Co-occurrence of a novel PDGFRB variant and likely pathogenic variant in CASR in an individual with extensive intracranial calcifications and hypocalcaemia

No abstract available

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU

Trust Perceptions of Online Travel Information by Different Content Creators: Some Social and Legal Implications

Consumers are increasingly turning to the online environment to provide information to assist them in making purchase decisions related to travel products. They often rely on travel recommendations from different sources, such as sellers, independent experts and, increasingly, other consumers. A new type of online content, usergenerated content (UGC), provides a number of legal and social challenges to providers and users of that content, especially in relation to areas such as defamation, misrepresentation and social embarrassment. This paper reports research that examined the level of trustworthiness of online travel information from these different sources. The study used a survey of Australian travel consumers (n= 12,000) and results support the notion that there are differences in the level of trust for online travel information from different sources. Respondents ‘tended to agree’ that they trusted information provided by travel agents, information from commercial operators and comments made by travellers on third party websites. However, the highest level of trust was afforded to information provided on State government tourism websites. These results suggest that greater trust is placed in online travel comments when they are on a specific travel website than when they are on a more generic social networking website. However, respondents were ‘not sure’ that they trusted comments made by travellers on weblogs and on social networking sites. Some 88% of respondents that had not visited UGC websites (or were unsure if they had) indicated that they thought that UGC would be useful in the future – suggesting that they feel that any concerns they may have in relation to legal and social problems resulting from its use will be resolved

Systems Biology Approach to Late-Onset Alzheimer\u27s Disease Genome-Wide Association Study Identifies Novel Candidate Genes Validated Using Brain Expression Data and \u3cem\u3eCaenorhabditis elegans\u3c/em\u3e Experiments

Introduction—We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer\u27s disease (LOAD) loci. Methods—We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. Results—We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex. Discussion—Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex

Studying interactions among anthropogenic stressors in freshwater ecosystems: A systematic review of 2396 multiple‐stressor experiments

Understanding the interactions among anthropogenic stressors is critical for effective conservation and management of ecosystems. Freshwater scientists have invested considerable resources in conducting factorial experiments to disentangle stressor interactions by testing their individual and combined effects. However, the diversity of stressors and systems studied has hindered previous syntheses of this body of research. To overcome this challenge, we used a novel machine learning framework to identify relevant studies from over 235,000 publications. Our synthesis resulted in a new dataset of 2396 multiple‐stressor experiments in freshwater systems. By summarizing the methods used in these studies, quantifying trends in the popularity of the investigated stressors, and performing co‐occurrence analysis, we produce the most comprehensive overview of this diverse field of research to date. We provide both a taxonomy grouping the 909 investigated stressors into 31 classes and an open‐source and interactive version of the dataset (https://jamesaorr.shinyapps.io/freshwater‐multiple‐stressors/). Inspired by our results, we provide a framework to help clarify whether statistical interactions detected by factorial experiments align with stressor interactions of interest, and we outline general guidelines for the design of multiple‐stressor experiments relevant to any system. We conclude by highlighting the research directions required to better understand freshwater ecosystems facing multiple stressors

Grassroots Agency: Participation and Conflict in Buenos Aires Shantytowns seen through the Pilot Plan for Villa 7 (1971–1975)

open access articleIn 1971, after more than a decade of national and municipal policies aimed at the top-down removal of shantytowns, the Buenos Aires City Council approved the Plan Piloto para la Relocalización de Villa 7 (Pilot Plan for the Relocation of Shantytown 7; 1971–1975, referred to as the Pilot Plan hereinafter). This particular plan, which resulted in the construction of the housing complex, Barrio Justo Suárez, endures in the collective memory of Argentines as a landmark project regarding grassroots participation in state housing initiatives addressed at shantytowns. Emerging from a context of a housing shortage for the growing urban poor and intense popular mobilizations during the transition to democracy, the authors of the Pilot Plan sought to empower shantytown residents in novel ways by: 1) maintaining the shantytown’s location as opposed to eradication schemes that relocated the residents elsewhere, 2) formally employing some of the residents for the stage of construction, as opposed to “self-help” housing projects in which the residents contributed with unpaid labor, and 3) including them in the urban and architectural design of the of the new housing. This paper will examine the context in which the Pilot Plan was conceived of as a way of re-assessing the roles of the state, the user, and housing-related professionals, often seen as antagonistic. The paper argues that residents’ fair participation and state intervention in housing schemes are not necessarily incompatible, and can function in specific social and political contexts through multiactor proposals backed by a political will that prioritizes grassroots agency

A RCT of a Transdiagnostic Internet-Delivered Treatment for Three Anxiety Disorders: Examination of Support Roles and Disorder-Specific Outcomes

BACKGROUND: Anxiety disorders share common vulnerabilities and symptoms. Disorder-specific treatment is efficacious, but few access evidence-based care. Administering transdiagnostic cognitive-behavioral therapy via the internet (iCBT) may increase access to evidence-based treatment, with a recent randomized controlled trial (RCT) providing preliminary support for this approach. This study extends those findings and aims to answer three questions: Is a transdiagnostic iCBT program for anxiety disorders efficacious and acceptable? Does it result in change for specific disorders? Can good clinical outcomes be obtained when guidance is provided via a Coach rather than a Clinician? METHOD: RCT (N = 131) comparing three groups: Clinician-supported (CL) vs. Coach-supported (CO) vs. waitlist control (Control). Individuals met DSM-IV criteria for a principal diagnosis of generalized anxiety disorder (GAD), social phobia (SP) or panic disorder with or without agoraphobia (Pan/Ag). Treatment consisted of an 8-lesson/10 week iCBT program with weekly contact from a Clinician or Coach, and follow-up at 3-months post-treatment. RESULTS: Outcomes for the pooled treatment groups (CL+CO) were superior to the Control group on measures of anxiety, depression and disability, were associated with medium to large effect sizes (Cohen's d = .76-1.44) (response rate = 89-100%), and were maintained at follow-up. Significant reductions were found on disorder-specific outcomes for each of the target diagnoses, and were associated with large effect sizes. CO participants achieved similar outcomes to CL participants at post-treatment, yet had significantly lower symptom severity scores on general anxiety, panic-disorder, depression and disability at follow-up (d = .45-.46). Seventy-four percent of CO and 76% of CL participants completed the program. Less than 70 minutes of Clinician or Coach time was required per participant during the program. DISCUSSION: This transdiagnostic iCBT course for anxiety appears to be efficacious, associated with significant change for three target disorders, and is efficacious when guided by either a Clinician or Coach. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000242022

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

The Function and Organization of Lateral Prefrontal Cortex: A Test of Competing Hypotheses

The present experiment tested three hypotheses regarding the function and organization of lateral prefrontal cortex (PFC). The first account (the information cascade hypothesis) suggests that the anterior-posterior organization of lateral PFC is based on the timing with which cue stimuli reduce uncertainty in the action selection process. The second account (the levels-of-abstraction hypothesis) suggests that the anterior-posterior organization of lateral PFC is based on the degree of abstraction of the task goals. The current study began by investigating these two hypotheses, and identified several areas of lateral PFC that were predicted to be active by both the information cascade and levels-of-abstraction accounts. However, the pattern of activation across experimental conditions was inconsistent with both theoretical accounts. Specifically, an anterior area of mid-dorsolateral PFC exhibited sensitivity to experimental conditions that, according to both accounts, should have selectively engaged only posterior areas of PFC. We therefore investigated a third possible account (the adaptive context maintenance hypothesis) that postulates that both posterior and anterior regions of PFC are reliably engaged in task conditions requiring active maintenance of contextual information, with the temporal dynamics of activity in these regions flexibly tracking the duration of maintenance demands. Activity patterns in lateral PFC were consistent with this third hypothesis: regions across lateral PFC exhibited transient activation when contextual information had to be updated and maintained in a trial-by-trial manner, but sustained activation when contextual information had to be maintained over a series of trials. These findings prompt a reconceptualization of current views regarding the anterior-posterior organization of lateral PFC, but do support other findings regarding the active maintenance role of lateral PFC in sequential working memory paradigms