Altered Forebrain and Hindbrain Development in Mice Mutant for theGsh-2Homeobox Gene

AbstractThe patterning of the mammalian brain is orchestrated by a large battery of regulatory genes. Here we examine the developmental function of theGsh-2nonclustered homeobox gene. Whole-mount and serial sectionin situhybridizations have been used to better defineGsh-2expression domains within the developing forebrain, midbrain, and hindbrain.Gsh-2transcripts are shown to be particularly abundant in the hindbrain and within the developing ganglionic eminences of the forebrain. In addition, mice carrying a targeted mutation ofGsh-2have been generated and characterized. Homozygous mutants uniformly failed to survive more than 1 day following birth. At the physiologic level the mutants experienced apnea and reduced levels of hemoglobin oxygenation. Histologically, the mutant brains had striking alterations of discrete components. In the forebrain the lateral ganglionic eminence was reduced in size. In the hindbrain, the area postrema, an important cardiorespiratory chemosensory center, was absent. The contiguous nucleus tractus solitarius, involved in integrating sensory input to maintain homeostasis, was also severely malformed in mutants. Immunohistochemistry was used to examine the mutant brains for alterations in the distribution of markers specific for serotonergic and cholinergic neurons. In addition,in situhybridizations were used to define expression patterns of the Dlx 2 and Nkx 2.1 homeobox genes in Gsh-2 mutant mice. The mutant lateral ganglionic eminences showed an abnormal absence of Dlx 2 expression. These results better define the genetic program of development of the mammalian brain, support neuromeric models of brain development, and further suggest similar patterning function for homeobox genes in phylogenetically diverse organisms

Design considerations for a multiple sclerosis fatigue mobile app MS Energize: A pragmatic iterative approach using usability testing and resonance checks.

Multiple sclerosis (MS) is a chronic neurological condition affecting around 2.2 million people worldwide. The illness includes a range of symptoms, with fatigue considered to be one of the most disabling. This paper describes how a pragmatic and iterative approach, supported by usability and resonance testing, was used to build a minimum viable product of MS Energize-or MS Energise in UK English regions. MS Energise is a mobile application focused on self-management of fatigue for people with MS. The iterative approach included various stages of testing, during which user feedback including comments about interface, navigation and content, was sought to inform incremental app development and continual improvement. Usability testing was conducted with 11 people with longstanding multiple sclerosis in New Zealand and the United Kingdom, and focused on particular sections of the app as well as the accessibility of the app to users with MS. Two participants contributed to further resonance testing post-release to ensure the app was perceived as relevant and useful to the user. The usability testing and resonance testing phases suggested that user experience of MS Energise was mostly positive. Participants provided a number of suggestions for improvements to aspects of content and design; some of which we implemented during our app development process. Findings will also contribute to future planning and design iteration to enhance the user experience. The next step is further improvement of MS Energise prior to a trial of its clinical and cost effectiveness

Evolution of Blood-Brain Barrier Permeability in Subacute Ischemic Stroke and Associations With Serum Biomarkers and Functional Outcome

Background and Purpose: In the setting of acute ischemic stroke, increased blood-brain barrier permeability (BBBP) as a sign of injury is believed to be associated with increased risk of poor outcome. Pre-clinical studies show that selected serum biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), matrix metallopeptidases (MMP), and vascular endothelial growth factors (VEGFs) may play a role in BBBP post-stroke. In the subacute phase of stroke, increased BBBP may also be caused by regenerative mechanisms such as vascular remodeling and therefore may improve functional recovery. Our aim was to investigate the evolution of BBBP in ischemic stroke using contrast-enhanced (CE) magnetic resonance imaging (MRI) and to analyze potential associations with blood-derived biomarkers as well as functional recovery in subacute ischemic stroke patients. Methods: This is an exploratory analysis of subacute ischemic stroke patients enrolled in the BAPTISe study nested within the randomized controlled PHYS-STROKE trial (interventions: 4 weeks of aerobic fitness training vs. relaxation). Patients with at least one CE-MRI before (v1) or after (v2) the intervention were eligible for this analysis. The prevalence of increased BBBP was visually assessed on T1-weighted MR-images based on extent of contrast-agent enhancement within the ischemic lesion. The intensity of increased BBBP was assessed semi-quantitatively by normalizing the mean voxel intensity within the region of interest (ROI) to the contralateral hemisphere ("normalized CE-ROI"). Selected serum biomarkers (high-sensitive CRP, IL-6, TNF-alpha, MMP-9, and VEGF) at v1 (before intervention) were analyzed as continuous and dichotomized variables defined by laboratory cut-off levels. Functional outcome was assessed at 6 months after stroke using the modified Rankin Scale (mRS). Results: Ninety-three patients with a median baseline NIHSS of 9 [IQR 6-12] were included into the analysis. The median time to v1 MRI was 30 days [IQR 18-37], and the median lesion volume on v1 MRI was 4 ml [IQR 1.2-23.4]. Seventy patients (80%) had increased BBBP visible on v1 MRI. After the trial intervention, increased BBBP was still detectable in 52 patients (74%) on v2 MRI. The median time to v2 MRI was 56 days [IQR 46-67]. The presence of increased BBBP on v1 MRI was associated with larger lesion volumes and more severe strokes. Aerobic fitness training did not influence the increase of BBBP evaluated at v2. In linear mixed models, the time from stroke onset to MRI was inversely associated with normalized CE-ROI (coefficient -0.002, Standard Error 0.007, p < 0.01). Selected serum biomarkers were not associated with the presence or evolution of increased BBBP. Multivariable regression analysis did not identify the occurrence or evolution of increased BBBP as an independent predictor of favorable functional outcome post-stroke. Conclusion: In patients with moderate-to-severe subacute stroke, three out of four patients demonstrated increased BBB permeability, which decreased over time. The presence of increased BBBP was associated with larger lesion volumes and more severe strokes. We could not detect an association between selected serum biomarkers of inflammation and an increased BBBP in this cohort. No clear association with favorable functional outcome was observed

Digitizing a Face-to-Face Group Fatigue Management Program: Exploring the Views of People With Multiple Sclerosis and Health Care Professionals Via Consultation Groups and Interviews.

BACKGROUND: Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS) and is the main reason why people with MS stop working early. The MS Society in the United Kingdom funded a randomized controlled trial of FACETS-a face-to-face group-based fatigue management program for people with multiple sclerosis (pwMS)-developed by members of the research team. Given the favorable trial results and to help with implementation, the MS Society supported the design and printing of the FACETS manual and materials and the national delivery of FACETS training courses (designed by the research team) for health care professionals (HCPs). By 2015 more than 1500 pwMS had received the FACETS program, but it is not available in all areas and a face-to-face format may not be suitable for, or appeal to, everyone. For these reasons, the MS Society funded a consultation to explore an alternative Web-based model of service delivery. OBJECTIVE: The aim of this study was to gather views about a Web-based model of service delivery from HCPs who had delivered FACETS and from pwMS who had attended FACETS. METHODS: Telephone consultations were undertaken with FACETS-trained HCPs who had experience of delivering FACETS (n=8). Three face-to-face consultation groups were held with pwMS who had attended the FACETS program: London (n=4), Liverpool (n=4), and Bristol (n=7). The interviews and consultation groups were digitally recorded and transcribed. A thematic analysis was undertaken to identify key themes. Toward the end of the study, a roundtable meeting was held to discuss outcomes from the consultation with representatives from the MS Society, HCPs, and pwMS. RESULTS: Key challenges and opportunities of designing and delivering an integrated Web-based version of FACETS and maintaining user engagement were identified across 7 themes (delivery, online delivery, design, group, engagement, interactivity, and HCP relationships). Particularly of interest were themes related to replicating the group dynamics and the lack of high-quality solutions that would support the FACETS' weekly homework tasks and symptom monitoring and management. CONCLUSIONS: A minimum viable Web-based version of FACETS was suggested as the best starting point for a phased implementation, enabling a solution that could then be added to over time. It was also proposed that a separate study should look to create a free stand-alone digital toolkit focusing on the homework elements of FACETS. This study has commenced with a first version of the toolkit in development involving pwMS throughout the design and build stages to ensure a user-centered solution

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747

HIV-1 DNA predicts disease progression and post-treatment virological control

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials

Progressive Activation of CD127+132− Recent Thymic Emigrants into Terminally Differentiated CD127−132+ T-Cells in HIV-1 Infection

AIM: HIV infection is associated with distortion of T-cell homeostasis and the IL-7/IL7R axis. Progressive infection results in loss of CD127+132- and gains in CD127-132+ CD4+ and CD8+ T-cells. We investigated the correlates of loss of CD127 from the T-cell surface to understand mechanisms underlying this homeostatic dysregulation. METHODS: Peripheral and cord blood mononuclear cells (PBMCs; CBMC) from healthy volunteers and PBMC from patients with HIV infection were studied. CD127+132-, CD127+132+ and CD127-132+ T-cells were phenotyped by activation, differentiation, proliferation and survival markers. Cellular HIV-DNA content and signal-joint T-cell receptor excision circles (sjTRECs) were measured. RESULTS: CD127+132- T-cells were enriched for naïve cells while CD127-132+ T-cells were enriched for activated/terminally differentiated T-cells in CD4+ and CD8+ subsets in health and HIV infection. HIV was associated with increased proportions of activated/terminally differentiated CD127-132+ T-cells. In contrast to CD127+132- T-cells, CD127-132+ T-cells were Ki-67+Bcl-2(low) and contained increased levels of HIV-DNA. Naïve CD127+132- T-cells contained a higher proportion of sjTRECs. CONCLUSION: The loss of CD127 from the T-cell surface in HIV infection is driven by activation of CD127+132- recent thymic emigrants into CD127-132+ activated/terminally differentiated cells. This process likely results in an irreversible loss of CD127 and permanent distortion of T-cell homeostasis

Measurement of the inclusive isolated-photon cross section in pp collisions at √s = 13 TeV using 36 fb−1 of ATLAS data

The differential cross section for isolated-photon production in pp collisions is measured at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC using an integrated luminosity of 36.1 fb. The differential cross section is presented as a function of the photon transverse energy in different regions of photon pseudorapidity. The differential cross section as a function of the absolute value of the photon pseudorapidity is also presented in different regions of photon transverse energy. Next-to-leading-order QCD calculations from Jetphox and Sherpa as well as next-to-next-to-leading-order QCD calculations from Nnlojet are compared with the measurement, using several parameterisations of the proton parton distribution functions. The predictions provide a good description of the data within the experimental and theoretical uncertainties. [Figure not available: see fulltext.

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe