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Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.

BackgroundWomen with SLE have an elevated risk of cardiovascular disease. Many women with SLE frequently report chest pain in the absence of obstructive coronary artery disease (CAD) due to coronary microvascular dysfunction (CMD), a form of ischemia with no obstructive CAD (Manchanda et al, 2022). Echocardiographic studies have shown that SLE patients have reduced left ventricular (LV) function, which may also correlate with higher SLE disease activity scores (Gegenava et al, 2020). As such, we used cardiac magnetic resonance imaging (cMRI) to investigate the relationship between SLE, related inflammatory biomarkers, and cardiac function in female SLE patients.MethodsWe performed stress cMRI in women with SLE and chest pain with no obstructive CAD (n=13, all met ACR 1997 criteria, table 1) and reference controls (n=22) using our published protocol (Aldiwani et al, 2022). We evaluated LV function, tissue characterization (T1 mapping, ECV), and delayed enhancement, using CV142 software (Circle Cardiovascular Imaging Inc, Calgary, AB, Canada). Myocardial perfusion reserve index (MPRI) was calculated using our published protocol (Thomson et al, 2015). SLEDAI and SLICC Damage Index (DI) were calculated per validated criteria (Bombardier et al, 1992, Gladman et al, 1997). Serum samples were analyzed for inflammatory markers and autoantibodies (table 1). Independent two-tailed t test was performed on clinical values with CMD and no CMD SLE subjects, and on cMRI values with all SLE subjects and controls. Correlation analysis was done on clinical values, and cMRI values on all SLE subjects.ResultsOverall, 40% of SLE subjects had MPRI values < 1.84, consistent with CMD. Compared to controls, SLE subjects had significantly lower LVEF, and higher LVESVi and LVMi (table 2). Corresponding to this, radial, longitudinal, and circumferential strain were significantly lower in the SLE subjects. In correlation analysis of serum inflammatory biomarkers to cMRI values in the SLE subjects, SLICC DI was related to worse cardiac function (lower radial, circumferential and longitudinal strain) and higher T1 time (table 3).Additionally, fasting insulin and ESR were negatively correlated with LVMi. Fasting insulin also negatively correlated with ECV. CRP had a positive association with LVESV index and CI and a negative association with longitudinal strain.ConclusionsAmong women with SLE with chest pain and no obstructive CAD, 40% have CMD. While evaluations of known inflammatory markers (such as CRP and ESR) predictably correlated with decreased cardiac function (Jha et al, 2022), our study found that decreased fasting insulin levels as a novel marker of diminished LV function. In addition, although studies have used SLEDAI as a marker of disease activity in cardiac dysfunction, we are the first to demonstrate that SLICC DI, an assessment of SLE damage, is also correlated with cardiac dysfunction in SLE. This indicates that SLE patients with higher SLICC DI and increased SLE-related damage could potentially have silent involvement in their cardiac tissue, and as such using SLICC DI is another tool that should be used to evaluate the association between SLE and LV dysfunction. [694]Abstract 904 Table 1Baseline characteristics of female SLE participants. There were no group difference in clinical and laboratory values in the SLE participants with and without CMD. Complement 3 (C3); Complement 4 (C4); Erythrocyte Sedimentation Rate (ESR); C-Reactive Protein (CRP); Antinuclear antibody (ANA); Ribonucleoprotein (RNP); Smith (Sm); Anti- topoisomerase I antibody (Scl-70). Mean ±SD [ range ] SLE patients (n=13) CMD (n=5) No CMD (n=8) P values Age 46 ± 6 years 43 [37–51] years 48 [43–57] years NS SLICC 1.9 ± 2.5 2.8 ± 3 [0–6] 1.4 ± 2 [0–6] NS SLEDAI 0.5 ± 1 0.8 ± 0.8 [0–2] 0.4 ± 1 [0–3] NS Clinical Labs Fasting Blood Sugar(mg/dl) 77.6 ± 8.6 80.2 ± 6.5 [72–90] 75.5 ± 10.1 [65–91] NS Fasting Insulin (mIU/ml) 9.2 ± 11.3 14.8 ± 15.4 [2–42] 4.5 ± 2.5 [1.4–7.6] NS Serum Creatinine (mg/dL) 0.70 ± 0.08 0.67 ± 0.12 [0.55–0.84] 0.72 ± 0.03 [0.66–0.76] NS Serum Protein (g/dL) 7.29 ± 0.96 7.58 ± 1.47 [6.4–10.1] 7.09 ± 0.40 [6.8–7.9] NS C3 (mg/dL) 114 ± 30 124 ± 34 [81–153] 108 ± 26 [77–156] NS C4 (mg/dL) 26 ± 12 20 ± 11 [10–32] 29 ± 12 [22–51] NS ESR (mm/hr) 20.5 ± 20.5 32 ± 24 [16–73] 14 ± 16 [1–47] NS CRP (mg/dL) 3.2 ± 4.8 2.6 ± 2.2 [0.4–5.4] 3.6 ± 6.0 [0.2–17.9] NS Anti-ANA 434 ± 273 424 ± 299 [50–640] 440 ± 277 [80–640] NS Anti-DNA <10 <10 <10 — RNP Antibody 42.3 ± 58 68 ± 70.4 [2–156] 26.3 ± 46.8 [2–133] NS Anti-Sm 13.9 ± 18.7 17.2 ± 20.6 [2–52] 11.9 ± 18.6 [1–51] NS SSA (Ro) 22.8 ± 38.6 42.8 ± 55 [2–104] 10.4 ± 19.2 [1–56] NS SSB (La) 12.2 ± 28.4 22.8 ± 45.5 [2–104] 5.5 ± 8.3 [1–25] NS Anti-Scl 6 ± 7 4.2 ± 3.3 [2–10] 1 ± 25 [1–25] NS Abstract 904 Table 2Comparison of cardiac MRI analysis between SLE participants and reference controls (RC). Left Ventricular (LV) End Diastolic Volume (LVEDV); LV End Systolic Volume (LVESV); LV Systolic Volume (LVSV); Ejection Fraction (EF); LV Mass (LVM); LV End Systolic Diameter (LVESD); Body Surface Area (BSA); LVEDV/BSA (LVEDV index); LVESV/BSA (LVESV index); LVSV/BSA (LVSV index); LVM/BSA (LVM index); CO/BSA (cardiac index), Extracellular Volume Fraction (ECV). Variable SLE (n=13) RC (n=22) p-value LVEDV (ml) 127 ± 34 114 ± 18 NS LVESV (ml) 53 ± 20 42 ± 10 0.0339 LVSV (ml) 75 ± 18 73 ± 10 NS EF (%) 59 ± 7 64 ± 5 0.0242 LVM/LVESD (g/dL) 0.66 ± 0.08 0.62 ± 0.07 NS LVEDV/BSA (LVEDVi, mL/m2) 72.02 ± 15.4 67.40 ± 9.3 NS LVESV/BSA (LVESVi, mL/m2) 29.9 ± 10.2 24.5 ± 5.6 0.0481 LVSV/BSA (LVSVi, mL/m2) 42.56 ± 8.2 42.92 ± 5.4 NS LVM/BSA (LVMi, g/m2) 47.31 ± 9.3 41.34 ± 4.3 0.0141 CO/BSA (CI, L/min/m2) 3 ± 1 2.6 ± 0.3 NS LVM (g) 83 ± 20 70 ± 9 0.0119 Radial Strain 29.70 ± 6.2 34.37 ± 5.8 0.0306 Circumferential Strain -17.94 ± 2.5 -19.73 ± 2 0.0251 Longitudinal Strain -18.40 ± 2.2 -20.10 ± 1.9 0.0202 T1 1263 ± 35 1259 ± 56 (n=11) NS ECV 29 ± 3 29.3 ± 2.3 (n=11) NS Abstract 904 Table 3Correlation analysis of cardiac function versus clinical values from SLE participants in the study. The Spearman r coefficient and p value (p) is shown. LVESV: left ventricular end-systolic volume; LVEDV: left ventricular end-diastolic volume; LVSV: left ventricular systolic volume; EF: ejection fraction; LVM: left ventricular mass; BSA: body surface area; ECV: extracellular volume.

Around 13% of fossil fuels globally are used for non-combustion purposes. Fossil fuel processing plants, such as petroleum refineries, exhibit interdependent material and energy system dynamics, making the transition away from fossil fuels in energy systems more challenging without addressing the non-energy outputs. This study explores the future role of fossil fuels for non-energy purposes in climate-stringent scenarios with restrictions on alternative feedstock availability, focusing on the primary chemicals sector. Using a global integrated assessment model with detailed refining and primary chemicals sectors, findings across various scenarios reveal that up to 62% of total feedstock use in the chemical sector could be provided by alternative sources by 2050. This would require significant scale-up in biomass utilisation and carbon capture technologies. Annual CO 2 emissions from the chemical sector could be reduced to as low as −1Gt CO 2 by the same year if carbon storage in non-recycled and non-incinerated bioplastics is accounted for. The chemical sector is both hard-to-abate and hard-to-defossilize. This study shows how limiting the availability of alternative carbon feedstocks impacts climate goals and efforts to phase out fossil fuels.

Interleukin-15 (IL-15) is an immunomodulatory cytokine that affects body mass regulation independent of lymphocytes; however, the underlying mechanism(s) involved remains unknown. In an effort to investigate these mechanisms, we performed metabolic cage studies, assessed intestinal bacterial diversity and macronutrient absorption, and examined adipose mitochondrial activity in cultured adipocytes and in lean IL-15 transgenic (IL-15tg), overweight IL-15 deficient (IL-15-/-), and control C57Bl/6 (B6) mice. Here we show that differences in body weight are not the result of differential activity level, food intake, or respiratory exchange ratio. Although intestinal microbiota differences between obese and lean individuals are known to impact macronutrient absorption, differing gut bacteria profiles in these murine strains does not translate to differences in body weight in colonized germ free animals and macronutrient absorption. Due to its contribution to body weight variation, we examined mitochondrial factors and found that IL-15 treatment in cultured adipocytes resulted in increased mitochondrial membrane potential and decreased lipid deposition. Lastly, IL-15tg mice have significantly elevated mitochondrial activity and mass in adipose tissue compared to B6 and IL-15-/- mice. Altogether, these results suggest that IL-15 is involved in adipose tissue regulation and linked to altered mitochondrial function.

Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI > 25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1 , HBA2 , MT-RNR1 , MT-RNR2 , EGFL6 and FDCSP expression to be differentially expressed in breast tissues from metformin-treated postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that postmenopausal breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors. Trial registration : MetBreCs trial is registered at European Union Clinical Trials Register (EudraCT Protocol # 2015-001001-14) on 07/10/2015.

Abstract EP2.2, e-Poster Terminal 2, September 3, 2025, 13:05 - 14:00 Aim The Swiss Health Network for Equity (SH4E) emerged from the European “Migrant Friendly Hospital” project initiated in 2005. In 2010, Switzerland replicated this initiative to address health equity issues for migrant populations. The Swiss Federal Office of Public Health (FOPH) supported selected hospitals in developing competence centers for migrants as part of the national “Migration and Health” program. Today, forced migrants in Switzerland represent 132’699 people including Ukrainian people. Methods Initially, the FOPH mandated healthcare institutions to develop and address equity aspects of care for migrant populations. This led to the establishment of a national network, which evolved into the formal creation of the SH4E association in 2023. The network transitioned from initial federal funding and coordination to a progressive autonomization process. SH4E now operates through member contributions and federal office subsidies. Results Currently, 20 institutions representing Switzerland’s three linguistic regions are members of SH4E, including hospitals and ambulatory care centers. The network’s legal structure and autonomy allow for greater freedom in advocacy and policy engagement. Activities include regional and national training sessions, an annual national forum, and regional events on migration health topics. SH4E facilitates the sharing of best practices among members, strengthens access to community interpreting services including signing, and actively participates in research projects. The network plays a crucial role in intersectional situations where forced migration adds an LGBTIQ+ appurtenance or disabilities. Conclusion SH4E serves as an example of an independent nationwide network of health institutions. It functions as a migrant health observatory and a promotor of health equity. In a global context of rising far-right sentiments and anti-migrant discourse, such a network is indispensable for defending the fundamental rights of migrant populations to equitable access to healthcare.

Background Febrile neutropenia (FN) is a common occurrence during chemotherapy. Granulocyte colony-stimulating factors (G-CSFs) can significantly reduce the risk of FN. International guidelines recommend G-CSF for patients receiving chemotherapy with FN risk of ≥20% or 10% to 20% with defined risk factors. Prophylaxis is not typically recommended for FN risk of < 10%; however, few studies have investigated FN incidence in lower-risk patients in real-world settings and tried to identify higher-risk subgroups. Methods This real-world prospective, observational, multinational study aims to estimate the rate of development of FN with a chemotherapy line expected to be associated with a 10% to 20% risk of FN. Eligible patients (> 18 years of age) will have a solid tumour or Hodgkin/non-Hodgkin lymphoma and a planned chemotherapy regimen with expected risk of FN of 10% to 20% (according to published guidelines). Patients will be observed for the duration of the chemotherapy line (first cycle administered without FN prophylaxis). Primary endpoint is incidence of FN after the first chemotherapy cycle. Secondary outcomes include: FN-associated morbidity and mortality; time to first FN occurrence; other FN risk factors and impact of FN on quality of life. A risk model using occurrence of FN as a binary outcome will be developed. Data will be stratified by age, comorbidities and other risk factors. Discussion This study will provide insight into the real FN risk for common chemotherapy regimens and predictive factors for FN, including patients generally excluded from randomised clinical trials, from which reported FN rates have been variable. This study builds on knowledge of predictive factors from other research and will provide information on patients with 10% to 20% FN risk.

Ocean warming is increasing the frequency, extent, and severity of tropical-coral bleaching and mortality. During 2014–2017, marine heatwaves caused the Third Global Coral Bleaching Event. We analyze data from 15,066 reef surveys globally during 2014–2017. Across all surveyed reefs, 80% and 35% experienced moderate or greater (affecting >10% of corals) bleaching and mortality, respectively. We assess the global extent of coral bleaching and mortality by applying bleaching response curves calibrated from surveyed reefs to predict bleaching globally, based on comprehensive remote-sensing of heat stress. These models predict that 51% and 15% of the world’s coral reefs suffered moderate or greater bleaching and mortality, respectively, during one or multiple years, surpassing damage from any prior global coral bleaching event. Our findings demonstrate that the impacts of ocean warming on coral reefs are accelerating, with the near certainty that ongoing warming will cause large-scale, possibly irreversible, degradation of these essential ecosystems. With heat stress levels during this event surpassing those observed previously, the National Oceanic and Atmospheric Administration developed more extreme Bleaching Alert levels that are now being used during the ongoing Fourth Global Coral Bleaching Event. From 2014–2017, marine heatwaves caused global mass coral bleaching, where the corals lose their symbiotic algae. The authors find, this event exceeded the severity of all prior global bleaching events in recorded history, with approximately half the world’s reefs bleaching and 15% experiencing substantial mortality.

Stress-induced mitophagy, a tightly regulated process that targets dysfunctional mitochondria for autophagy-dependent degradation, mainly relies on two proteins, PINK1 and Parkin, which genes are mutated in some forms of familiar Parkinson’s Disease (PD). Upon mitochondrial damage, the protein kinase PINK1 accumulates on the organelle surface where it controls the recruitment of the E3-ubiquitin ligase Parkin. On mitochondria, Parkin ubiquitinates a subset of mitochondrial-resident proteins located on the outer mitochondrial membrane, leading to the recruitment of downstream cytosolic autophagic adaptors and subsequent autophagosome formation. Importantly, PINK1/Parkin-independent mitophagy pathways also exist that can be counteracted by specific deubiquitinating enzymes (DUBs). Down-regulation of these specific DUBs can presumably enhance basal mitophagy and be beneficial in models in which the accumulation of defective mitochondria is implicated. Among these DUBs, USP8 is an interesting target because of its role in the endosomal pathway and autophagy and its beneficial effects, when inhibited, in models of neurodegeneration. Based on this, we evaluated autophagy and mitophagy levels when USP8 activity is altered. We used genetic approaches in D. melanogaster to measure autophagy and mitophagy in vivo and complementary in vitro approaches to investigate the molecular pathway that regulates mitophagy via USP8. We found an inverse correlation between basal mitophagy and USP8 levels, in that down-regulation of USP8 correlates with increased Parkin-independent mitophagy. These results suggest the existence of a yet uncharacterized mitophagic pathway that is inhibited by USP8.

Objective: Gather and describe general characteristics of different protocols of risk stratification for cardiac patients undergoing exercise. Methods: We conducted searches in LILACS, IBECS, MEDLINE, Cochrane Library, and SciELO electronic databases, using the following