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Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species-random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

Abstract Vitality Forms (VFs) constitute the dynamic essence of human actions, providing insights into how individuals engage in activities. The ability to perceive and express VFs during interpersonal interactions is pivotal for understanding others’ intentions, behaviors, and fostering effective social communication. Despite their ubiquity in all actions, research exploring the role of VFs in neurodivergent conditions related to social and communicative skills, particularly in autism, remains limited. This study aims to investigate the expression of different VFs during the execution of both social and non-social actions in children with an Autism Spectrum Condition (ASC) in comparison to neurotypical children (NT). ASC children and NT children were asked to move a small bottle either towards a target point (non-social context) or moving it towards a receiver (social context) with different VFs specifically neutral, gentle, or rude. Videotaped tasks were subsequently analyzed to study kinematic parameters characterizing VFs. Our results highlighted three main findings: (1) overall, ASC children are able to tune the motor profile of their actions, effectively conveying both gentle and rude VFs; (2) distinct kinematic parameters in the execution of VFs are able to distinguish autistic children from NT children; (3) the social context significantly influences the child’s ability to express positive and negative VFs in autism. Taken together, these findings provide new insights to understand how VFs contribute to the complex dynamics of social communication in neurodivergent autistic children, providing a valuable contribution for future interventions and support strategies.

Linguistic strategies humans use for communication are designed to meet the informational needs of their addressees. Speakers not only adapt their speech but also increase the rate of iconic gestures to enhance the clarity of a message for children. Although sign languages allow signers to take advantage of iconicity far more than what is possible in speech, little is known about whether signers use iconicity as a strategy in child-directed communication. In the present study, we used automatic video pose estimation to analyze descriptions aimed at a child (12yo) vs. an adult produced by 7 deaf adult signers of Italian Sign Language. Overall, signers used iconic constructions more than lexical signs and with comparable frequency in descriptions for both age groups. However, iconic constructions were longer in duration for children. Thus, the present study presents the first evidence that, unlike speakers, signers do not modulate quantitative but only qualitative aspects of iconicity for children.

Abstract Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species—random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis.

Introduction: Metastatic breast cancer (MBC) presents an enduring and significant challenge for affected women, requiring sustained commitment over the years. Case Presentation: This paper presents a case of a woman affected by bone and visceral MBC with a very long 20-year survival, excellent quality of life, and high resilience. She is now 51 years old and underwent quadrantectomy for breast cancer in 2005, and in 2013, she developed a recurrence with bone and liver metastases. Despite the widespread stage of the disease with visceral compromise, the patient was treated with a multidisciplinary approach that included surgery, chemotherapy, radiotherapy, hormone therapy, bone target agents, metabolic radiotherapy, and ozone therapy for medication-related osteonecrosis of the jaw. Multidisciplinary management results in a complete clinical and metabolic response to treatment in a visceral metastatic setting. Conclusion: This report supports the possibility of achieving unusual survival outcomes in patients with MBC. This study also highlights the importance of resilience in breast cancer patients who continue to manage their disease and pursue treatment for over 2 decades. Understanding these resilience factors can improve clinical practice and support patients’ long-term care.

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Cellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in metazoan cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-κB, p53, and C/EBPβ. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouse Mus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratory Mus musculus. We used allele-specific expression profiling to catalog senescence-dependent cis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, upstream stimulatory factor 2 (USF2), for molecular validation. In acute irradiation experiments, cells lacking USF2 had compromised DNA damage repair and response. Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program-shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.

IntroductionIn the last decades, dermal fillers have gained widespread acceptance for cosmetic purposes since their approval for different health conditions, including lip augmentation and aesthetic intervention of the face. Unfortunately, while filler lip procedures are performed using biomaterials with improved physical characteristics, they are not devoid of adverse drug reactions (ADRs), including those with late-onset.MethodsThis systematic aims to investigate the ADRs associated with lip augmentation procedures using dermal fillers. A systematic review search was conducted in Medline/PubMed, Scopus, Web of Science to answer the PEO question: What are the ADRs in patients undergoing lip augmentation procedures with dermal fillers, and how frequent are they?ResultsThe risk of bias was assessed, and a systematic review was conducted. Nineteen studies were included. In total, 30 patients affected by filler lip ADRs were analyzed, of which 29 were females and only 1 was male with a mean age of 50.9 ± 12.8 years. Hyaluronic acid was the most commonly dermal filler used and granulomatous foreign body reaction was the most common filler lip reaction reported. The mean time between filler lip injection and granulomatous foreign body reaction onset was 57.9 ± 54 months (median 24 months).DiscussionNo study reported ADRs to regulatory authorities. Our results indicate that adverse reactions can occur even long-term after the aesthetic procedure. Therefore, ongoing short-term and long-term follow-up visits are essential, as biocompatible materials are not free from ADRs. Additionally, a lack of reporting ADRs to regulatory authorities has emerged, which is crucial for patient safety.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=534656, identifier: CRD42024534656.

In 2022, the World Health Organization (WHO) released a landmark report on oral health, emphasizing the staggering global prevalence of oral disorders, which affect approximately 3 [...]

Abstract Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome‐wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English‐language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross‐sectional studies, 13.4% animal studies, 4.8% genome‐wide studies, 5.8% epigenome‐wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long‐term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early‐life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome‐wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long‐term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW‐associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

This article presents the results of a study on plant diversity at different levels in residual forest stands, located in the historical Favorita Park in Palermo, Italy (established and named in 1799 by King Ferdinand IV of the House of Bourbon). These forest aspects have naturally evolved for over two centuries, under minimal conditions of anthropogenic disturbance (e.g. deforestation, fires, grazing activities, etc.). This is especially true in the area known as “Bosco Niscemi”, spread over about 8.5 hectares, in the centre of the park. Bosco Niscemi is characterized by the widespread presence of old trees, abundant necromass and litter. In this study, four different soil profiles were analysed, and classified as follows: (i) Solimovic Regosol (Arenic); ii) Eutric Arenosol (Chromic); (iii) and (iv) Skeletic Regosol (Ochric). From a phytosociological point of view, four forest communities have been identified, two of which are described as new associations (Viburno tini-Phillyreetum latifoliae ass. nova and Teucrio flavi-Phillyreetum latifoliae ass. nova). The species richness was also found to be noteworthy, with the co-occurrence of several taxa (phanerogams and cryptogams) that are of biogeographic interest or rare in Sicily, including: i) vascular flora (e.g. Viburnum tinus and Arbutus unedo, both very rare throughout the western sector of Sicily); ii) bryophytes [Cryphaea heteromalla (new record of a very rare species in Sicily) as well as Hypnum cupressiforme and Leptodon smithii, also never previously found at such low altitudes]; iii) lichens (e.g. Bacidia rosella, Gyalecta derivata, Ramalina roesleri and Waynea stoechadiana); iv) mushrooms (e.g. Eichleriella leucophaea, only known location in Italy). Based on the scientific documentation produced in this study, these woods can be reported as “old-growth forests” to be included in the “National Network” that has been recently established in Italy (Ministerial Decree of 23 June 2023). This area might serve as an ideal control for urban environmental studies, given its pristine ecological setting.

Urban mobility is a current and hot topic for local administrations, and not only due to the numerous road accidents in urban areas, often caused by the incorrect behaviour of scooter drivers. The diffusion of electric scooters occurred, above all, after the pandemic. While on the one hand, social distancing has forced many to re-evaluate traveling by car, there are many citizens who have adopted innovations such as pedal-assisted bicycles and, above all, electric scooters - the latter being the protagonists of a real boom. In addition to ensuring fast travel and ease of use, the electric scooter and its use have sparked public debate regarding safety and apparent deregulation. Very often in Italy and beyond, the use of electric scooters is associated with a perception of fear and scepticism about micro-mobility, as well as the diffusion of some models relating to sustainable mobility. This derives in part from the previous characteristics of the vehicles produced and manufactured in China that do not comply with the law, and in that case, are truly dangerous. But given the recent rules at both the Italian and European levels, we are very often protected against products that do not comply with the laws, and therefore, we have greater road safety. The recent legislation on use on Italian roads has changed the characteristics of users, vehicles, and infrastructures in which to circulate. The safety of the electric scooter has been a long-debated topic, especially since this vehicle has seen a boom in sales and rentals since 2020, thanks to the incentives for the purchase and the willingness of Italians to use public transport less and less. To define the choice of an electric scooter as a sustainable modal choice, it is necessary, beyond safety, to investigate the perception of users in terms of gender equity, use in the first and last mile, and perception in terms of green transport modes. Starting from this, a survey was implemented, and subsequently, a descriptive statistical analysis was conducted on about 550 users in the metropolis of Palermo in Sicily. The results related to the period 2019-2022 showed that the electric scooter is certainly a practical and green vehicle but must be driven with the same attention we pay in cars or motorcycles. The chi-square analysis defined the trend variations connected to the users' psychosocial parameters according to the user's gender and age. The scenario shows the need for timely interventions, above all to protect vehicle users but also pedestrians who are often involved in accidents due to the use of vehicles on sidewalks. The survey shows that scooter users are the first to request more safety, starting with the creation of protected lanes such as cycle paths or dedicated areas.

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

IntroductionMedication-related osteonecrosis of the Jaw (MRONJ) is an adverse drug reaction that affects the mandible and maxilla of patients exposed to BMA and AA therapies, causing the progressive destruction and death of bone. To date, oral health preventive measures remain the most effective strategy to reduce MRONJ incidence, and, in this sense, the major goal is to diagnose, treat, and eradicate any oral diseases that could compromise oral health. The present systematic review aims to investigate the awareness of MRONJ among patients assuming BMAs.MethodsA systematic literature search was performed, selecting studies that concern the awareness of patients of the risk of MRONJ.ResultsSix studies were included in this review. In total, 483 patients were evaluated. Of the 483 included patients, 391 were not aware of the possibility of MRONJ onset (391/483, 81%) and 92 were aware of it (92/483, 19%).DiscussionThe problem of patient's lack of awareness with respect to MRONJ risk presents different layers of complexity (“what?”, “who?”, “where?”, “when?” and “why?”). Among its causal factors, there are an inadequate level of communication with patients and the lack of collaboration between healthcare professionals, which is related to an individualistic view of liability and deontological duties. MRONJ is a drug adverse reaction that can greatly affect the quality of life of patients if not promptly diagnosed and treated. Therefore, patients must be fully aware of the risks of adverse and the importance of preventive measures, which imply effective and exhaustive communication by each member of the multidisciplinary team. Effective teamwork and collaborative care should be promoted to positively impact patients' awareness.

Abstract Objective Pediatric tracheostomy is associated with high morbidity and mortality, yet clinician knowledge and quality of tracheostomy care may vary widely. In situ simulation is effective at detecting and mitigating related latent safety threats, but evaluation via retrospective video review has disadvantages (eg, delayed analysis, and potential data loss). We evaluated whether a novel mobile application is accurate and reliable for assessment of in situ tracheostomy emergency simulations. Methods A novel mobile application was developed for assessment of tracheostomy emergency in situ simulation team performance. After 1.25 hours of training, 6 raters scored 10 tracheostomy emergency simulation videos for the occurrence and timing of 12 critical steps. To assess accuracy, rater scores were compared to a reference standard to determine agreement for occurrence or absence of critical steps and a timestamp within ±5 seconds. Interrater reliability was determined through Cohen's and Fleiss' kappa and intraclass correlation coefficient. Results Raters had 86.0% agreement with the reference standard when considering step occurrence and timing, and 92.8% agreement when considering only occurrence. The average timestamp difference from the reference standard was 1.3 ± 18.5 seconds. Overall interrater reliability was almost perfect for both step occurrence (Fleiss' kappa of 0.81) and timing of step (intraclass correlation coefficient of 0.99). Discussion Using our novel mobile application, raters with minimal training accurately and reliably assessed videos of tracheostomy emergency simulations and identified areas for future refinement. Implications for Practice With refinements, this innovative mobile application is an effective tool for real‐time data capture of time‐critical steps in in situ tracheostomy emergency simulations.

Logistic regression has been a widely used prediction technique to analyze categorical variables. However, if the assumptions are violated the results may be biased. The study in this paper applied an analytical technique namely generalized ordered logit model. A case study of using urban light rail under pandemic conditions was applied for the analysis. The results suggested that logistic regression should not be applied before exploring the multicollinearity and applying the test of parallel lines. If the assumptions are violated, generalized ordered logit model should be considered. Regarding the predictive variables, sociodemographic, socioeconomic and travel pattern, related variables were found to have a statistically significant impact on the perception of safety and infrastructure of urban light rail. The outcomes of the study would provide a deeper understanding of developing regression models for categorical variables for future studies.