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Background: The endometriosis painful symptoms-4 dimensions ENDOPAIN-4D is a multidimensional questionnaire designed to assess endometriosis-related pain. This study aimed to translate, culturally adapt, and validate ENDOPAIN-4D for European Portuguese.

Methodology: Translation and content validity assessment were assessed in 32 women with endometriosis. For psychometric validation, 386 patients completed an online sociodemographic and clinical questionnaire, the Portuguese ENDOPAIN-4D, and the Endometriosis Health Profile Questionnaire-30 (EHP-30). Statistical analyses included descriptive statistics, exploratory factor analysis, internal consistency, item-total correlation, and concurrent validity.

Results: Factor analysis of the "usual pain" dimension supported the original four-factor structure, accounting for 63.7% of variance (Cronbach's α = 0.91). A novel three-factor structure was identified for the "worst pain" dimension, previously psychometrically untested, with good internal consistency (Cronbach's α = 0.83) and acceptable item-total correlations. Concurrent validity with the EHP-30 ranged from weak to strong across domains.

Conclusions: The Portuguese ENDOPAIN-4D is a culturally adapted and validated instrument for multidimensional pain assessment in European Portuguese women with endometriosis, with validity likely limited for other Portuguese-speaking communities. The newly identified three-factor structure for worst pain may aid individualized pain management and follow-up in clinical and psychosomatic care. Further studies should evaluate concurrent validity and the stability and responsiveness of the new algorithms.

Estimates of the added benefit from COVID-19 vaccine booster doses can inform seasonal vaccine recommendations. We set out to estimate COVID-19 vaccine effectiveness (VE), avoiding common sources of bias. We chose a modified screening method, using only vaccinated cases of symptomatic COVID-19 recorded in the mandatory infectious disease reporting system, with data from a vaccination registry. Effect estimates were obtained by Bayesian logistic regression, comparing outcomes within dose strata between immunized (15-21d after vaccination) and not yet immunized (up to 7d). VE estimates were calculated recursively and relative VE estimates were obtained to quantify the added benefit of booster doses. We found VE for clinical illness to be around 90% during the predominance of the SARS-CoV-2 Alpha variant. During the Delta period, VE was distinctly lower, but did not decrease much further. The first booster dose added substantial protection during the Delta period, but that benefit became marginal during the Omicron period in the 18+. The effect of second booster doses, which became widespread only during the Omicron period, was modest. Using a novel, vaccinated-only study design we found that two doses of a COVID-19 vaccine offered substantial protection from symptomatic COVID-19, even during the Omicron period. One booster dose was highly effective during the Delta period, but the effect became modest during the Omicron period, when second booster doses offered, but a marginal benefit.

Cisplatin-based concurrent chemoradiation (CRT) remains the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), yet recurrence rates remain high. Attempts to combine immune checkpoint inhibitors with CRT have not improved outcomes, underscoring the need to better understand CRT-driven immunologic dynamics. Here, we performed longitudinal, multidimensional profiling of peripheral immunity in patients with LA-HNSCC at baseline (BSL), one month (CRT-1M), and three months (CRT-3M) after platinum-based CRT. CRT induced a transient reduction in tumor-reactive Th1 responses at CRT-1M, followed by marked expansion by CRT-3M. Consistently, genes involved in T-cell activation, polarization, and exhaustion exhibited a biphasic pattern with delayed upregulation at CRT-3M. Transcriptomic analyses of blood lymphocytes revealed an early shift from B-cell- to T-cell-mediated pathways over time during CRT. Integrated analyses including immunosuppressive cells and soluble mediators showed that the early decline in tumor-reactive T cells coincided with increased immunosuppressive cells, T-cell exhaustion, and elevated protumoral cytokines such as IL-8, IL-1β, and IL-10. In contrast, robust expansion of tumor-reactive T cells dominated the peripheral immune landscape at CRT-3M. Together, these data reveal the dynamic remodeling of peripheral immunity following platinum-based CRT and identify a delayed peripheral immune activation phase that may represent an optimal window for combining CRT with immune checkpoint blockade.

Aluminum (Al³⁺) toxicity is a major limitation to plant productivity in acidic soils, disrupting cellular homeostasis, redox balance, and nutrient uptake. Brassinosteroids are key regulators of plant stress signaling, yet their role in Al³⁺ tolerance remains insufficiently understood. Here, we investigated the signaling functions of 24-epibrassinolide (24-EBL) in mediating aluminum stress responses in Nicotiana tabacum grown under soilless culture conditions. Exogenous 24-EBL significantly alleviated Al³⁺-induced photosynthetic inhibition, as reflected by increased transpiration rate (Tr), stomatal conductance (Gs), net photosynthetic rate (Pn), electron transport rate (ETR), and effective quantum yield of PSII (ΦPSII). Enhanced non-photochemical quenching (NPQ) indicated improved dissipation of excess excitation energy, suggesting photoprotective regulation. At the molecular level, 24-EBL treatment upregulated the antioxidant defense genes CAT1, NtPOD1, and NtSOD3, leading to increased enzymatic activities and reduced reactive oxygen species (ROS) accumulation, thereby preserving membrane stability. Notably, 24-EBL modulated metal detoxification pathways by inducing the expression of the phytochelatin-related genes Pr8 and Pr2, along with Al-ATPase transporters associated with vacuolar sequestration. This was accompanied by altered ion homeostasis, where enhanced Ca²⁺ and K⁺ uptake antagonized Al³⁺ accumulation and restricted its translocation to shoots. The marked upregulation of calmodulin (CaM) suggests that Ca²⁺-dependent signaling plays a central role in 24-EBL-mediated aluminum tolerance. Correlation analysis revealed strong associations between CaM expression, photosynthetic efficiency, antioxidant capacity, and metal detoxification markers. Together, these findings indicate that 24-EBL enhances aluminum tolerance in tobacco through a coordinated signaling network involving Ca²⁺-mediated signal transduction, redox regulation, and metal homeostasis. This study highlights brassinosteroid-calcium crosstalk as a key regulatory module in plant adaptation to aluminum stress.

Vaccination remains one of the most cost-effective methods for disease prevention. However, utilization of self-paid vaccines, including EV71, varicella, influenza, and DTaP-IPV-Hib in this study, remains insufficient among children under six in China. To investigate the determinants of willingness to vaccinate (WTV) for self-paid vaccines and assess cost-WTV heterogeneity, we conducted structured-questionnaire surveys with 2212 randomly selected households in Hangzhou, each with at least one child under six. Multiple regression analysis was used to identify the key determinants of WTV, and a mixed-effect model was employed to analyze the correlation between vaccine cost and WTV, further segmenting the data with unsupervised clustering techniques. Our findings highlighted impact of vaccination cost as a pivotal factor influencing the WTV for self-paid vaccines. We categorized the population into four groups based on their sensitivity to vaccine cost. Families with one child, children aged 1-3 y, highly-educated parents, and higher socioeconomic status consistently exhibited high WTV. Our analysis offers targeted strategies to enhance vaccine uptake and improve immunization coverage.

Objective: Clear-cell renal cell carcinoma (ccRCC) is an immune-desert tumor. This study investigates the role of ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) as a potential therapeutic target and immune-checkpoint enzyme in ccRCC.

Methods: ENPP3 expression and its link to hypoxia and prognosis were analyzed in ccRCC. Functional roles were tested using gain/loss-of-function studies in vitro and in xenograft models, followed by therapeutic anti-ENPP3 antibody administration, alone or with anti-PD-L1. Mechanisms were explored via promoter analysis, cGAMP measurement, flow cytometry, cytokine profiling, and in vivo neutralization with STING- or interferon-α/β receptor-1 (IFNAR1) blocking antibodies.

Results: ENPP3 is hypoxia-inducible via HIF-1α, upregulated in ccRCC, and predicts poor prognosis. ENPP3 overexpression accelerated tumor growth, while its knockdown or antibody blockade inhibited progression and synergized with anti-PD-L1. Mechanistically, ENPP3 hydrolyzes extracellular cGAMP. Its depletion elevated extracellular cGAMP, expanded anti-tumor immune cells (M1 macrophages, cDC1s, and cytotoxic T cells), reduced Tregs, and induced a STING- and IFNAR1-dependent type I interferon signature in macrophages. The anti-tumor efficacy of ENPP3 blockade was abrogated by IFNAR1 inhibition.

Conclusion: ENPP3 is a hypoxia-driven, cGAMP-targeting innate immune checkpoint in ccRCC. Its inhibition reactivates STING-dependent anti-tumor immunity, providing a strong preclinical rationale for targeting ENPP3 therapeutically.

Women's autonomy in fertility decision-making is essential for improved health and social outcomes. Guided by the social-ecological model, this investigation explores multilevel influences on the fertility autonomy of women with an unmet need for family planning in rural Uganda. We conducted four focus groups with men and women (n = 26), and 15 key informant interviews with community leaders and individuals involved in the provision of family planning. The data were analyzed thematically. The results highlight how community-level norms reinforce gender inequalities in decision-making and underpin beliefs to not limit men's number of children. Religious norms and polygamy practices were shown to influence attitudes towards family size and family planning, as well as shape relationship dynamics related to fertility. Concerns about poverty were identified as a driver of shifting preferences and increasing acceptance of family planning. Results showcase how health system weaknesses limit women's access to family planning services, contribute to mistrust of health systems and drive misinformation about contraceptives, especially among men. This study underscores the need for multifaceted gender transformative interventions to increase women's fertility autonomy. This study also highlights health system strengthening, religious leader endorsement and male engagement as approaches to increase women's autonomous use of family planning.

Posterior reversible encephalopathy syndrome (PRES) is a neurological complication linked to preeclampsia and eclampsia. This study compared the clinical and radiological features of PRES in patients with these conditions. This retrospective single-center cohort study from 2010 to 2024 included patients diagnosed with preeclampsia and eclampsia who underwent MRI due to neurological symptoms. Two radiologists, blinded to the clinical data, re-evaluated the MRIs twice. PRES cases were assessed based on the sites and patterns of involvement. Maternal and perinatal outcomes, along with laboratory characteristics, were reviewed through medical records. The study included 157 patients with preeclampsia and eclampsia who underwent MRI for neurological symptoms. PRES was diagnosed in 55 patients (35.0%), with a higher incidence of eclampsia (64.71%) compared to preeclampsia (20.75%). Patients with PRES were younger, had lower gravidity and parity, and were at an earlier gestational age than those with normal MRI findings. The parietal and occipital regions were the most affected in both preeclampsia and eclampsia patients with PRES. Parietal lobe and bilateral involvement were more common in the eclampsia group. Atypical involvement, including brainstem and cerebellar lesions, was observed in both groups. These findings suggest that eclampsia may represent a neurological manifestation of PRES.

This paper describes the initiation of the Naapinneq project and the first collaborative gathering in Iqaluit, Nunavut (Canada). While the broader project aims to revitalize culturally grounded parenting programs, this paper focuses on documenting its initiation and early collaborative learning. The focus was on the MANU program in Kalaallit Nunaat and the Inunnguiniq Parenting/Child‑rearing program in Nunavut. Using a community‑based participatory research approach, the paper draws on qualitative insights from the collaborative gathering-centered on participation in the Inunnguiniq facilitator workshop at the Qaujigiartiit Health Research Centre-and on a desk‑based comparison of core program documents. Reflections were documented through Sharing Circles, round‑table discussions, and a short questionnaire. Results highlight three interlinked insights: culturally grounded programs can support personal and collective healing; language, land, and kinship are foundational to child‑rearing; and circumpolar collaboration accelerates practice change and innovation. Project group members reported tangible changes, including adapting MANU to better reflect Kalaallit realities, initiating new collaborations, and advocating for culturally grounded approaches in early childhood and family services. Grounding parenting programs in Indigenous relational paradigms can strengthen cultural fit, community ownership, and sustained impact. Early learnings point to the healing potential of culturally grounded programs and to the value of cross‑border partnership for accelerating practice change.

Objective: To explore the synergistic effect of nano-pearl powder (NPP) and adipose-derived stem cell exosomes (ADSC-Exos) on the osteogenic potential of MC3T3-E1 cells.

Methods: The water-soluble matrix of NPP (NPP-WSM) was extracted via freeze-drying, and ADSC-Exos were isolated by ultracentrifugation. NPP-WSM was incorporated into ADSC-Exos through co-incubation to generate NPP-WSM-Exos. MC3T3-E1 cells were treated with NPP-WSM or NPP-WSM-Exos. Cell proliferation and migration were evaluated using CCK-8 and wound-healing assays, respectively. Osteogenic differentiation was assessed by Alizarin Red S staining and alkaline phosphatase (ALP) activity. The expression of osteogenesis-related genes (COL1A1, RUNX2, OCN, and OPN) was measured by qPCR and Western blotting. Transcriptome sequencing (RNA-seq) was conducted to identify signaling pathways activated by NPP-WSM-Exos.

Results: NPP-WSM-Exos displayed distinct exosome morphology and biomarkers, confirming their successful preparation. Significantly, NPP-WSM-Exos enhanced the viability of MC3T3-E1 cells compared to NPP-WSM alone and upregulated the expression of osteogenic genes, including COL1A1, RUNX2, OCN, and OPN, at both the transcriptional and translational levels. Additionally, NPP-WSM-Exos strongly promoted mineralization, as evidenced by the increased calcification observed through Alizarin Red S staining, and elevated alkaline phosphatase (ALP) activity, indicating excellent potential for osteogenic differentiation. Transcriptome sequencing showed that NPP-WSM-Exos significantly enhanced the PI3K/AKT pathway in MC3T3-E1 cells, while protein level detection indicated that NPP-WSM-Exos could increase AKT phosphorylation levels and inhibit GSK3β activity to improve osteogenic efficiency.

Conclusion: The use of adipose-derived stem cell exosomes to encapsulate NPP-WSM can increase the utilization of WSM, promote the proliferation of MC3T3-E1, and enhance the osteogenic differentiation ability.