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We study a class of variational problems involving both bulk and interface energies. The bulk energy is of Dirichlet type albeit of very general form allowing the dependence from the unknown variable u and the position x . We employ the regularity theory of Λ -minimizers to study the regularity of the free interface. The hallmark of the paper is the mild regularity assumption concerning the dependence of the coefficients with respect to x and u that is of Hölder type.

The performance-based optimum seismic design of steel frames is one of the most complicated and computationally demanding structural optimization problems. Metaheuristic optimization methods have been successfully used for solving engineering design problems over the last three decades. A very recently developed metaheuristic method called school-based optimization (SBO) will be utilized in the performance-based optimum seismic design of steel frames for the first time in this study. The SBO actually is an improved/enhanced version of teaching–learning-based optimization (TLBO), which mimics the teaching and learning process in a class where learners interact with the teacher and between themselves. Ad hoc strategies are adopted in order to minimize the computational cost of SBO results. The objective of the optimization problem is to minimize the weight of steel frames under interstory drift and strength constraints. Three steel frames previously designed by different metaheuristic methods including particle swarm optimization, improved quantum particle swarm optimization, firefly and modified firefly algorithms, teaching–learning-based optimization, and JAYA algorithm are used as benchmark optimization examples to verify the efficiency and robustness of the present SBO algorithm. Optimization results are compared with those of other state-of-the-art metaheuristic algorithms in terms of minimum structural weight, convergence speed, and several statistical parameters. Remarkably, in all test problems, SBO finds lighter designs with less computational effort than the TLBO and other methods available in metaheuristic optimization literature.

Circadian rhythms are endogenous oscillations in nearly all organisms, from prokaryotes to humans, allowing them to adapt to cyclical environments for close to 24 h. Circadian rhythms are regulated by a central clock, based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1ε/δ (CK1ε/δ) phosphorylation. In the nematode Caenorhabditis elegans , period and casein kinase 1ε/δ are conserved as lin-42 and kin-20 , respectively. Here, we studied the involvement of lin-42 and kin-20 in the circadian rhythms of the adult nematode using a bioluminescence-based circadian transcriptional reporter. We show that mutations of lin-42 and kin-20 generate a significantly longer endogenous period, suggesting a role for both genes in the nematode circadian clock, as in other organisms. These phenotypes can be partially rescued by overexpression of either gene under their native promoter. Both proteins are expressed in neurons and epidermal seam cells, as well as in other cells. Depletion of LIN-42 and KIN-20, specifically in neuronal cells after development, was sufficient to lengthen the period of oscillating sur-5 expression. Therefore, we conclude that LIN-42 and KIN-20 are critical regulators of the adult nematode circadian clock through neuronal cells.

Steel porous materials are multifunctional lightweight materials with a great potential in several applications. Their properties are strongly influenced by type, dimension and distribution of pores. Selective laser melting (SLM) is one of the most important additive manufacturing technologies, which allows to properly control the main parameters that affect the behavior of manufactured porous materials. The purpose of this study is to simulate the room temperature compression behavior of steel specimens with large spherical pores built via SLM. Such a construction is a highly innovative manufacturing concept. The numerical simulation covers the whole deformation range undergone by specimens that is up to 80% nominal strain. In this regard, three finite element models of the specimens subjected to uniaxial compression are developed including different levels of detail. The Hollomon model is selected as the constitutive model given in input to the FE simulations. Although experimental tests highlight a highly nonlinear behavior entailing plastic collapse of porous samples, numerical simulations can accurately reproduce experimental results. Modeling issues that may contribute to limit the computational cost of simulations yet preserving good level of accuracy of FE results also are discussed in the article.

Background:Chronic pain is one of the most critical symptoms reported by patients with Rheumatoid Arthritis, and even when joint inflammation improves, disabling residual pain may persist in a significant number of patients. During chronic inflammation, microglial cells, characterized by TMEM119 expression, acquire an activated phenotype characterized by the production of different pro-inflammatory cytokines and pain-related molecules, leading to a neuroinflammation process. Among these mediators, the brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is pivotal in generating abnormal pain perception, leading to nociplastic pain (1). IL-6, a Janus Kinase 1 (JAK1)-dependent pro-inflammatory cytokine, seems critical for the production of BDNF (2). Treatment with Upadacitinib, a JAK1 inhibitor, has been proven effective in improving disease activity and relieving pain quickly (3); nonetheless, the biological mechanisms underlying its efficacy in pain perception still need further investigation.Objectives:This study aims to investigate whether and how Upadacitinib may affect pain-related and neuroinflammation-related molecules expression in monocyte-derived microglia, specifically regarding BDNF.Methods:Microglia were differentiated from monocytes by treatment with NGF, MCP-1, IL-34, GM-CSF, and M-CSF for 14 days and further activated toward a pro-inflammatory phenotype using LPS and IFN-gamma, as summarized in Figure 1A. For all the experiments, microglia were exposed to six conditions in a culture medium for 48 hours: A1 untreated, A2 IL-6, A3 IL-6+Upadacitinib 0.1 uM, B1 IL-6+Upadacitinib 1 uM, B2 Upadacitinib 0.1 uM, and B3 Upadacitinib 1 uM. TMEM119 and BDNF expression in microglia was evaluated by immunofluorescence. Intracellular BDNF levels were analyzed by flow cytometry and Western Blot. In all the culture conditions, microglia underwent RNA-sequencing analysis. RNA from microglia was extracted using all prep DNA/RNA/miRNA universal kits (Qiagen, Germany), and bulk RNA sequencing was carried out using the Illumina system. Heatmaps were generated in RStudio statistical software (R version 3.3.0+; Boston, MA, USA) with the NMF package. All the other statistical analyses have been performed using GraphPad Prism v.10 (Boston, MA, USA).Results:TMEM199, a microglia marker, was expressed at baseline condition (Figure 1B) and BDNF (Figure 1C). Flow cytometry analysis showed that the treatment of Upadacitinib, both at the concentration of 0.1 uM and 1 uM, alone and in combination with IL-6, reduced BDNF levels in microglial cells compared to the untreated (A1) and IL-6 (A2) conditions (Figure 1D, * p<0.05). Western blot analysis confirmed that microglia treated with the combination of IL-6 and Upadacitinib (both 0.1 uM and 1 uM) showed a decreased production of BDNF compared to the microglia treated with IL-6 alone (p<0.0001). Transcriptomic analysis showed that Upadacitinib is able to reduce gene expression of JAK/STAT signaling (Figure 1E). Moreover, the neuroinflammation-related pathways are affected by Upadacitinib treatment toward a less pro-inflammatory phenotype (Figure 1F). Furthermore, Upadacitinib treatment, alone or in combination with IL-6, induces a modulation of acute and chronic pain-related genes.Conclusion:Our results show that Upadacitinib is crucial in modulating gene expression in microglia, characterized by decreased JAK/STAT, neuroinflammatory, acute, and chronic pain-related pathways. Moreover, in this cell type, Upadacitinib reduces the production of BDNF, a molecule involved in pain perception and nociplastic mechanisms.REFERENCES:[1] Atta AA et al, Inflammopharmacology 2023;31:1053-67[2] Schulte-Herbrüggen O et al, J Neuroimmunol 2005;160:204-9[3] Bergman M et al, Arthritis Res Ther 2022;24:155Acknowledgements:NIL.Disclosure of Interests:Luca Navarini Sanofi, GSK, AbbVie, Novartis, AbbVie, MSD, Italfarmaco, UCB, Novartis, Janssen-Cilag, GSK, Eli-Lilly, Sanofi, Marta Vomero: None declared, Erika Corberi: None declared, Onorina Berardicurti: None declared, Giulia Imperatori: None declared, Damiano Currado: None declared, Lyubomyra Kun: None declared, Francesca Trunfio: None declared, Francesca Saracino: None declared, Ludovica Lamberti: None declared, Annalisa Marino: None declared, Livia La Barbera: None declared, Paraskevi Krashia: None declared, Marcello D’Amelio: None declared, Roberto Giacomelli: None declared

Background:In rheumatic diseases, increasing emphasis is put on the role of psychosocial factors in the experience of pain. Among these factors, pain catastrophizing (PC), an inclination to exaggerate in describing pain, to ruminate, or to feel helplessness about it, has emerged. While associated with subjective perception, PC doesn’t align with inflammation biomarkers. The mechanisms underlying these effects remain not fully elucidated, positioning PC as a key variable that might shed light on why certain patients struggle to achieve treatment targets. Many studies demonstrate impact of Rheumatoid Arthritis (RA) on physical, psychological, and social aspects, impairing quality of life. In RA patients, PC is more prevalent than in the general population, impacting drug retention.Objectives:We aimed to evaluate PC and its related domains (Rumination, Magnification, and Helplessness) in RA patients and assess its impact on disease activity in models adjusted for different psychometric domains, such as anxious and depressive symptoms.Methods:We conducted a multi-center, cross-sectional, observational study on consecutive RA patients fulfilling ACR/EULAR criteria. Comorbidities and antibody status were collected at enrolment. Disease activity has been assessed with composite indices, such as Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI). For assessment of physical, psychological, and social status validated questionnaires have been administered: Health Assessment Questionnaire, Hospital Anxiety and Depression Scale, Trait Hope Scale and its domain Agency and Pathway, Acceptance and Action Questionnaire and Compassionate Engagement and Action Scales. Furthermore, PC has been assessed using the Pain Catastrophising Scale (PCS), characterized by 3 domains: rumination, magnification and helplessness. Univariate and multivariable regressions were performed to evaluate possible predictors of disease activity, including PC and its domains. All the statistical analysis has been performed using Stata v. 14 (College Station, Texas, USA)Results:We enrolled 158 RA patients (age 61 (51-69) years, males/females 29.11/70.9%). In this subset, we observed that the median CDAI value was 8.05 (2-14.5) and SDAI 8.14 (2.26-14.7). Concomitant fibromyalgia was present in 17.97% and lung involvement (LI) in 6.8% of participants. The analysis of the PCS showed a median value of 17 (8-26) and its specific domains showed helplessness 6 (2-11), Rumination 7 (3-11), Magnification 2 (1-4). The main demographic, anthropometric, and clinical characteristics of the study population are reported in Table 1. Using the cut-off point marking the difference of clinically significant from non-significant PC (PCS=30), patients with PCS >30 showed a positive association with the values of tender joints (p=0.0007), swollen joints (p=0.0336), VAS pain (p=0.0086), patients’ global assessment (p=0.0002), physician global assessment (p=0.0129), CDAI (p<0.0001), SDAI (p=0.0001) and LI (p=0.013). Univariable and multivariable regression considering SDAI as a dependent variable are summarized in Table 2. In multivariable analysis, PCS is independently associated with SDAI (coeff 0.22467, 95%CI 0.923 to 0.357, p=0.001), whilst anxious and depressive symptoms are not. The same results were reported for the PCS domains helplessness (coeff 0.5947942, 95%CI 0.3032154 to 0.8863731, p<0.0001) and rumination (coeff 0.4921229, 95%CI 0.2190804 to 0.7651653, p=0.001) but not for magnification (p=0.4).Conclusion:In our study, we found that PC, a maladaptive cognitive perception of pain, negatively impacts disease activity, thus limiting the achievement of therapeutic targets. We established a significant association between PCS (total PCS and domains: rumination, magnification, helplessness) and SDAI levels, confirming PC’s interference with achieving low disease activity and remission. Notably, PC is associated with SDAI independently from anxious and depressive symptoms, the latter previously associated with disease activity. Thus, PC might mediate the relationship between depressive symptoms and RA disease activity.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Hope is a goal-orientated cognitive construct comprising two components: pathways (achieving goals strategy) and agency (inspiring thoughts motivating to pursue goals). In rheumatic diseases, Hope is related to compliance and correlates with depression and symptoms worsening. Patients who experience chronic pain often tend to develop anxiety, depression, and a lack of hope regarding the improvement of their clinical condition. All of these can further increase the severity of the disease and resistance to various treatments.Objectives:The present study aims to assess Hope levels in patients with Fibromyalgia (FM) compared to healthy subjects (HS) and investigate whether a Mindfulness-based stress reduction (MBSR) intervention could increase Hope levels in FM patients and improve their physical and psychological status.Methods:64 FM female patients were consecutively enrolled in Campus Bio-Medico of Rome outpatient clinics and randomly assigned to either an MBSR intervention (n=31, consisting of 6 online sessions once a week) or not (n = 32). Moreover, 47 age- and sex-matched HS were recruited. All the groups completed the Adult Hope Scale (AHS) questionnaire at baseline. Only FM patients completed psychometric questionnaires at baseline and after three months: AHS, HADS to detect anxiety and depression symptoms, VAS-pain to assess pain, SCS to assess self-compassion, RS-14 to assess resilience, PCS to assess pain catastrophizing, SF-36 to assess health-related quality of life, PSS to assess stress, TAS-20 to assess alexithymia. FM disease severity has been evaluated by WPI, SSS, FSS, and FIQ-R. Continuous variables have been analyzed using the Mann-Whitney test for independent observations and the Wilcoxon test for paired data, while contingency tables have been analyzed using the Chi2 test. The statistical analysis has been performed using Stata v.14.Results:Comparative analysis at baseline showed that patients with FM have lower levels of hope as compared with HS [AHS 26 (24-27) and 22 (19-24), respectively, p<0.0001]. Both AHS Agency [13 (12-14) in FM group and 10 (9-12) in HS, p<0.0001] and AHS Pathways [13 (12-14) in FM group and 12 (10-13) in HS, p <0.0001] are reduced in FM patients compared to HS (Table 1). FM patients assigned to the MBSR group showed a significant improvement comparing baseline and after MBSR in WPI (p= 0.0300), SSS (p= 0.0141), FSS (p= 0.0104), FIQ-R (p <0.0001), HADS (p= 0.0005), PCS (p=0.0004), VAS-pain (p=0.0006) and PSS (p=0.0431). However, comparing baseline and after MBSR FM patients did not show improvement in SCS (p= 0.0888) [although statistically significant results were achieved in the SCS self-judgement (p= 0.0345) and SCS Isolation (p= 0.0078) subdomains], TAS-20 (p= 0.4535), RS-14 (p=0.0885) and SF-36 (p= 0.0545) [although significant variations were observed in the SF-36 Physical Functioning (p=0.0493), SF-36 Role-physical (p= 0.0028), SF-36 Social Functioning (p= 0.0003), and SF-36 Bodily Pain (p= 0.0001)] (Table 2). FM patients not undergoing MBSR intervention did not improve comparing baseline and after MBSR in any questionnaire.Conclusion:Hope levels in FM patients are significantly reduced compared to the healthy population. In FM, MBSR intervention induces improvement in the levels of Hope and, more specifically, its Agency component. This increase is associated with simultaneous improvement in physical function and various psychometric variables. Indeed, there is a reduction in anxiety, depression, perceived stress, and VAS-pain, as well as an improvement in FIQ-R and FSS, scores commonly used in clinical practice to assess the severity and impact of the disease on daily life. Therefore, MBSR is a promising treatment method for Fibromyalgia Syndrome. This chronic and debilitating condition still requires studies to investigate various aspects of the disease, including the identification of specific and effective therapies to improve patients’ quality of life.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Psoriatic Arthritis (PSA) is one of the most common inflammatory arthritis. PSA induces joint pain and inflammation, as well as a reduction in quality of life and workability. According to EULAR recommendations, regular physical activity is strongly recommended in patients with inflammatory arthritis, to maintain adequate joint movement and reduce cardiovascular risk, which is increased in PsA. However, the presence of pain and joint deformities could limit the ability of PsA patients to exercise. Furthermore, psychosocial factors are important determinants of pain experience in patients with inflammatory arthritis. The Fear Avoidance Model is used widely to explain how psychological factors affect the experience of pain and the development of chronic pain and disability, suggesting that patients with fear avoidance beliefs are less likely to confront pain-related problems and are less active in the coping process.Many questionnaires have been developed to identify fear avoidance beliefs. Among them, the Fear-Avoidance Beliefs Questionnaire (FABQ) is a 16-item questionnaire that assesses a person’s fear-avoidance beliefs about physical activity and work.Objectives:Our study aimed to evaluate the prevalence of physical activity avoidance in patients with PsA. Moreover, we assessed the demographic, PsA-related, and psychometric variables independently associated with physical activity avoidance.Methods:A single-center, cross-sectional, observational study has been carried out on consecutive PsA patients, fulfilling CASPAR criteria. Physical activity avoidance and associated potential psychological domains have been assessed with validated questionnaires. In particular, FABQ (Fear Avoidance Beliefs Questionnaire) has been used to assess how a patient’s fear of pain may contribute to avoiding physical activity. Additionally, uni- and multivariate linear regressions have been performed to evaluate demographic, pathology-related, or psychometric factors potentially related to physical activity avoidance. All the statistical analysis has been performed using Stata v.14 (College Station, Texas, USA).Results:The main demographic, anthropometric, and clinical characteristics of the study population are reported in Table 1. Particularly, patients showed age 56 (33-74) years, males/females ratio 30.8%/69.2%, Disease Activity in PsA (DAPSA) 14.3 (1.5-29.7), BASDAI 5.45 (1.1-8.72). PsA patients with FABQ PA≥ 15 (cut-off point marking high levels of fear-avoidance beliefs related to physical activity) represent 27.69 % of the population. Concomitant fibromyalgia was present in 37.1% of the participants. We observed that the proportion of patients with fibromyalgia among those with FABQ PA≥ 15 was 52.9 %.PCS (Pain Catastrophising Scale) median value was 20.97 (1-40), SF36 PCS (Physical Component Score) median value was 35.3 (21.5-56.6) and FABQ PA median value was 11.4 (1-23).Moreover, patients with FABQ ≥15 showed a higher BASDAI, PCS, and SF36 PCS than patients with FABQ PA <15 (p-values 0.0002, 0.030, and 0.002, respectively).As reported in Table 2, in multivariable linear regression, independent predictors of physical activity avoidance were the SF36-PCS and anxiety symptoms assessed by HADS. No disease activity index was independently associated with FABQ.Conclusion:This study suggests that avoiding physical activity in PsA patients may depend on physical functioning and anxiety symptoms rather than disease activity.TJ: Tender Joints; SJ: Swollen Joints; PP: Patient Pain, PtGA: Patient Global Assessment; CRP: c-reactive protein; PASI: Psoriasis Area Severity Index; DAPSA: Disease Activity in PSoriatic Arthritis; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; mFABQ: modified Fear-Avoidance Belief Questionnaire; FABQ PA: FABQ Physical Activity; HAQ: Health Assessment Questionnaire; HADS: Hospital Anxiety and Depression Scale; PCS: Pain Catastrophising Scale; IPAQ: International Physical Activity Questionnaire; SF36 PCS: Short Form Health Survey 36, Physical Component Summary; SF36 MCS: SF36, Mental Component SummaryREFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.

This paper investigated the mechanical behavior of a new customized post system built up with a composite framework presently utilized for crowns, bridges, veneers and inlay/onlay dental restorations. The material has been shaped so to follow perfectly the profile of the root canal in order to take advantage of the better mechanical properties of composites with respect to metallic alloys commonly used for cast posts. The analysis has been carried out with 3D finite element models previously validated on the basis of experimental work. The new post system has been compared to a variety of restorations using either prefabricated or cast posts. The structural efficiency of the new restoration has been evaluated for an upper incisor under different loading conditions (mastication, bruxism, impact). Results prove that maximum stress values in restored teeth are rather insensitive to post types and materials. However, the new customized composite restoration allows to reduce significantly the stresses inside the dentinal regions where conservative clinical interventions are not possible.