Search

Background and Purpose: Sphingosine-1-phosphate (S1P) receptor modulator (SRM) drugs suppress immune system function by disrupting lymphocyte trafficking, but SRMs are broadly immunosuppressive with on-target liabilities. Another strategy to modulate the immune system is to block S1P transport. This study tests the hypothesis that blockers of S1P transport (STBs) mediated by Spinster homologue 2 (Spns2) approximate the efficacy of SRMs without their adverse events., Experimental Approach: We have discovered and optimized STBs to enable investigations of S1P biology and to determine whether S1P transport is a valid drug target. The STB SLF80821178 was administered to rodents to assess its efficacy in a multiple sclerosis model and to test for toxicities associated with SRMs or Spns2-deficient mice. Further, potential biomarkers of STBs, absolute lymphocyte counts (ALCs) in blood and S1P concentrations in plasma and lymph, were measured., Key Results: SLF80821178 resembles SRMs in that it is efficacious in a standard multiple sclerosis model but does not evoke bradycardia or lung leakage, common to the SRM drug class. Also, chronic SLF80821178 administration does not affect auditory responses in adult mice despite the neurosensorial hearing defect observed in Spns2-null mice. While both SRM and STB administration decrease ALCs, the maximal effect is less with an STB (45% vs. 90%). STBs have minimal effects on S1P concentration in plasma or thoracic duct lymph., Conclusion and Implications: We found nothing to invalidate Spns2-dependent S1P transport as a drug target. Indeed, STBs could be superior to SRMs as a therapy to modulate immune system function., (© 2025 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: We developed a prototype minimum data set (MDS) for English care homes, assessing feasibility of extracting data directly from digital care records (DCRs) with linkage to health and social care data., Methods: Through stakeholder development workshops, literature reviews, surveys and public consultation, we developed an aspirational MDS. We identified ways to extract this from existing sources, including DCRs and routine health and social care datasets. To address gaps, we added validated measures of delirium, cognitive impairment, functional independence and quality of life to DCR software. Following routine health and social care data linkage to DCRs, we compared variables recorded across multiple data sources, using a hierarchical approach to reduce missingness where appropriate. We reported proportions of missingness, mean and standard deviation (SD) or frequencies (%) for all variables., Results: We recruited 996 residents from 45 care homes in three English Integrated Care Systems. 727 residents had data included in the MDS. Additional data were well completed (<35% missingness at wave 1). Competition for staff time, staff attrition and software-related implementation issues contributed to missing DCR data. Following data linkage and combining variables where appropriate, missingness was reduced (≤4% where applicable)., Discussion: Integration of health and social care is predicated on access to data and interoperability. Despite governance challenges we safely linked care home DCRs to statutory health and social care datasets to create a viable prototype MDS for English care homes. We identified issues around data quality, governance, data plurality and data completion essential to MDS implementation going forward., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Defense and Security Personnel (DSP) often have to operate in the presence of stressful demands. Prior research has identified factors and processes associated with DSP being able to perform resiliently in demanding situations and settings. The aim of the present study was to develop a resilient performance training programme for UK defense and security operators. An intervention mapping (IM) method was used to guide the development of the programme. Typically, IM follows six sequential phases. In the present work, these phases were shaped by insights from prior research (e.g. systematic review and end user interviews), the input of a dedicated working group ( N  = 13) and from practitioner focus groups. During the IM process, the importance of programme flexibility was emphasized by practitioners. As such, the enAbling REsilieNt performAnce (ARENA) training programme was designed to be agile and include both face-to-face training and online learning modules. Theoretical behavior change principles, closely aligned to findings of earlier work on resilient defense and security performance, were used to underpin programme content and delivery. Future research should seek to gather data on the impact of the ARENA programme, in the targeted biological, psychological and social factors that previously been associated with resilient performances.

Background: The BRIGhTMIND study was a double-blind RCT comparing repetitive transcranial magnetic stimulation at a standard simulation site (the "F3" location given by the International 10-20 system, F3-rTMS) versus connectivity-guided intermittent theta burst stimulation (cgiTBS) for treatment-resistant depression. This present study reports the acceptability, safety, and tolerability of F3-rTMS versus cgiTBS., Methods: The present study used quantitative and qualitative methods. Two hundred fifty-four participants were included in the quantitative BRIGhTMIND acceptability and safety analysis (n = 126 F3-rTMS, n = 128 cgiTBS). Qualitative analysis included interviews for 15 participants (n = 7 F3-rTMS, n = 8 cgiTBS) and 582 written comments made by any participant randomised to the BRIGhTMIND trial regarding their experience of TMS and the study. Statistical analyses were used to explore differences between F3-rTMS and cgiTBS, as well as associations between acceptability, impression of change and safety. Qualitative data was analysed using an inductive thematic framework approach., Outcomes: Acceptability, TMS benefits/negative effects and impression of improvement ratings did not differ across the two treatment protocols, with ratings maintained long-term (71.4 % rated TMS acceptable, 48.8 % indicated benefits of TMS outweighed negative effects and 52.2 % feeling somewhat or much better at 26 week follow-up n = 203). Impression of improvement was positively associated with acceptability and TMS benefits. Qualitative themes included participants' TMS experience, TMS response variability, and lay theories of effectiveness. Safety profiles were comparable between F3-rTMS and cgiTBS, with 74.5 % of participants (n = 190/254) experiencing at least one adverse event possibly, probably, or definitely related to TMS. The majority of adverse events were transient and mild, with a sizeable number requiring simple treatments or small adjustments to TMS intensity and coil positioning. The F3-rTMS group had a significantly greater proportion of participants that required small adjustments to TMS to tolerate treatment compared to the cgiTBS group. Serious adverse events were rare, with one serious event in each treatment arm possibly related to TMS (F3-rTMS- psychotic episode, cgiTBS-manic episode)., Conclusion: F3-rTMS and cgiTBS are comparably safe, tolerable and highly acceptable interventions for treatment-resistant depression. BRIGhTMIND systematically collected data from a large sample, providing evidence to meet the information needs of patients, clinicians and policy makers., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: This study aimed to adapt and assess the content validity of the ASCOT Easy Read (ASCOT-ER) for older people accessing social care., Methods: A co-production working group of 8 older social care users and their supporters was established to evaluate the comprehensibility and relevance of the ASCOT-ER images, wording and layout. Changes made by the working group were iteratively tested using cognitive interviewing techniques (think aloud) with 25 older social care users not able to self-complete the original ASCOT., Results: Co-research with people with dementia and their supporters was critical to the development of an effective and accessible tool. Issues identified with comprehension, recall, judgement and response were addressed through iterative adjustments to design, layout and wording. An unexpected finding was that illustrations were disliked or disregarded by the majority of people, and, in particular, those living with dementia. This result contrasts with the typical assumption of easy read approaches, where illustrations are expected to enhance comprehension., Conclusion: The ASCOT-ER measure for older people is suitable for older people using social care services with mild to moderate dementia, mild cognitive impairment and other age-related needs. The revisions applied were designed to improve comprehension, judgement and response for this group and even those who were most cognitively impaired experienced fewer issues by the final round of testing. Nonetheless, some prompting was still required, particularly for those with higher levels of cognitive impairment and it is likely that some respondents will require the questionnaire to be administered in an interview format., Competing Interests: Declarations. Competing interests: The authors have no relevant financial interests to declare. Non-financial interests: AMT, SER and JC are members of the ASCOT advisory team ( www.pssru.ac.uk/ascot ). Ethics approval: Approval was granted by the Coventry and Warwick Research Ethics Committee, The Old Chapel, Royal Standard Place, Nottingham (14th December 2022, Reference 22/WM/0234). Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s).)