True infliximab resistance in rheumatoid arthritis: a role for lymphotoxin α?

Background: The combination of methotrexate and the anti-tumour necrosis factor (TNF) antibody infliximab is a very effective treatment for rheumatoid arthritis (RA). However, a proportion of patients are not responsive to this treatment. Inefficacy may represent a TNF independent disease or insufficient drug at the site of action. Case report: A patient with RA resistant to repeated high dose infliximab infusions and intra-articular infliximab into an inflamed knee is described. No beneficial clinical effect was observed. Pre-injection arthroscopic biopsy of the study knee demonstrated TNF staining but also confirmed the presence of lymphotoxin (LT or TNFß) on immunohistochemistry. Subsequent treatment with etanercept (which blocks LT as well as TNF) resulted in clinical remission of disease. Conclusion: This case suggests that resistance to TNF blockade may occur when TNF is not the dominant inflammatory cytokine and suggests that LT may have a pathogenic role in RA

Development of the PsAQoL: a quality of life instrument specific to psoriatic arthritis

Background: Patient reported outcome measures used in studies of psoriatic arthritis (PsA) have been found to be inadequate for determining the impact of the disease from the patient’s perspective. Objective: To produce the PsAQoL, a PsA-specific quality of life (QoL) instrument, employing the needs based model of QoL that would be relevant and acceptable to respondents, valid, and reliable. Methods: Content was derived from qualitative interviews conducted with patients with PsA. Face and content validity were assessed by field test interviews with a new sample of patients with PsA. A postal survey was conducted to improve the scaling properties of the new measure. Finally, a test-retest postal survey was used to identify the final measure and to test its scaling properties, reliability, internal consistency, and validity. Results: Analysis of the qualitative interview transcripts identified a 51 item questionnaire. Field test interviews confirmed the acceptability and relevance of the measure. Analysis of data from the first postal survey (n = 94) reduced the questionnaire to 35 items. Rasch analysis of data from the test-retest survey (n = 286) identified a 20 item version of the PsAQoL with good item fit. This version had excellent internal consistency (a = 0.91), test-retest reliability (0.89), and validity. Conclusions: The PsAQoL is a valuable tool for assessing the impact of interventions for PsA in clinical studies and trials. It is well accepted by patients, taking about three minutes to complete, is easy to administer, and has excellent scaling and psychometric properties

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

Aims The mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and selective inhibitor of TASK-1 and TASK-1/TASK-3 heterodimer channels, than TASK-3. Here we investigate the direct effect of doxapram and chirally separated, individual positive and negative enantiomers of the compound, on both human and mouse, homodimeric and heterodimeric variants of TASK-1 and TASK-3. Methods Whole-cell patch clamp electrophysiology on tsA201 cells was used to assess the potency of doxapram on cloned human or mouse TASK-1, TASK-3 and TASK-2 channels. Mutations of amino acids in the pore-lining region of TASK-3 channels were introduced using site-directed mutagenesis. Results Doxapram was an equipotent inhibitor of human TASK-1 and TASK-3 channels, compared with mouse channel variants, where it was more selective for TASK-1 and heterodimers of TASK-1 and TASK-3. The effect of doxapram could be attenuated by either the removal of the C-terminus of human TASK-3 channels or mutations of particular hydrophobic residues in the pore-lining region. These mutations, however, did not alter the effect of a known extracellular inhibitor of TASK-3, zinc. The positive enantiomer of doxapram, GAL-054, was a more potent antagonist of TASK channels, than doxapram, whereas the negative enantiomer, GAL-053, had little inhibitory effect. Conclusion These data show that in contrast to rodent channels, doxapram is a potent inhibitor of both TASK-1 and TASK-3 human channels, providing further understanding of the pharmacological profile of doxapram in humans and informing the development of new therapeutic agents

No safety without emotional safety

This Personal View highlights how emotional safety is required for a person to keep themselves physically safe. We explain how trying to control behaviour to increase physical safety in the short term can carry the unintended consequence of reducing emotional safety, which might in turn result in higher levels of stress and hopelessness. We use examples from institutions with psychiatric inpatients to describe these processes. We argue that emotional and physical safety cannot be separated, and therefore that the absence of emotional safety compromises basic care either in an acute crisis or in the long term. Staff who fear being criticised, and so feel driven to take autonomy and responsibility away from patients, unwittingly undermine patients' experience of being empathically understood and supported, adding to patients' sense of emotional turmoil and lack of safety. We suggest that a change in culture and regulatory reform is required to bring psychiatric care more in line with the psychological needs of patients to achieve both physical and emotional safety

Efficacy of cognitive behaviour therapy versus anxiety management for body dysmorphic disorder: a randomised controlled trial

Background: The evidence base for the effectiveness of cognitive behaviour therapy (CBT) for treating Body Dysmorphic Disorder (BDD) is weak. Aims: To determine if CBT is more effective than anxiety management (AM) in an out-patient setting. Method: A single blind, stratified parallel-group randomized controlled trial. The primary endpoint was at 12 weeks, and the Yale Brown Obsessive Compulsive Scale for BDD (BDD-YBOCS) was the primary outcome measure. Secondary measures for BDD included the Brown Assessment of Beliefs (BABS), the Appearance Anxiety Inventory (AAI) and the Body Image Quality of Life Inventory (BIQLI). The outcome measures were collected at baseline and week 12. The CBT group, unlike the AM group, had 4 further weekly sessions that were analysed for their added value. Both groups then completed measures at their 1-month follow-up. Forty-six participants, with DSM-IV diagnosis of BDD including those with a delusional BDD were randomly allocated to either CBT or AM. Results: At 12 weeks, CBT was found to be significantly superior to AM on the BDD-YBOCS ( = -7.19, S.E. () = 2.61, p < .01, C.I. = -12.31, -2.07, d 0.99) as well as the secondary outcome measures of the BABS, AAI and BIQL. Further benefits occurred by Week 16 within the CBT group. There were no differences in outcome for those with delusional BDD or depression. Conclusions: CBT is an effective intervention for people with BDD even with delusional beliefs or depression and is more effective than anxiety management over 12 weeks

Detecting Sarcasm in Multimodal Social Platforms

Sarcasm is a peculiar form of sentiment expression, where the surface sentiment differs from the implied sentiment. The detection of sarcasm in social media platforms has been applied in the past mainly to textual utterances where lexical indicators (such as interjections and intensifiers), linguistic markers, and contextual information (such as user profiles, or past conversations) were used to detect the sarcastic tone. However, modern social media platforms allow to create multimodal messages where audiovisual content is integrated with the text, making the analysis of a mode in isolation partial. In our work, we first study the relationship between the textual and visual aspects in multimodal posts from three major social media platforms, i.e., Instagram, Tumblr and Twitter, and we run a crowdsourcing task to quantify the extent to which images are perceived as necessary by human annotators. Moreover, we propose two different computational frameworks to detect sarcasm that integrate the textual and visual modalities. The first approach exploits visual semantics trained on an external dataset, and concatenates the semantics features with state-of-the-art textual features. The second method adapts a visual neural network initialized with parameters trained on ImageNet to multimodal sarcastic posts. Results show the positive effect of combining modalities for the detection of sarcasm across platforms and methods.Comment: 10 pages, 3 figures, final version published in the Proceedings of ACM Multimedia 201

The MASSIVE Survey - X. Misalignment between Kinematic and Photometric Axes and Intrinsic Shapes of Massive Early-Type Galaxies

We use spatially resolved two-dimensional stellar velocity maps over a $107"\times 107"$ field of view to investigate the kinematic features of 90 early-type galaxies above stellar mass $10^{11.5}M_\odot$ in the MASSIVE survey. We measure the misalignment angle $\Psi$ between the kinematic and photometric axes and identify local features such as velocity twists and kinematically distinct components. We find 46% of the sample to be well aligned ($\Psi < 15^{\circ}$), 33% misaligned, and 21% without detectable rotation (non-rotators). Only 24% of the sample are fast rotators, the majority of which (91%) are aligned, whereas 57% of the slow rotators are misaligned with a nearly flat distribution of $\Psi$ from $15^{\circ}$ to $90^{\circ}$. 11 galaxies have $\Psi \gtrsim 60^{\circ}$ and thus exhibit minor-axis ("prolate") rotation in which the rotation is preferentially around the photometric major axis. Kinematic misalignments occur more frequently for lower galaxy spin or denser galaxy environments. Using the observed misalignment and ellipticity distributions, we infer the intrinsic shape distribution of our sample and find that MASSIVE slow rotators are consistent with being mildly triaxial, with mean axis ratios of $b/a=0.88$ and $c/a=0.65$. In terms of local kinematic features, 51% of the sample exhibit kinematic twists of larger than $20^{\circ}$, and 2 galaxies have kinematically distinct components. The frequency of misalignment and the broad distribution of $\Psi$ reported here suggest that the most massive early-type galaxies are mildly triaxial, and that formation processes resulting in kinematically misaligned slow rotators such as gas-poor mergers occur frequently in this mass range.Comment: Accepted to MNRA

The application of mHealth to mental health: opportunities and challenges

Recent advances in smartphones and wearable biosensors enable the gathering of ‘real-time’ psychological, behavioural and physiological data, in increasingly precise and unobtrusive ways. It is therefore now possible to collect moment-to-moment information about an individuals’ moods, cognitions and activities, as well as automated data about their whereabouts, behaviour and physiological states. In this paper, we discuss the potential of these new mobile digital technologies for transforming mental health research and clinical practice. By drawing on a recent research project, we illustrate how traditional boundaries between research and clinical practice are becoming increasingly blurred and how in turn, this is leading to exciting new developments in the assessment and management of common mental disorders. The potential risks and key challenges associated with applying mobile technology to mental health are also discussed

Phenotypically determined resistance of Neisseria gonorrhoeae to normal human serum: environmental factors in subcutaneous chambers in guinea pigs

Some gonococci obtained from human urethral exudate or from subcutaneously implanted chambers in guinea pigs show a resistance to killing by human serum which is lost on subculture in vitro after a few generations. The environmental factors which may influence the phenotypic expression of resistance to serum killing were investigated in guinea pig chambers and in chamber fluid in vitro. The redox potential in chambers before and after infection was lower than that of heart blood but conditions were not anaerobic; H2O2 increased the redox potential but did not decrease gonococcal serum resistance. The chambers were slightly alkaline before and after infection. When the concentration of glucose (depleted in infected chambers by the abundant polymorphonuclear cells) was restored to excess, the serum resistance of the gonococci was unaffected. Concentrations of free amino acids in chambers changed little during infection. Gonococci adapted to growth in chambers and subsequently rendered serum-sensitive by growing once on agar reverted to serum-resistance after 0.5 to 1 h incubation in chamber fluid in vitro at 37°C but not at 25°C or 4°C. After 16 to 24 h growth at 37°C, resistance was again lost. The reversion to serum resistance did not occur in a complex laboratory medium. Examination of the chamber fluid after growth of gonococci in vitro showed depletion of lactate, glutamine and proline