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Abstract Background Atopic dermatitis (AD) significantly impacts health‐related quality of life (HRQoL) in children and their caregiver(s)/family. Measures to assess HRQoL include the Children's Dermatology Life Quality Index (CDLQI), Infants' Dermatitis Quality of Life Index (IDQoL) and Dermatitis Family Impact (DFI) questionnaire. Currently, there are no established clinically meaningful within‐person change thresholds for these measures in young children (6 months to 5 years) and their caregiver(s)/family. Objectives To determine the clinically meaningful within‐person change thresholds for CDLQI (4–5 years), IDQoL (

With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR

IntroductionStress and trauma are significant risk factors for many neuropsychiatric disorders and diseases, including anxiety disorders. Stress-induced anxiety symptoms have been attributed to enhanced excitability in circuits controlling fear, anxiety, and aversion. A growing body of evidence has implicated GABAergic neurons of the ventral tegmental area (VTA) in aversion processing and affective behavior.MethodsWe used an unpredictable footshock (uFS) model, together with electrophysiological and behavioral approaches, to investigate the role of VTA GABA neurons in anxiety-related behavior in mice.ResultsOne day after a single uFS session, C57BL/6J mice exhibited elevated anxiety-related behavior and VTA GABA neuron excitability. The enhanced excitability of VTA GABA neurons was correlated with increased glutamatergic input and a reduction in postsynaptic signaling mediated via GABAA and GABAB receptors. Chemogenetic activation of VTA GABA neurons was sufficient to increase anxiety-related behavior in stress-naïve mice. In addition, chemogenetic inhibition of VTA GABA neurons suppressed anxiety-related behavior in mice exposed to uFS.DiscussionThese data show that VTA GABA neurons are an early substrate for stress-induced anxiety-related behavior in mice and suggest that approaches mitigating enhanced excitability of VTA GABA neurons may hold promise for the treatment of anxiety provoked by stress and trauma.

Aims Patients with severe mental illness are at a significantly higher risk of poor physical health outcomes than the general population and die on average 15–20 years earlier. The Royal College of Psychiatrists has published extensively on how to improve routine physical health monitoring in this cohort. Despite this, there is little data or guidance on improving emergency medical care for this cohort. We aimed to analyse and optimise the process of patients being sent to general hospital on an emergency basis. Methods A review was undertaken of the clinical notes for medical emergencies over a 12 month period by two core psychiatry trainees. Site visits and interviews with local A&E department clinicians, the covering General Practitioner and pharmacy were completed. A questionnaire was distributed to all nursing staff to gather their perspective on the considerations for emergency medical transfers out of The State Hospital. Results On review of the case notes, 44/44 emergency outings were deemed to be clinically necessary for investigations/interventions that would not have been possible on-site. Qualitative methodology highlighted a disconnect amongst staff groups and stake holders regarding thresholds for transfers relating to medical emergencies leading to a high level of staff dissatisfaction. Conclusion The interface between psychiatric and medical services is an area of risk to patients. Levels of staff confidence, knowledge and available resources all contribute to the risk of transfer. Further work is required to explore other aspects of patient care and treatment which can be impacted as a consequence of emergency transfers.

Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its sensitivity to the strength of depolarization remains unknown. Also unknown is whether activity history of graded potential changes influence future neuronal activity. In this work with dissociated rat cortical neurons, we found that mild depolarization-mediated by elevated extracellular potassium (K+)-induces a wide array of rapid IEGs and transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, and signaling via calcineurin or mitogen-activated protein kinase. Furthermore, as measured by multiple electrode arrays and calcium imaging, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity via calcium- and N-methyl-d-aspartate receptor-dependent mechanisms. Collectively, this work suggests that a recent history of graded potential changes acutely depress neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during synaptic plasticity processes.

Objectives: The aim of this research was to acquire knowledge about the female dental workforce, identifying factors to pursue specialty training and career choices and working in dental institutions/associations. Methods: An original online questionnaire was developed, validated (n = 22), and sent to 189 member associations in 133 countries of the Women Dentists Worldwide section of the FDI World Dental Federation. Results: In all, 3232 female dentists from 81 countries participated. Results were divided into 5 geographic areas by continent. Difference in proportion amongst questionnaire items was evaluated with χ2 test or Fisher exact test. Ordinal multinomial linear regression analysis was performed to evaluate the association of questionnaire items with total work experience in dentistry (in years), motivation to study dentistry, type of specialisation, working hours per week, perception of female dentists about working hours, sex-based inequalities, job security after maternity leaves, as well as involvement in political organisations within their country of residence and their role in dental associations. A majority of participating female dentists are self-employed (57.7%), and 60.0% have 10 to 30 years of experience. The most popular form of practice is the single private practice (29.7%), followed by the group private practice (28.8%). Further, 44.8% work 31 to 40 h/wk, 29.1% part-time up to 30 h/wk, and 26.0% more than 40 h/wk. Conclusions: Women are still poorly represented in professional organisations, and few are officers in representative assemblies, members of the board, or president. Family life with children influences perceptions and has an impact on professional life, especially in academia and political/professional associations, so that taking on leadership positions poses additional challenges.

Heat sinks are a fundamental component of power electronics converters, so it is important to have a reliable method to study and optimize their size. Thermal analysis of heat sinks can be a complex problem as it involves different heat transfer mechanisms, and it is often necessary to use finite element simulations to obtain accurate results. However, these simulations, being very slow, are relegated to the validation process. This paper proposes a thermal model of heat sinks based on artificial neural networks. The model, unlike previous state-of-the-art models that only obtain the average temperature of the heat sink, is able to obtain a thermal map of the heat sink surface, as if it were an image, by using convolutional layers. The main advantage of this approach is that using these convolutional layers, the model is able to efficiently process how the elements are distributed on the heat sink. This model, valid for heat sinks of very different sizes in both laminar and turbulent flow, has an error of less than 1.5% and is 1500 times faster than finite element simulations, so it can be easily used in brute-force optimization processes, where many different designs need to be analyzed.

Abstract Background The current standard of care in the neoadjuvant setting for high-risk HER2-positive (HER2 +) breast cancer is to combine systemic chemotherapy with dual HER2 blockade, trastuzumab and pertuzumab. Targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer. To improve treatment-associated toxicity, chemotherapy-sparing approaches are currently being investigated. Trastuzumab deruxtecan (T-DXd) is an HER2-directed antibody–drug-conjugate (ADC) with promising results in the metastatic setting for HER2-positive breast cancer. The SHAMROCK study investigates neoadjuvant T-DXd in early stage HER2-positive breast cancer, using pathological complete response (pCR) rate as the primary endpoint. Methods This is a phase II open-label, single arm, adaptive multi-centre trial of T-DXd in the neoadjuvant setting in stage 2–3 HER2-positive breast cancer. Eligible patients will receive 5.4 mg/kg of T-DXd intravenously every 3 weeks for up to 6 cycles. A repeat biopsy will performed after 2 cycles for the RNA disruption index (RDI) score assessment. According to their likelihood of pCR, as determined by the RDI score, patients will either undergo 4 or 6 cycles of T-DXd prior to imaging. Patients with imaging complete response (iCR) after either 4 or 6 cycles will proceed to surgery. Patients who do not achieve iCR will either undergo further systemic therapy or proceed to surgery. Discussion The SHAMROCK study is a chemotherapy-sparing approach to curative intent treatment, investigating neoadjuvant T-DXd. We hypothesise that neoadjuvant T-DXd will have a high pCR rate and be associated low toxicity in early stage HER2-positive breast cancer. Trial registration EudraCT Number: 2022–002485-32; ClinicalTrials.gov identifier: NCT05710666; Cancer Trials Ireland study number: CTRIAL-IE 22–01.

Using data from the Disentangling Inclusion in Primary Physical Education (DIPPE) Erasmus+ project, this study aimed at investigating teachers' practices related to inclusion of children with additional needs (AN) in primary physical education (PE) and identifying supports that could enhance these practices. Responses from 1170 primary teachers across nine European countries to an online questionnaire were analysed. Although inclusion was regarded as important, only 30% of children with AN were reported as being always included and engaged in PE. Teachers considered guidance on children's motor needs and video-based resources particularly useful in promoting inclusion. Implications of the findings within the DIPPE project and more broadly are discussed.

Introduction There has been a 1000% increase in referrals for assessment of adult ADHD within Scotland over the past three years (The Scottish Government. 2023. NAIT adult Neurodevelopmental Pathways Report). These referrals are sent by general practitioners to the local community mental health team. The most junior clinicians (doctors who are pre-membership with the Royal College of Psychiatrists) in the team are often responsible for undertaking the initial assessment of these patients. Patients have on average waited almost a year to be seen and expectations are high. Objectives The diagnosis of ADHD can be challenging, and adult ADHD is still a relatively new and evolving diagnostic entity. We set out to explore how junior clinicians were coping with this in their daily practice. Methods We developed a questionnaire that was sent to all junior clinicians working within Argyll & Bute (n=8) via an anonymised email link. The link was open for 1 week and then results were analysed. Results The response rate to our survey was 87.5%. Prior to starting their current roles none of the respondents had ever undertaken an ADHD assessment before. All respondents answered “No” when asked if they felt they had adequate knowledge on ADHD in order to perform assessments. Only 14% (n=1) felt they had access to adequate resources about how to make an ADHD diagnosis. Participants were asked on a scale of 1-10 (1= not at all,10= very) to rate their confidence in conducting ADHD assessments. The average confidence score was 2.43. There was a space for free text feedback in which participants reported the following: “felt thoroughly out my depth”, “I felt chucked in the deep end”, “I felt very under qualified” Image: Conclusions Our results showed that junior clinicians did not feel confident or knowledgeable about undertaking adult ADHD assessments. In response to this we have now produced, in association with the consultant psychiatrists within our health board, an informative and engaging quick reference poster which explains how to undertake an ADHD assessment (see QR code attached as Image 1). It contains useful pointers about diagnosis, and more importantly guidance on language/phrases to use when explaining to patients whether or not you feel a diagnosis of ADHD is appropriate. It then also explains next steps that can be offered i.e. psychological support/medication options and how to prescribe these. We plan to send out a repeat questionnaire to the next cohort of junior clinicians to assess if they have improved confidence in managing and diagnosing ADHD following this intervention. Disclosure of Interest None Declared

Background Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.Methods In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).Results Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58–74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7–3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4–3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.Conclusions Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.