The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

Interleukin-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumour microenvironment of cancer patients, where concentrations correlate with the grade of malignancy. In prostate cancer, interleukin-4 has been associated with activation of the androgen receptor, increased proliferation and activation of survival pathways such as Akt and NF-κB. However, its role in therapy resistance has not yet been determined. Here we investigate the influence of interleukin-4 on primary epithelial cells from prostate cancer patients. Our data demonstrate an increase in the clonogenic potential of these cells when cultured in the presence of interleukin-4. In addition, a Phospho-Kinase Array revealed that in contrast to previously published work, signal transducer and activator of transcription6 (STAT6) is the only signalling molecule activated after interleukin-4 treatment. Using the STAT6-specific inhibitor AS1517499 we could confirm the role of STAT6 in increasing colony-forming frequency. However, clonogenic recovery assays revealed that interleukin-4 does not rescue the effects of either irradiation or docetaxel treatment. We therefore propose that although the interleukin-4/STAT6 axis does not appear to be involved in therapy resistance, it does play a crucial role in the colony-forming abilities of the basal cell population in prostate cancer. IL-4 may therefore contribute to disease relapse by providing a niche that is favourable for the clonogenic growth of prostate cancer stem cells

Using the theoretical domains framework to investigate clinicians’ behavioural determinants of antimicrobial prescribing in Qatar.

Introduction: A recent systematic review by Talkhan et al demonstrated the need for theoretically based behaviour change interventions in this area. [1] For development of such complex interventions, emphasis should be placed on using theory to systematically identify behavioural determinants of antimicrobial prescribing. Aim: To identify and quantify clinicians’ behavioural determinants of antimicrobial prescribing in Qatar. Methods: This cross-sectional survey is part of a multi-phase explanatory, sequential mixed methods PhD project in Qatar. Questionnaires were distributed (online and paper based) to all doctors (~4,000) and pharmacists (~400) within Hamad Medical Corporation (HMC, the main healthcare provider). The questionnaire was developed with reference to the Determinants of Implementation Behaviour Questionnaire (a generic questionnaire derived from the 14 theoretical domains of the Theoretical Domains Framework, TDF). [2] Each item was presented as a 5-point Likert scale (scored 5=Strongly agree to 1=Strongly disagree). Personal and practice demographics were also collected for data contextualisation. The draft questionnaire was reviewed for face/content validity by an expert panel of six researchers in Qatar and the UK with experience in the use of the TDF, followed by ‘Think aloud’ testing and piloting. Analysis investigated the behavioural determinants and influential factors through descriptive, principal component analysis (PCA) and inferential analysis. Ethics approval was granted from a UK university and HMC. Results: In total, 535 responses were received, 339 (63.4%) from doctors and 196 (36.6%) from pharmacists. Respondents were predominantly male, 346 (64.7%). Just over half (n=285, 53.3%) had ≤ 5 years’ experience as health professionals. PCA showed a three component (C) solution with components incorporating a number of questionnaire items labelled: ‘Guidelines compliance’ (C1 with 8 items), ‘Influences on prescribing’ (C2 with 7 items) and ‘Self-efficacy’ (C3 with 5 items) in prescribing/recommendation activity. A scale score for each respondent was calculated through summation of Likert scores for the relevant questionnaire items within each component. These scales had high internal reliability (Cronbach’s alpha all >0.7) showing consistency in response between component items indicating statistical appropriateness for developing scales. The median score (possible scale range, midpoint) for each scale was C1, 32 (8 to 40, 24), C2, 26 (7 to 35, 21) and C3, 20, (5 to 25, 15). By way of example Table 1 shows levels of agreement for items in C2. This shows lower levels of agreement than C1 scale with the median scale score (26) closer to the midpoint (21) indicating that respondents had less positive views. Inferential analysis using these scale scores and free text analysis is in progress. Conclusion: A theoretical basis was used throughout providing insights to behavioural determinants for the development of a theory-based behaviour change intervention. Preliminary results suggest that social influences, staff development and quality monitoring may be useful targets for behaviour change interventions to improve antimicrobial prescribing practice. Limitations include potential social desirability bias and focus on one healthcare organisation/country in the Middle East which may limit generalisability of findings. More in-depth exploration is required to select and test appropriate linked theory-based behaviour change techniques

Direct Radiation Pressure Measurements for Lightsail Membranes

Ultrathin lightsails propelled by laser radiation pressure to relativistic speeds are currently the most promising route for flyby-based exoplanet exploration. However, there has been a notable lack of experimental characterization of key parameters essential for lightsail propulsion. Therefore, a model platform for optomechanical characterization of lightsail prototypes made from realistic materials is needed. We propose an approach for simultaneous measurement of optical forces and driving powers, which capitalizes on the multiphysics dynamics induced by the driving laser beam. By modelling the lightsail with a 50-nm thick silicon nitride membrane suspended by compliant micromechanical springs, we quantify force from off-resonantly driven displacement and power from heating-induced mechanical mode softening. This approach allows us to calibrate the measured forces to the driving powers by operating the device as a mechanical bolometer. We report radiation pressure forces of 80 fN using a collimated pump beam of 100 W/cm2 and noise-robust common-path interferometry. As lightsails will inevitably experience non-normal forces, we quantify the effects of incidence angle and spot size on the optical force and explain the nonintuitive trend by edge scattering. Our results provide a framework for comprehensive lightsail characterization and laboratory optomechanical manipulation of macroscopic objects by radiation pressure forces

Central nervous system demyelination associated with etanercept in a 51 years old woman

There are few case reports documenting a new onset of demyelinating processes in patients receiving anti-tumour necrosis factor alpha therapy (anti-TNF alpha) for chronic inflammatory arthropathies. Whether anti-TNF alpha therapy induces new onset demyelination or just exacerbates pre-existing latent multiple sclerosis is not fully understood. We are reporting a 51-year-old woman without a prior history of multiple sclerosis, who developed demyelinating brain lesions three months after starting Etanercept. Her symptoms partially resolved on cessation of the drug. Our case was unusual compared to some previous case reports, as the patient's age at presentation was beyond that for idiopathic multiple sclerosis. This may strengthen the hypothesis of a causal relationship between new onset demyelination and Etanercept; however, exacerbation of pre-existing demyelinating process by Etanercept in this patient still cannot be totally excluded. We recommend doing magnetic resonance imaging (MRI) of the brain before starting patients on anti-TNF alpha therapy to exclude latent demyelination. In addition, new onset demyelination following anti-TNF alpha therapy should be reported and studied thoroughly as this may yield a significant advancement in our understanding of the pathogenesis of multiple sclerosis. Long-term follow-up of these cases is also important to determine the long-term prognosis and the rate of relapse of demyelinating process in this group of patients

Dramatic outcomes in epilepsy: depression, suicide, injuries, and mortality

In this narrative review, we will discuss some of the significant risks and dramatic consequences that are associated with epilepsy: depression, suicide, seizure-related injuries, and mortality, both in adults and in children. Considering the high prevalence of depression among people with epilepsy (PWE), routine and periodic screening of all PWE for early detection and appropriate management of depression is recommended. PWE should be screened for suicidal ideation regularly and when needed, patients should be referred for a psychiatric evaluation and treatment. When starting an antiepileptic drug (AED) or switching from one to another AED, patients should be advised to report to their treating physician any change in their mood and existence of suicidal ideation. The risk of injuries for the general epilepsy population is increased only moderately. The risk is higher in selected populations attending epilepsy clinics and referral centers. This being said, there are PWE that may suffer frequent, severe, and sometimes even life-threatening seizure-related injuries. The most obvious way to reduce risk is to strive for improved seizure control. Finally, PWE have a 2–3 times higher mortality rate than the general population. Deaths in PWE may relate to the underlying cause of epilepsy, to seizures (including sudden unexpected death in epilepsy [SUDEP] and seizure related injuries) and to status epilepticus, as well as to other conditions that do not appear directly related to epilepsy. Improving seizure control and patient education may be the most important measures to reduce epilepsy related mortality in general and SUDEP in particular

Reducing broad-spectrum antibiotic use in intensive care unit between first and second waves of COVID-19 did not adversely affect mortality

Background: The COVID-19 pandemic increased the use of broad-spectrum antibiotics due to diagnostic uncertainty, particularly in critical care. Multi-professional communication became more difficult, weakening stewardship activities. Aim: To determine changes in bacterial co-/secondary infections and antibiotics used in COVID-19 patients in critical care, and mortality rates, between the first and second waves. Methods: Prospective audit comparing bacterial co-/secondary infections and their treatment during the first two waves of the pandemic in a single-centre teaching hospital intensive care unit. Data on demographics, daily antibiotic use, clinical outcomes, and culture results in patients diagnosed with COVID-19 infection were collected over 11 months. Findings: From March 9th, 2020 to September 2nd, 2020 (Wave 1), there were 156 patients and between September 3rd, 2020 and February 1st, 2021 (Wave 2) there were 235 patients with COVID-19 infection admitted to intensive care. No significant difference was seen in mortality or positive blood culture rates between the two waves. The proportion of patients receiving antimicrobial therapy (93.0% vs 81.7%; P < 0.01) and the duration of meropenem use (median (interquartile range): 5 (2–7) vs 3 (2–5) days; P = 0.01) was lower in Wave 2. However, the number of patients with respiratory isolates of Pseudomonas aeruginosa (4/156 vs 21/235; P < 0.01) and bacteraemia from a respiratory source (3/156 vs 20/235; P < 0.01) increased in Wave 2, associated with an outbreak of infection. There was no significant difference between waves with respect to isolation of other pathogens. Conclusion: Reduced broad-spectrum antimicrobial use in the second wave of COVID-19 compared with the first wave was not associated with significant change in mortality

Theoretical approaches in the development and evaluation of behaviour change interversions that improve clinicians' antimicrobial prescribing: a systematic review.

Antimicrobial resistance (AMR) and its threats have long been recognised. Many countries have developed antimicrobial stewardship programmes with strategies to optimise antimicrobial prescribing, minimise AMR and improve outcomes. There remains a need for behaviour change interventions at clinician level to promote appropriate prescribing. Theories should be used for developing and evaluating interventions to change human behaviour. Aim/Objectives: The aim of this review was to critically appraise, synthesise and present the available evidence for theoretical approaches in the development and evaluation of behaviour change interventions designed to improve clinicians' antimicrobial prescribing. Research Design and Methodology: The systematic review protocol was developed and registered with the International Prospective Register of Systematic Reviews (CRD42018098586). MEDLINE, PubMed, Cumulative Index of Nursing and Allied Health Literature, International Pharmaceutical Abstracts, PsycINFO, ScienceDirect, The Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination, Database of Abstracts of Reviews of Effectiveness, Joanna Briggs Institute Library and Google Scholar were searched for peer-reviewed, English-language studies investigating theoretically based behaviour change interventions designed to improve clinicians’ antimicrobial prescribing in any healthcare setting. Additional studies were obtained from the bibliographies of retrieved papers. Two review authors independently extracted data and assessed study quality. Clinical and methodological heterogeneity limited data synthesis. Results: The searches resulted in 4227 potentially relevant papers after duplicates removal. Screening of titles/abstracts led to retrieval and dual assessment of 38 full-text papers. Of those, a total of 14 studies (4 qualitative, 5 quantitative and 5 mixed-methods) met the inclusion criteria and were included in the systematic review. Most of studies included were from the UK (n = 8) and most were published in 2008 and in 2017 (n = 6); none was published before 2008. The majority of studies were carried out in primary care settings (n = 10) targeting upper respiratory tract infections (n = 7). Theoretical approaches used to inform the design and choice of intervention varied across included studies. The most common included: Theory of Planned Behaviour, Social Cognitive Theory and Operant Learning Theory. Conclusion/Discussion: This systematic review is the first to investigate theoretically based behaviour change interventions for antimicrobial prescribing. Only a small number of primary research studies involving theory in intervention development and evaluation were identified. There is a need for further research in this area. Restricting the review to papers published in English may have been a limitation

An exploration of the association between premorbid weight status on patient and caregiver factors at pre and post-treatment among youth with anorexia nervosa/atypical anorexia nervosa

Patients with atypical anorexia nervosa (AAN) or anorexia nervosa (AN) with premorbid history of higher weight (PHW; median BMI&nbsp;≥&nbsp;85th %ile) may report greater eating disorder (ED) pathology, anxiety, and depression, than patients with premorbid history of lower weight (PLW; mBMI &lt;85th %ile). Less is known about caregiver attitudes or treatment outcome related to premorbid weight history. The current study examined associations between premorbid weight history and patient/caregiver factors at presentation, during treatment, and end of treatment among adolescents (N&nbsp;=&nbsp;138) diagnosed with AN/AAN and their caregivers who received interdisciplinary ED treatment. The sample comprised adolescents with PHW (n&nbsp;=&nbsp;58, 40.6&nbsp;%) or PLW (n&nbsp;=&nbsp;82, 59.4&nbsp;%). Adolescents with PHW did not differ with regard to patient- or caregiver-reported ED symptoms, comorbid psychopathology, rates of treatment completion, and attainment of estimated body weight compared to PLW (ps&nbsp;&gt;&nbsp;.05). Adolescents with PHW (vs. PLW) were more likely to be diagnosed with AAN (67.9&nbsp;%, p&nbsp;&lt;&nbsp;.001), identify as cisgender male (p&nbsp;&lt;&nbsp;.001) and to have lost more weight prior to presentation (p&nbsp;&lt;&nbsp;.001). Perceived caregiver burden was lower among adolescents with PHW vs. PLW (p&nbsp;&lt;&nbsp;.001). Further research should expand on this preliminary study exploring associations between premorbid weight history on patient and caregiver factors at treatment presentation and conclusion to enhance the efficacy of evidence-based treatment across the weight-spectrum