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Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Abstract This study examined the presence of autistic traits in a sample of adult women diagnosed with different Eating Disorders (ED), and explored the concurrent role of autistic traits and sensory sensitivity in influencing both their eating disorder symptomatology and their autism-related eating behaviours. Seventy-five women with different ED (Anorexia Nervosa, Bulimia Nervosa, Binge-Eating Disorder, Other Specified Feeding or Eating Disorder) completed the Eating Attitude Test (EAT-26), the Autism Quotient (AQ), the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R), the Sensory Perception Quotient - Short Form 35 item (SPQ-SF35) and the Swedish Eating Assessment for Autism Spectrum Disorders (SWEAA). Twelve percent of participants scored above the cut-off on both the AQ and the RAADS-R, while 68% scored above the cut-off on the RAADS-R only. A mediation analysis revealed that the association between sensory sensitivity (SPQ-SFR35) and scores on both the EAT-26 and the SWEAA was significantly mediated by the presence of autistic traits (RAADS-R). These findings, first, confirm the presence of autistic traits in individuals with ED; second, they show that a lower sensory threshold (i.e., a higher sensory sensitivity) is associated with a higher presence of autistic traits which were, in turn, positively associated with dysfunctional eating behaviours typical of ED and ASD. This study ultimately highlights the importance of further research on autistic traits across all diagnostic categories of ED.

Abstract This novel study applies targeted functional proteomics to examine tissues and cells obtained from a cohort of individuals with severe obesity who underwent bariatric surgery (BS), using a Reverse-Phase Protein Array (RPPA). In obese individuals, visceral adipose tissue (VAT), but not subcutaneous adipose tissue (SAT), shows activation of DNA damage response (DDR) markers including ATM, ATR, histone H2AX, KAP1, Chk1, and Chk2, alongside senescence markers p16 and p21. Additionally, stress-responsive metabolic markers, such as survivin, mTOR, and PFKFB3, are specifically elevated in VAT, suggesting both cellular stress and metabolic dysregulation. Conversely, peripheral blood mononuclear cells (PBMCs), while exhibiting elevated mTOR and JNK levels, did not present significant changes in DDR or senescence markers. Following BS, unexpected increases in phosphorylated ATM, ATR, and KAP1 levels, but not in Chk1 and Chk2 nor in senescence markers, were observed. This was accompanied by heightened levels of survivin and mTOR, along with improvement in markers of mitochondrial quality and health. This suggests that, following BS, pro-survival pathways involved in cellular adaptation to various stressors and metabolic alterations are activated in circulating PBMCs. Moreover, our findings demonstrate that the DDR has a dual nature. In the case of VAT from individuals with obesity, chronic DDR proves to be harmful, as it is associated with senescence and chronic inflammation. Conversely, after BS, the activation of DDR proteins in PBMCs is associated with a beneficial survival response. This response is characterized by metabolic redesign and improved mitochondrial biogenesis and functionality. This study reveals physiological changes associated with obesity and BS that may aid theragnostic approaches.

Abstract Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aβ accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aβ-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aβ. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aβ from glutamatergic terminals. We believe that the selective pruning of Aβ-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.

Aim of the present study was to evaluate the relationship between sensory sensitivity and autistic eating behaviours or Eating Disorders (EDs) symptomatology, in a group of 75 adults with Autism Spectrum Disorders (ASDs) without intellectual disabilities, through a series of self-report questionnaires. We found that, controlling for demographic and clinical features: (i) hypersensitivity in the vision domain predicted higher levels of both EDs symptoms and autistic eating behaviours; (ii) hyposensitivity in the taste domain predicted higher levels of EDs symptoms. This gives preliminary evidence that not only in children diagnosed with ASDs, but even in adult individuals, the threshold of sensory sensitivity is associated with dysfunctional eating behaviours.

This study explores the innovative use of CO2 laser technology in frenuloplasty, a significant shift from classic methods like scalpel surgery or electrocautery towards a minimally invasive approach. The research involved 15 patients aged 25 to 50, undergoing frenuloplasty with a CO2 laser system equipped with a 7-inch defocused handpiece, set at 20 Hz and 0.3 W. This method diverges from conventional laser techniques, focusing on controlled laser passes combined with manual traction to elongate the fibrous tissue of the frenulum. The results demonstrated that the CO2 laser technique allowed for a precise and progressive modification of the frenulum, significantly reducing the risks of hemorrhage and secondary intention fibrosis. The healing process was notably expedited, with patients reporting satisfactory outcomes within a two-week period. Statistically significant improvements were observed in patient-reported outcomes, as evidenced by the increases in the Short Form Health Survey (SF-12) scores, with the mean Physical Component Summary (PCS) score rising from 32.5 to 47.5 and the mean Mental Component Summary (MCS) score from 39.3 to 52.3 (p < 0.001 for both). The study concludes that CO2 laser frenuloplasty is an effective and safe technique, offering substantial benefits in terms of reduced healing time and enhanced patient satisfaction. The significant improvements in SF-12 scores underscore the positive impact on patient quality of life, advocating for the broader application of this technique in clinical practice. Further research is warranted to explore its potential in a wider clinical context.

Abstract Background Primitive location of melanoma could be a relevant prognostic factor. As regards the scalp, some studies indicate a particularly aggressive biological behaviour for this anatomical localisation. Objectives In this multicentric study, data regarding head–neck melanoma (HNM) have been revised. Methods The design of the study included two main phases. In this retrospective study, data regarding HNM have been collected and analysed. Results In summary, our data suggest that the posterior neck is the area most affected by thicker melanomas. Cheeks and neck melanoma are associated with reduced disease‐free years of life and overall survival compared with all other sites of HNM. Conclusions This study provides useful information in defining the clinical features of HNM, thus improving diagnosis and treatment strategies.

Introduction: The advent of biotechnological drugs has significantly changed the management of atopic dermatitis (AD) and the approach to the moderate-to-severe form of this chronic relapsing disease. Objectives: The aim of our review is to summarize the current literature on anti-interleukin (IL)-13 in atopic dermatitis. Methods: A literature search was organized and a systematic review was performed to summarize the most recent evidence supporting the efficacy and safety of tralokinumab. Results: Tralokinumab (anti-IL-13) 300 mg every 2 weeks subcutaneously has proven effective in several clinical trials in adults and adolescents with moderate to severe atopic dermatitis inadequately controlled with other topical or systemic therapies. Tralokinumab was found to be significantly superior in terms of efficacy in reducing IGA, EASI-75, NRS pruritus, and DLQI scale numbers. During follow-up, tralokinumab was well tolerated with limited severity of adverse events. Conclusion: Tralokinumab leads to statistically significant improvements in disease severity and outcome scores. It represents an effective treatment option for adults with moderate to severe AD, but further large-scale studies are needed to verify long-term superiority over other treatments.

Patients with anorexia nervosa (AN) typically hold altered beliefs about their body that they struggle to update, including global, prospective beliefs about their ability to know and regulate their body and particularly their interoceptive states. While clinical questionnaire studies have provided ample evidence on the role of such beliefs in the onset, maintenance, and treatment of AN, psychophysical studies have typically focused on perceptual and ‘local’ beliefs. Across two experiments, we examined how women at the acute AN (N = 86) and post-acute AN state (N = 87), compared to matched healthy controls (N = 180) formed and updated their self-efficacy beliefs retrospectively (Experiment 1) and prospectively (Experiment 2) about their heartbeat counting abilities in an adapted heartbeat counting task. As preregistered, while AN patients did not differ from controls in interoceptive accuracy per se, they hold and maintain ‘pessimistic’ interoceptive, metacognitive self-efficacy beliefs after performance. Modelling using a simplified computational Bayesian learning framework showed that neither local evidence from performance, nor retrospective beliefs following that performance (that themselves were suboptimally updated) seem to be sufficient to counter and update pessimistic, self-efficacy beliefs in AN. AN patients showed lower learning rates than controls, revealing a tendency to base their posterior beliefs more on prior beliefs rather than prediction errors in both retrospective and prospective belief updating. Further explorations showed that while these differences in both explicit beliefs, and the latent mechanisms of belief updating, were not explained by general cognitive flexibility differences, they were explained by negative mood comorbidity, even after the acute stage of illness.

Abstract Purpose The relationship between autistic traits and eating disturbances has been given considerable attention over the last decades. The rise of a dimensional approach to psychopathology has expanded the way we think about autism, acknowledging that subthreshold autistic manifestations span across the general population and are more pronounced in psychiatric patients. Here we investigated the prevalence of eating disorders and its potential relationship with autistic traits and sensory sensitivity in a group of patients who were referred for the first time to a mental health outpatient clinic, without a formal diagnosis yet. Methods 259 young adults (between 18 and 24 years old) completed: the Eating Attitude Test (EAT-26), the Swedish Eating Assessment for Autism Spectrum Disorders (SWEAA), the Autism Quotient (AQ), the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R), and the Sensory Perception Quotient—Short Form 35 item (SPQ-SF35). Results 23.55% of participants scored above the cut-off at the EAT-26, suggesting that they presented a risk for eating disorders and should be assessed by a specialized clinician; associations emerged between hypersensitivity in the touch and vision domain and both the EAT-26 and the SWEAA; the presence of autistic traits was largely associated with eating disturbances. Conclusions This study underlines the significance of the eating domain as a central psychopathological feature in the distress experienced by young adults with general psychiatric symptoms and psychological suffering; it adds evidence to the association between autistic traits and eating disorders and opens to new research questions about the role of subthreshold autistic traits in general psychopathology. Level of evidence: Level I: Evidence obtained from experimental studies.

Abstract In recent years, research focused on the multifaceted landscape and functions of cancer-associated fibroblasts (CAFs) aimed to reveal their heterogeneity and identify commonalities across diverse tumors for more effective therapeutic targeting of pro-tumoral stromal microenvironment. However, a unified functional categorization of CAF subsets remains elusive, posing challenges for the development of targeted CAF therapies in clinical settings. The CAF phenotype arises from a complex interplay of signals within the tumor microenvironment, where transcription factors serve as central mediators of various cellular pathways. Recent advances in single-cell RNA sequencing technology have emphasized the role of transcription factors in the conversion of normal fibroblasts to distinct CAF subtypes across various cancer types. This review provides a comprehensive overview of the specific roles of transcription factor networks in shaping CAF heterogeneity, plasticity, and functionality. Beginning with their influence on fibroblast homeostasis and reprogramming during wound healing and fibrosis, it delves into the emerging insights into transcription factor regulatory networks. Understanding these mechanisms not only enables a more precise characterization of CAF subsets but also sheds light on the early regulatory processes governing CAF heterogeneity and functionality. Ultimately, this knowledge may unveil novel therapeutic targets for cancer treatment, addressing the existing challenges of stromal-targeted therapies.

Background/Objectives: The diagnosis of Autism Spectrum Disorders (ASD) is undergoing significant revisions, impacting prevalence estimates in the general population. Moreover, the rise of a dimensional perspective on psychopathology has broadened our understanding of autism, recognizing that subthreshold autistic features extend throughout the general population. However, there remains a limited understanding of the prevalence of ASD traits in individuals with psychiatric disorders, particularly in young adults, who are at an age where several mental health conditions emerge. The aim of this study was to evaluate the prevalence of ASD traits in a sample of young adults (18–24 years old) attending a generalized mental health outpatient clinic. Methods: A total of 259 young adult patients completed the self-report screening questionnaires Autism Quotient (AQ) and Ritvo Autism and Asperger Diagnostic Scale-Revised (RAADS-R). Results: A total of 16.2% of our sample scored above the cut-off in both scales; this percentage decreased to 13.13% when restricting the RAADS-R cut-off to >119, as suggested for clinical samples. The association with sociodemographic features is discussed. Conclusions: We argue that screening for autistic traits should be integrated into the assessment of young adults presenting with nonspecific psychiatric symptoms or psychological distress. Although there is ongoing debate over the use of self-report screening tools, a positive result on both the AQ and RAADS-R should prompt clinicians to pursue a comprehensive diagnostic evaluation using structured or semi-structured interviews.

Background and Objectives: Melasma, a hypermelanotic dermatologic condition that mainly affects women, poses challenges due to its complex etiology involving environmental and genetic factors. Its pathophysiology, marked by intricate histological changes, is not fully understood. This study explored the efficacy and safety of a new 785 nm picosecond laser in treating facial melasma. Materials and Methods: An 11-participant cohort, comprising women with Fitzpatrick phototypes II-III, underwent a treatment protocol with a new 785 nm picosecond laser. The clinical evaluation used the Global Aesthetic International Score (GAIS) and the Five-Point Likert Scale Questionnaire. The aim of the study was to understand the capacity of the 785 nm wavelength laser to interact with both the pigmentary and vascular components of melasma. Results: The GAIS outcomes revealed excellent (18.2%), good (54.5%), poor (18.2%), and no results (9.1%). The Likert Scale responses varied from very satisfied (18.2%) to slightly satisfied (9.1%). Clinical images at three months demonstrated resolution of melasma with no adverse events. Conclusions: This non-invasive procedure showed positive outcomes and high patient tolerance, emphasizing its potential in melasma management. However, in order to fully understand the interactions of pigmentary and vascular components with the 785 nm wavelength laser, further research is required. The small cohort represents a limitation for this study, therefore studies that include a larger number of patients are needed to assess the effectiveness of this laser treatment for facial melasma.

Chimeric antigen receptor (CAR) T-cell therapy has achieved notable success in treating hematological cancers but faces significant challenges in solid-tumor treatment and overall efficacy. Key limitations include T-cell exhaustion, tumor relapse, immunosuppressive tumor microenvironments (TME), immunogenicity, and antigen heterogeneity. To address these issues, various genetic engineering strategies have been proposed. Approaches such as overexpression of transcription factors or metabolic armoring and dynamic CAR regulation are being explored to improve CAR T-cell function and safety. Other efforts to improve CAR T-cell efficacy in solid tumors include targeting novel antigens or developing alternative strategies to address antigen diversity. Despite the promising preclinical results of these solutions, challenges remain in translating CAR T-cell therapies to the clinic to enable economically viable access to these transformative medicines. The efficiency and scalability of autologous CAR T-cell therapy production are hindered by traditional, manual processes which are costly, time-consuming, and prone to variability and contamination. These high-cost, time-intensive processes have complex quality-control requirements. Recent advancements suggest that smaller, decentralized solutions such as microbioreactors and automated point-of-care systems could improve production efficiency, reduce costs, and shorten manufacturing timelines, especially when coupled with innovative manufacturing methods such as transposons and lipid nanoparticles. Future advancements may include harmonized consumables and AI-enabled technologies, which promise to streamline manufacturing, reduce costs, and enhance production quality.

IntroductionDistinguishing tremor-dominant Parkinson's disease (tPD) from essential tremor with rest tremor (rET) can be challenging and often requires dopamine imaging. This study aimed to differentiate between these two diseases through a machine learning (ML) approach based on rest tremor (RT) electrophysiological features and structural MRI data.MethodsWe enrolled 72 patients including 40 tPD patients and 32 rET patients, and 45 control subjects (HC). RT electrophysiological features (frequency, amplitude, and phase) were calculated using surface electromyography (sEMG). Several MRI morphometric variables (cortical thickness, surface area, cortical/subcortical volumes, roughness, and mean curvature) were extracted using Freesurfer. ML models based on a tree-based classification algorithm termed XGBoost using MRI and/or electrophysiological data were tested in distinguishing tPD from rET patients.ResultsBoth structural MRI and sEMG data showed acceptable performance in distinguishing the two patient groups. Models based on electrophysiological data performed slightly better than those based on MRI data only (mean AUC: 0.92 and 0.87, respectively; p = 0.0071). The top-performing model used a combination of sEMG features (amplitude and phase) and MRI data (cortical volumes, surface area, and mean curvature), reaching AUC: 0.97 ± 0.03 and outperforming models using separately either MRI (p = 0.0001) or EMG data (p = 0.0231). In the best model, the most important feature was the RT phase.ConclusionMachine learning models combining electrophysiological and MRI data showed great potential in distinguishing between tPD and rET patients and may serve as biomarkers to support clinicians in the differential diagnosis of rest tremor syndromes in the absence of expensive and invasive diagnostic procedures such as dopamine imaging.

Summary: Background: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA11a linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response. Methods: Methods involved RNA-SEQ on NSCLC cells with depleted hMENA isoforms. A retrospective observational study assessed tissues from surgically treated N0 patients with NSCLC, using immunohistochemistry for tumoral and stromal hMENA isoforms, fibronectin, and TLS presence. ICB-treated patient tumors were analyzed using Nanostring nCounter and GeoMx spatial transcriptomics. Multiparametric flow cytometry characterized B cells and tissue-resident memory T cells (TRM). Survival and ICB response were estimated in the cohort and validated using bioinformatics pipelines in different datasets. Findings: Findings indicate that hMENA11a in NSCLC cells upregulates the TLS regulator LTβR, decreases fibronectin, and favors CXCL13 production by TRM. Conversely, hMENAΔv6 in CAFs inhibits LTβR-related NF-kB pathway, reduces CXCL13 secretion, and promotes fibronectin production. These patterns are validated in N0 NSCLC tumors, where hMENA11ahigh expression, CAF hMENAΔv6low, and stromal fibronectinlow are associated with intratumoral TLS, linked to memory B cells and predictive of longer survival. The hMENA isoform pattern, fibronectin, and LTβR expression broadly predict ICB response in tumors where TLS indicates an anti-tumor immune response. Interpretation: This study uncovers hMENA alternative splicing as an unexplored contributor to TLS-related Tumor Immune Microenvironment (TIME) and a promising biomarker for clinical outcomes and likely ICB responsiveness in N0 patients with NSCLC. Funding: This work is supported by AIRC (IG 19822), ACC (RCR-2019-23669120), CAL.HUB.RIA Ministero Salute PNRR-POS T4, “Ricerca Corrente” granted by the Italian Ministry of Health.

Abstract Background Immune checkpoint blockade (ICB) has significantly prolonged survival of non-small cell lung cancer (NSCLC) patients, although most patients develop mechanisms of resistance. Recently single-cell RNA-sequencing (scRNA-Seq) revealed a huge T-cell phenotypic and (dys)functional state variability. Accordingly, T-cell exhaustion is recognized as a functional adaptation, with a dynamic progression from a long-lived “pre-exhausted stem-like progenitor” to a “terminally exhausted” state. In this scenario it is crucial to understand the complex interplay between co-stimulatory and inhibitory molecules in CD8+ T-cell functionality. Methods To gain a baseline landscape of the composition, functional states, and transcriptomic signatures predictive of prognosis, we analyzed CD8+ T-cell subsets characterized by the presence/absence of PD1 and CD28 from periphery, adjacent non-tumor tissue and tumor site of a cohort of treatment-naïve NSCLC patients, by integrated multiparametric flow cytometry, targeted multi-omic scRNA-seq analyses, and computational pipelines. Results Despite the increased PD1 levels, an improved PD1+CD28+ T-cell polyfunctionality was observed with the transition from periphery to tumor site, associated with lack of TIGIT, TIM-3 and LAG-3, but not with Ag-experienced-marker CD11a. Differently from CD28+ T cells, the increased PD1 levels in the tumor were associated with reduced functionality in PD1+CD28− T cells. CD11ahigh, although expressed only in a small fraction of this subset, still sustained its functionality. Absence of TIGIT, TIM-3 and CTLA-4, alone or combined, was beneficial to CD28− T cells. Notably, we observed distinct TRM phenotypes in the different districts, with CD28+ T cells more capable of producing TGFβ in the periphery, potentially contributing to elevated CD103 levels. In contrast CD28− TRM mainly produced CXCL13 within the tumor. ScRNA-seq revealed 5 different clusters for each of the two subsets, with distinctive transcriptional profiles in the three districts. By interrogating the TCGA dataset of patients with lung adenocarcinoma (LUAD) and metastatic NSCLC treated with atezolizumab, we found signatures of heterogeneous TRM and "pre-exhausted" long-lived effector memory CD8+ T cells associated with improved response to ICB only in the presence of CD28. Conclusions Our findings identify signatures able to stratify survival of LUAD patients and predict ICB response in advanced NSCLC. CD28 is advocated as a key determinant in the signatures identified, in both periphery and tumor site, thus likely providing feasible biomarkers of ICB response. Graphical Abstract

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

IgE-mediated food allergy is characterized immunologically by a type 1 immune response triggered upon exposure to specific foods and clinically by a broad range of manifestations and variable severity. Our understanding of food allergy within the allergic march of atopic dermatitis (AD) is still incomplete despite the related risk of unpredictable and potentially severe associated reactions such as anaphylactic shock. The aim of this pilot study was to investigate the effects of dupilumab, an IL-4/IL-13 monoclonal antibody approved for AD, on the allergic sensitization profile of patients with AD and type 1 hypersensitivity-related comorbidities, including oral allergy syndrome, anaphylaxis, and gastrointestinal disorders. We conducted an observational pilot study with a longitudinal prospective design, enrolling 20 patients eligible for treatment with dupilumab. Laboratory exams for total serum IgE, specific IgE, and molecular allergen components were performed at baseline and after 16 weeks of therapy. Our results demonstrate a statistically significant decrease in molecular components, specific IgE for trophoallergens, and specific IgE for aeroallergens following treatment with dupilumab. We suggest that modulating type 2 immunity may decrease IgE-mediated responses assessed with laboratory exams and therefore could minimize allergic symptoms in polysensitized patients. Upcoming results of randomized controlled trials investigating dupilumab in food allergy are highly anticipated to confirm its potential effect in the treatment of IgE-mediated food allergies.

The investigation into advanced structural materials, such as composite materials, has revealed numerous possibilities within the field of bridge engineering. Glass-fiber-reinforced polymers (GFRPs) are notable among these materials, particularly in footbridge construction, encompassing both arch and cable-stayed designs. While GFRPs boast advantages, such as their high strength-to-weight ratio, they may exhibit some deficiencies, particularly when subjected to dynamic loads induced by wind or pedestrian forces. Two noteworthy global examples are the Lleida arch bridge (Spain, 2001) and the Aberfeldy cable-stayed bridge (Scotland, 1992). These structures have recently undergone comprehensive studies by the authors to assess their behavior when subjected to specific conditions regarding pedestrian traffic and vibrations induced by under-passing trains, as far as Lleida is concerned. The methodologies employed in these studies are detailed herein, incorporating the relevant scientific literature and technical regulations that provide guidance on fundamental principles for bridge design, pedestrian modelling, and acceleration thresholds aimed at minimizing discomfort. While the framework of principles is clear, the regulations are extensive, requiring designers to have a comprehensive understanding of the diverse outcomes achievable through various approaches. Therefore, the provided state-of-the-art overview serves as a roadmap for assessing the performance of an innovative cable-stayed bridge recently proposed by one of the authors. Initially designed with six spans, this prototype has been reconfigured here as a three-span train station overpass. The analyses conducted allowed for the assessment of induced accelerations. According to current accredited standards, the resulting comfort classification is considered minimal, even if, for crowded conditions, more specific studies are required.

The prevalence of skin aging and the request for effective treatments have driven dermatological research towards natural solutions. This study investigates the anti-aging efficacy of two bioactive natural polyphenols, Oleocanthal and Oleacein, in a skincare formulation. A single-blind, randomized clinical trial involved 70 participants, using a comprehensive exclusion criterion to ensure participant safety and study integrity. Participants applied the Oleocanthal and Oleacein 1% serum formulation twice daily for 30 days. The efficacy was objectively assessed using the VISIA® Skin Analysis System at baseline, after 15 days, and after 30 days. Results indicated significant wrinkle reduction in most groups. For women aged 45–79 years, the mean change was −33.91% (95% CI: −46.75% to −21.07%). For men aged 20–44 years, it was −51.93% (95% CI: −76.54% to −27.33%), and for men aged 45–79 years, it was −46.56% (95% CI: −58.32% to −34.81%). For women aged 20–44 years, the change was −25.68% (95% CI: −63.91% to 12.54%), not statistically significant. These findings highlight the potential of EVOO-derived polyphenols in anti-aging skincare, particularly for older adults. This research paves the way for further exploration into natural compounds in dermatology, particularly for aging skin management.

Abstract Functional movement disorders (FMD) are characterized by the presence of neurological symptoms that cannot be explained by typical neurological diseases or other medical conditions. First evidence showed that, compared to healthy controls (CTR), FMD patients presented increased levels of glutamate+glutamine in the anterior cingulate cortex/medial prefrontal cortex, and decreased levels of glutamate in the cerebrospinal fluid, suggesting that a glutamatergic dysfunction might play a role in FMD pathophysiology. In this study, 12 FMD patients and 20 CTR were recruited and underwent venous blood sampling and urine collection: levels of glutamate, BDNF, dopamine, oxidative stress, creatinine, neopterin, and uric acid were analyzed. Participants also underwent a psychometric assessment investigating depression, anxiety, and alexithymia. We found that levels of glutamate, BDNF, and dopamine were significantly lower in the blood of FMD patients than CTR. Glutamate and dopamine levels were positively associated with levels of alexithymia. Our findings give further evidence that glutamatergic dysfunction might be involved in the pathophysiology of FMD, possibly representing a biomarker of disease; moreover, since glutamatergic and dopaminergic systems are closely interconnected, our results might have a relevance in terms of treatment options for FMD patients.

ObjectiveTo investigate the performance of structural MRI cortical and subcortical morphometric data combined with blink-reflex recovery cycle (BRrc) values using machine learning (ML) models in distinguishing between essential tremor (ET) with resting tremor (rET) and classic ET.MethodsWe enrolled 47 ET, 43 rET patients and 45 healthy controls (HC). All participants underwent brain 3 T-MRI and BRrc examination at different interstimulus intervals (ISIs, 100–300 msec). MRI data (cortical thickness, volumes, surface area, roughness, mean curvature and subcortical volumes) were extracted using Freesurfer on T1-weighted images. We employed two decision tree-based ML classification algorithms (eXtreme Gradient Boosting [XGBoost] and Random Forest) combining MRI data and BRrc values to differentiate between rET and ET patients.ResultsML models based exclusively on MRI features reached acceptable performance (AUC: 0.85–0.86) in differentiating rET from ET patients and from HC. Similar performances were obtained by ML models based on BRrc data (AUC: 0.81–0.82 in rET vs. ET and AUC: 0.88–0.89 in rET vs. HC). ML models combining imaging data (cortical thickness, surface, roughness, and mean curvature) together with BRrc values showed the highest classification performance in distinguishing between rET and ET patients, reaching AUC of 0.94 ± 0.05. The improvement in classification performances when BRrc data were added to imaging features was confirmed by both ML algorithms.ConclusionThis study highlights the usefulness of adding a simple electrophysiological assessment such as BRrc to MRI cortical morphometric features for accurately distinguishing rET from ET patients, paving the way for a better classification of these ET syndromes.

Abstract Background Nearly two-thirds of individuals with a mental disorder start experiencing symptoms during adolescence or early adulthood, and the onset of a mental disorder during this critical life stage strongly predicts adverse socioeconomic and health outcomes. Subthreshold manifestations of autism spectrum disorders (ASDs), also called autistic traits (ATs), are known to be associated with a higher vulnerability to the development of other psychiatric disorders. This study aimed to assess the presence of ATs in a population of young adults seeking specialist assistance and to evaluate the study population across various psychopathological domains in order to determine their links with ATs. Methods We recruited a sample of 263 adolescents and young adults referring to a specialized outpatient clinic, and we administered them several self-report questionnaires for the evaluation of various psychopathological domains. We conducted a cluster analysis based on the prevalence of ATs, empathy, and sensory sensitivity scores. Results The cluster analysis identified three distinct groups in the sample: an AT cluster (22.43%), an intermediate cluster (45.25%), and a no-AT cluster (32.32%). Moreover, subjects with higher ATs exhibited greater symptomatology across multiple domains, including mood, anxiety, eating disorder severity, psychotic symptoms, and personality traits such as detachment and vulnerable narcissism. Conclusions This study highlights the importance of identifying ATs in young individuals struggling with mental health concerns. Additionally, our findings underscore the necessity of adopting a dimensional approach to psychopathology to better understand the complex interplay of symptoms and facilitate tailored interventions.

This Letter reports the first observation of the onset of fully developed turbulence in the solar corona. Long time series of white-light coronal images, acquired by Metis aboard Solar Orbiter at 2 minutes cadence and spanning about 10 hr, were studied to gain insight into the statistical properties of fluctuations in the density of the coronal plasma in the time domain. From pixel-by-pixel spectral frequency analysis in the whole Metis field of view, the scaling exponents of plasma fluctuations were derived. The results show that, over timescales ranging from 1 to 10 hr and corresponding to the photospheric mesogranulation-driven dynamics, the density spectra become shallower moving away from the Sun, resembling a Kolmogorov-like spectrum at 3 R _⊙ . According to the latest observation and interpretive work, the observed 5/3 scaling law for density fluctuations is indicative of the onset of fully developed turbulence in the corona. Metis observation-based evidence for a Kolmogorov turbulent form of the fluctuating density spectrum casts light on the evolution of 2D turbulence in the early stages of its upward transport from the low corona.

ABSTRACTThe impact of radiotherapy (RT) on immune cell status in prostate cancer (PCa) is only partially determined. The aim of this study was to assess the effect of different RT strategies on peripheral B, T, and Natural killer (NK) lymphocytes at precise longitudinal time-points in PCa. 18 patients treated with stereotactic body radiation therapy (SBRT) (40 Gy/3FRX), definitive moderate-hypofractionation (62 Gy/20FRX), or post-operative conventional-fractionation RT (66–69 Gy/30FRX) were prospectively evaluated for the immune cell profile in terms of immune cell composition, differentiation stage, cytokine production and inhibitory receptor (IR) expression. The immune-monitoring of the 18 patients revealed that RT affects the balance of systemic immune cells, with the main differences observed between SBRT and conventionally fractionated RT. SBRT favorably impacts immune response in term of increased B cells, central-memory and effector-memory CD8+ T cells, along with decreased Treg cells after treatment. On the contrary, conventional fractionated RT had a long-term negative effect on the systemic immune profile, including a decrease of total lymphocyte counts accompanied by an increase of neutrophils-to-lymphocytes ratio. Total B and T cells decreased and Treg-to-CD8+ ratio increased. Functionality of T lymphocytes were not affected by any of the 3-fractionation schedules. Interestingly, SBRT significantly up-regulates the expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) in CD8+ T cells in the absence of other IRs. Our results indicate the relevance of systematic immunomonitoring during RT to identify novel immune-related target to design trials of combined radio-immunotherapy as a promising strategy in the clinical management of PCa.

Abstract Background Solid tumors are often riddled with hypoxic areas, which develops as a result of high proliferation. Cancer cells willingly adapt and thrive in hypoxia by activating complex changes which contributes to survival and enhanced resistance to treatments, such as photon radiation. Photon radiation primarily relies on oxygen for the production of reactive oxygen species to induce DNA damage. The present in-vitro study aimed at investigating the biochemical responses of hypoxic non-small cell lung cancer (NSCLC) cells, particularly the effects on the DNA damage repair systems contributing to more radioresistant phenotypes and their pro- and anti-oxidant potential, within the first 24 h post-IR. Methods NSCLC cell lines (H460, A549, Calu-1) were irradiated using varying X-ray doses under normoxia (21% O2) and hypoxia (0.1% O2). The overall cell survival was assessed by clonogenic assays. The extent of irradiation (IR)-induced DNA damage was evaluated by analyzing γ-H2AX foci induction and the altered expression of repair genes involved in non-homologous end joining and homologous recombination pathways. Moreover, cell-altered responses were investigated, including the nuclear and cytosolic hydrogen peroxide (H2O2) production, as well as the associated anti-oxidant potential, in particular some components related to the glutathione system. Results Analysis of clonogenic survival revealed an enhanced radioresistance of the hypoxic NSCLC cells associated with reduced DNA damage and a downregulation of DNA repair genes. Moreover, nuclear H2O2 levels were IR-induced in a dose-dependent manner only under normoxia, and directly correlated with the DNA double-strand breaks. However, the observed nuclear H2O2 reduction in hypoxia appeared to be unaffected by IR, thus highlighting a possible reason for the enhanced radioresistance of the hypoxic NSCLC cells. The cellular antioxidant capacity was upregulated by IR in both oxygen conditions most likely helping to counteract the radiation effect on the cytosolic H2O2. Conclusions In conclusion, our data provide insight into the adaptive behavior of radiation-resistant hypoxic NSCLC cells, in particular their DNA repair and oxidative stress responses, which could contribute to lower DNA damage and higher cell survival rates following X-ray exposure. These findings may therefore help to identify potential targets for improving cancer treatment outcomes.

Abstract Background Pronectins™ are a new class of fibronectin-3-domain 14th-derived (14Fn3) antibody mimics that can be engineered as bispecific T cell engager (BTCE) to redirect immune effector cells against cancer. We describe here the in vitro and in vivo activity of a Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) against Epithelial Ovarian Cancer (EOC). Methods pAXLxCD3ε T-cell mediated cytotoxicity was evaluated by flow cytometry and bioluminescence. pAXLxCD3ε mediated T-cell infiltration, activation and proliferation were assessed by immunofluorescence microscopy and by flow cytometry. Activity of pAXLxCD3ε was also investigated in combination with poly-ADP ribose polymerase inhibitors (PARPi). In vivo antitumor activity of pAXLxCD3ε was evaluated in immunocompromised (NSG) mice bearing intraperitoneal or subcutaneous EOC xenografts and immunologically reconstituted with human peripheral blood mononuclear cells (PBMC). Results pAXLxCD3ε induced dose-dependent cytotoxicity by activation of T lymphocytes against EOC cells, regardless of their histologic origin. The addition of PARPi to cell cultures enhanced pAXLxCD3ε cytotoxicity. Importantly, in vivo, pAXLxCD3ε was highly effective against EOC xenografts in two different NSG mouse models, by inhibiting the growth of tumor cells in ascites and subcutaneous xenografts. This effect translated into a significantly prolonged survival of treated animals. Conclusion pAXLxCD3ε is an active therapeutics against EOC cells providing a rational for its development as a novel agent in this still incurable disease. The preclinical validation of a first-in-class agent opens the way to the development of a new 14Fn3-based scaffold platform for the generation of innovative immune therapeutics against cancer.