature rises, which indicate heating effects for both dry and normal eyes. XFdtd, a widely used commercial software based on the Finite-Difference Time Domain (FDTD) method, was employed to evaluate the radiation absorption and resulting temperature changes. The outcomes of this study demonstrated a crucial finding, i.e., that changes in the water ratio and thickness of the tear film, which are associated with an increased risk of dry eye syndrome, directly impact the absorption of mmW and THz waves by the cornea. This insight provides valuable evidence supporting the interconnection between tear film properties and the vulnerability of the cornea to RF radiation.

Mutations in human pluripotent stem cells (PSC) and whether any form during culture prior to use in a human clinical context are a concern. Here, the authors use hPSCs derived to cGMP standards and show they have low mutation rates after culture, noting this decreases on culturing in low (5%) oxygen conditions.

Due to increasing interest in imaging, industrial, and the development of wireless communication operating at THz frequencies, it is crucial to ascertain possible health impacts arising from exposure to THz radiation. This paper reports on the pilot study of transmittance and absorbance spectra of the porcine cornea following THz frequency irradiation at a synchrotron THz/Far-IR beamline. The exposure period was 4 hours. One cornea was exposed to the radiation, with a second cornea acting as a control. An Attenuated Total Reflection (ATR) apparatus was used, and the frequency range of 2.4 to 8 THz was selected to evaluate any changes. It was found that the synchrotron THz radiation intensities are too low to produce induced corneal injury, but may lead to subtle changes in the state of water. Our results suggest that THz spectroscopy is a promising modality for corneal tissue hydration sensing.

Mobile communication has achieved enormous technology innovations over many generations of progression. New cellular technology, including 5G cellular systems, is being deployed and making use of higher frequencies, including the Millimetre Wave (MMW) range (30–300 GHz) of the electromagnetic spectrum. Numerical computational techniques such as the Finite Difference Time Domain (FDTD) method have been used extensively as an effective approach for assessing electromagnetic fields’ biological impacts. This study demonstrates the variation of the accuracy of the FDTD computational simulation system when different meshing sizes are used, by using the interaction of the critically sensitive human cornea with EM in the 30 to 100 GHz range. Different approaches of base cell size specifications were compared. The accuracy of the computation is determined by applying planar sensors showing the detail of electric field distribution as well as the absolute values of electric field collected by point sensors. It was found that manually defining the base cell sizes reduces the model size as well as the computation time. However, the accuracy of the computation decreases in an unpredictable way. The results indicated that using a cloud computing capacity plays a crucial role in minimizing the computation time.

Background: Massively multiplayer online games (MMOs) evolve online, whilst engaging large numbers of participants who play concurrently. Their online socialization component is a primary reason for their high popularity. Interestingly, the adverse effects of MMOs have attracted significant attention compared to their potential benefits.Methods: To address this deficit, employing PRISMA guidelines, this systematic review aimed to summarize empirical evidence regarding a range of interpersonal and intrapersonal MMO well-being outcomes for those older than 13.Results: Three databases identified 18 relevant English language studies, 13 quantitative, 4 qualitative and 1 mixed method published between January 2012 and August 2020. A narrative synthesis methodology was employed, whilst validated tools appraised risk of bias and study quality.Conclusions: A significant positive relationship between playing MMOs and social well-being was concluded, irrespective of one's age and/or their casual or immersed gaming patterns. This finding should be considered in the light of the limited: (a) game platforms investigated; (b) well-being constructs identified; and (c) research quality (i.e., modest). Nonetheless, conclusions are of relevance for game developers and health professionals, who should be cognizant of the significant MMOs-well-being association(s). Future research should focus on broadening the well-being constructs investigated, whilst enhancing the applied methodologies.

Abstract Background Fetal alcohol spectrum disorder (FASD) is a highly prevalent neurodevelopmental disorder associated with prenatal alcohol exposure. Early identification can improve functioning for individuals and reduce costs to society. Gold standard methods of diagnosing FASD rely on specialists to deliver intensive, multidisciplinary assessments. While comprehensive, prevalence rates highlight that this assessment model cannot meet demand, nor is it feasible in remote areas where specialist services are lacking. This project aims to expand the capabilities of remote practitioners in north Queensland, Australia, where 23–94% of the community identify as First Nations people. Integrating cultural protocols with the implementation science theories of Knowledge-To-Action, Experience-Based Co-Design, and RE-AIM, remote practitioners with varying levels of experience will be trained in a co-designed, culturally appropriate, tiered neurodevelopmental assessment process that considers FASD as a potential outcome. This innovative assessment process can be shared between primary and tertiary health care settings, improving access to services for children and families. This project aims to demonstrate that neurodevelopmental assessments can be integrated seamlessly with established community practices and sustained through evidence-based workforce development strategies. Methods The Yapatjarrathati project (named by the local First Nations community and meaning ‘to get well’) is a mixed-method implementation trial of a tiered assessment process for identifying FASD within a remote Australian community. In collaboration with the community, we co-designed: (a) a culturally sensitive, tiered, neurodevelopmental assessment process for identifying FASD, and (b) training materials that up-skill remote practitioners with varying levels of expertise. Qualitative interviews for primary, secondary and end users will be undertaken to evaluate the implementation strategies. RE-AIM will be used to evaluate the reach, effectiveness, adoption, implementation and maintenance of the assessment and training process. Discussion Co-designed with the local community, integrated with cultural protocols, and based on implementation science theories, the assessment and training process from this project will have the potential to be scaled-up across other remote locations and trialed in urban settings. The Yapatjarrathati project is an important step towards increasing the availability of neurodevelopmental services across Australia and empowering remote practitioners to contribute to the FASD assessment process.

ObjectiveTo evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus.DesignRandomised, double-blind, placebo-controlled clinical trial.Setting15 hospitals in Italy and five hospitals in the UK.Participants44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment.Intervention30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1).Primary and secondary outcome measuresThe primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus.ResultsThe trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was −2.78 (SD: 2.64) points in the 30 mg group, −3.04 (SD: 3.06) points in the 10 mg group and −3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity.ConclusionsOrvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible.Trial registration numberEudraCT2013-002763-25.

In Huntington's disease (HD), accurate estimates of expected future motor impairments are key for clinical trials. Individual prognosis is only partially explained by genetics. However, studies so far have focused on predicting the time to clinical diagnosis based on fixed impairment levels, as opposed to predicting impairment in time windows comparable to the duration of a clinical trial. Here we evaluate an approach to both detect atrophy patterns associated with early degeneration and provide a prognosis of motor impairment within 3 years, using data from the TRACK-HD study on 80 premanifest HD (pre-HD) individuals and 85 age- and sex-matched healthy controls. We integrate anatomical MRI information from gray matter concentrations (estimated via voxel-based morphometry) together with baseline data from demographic, genetic and motor domains to distinguish individuals at high risk of developing pronounced future motor impairment from those at low risk. We evaluate the ability of models to distinguish between these two groups solely using baseline imaging data, as well as in combination with longitudinal imaging or non-imaging data. Our models show improved performance for motor prognosis through the incorporation of imaging features to non-imaging data, reaching 88% cross-validated accuracy when using baseline non-longitudinal information, and detect informative correlates in the caudate nucleus and the thalamus both for motor prognosis and early atrophy detection. These results show the plausibility of using baseline imaging and basic demographic/genetic measures for early detection of individuals at high risk of severe future motor impairment in relatively short timeframes. Keywords: Future motor impairment prediction, Premanifest Huntington's disease, Classification, Structural MRI, TRACK-HD

A micro-optic collimator assembly represents an important platform for the realization of many commonly used fiber optic components and devices including optical isolators, circulators, gain flattening filters, and so on. In this paper, we investigate the incorporation of space division multiplexing (SDM) fibers (particularly, few mode fibers and multicore fibers) in a micro-optic collimator assembly and develop a technology base to provide fully integrated SDM components. A few exemplary SDM fiber isolators (e.g., 3 or 6-moded fiber isolator and a 32-core multicore fiber isolator) are successfully fabricated with low insertion loss and low mode (or core) dependent losses. Improved sharing of the functional optical element and significant device integration is efficiently achieved in these devices as will be required to ultimately realize the anticipated cost reduction benefits of SDM technology.

Sean Johnson Andrews has produced an engaging text of multifaceted value. His work, particularly the opening chapters, provides a concise history of the Birmingham Centre for Contemporary Cultural Studies (CCCS), the (early) Frankfurt School Critical Theory, and the Political Economy of Communication (PEC). Although the histories and notable figureheads of these schools will be broadly familiar to most scholars working in the realm of cultural studies, these opening chapters would be an excellent introduction to the field for either a general readership or students. Indeed, this would make a good textbook in many contexts.

Magnetic resonance imaging (MRI) studies have identified aberrant cortical structure in Alzheimer's disease (AD). The association between MRI-derived cortical morphometry measures and β-amyloid, however, remains poorly understood. In this study, we explored the potential relationship between early alterations in cortical thickness and later stage β-amyloid deposition, using a novel approach, in a transgenic AD mouse model. We acquired longitudinal anatomical MRI scans from mutant amyloid precursor protein (APP) transgenic mice and age-matched wild-type mice at 1 and 3.5 months-of-age, and employed fully-automated image processing methods to derive objective, quantitative measures of cortical thickness on a region-of-interest basis. We also generated 3D quantitative immunohistochemistry (qIHC) volumes of deposited β-amyloid burden from 18 month-old transgenic mice using an automated, production-level process. These studies revealed thinner cortex in most regions in the 1 month-old transgenic mice relative to age-matched wild-types, with the exception of the frontal, perirhinal/entorhinal, posterior cingulate, and retrosplenial cortical regions. Between 1 and 3.5 months-of-age, the transgenic mice demonstrated stable or increasing cortical thickness, while the wild-type mice showed cortical thinning. Based on data from co-registered 3D MRI and qIHC volumes, we identified an association between abnormal, early, regional cortical thickness change over 2.5 months and later β-amyloid deposition. These observations suggest that the spatio-temporal pattern of early (pre-plaque) alterations in cerebral cortical structure is indicative of regional predisposition to later β-amyloid pathology in a transgenic AD mouse model.

The role of E-cadherin in epithelial barrier function of cultured autologous oral mucosa epithelial cell sheet (CAOMECS) grafts was examined. CAOMECS were cultured on a temperature-responsive surface and grafted onto rabbit corneas with Limbal Stem Cell Deficiency (LSCD). E-cadherin levels were significantly higher in CAOMECS compared to normal and LSCD epithelium. Beta-catenin colocalized with E-cadherin in CAOMECS cell membranes while phosphorylated beta-catenin was significantly increased. ZO-1, occludin, and Cnx43 were also strongly expressed in CAOMECS. E-cadherin and beta-catenin localization at the cell membrane was reduced in LSCD corneas, while CAOMECS-grafted corneas showed a restoration of E-cadherin and beta-catenin expression. LSCD corneas did not show continuous staining for ZO-1 or for Cnx43, while CAOMECS-grafted corneas showed a positive expression of ZO-1 and Cnx43. Cascade Blue® hydrazide did not pass through CAOMECS. Because E-cadherin interactions are calcium-dependent, EGTA was used to chelate calcium and disrupt cell adhesion. EGTA-treated CAOMECS completely detached from cell culture surface, and E-cadherin levels were significantly decreased. In conclusion, E cadherin high expression contributed to CAOMECS tight and gap junction protein recruitment at the cell membrane, thus promoting cellular adhesion and a functional barrier to protect the ocular surface.

Huntington's disease (HD) is a late-onset, neurodegenerative disease for which there are currently no cures nor disease-modifying treatments. Here we report the identification of several potential anti-inflammatory targets for HD using an ex vivo model of HD that involves the acute transfection of human mutant huntingtin-based constructs into rat brain slices. This model recapitulates key components of the human disease, including the formation of intracellular huntingtin protein (HTT)-containing inclusions and the progressive neurodegeneration of striatal neurons—both occurring within the native tissue context of these neurons. Using this “high-throughput biology” screening platform, we conducted a hypothesis-neutral screen of a collection of drug-like compounds which identified several anti-inflammatory targets that provided neuroprotection against HTT fragment-induced neurodegeneration. The nature of these targets provide further support for non-cell autonomous mechanisms mediating significant aspects of neuropathogenesis induced by mutant HTT fragment proteins.