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Valentina Perrone, Melania Leogrande, Maria Cappuccilli, Stefania Saragoni, Andrea Cinti Luciani, Luca Degli Esposti CliCon S.r.l., Società Benefit, Health, Economics & Outcomes Research, Bologna, 40137, ItalyCorrespondence: Valentina Perrone, CliCon S.r.l. Società Benefit, Health, Economics & Outcomes Research, Via Murri 9, Bologna, 40137, Italy, Tel +39 0544 38393, Fax +39 0544 212699, Email valentina.perrone@clicon.itPurpose: To describe patients with hormone receptor positive and human epidermal growth factor receptor 2 negative metastatic breast cancer (HR+/HER2- mBC) in Italy for demographic and clinical variables, comorbidity profile, metastases and therapeutic pathways.Patients and Methods: From 2017 to 2021, HR+/HER2- mBC patients were extrapolated from administrative databases of healthcare entities covering a catchment area of about 3 million health-assisted women. The study included patients with a hospital discharge diagnosis for mBC; AND with specific prescriptions of therapies for HR+; AND without HER2-targeted therapy; OR with at least one prescription for CDK4/6 inhibitors. The following data were collected: age at inclusion, previous drug prescriptions, causes of hospitalization, site and number of metastases, therapeutic pathways and drug utilization during follow-up.Results: The study was focused on 6603 women with HR+/HER2- mBC subtype, at least two prior systemic therapies for metastatic status or at least one endocrine-based therapy, at least one taxane prescription and at least one CDK4/6 inhibitor prescription and at least 12-months of data available before and after inclusion. Mean age was 59 years; the most common pre-existing conditions were hypertension (53.7%), distantly followed by chronic obstructive pulmonary disease, diabetes and cardiovascular disease. The analysis of treatment patterns during follow-up, which considered 3-month or 6-month gaps for identification of two different aspecific chemotherapies, showed that 97% (N = 236) had a subsequent line and 86% (N = 211) a further treatment during follow-up. The most common prior anticancer treatments, found in almost all patients, were endocrine therapy and CKD4/6i, with 66% patients receiving an aspecific chemotherapy.Conclusion: This real-world analysis provides key insights into HR+/HER2- mBC in Italy, highlighting treatment patterns, rising diagnoses in younger women, and challenges in managing heavily pretreated patients. It emphasizes the need for further research on treatment sequencing, emerging therapies, and prior treatment duration to enhance clinical decision-making and patient care.Keywords: administrative databases, cancer therapies, endocrine therapy, metastatic status

Abstract In the last decades, the availability of multi-source, multi-scale, and multi-resolution remote sensing data and the consequent progress of processing techniques brought a significant positive impact for landslide detection. As a result, nowadays also public institutions dealing with geo-hazard management worldwide regularly use satellite data and products in landslide investigations. Due to the complexity of the phenomenon which might involve the displacement of massive rocks, soil, and both wet and dry vegetation from hillslopes, and the significant impact on the safety of the population and road infrastructure, the development of specific procedures for the rapid detection of landslides is extremely challenging. This is particularly important in the first phases of landslide risk management to evaluate the extension of the area involved by the movement and proceed with an initial delimitation of the so-called alarm zone, where preventive evacuation must be applied. In this study, the wide-ranging Tasseled Cap Transformation (TCT) is proposed as a not-sophisticated and rapid method able to detect different land-change features simultaneously by processing only two (pre- and post-event) Sentinel-2 images. The RGB color composite image obtained by stacking δTCTBrightness, δTCTGreenness, and δTCTWetness, as the intensity of red (R), green (G) and blue (B) was able to provide information on landscape changes supported by the physical nature of the TCT indices, by associating the colors to the physical characteristics of the changes. The method tested over the Pomarico site in Basilicata region (Southern Italy), was able to define the footprint of a landslide occurred in 2019 with a good accuracy (ACC = 0.95). Therefore, the proposed procedure is effective to detect landslides involving land-surface spectral changes (the majority), without the need of additional in-situ information. Furthermore, the free availability of the Sentinel-2 database and its frequent revisit times guarantee its global exportability.

Abstract Copy number alterations (CNAs) play a fundamental role in cancer development and constitute a potential tool for tailored treatments. The CNAs recognition in formalin fixed paraffin embedded (FFPE) material for diagnostic purposes has relied for years mainly on fluorescence in situ hybridization. The introduction of other procedures, such as Next-Generation Sequencing has dramatically improved CNAs discovery at genome-wide level. The detection of CNAs by NGS in FFPE material is, nonetheless, a complex issue, which still requires validation studies. Herein, the CNAs detection by a widely used NGS assay (Oncomine Comprehensive Assay plus®, OCA+) were evaluated in 14 FFPE samples mirroring diagnostic daily practice and compared to a whole-genome assay. OCA+, a targeted DNA panel, showed lower CNAs detection sensitivity and equal specificity for gains and losses. According to proprietary software pipeline, OCA+ accurately identified gains characterized by CN ≥ 5,2. No significant threshold maximizing the difference between true and false positive losses was found. Orthogonal FISH tests validated seven CNAs characterized by CN gain ≥ 6 or complete loss. Considering the CNAs growing significance in precision medicine, our findings further prompt towards a robust validation of NGS detection in FFPE materials.

Abstract Aims Individual prognostic assessment and disease evolution pathways are undefined in chronic heart failure (HF). The application of unsupervised learning methodologies could help to identify patient phenotypes and the progression in each phenotype as well as to assess adverse event risk. Methods and results From a bulk of 7948 HF patients included in the MECKI registry, we selected patients with a minimum 2‐year follow‐up. We implemented a topological data analysis (TDA), based on 43 variables derived from clinical, biochemical, cardiac ultrasound, and exercise evaluations, to identify several patients' clusters. Thereafter, we used the trajectory analysis to describe the evolution of HF states, which is able to identify bifurcation points, characterized by different follow‐up paths, as well as specific end‐stages conditions of the disease. Finally, we conducted a 5‐year survival analysis (composite of cardiovascular death, left ventricular assist device, or urgent heart transplant). Findings were validated on internal (n = 527) and external (n = 777) populations. We analyzed 4876 patients (age = 63 [53–71], male gender n = 3973 (81.5%), NYHA class I–II n = 3576 (73.3%), III–IV n = 1300 (26.7%), LVEF = 33 [25.5–39.9], atrial fibrillation n = 791 (16.2%), peak VO2% pred = 54.8 [43.8–67.2]), with a minimum 2‐year follow‐up. Nineteen patient clusters were identified by TDA. Trajectory analysis revealed a path characterized by 3 bifurcation and 4 end‐stage points. Clusters survival rate varied from 44% to 100% at 2 years and from 20% to 100% at 5 years, respectively. The event frequency at 5‐year follow‐up for each study cohort cluster was successfully compared with those in the validation cohorts (R = 0.94 and R = 0.84, P

Abstract Background Metabolism is error prone. For instance, the reduced forms of the central metabolic cofactors nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), can be converted into redox-inactive products, NADHX and NADPHX, through enzymatically catalyzed or spontaneous hydration. The metabolite repair enzymes NAXD and NAXE convert these damaged compounds back to the functional NAD(P)H cofactors. Pathogenic loss-of-function variants in NAXE and NAXD lead to development of the neurometabolic disorders progressive, early-onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL)1 and PEBEL2, respectively. Methods To gain insights into the molecular disease mechanisms, we investigated the metabolic impact of NAXD deficiency in human cell models. Control and NAXD-deficient cells were cultivated under different conditions, followed by cell viability and mitochondrial function assays as well as metabolomic analyses without or with stable isotope labeling. Enzymatic assays with purified recombinant proteins were performed to confirm molecular mechanisms suggested by the cell culture experiments. Results HAP1 NAXD knockout (NAXDko) cells showed growth impairment specifically in a basal medium containing galactose instead of glucose. Surprisingly, the galactose-grown NAXDko cells displayed only subtle signs of mitochondrial impairment, whereas metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway in those cells as well as in NAXD patient-derived fibroblasts. We identified inhibition of 3-phosphoglycerate dehydrogenase as the root cause for this metabolic perturbation. The NAD precursor nicotinamide riboside (NR) and inosine exerted beneficial effects on HAP1 cell viability under galactose stress, with more pronounced effects in NAXDko cells. Metabolomic profiling in supplemented cells indicated that NR and inosine act via different mechanisms that at least partially involve the serine synthesis pathway. Conclusions Taken together, our study identifies a metabolic vulnerability in NAXD-deficient cells that can be targeted by small molecules such as NR or inosine, opening perspectives in the search for mechanism-based therapeutic interventions in PEBEL disorders. Graphical Abstract

Highlights Primary care clinic structures and operations may influence early MOUD discontinuation. Flexible scheduling can improve early MOUD retention but must be balanced with clinic efficiency. Multidisciplinary teams can improve retention but require additional resources. Addressing comorbid pain and polydrug use early in the treatment process can help prevent MOUD discontinuation.

This paper presents the Early Basketball Protocol, a sports-based intervention designed to improve motor and socio-emotional skills in autistic preschoolers. Recognizing the paucity of sports protocols for younger autistic children, we developed this protocol using basketball rules to foster an inclusive setting where autistic preschoolers (n = 4) and their typically developing peers (n = 13) could engage in activities together. The protocol aims to simultaneously develop motor and socio-emotional skills through inclusive sports activities. Due to the COVID-19 pandemic, the effectiveness of the protocol was evaluated using parent-reported measures. A narrative approach synthesized the parental answers, and a pre–post-test analysis evaluated the preliminary application of the EB protocol based on parent-reported perceptions. Encouraging longitudinal results emerged, particularly in the improvement of socio-emotional skills for all participants. However, the early disruption of activities due to the pandemic may have contributed to the lack of improvement in gross motor skills. The paper discusses the practical implications of these findings and outlines future research directions, emphasizing the critical role of social inclusion.

Abstract Northern Thailand and its neighbouring regions are home to several minority ethnic groups known as hill tribes, each with their own language and customs. Hill tribe communities live mostly in remote agricultural communities, face barriers in accessing health, and have a lower socio-economic status compared to the main Thai ethnic group. Due to their increased risk of infectious diseases, they are often participants in our research projects. To make sure our work is in line with the interests of hill tribe communities and respects their beliefs and customs, we set up a hill tribe community advisory board. We consult the members before, during, and after our projects are carried out. This manuscript recounts how we set up the community advisory board and our reflections following one year of activities. Our experience strongly supports engaging with community advisory boards when working with minority ethnic groups in lower and middle-income settings. In particular, we found that over time, as researchers and members familiarise with one another and their respective environments, exchanges gain meaning and benefits increase, stressing the advantages of long-term collaborations over short or project-based ones.

Abstract NPM1 is an abundant nucleolar chaperone that, in addition to facilitating ribosome biogenesis, contributes to nucleolar stress responses and tumor suppression through its regulation of the p14 Alternative Reading Frame tumor suppressor protein (p14ARF). Oncogenic stress induces p14ARF to inhibit MDM2, stabilize p53 and arrest the cell cycle. Under non-stress conditions, NPM1 stabilizes p14ARF in nucleoli, preventing its degradation and blocking p53 activation. However, the mechanisms underlying the regulation of p14ARF by NPM1 are unclear because the structural features of the p14ARF-NPM1 complex were elusive. Here we show that p14ARF assembles into a gel-like meso-scale network upon phase separation with NPM1. This assembly is mediated by intermolecular contacts formed by hydrophobic residues in an α-helix and β-strands within a partially folded N-terminal portion of p14ARF. These hydrophobic interactions promote phase separation with NPM1, enhance p14ARF nucleolar partitioning, restrict NPM1 diffusion within condensates and nucleoli, and reduce cellular proliferation. Our structural analysis provides insights into the multifaceted chaperone function of NPM1 in nucleoli by mechanistically linking the nucleolar localization of p14ARF to its partial folding and meso-scale assembly upon phase separation with NPM1.

Abstract Background Endocrine therapy (ET) has improved the clinical outcomes of Estrogen receptor alpha-positive (ERɑ +) breast cancer (BC) patients, even though resistance to ET remains a clinical issue. Mutations in the hormone-binding domain of ERɑ represent an acquired intrinsic mechanism of ET resistance. However, the latter also depends on the multiple functional interactions between BC cells and the tumor microenvironment (TME). Here, we investigated how the most common Y537S-ERɑ mutation may influence the behavior of fibroblasts, the most prominent component of the TME. Methods We conducted coculture experiments with normal human foreskin fibroblasts BJ1-hTERT (NFs), cancer-associated fibroblasts (CAFs), isolated from human BC specimens, and Y537S CRISPR-expressing MCF-7 BC cells (MCF-7YS). Mass spectrometry (MS) and Metacore analyses were performed to investigate how the functional interactions between BC cells/fibroblasts may affect their proteomic profile. The impact of fibroblasts on BC tumor growth and metastatic potential was evaluated in nude mice. Results Mutant BC conditioned medium (CM) affected the morphology/proliferation/migration of both NFs and CAFs. 198 deregulated proteins signed the proteomic similarity profile of NFs exposed to the YS-CM and CAFs. Among the upregulated proteins, Yes-associated protein 1 (YAP1) was the main central hub in the direct interaction network. Increased YAP1 protein expression and activity were confirmed in NFs treated with MCF-7YS-CM. However, YAP1 activation appears to crosstalk with the insulin growth factor-1 receptor (IGF-1R). Higher amount of IGF-1 were noticed in the MCF-7YS-CM cells compared to the MCF-7P, and IGF-1 immunodepletion reversed the enhanced YAP1 expression and activity. Mutant cells upon exposure to the NF- and CAF-CM exhibited an enhanced proliferation/growth/migration/invasion compared to the MCF-7P. MCF-7YS cells when implanted with CAFs showed an early relative increased tumor volume compared to YS alone. No changes were observed when MCF-7P cells were co-implanted with CAFs. Compared with that in MCF-7P cells, the metastatic burden of MCF-7YS cells was intrinsically greater, and this effect was augmented upon treatment with NF-CM and further increased with CAF-CM. Conclusions YS mutant BC cells induced the conversion of fibroblasts into CAFs, via YAP, which represent a potential therapeutic target which interrupt the functional interactions between mutant cells/TME and to be implemented in the novel therapeutic strategy of a subset of metastatic BC patients carrying the frequent Y537S mutations.

Electrochemotherapy (ECT) is an emerging therapeutic approach gaining growing interest for its potential immunomodulatory effects in cancer treatment. This narrative review systematically examines the current state of knowledge regarding the interplay between ECT and the immune system. Through an analysis of preclinical and clinical studies, the review highlights ECT capacity to induce immunogenic cell death, activate dendritic cells, release tumor antigens, trigger inflammatory responses, and occasionally manifest systemic effects—the abscopal phenomenon. These mechanisms collectively suggest the ECT potential to influence both local tumor control and immune responses. While implications for clinical practice appear promising, warranting the consideration of ECT as a complementary treatment to immunotherapy, the evidence remains preliminary. Consequently, further research is needed to elucidate the underlying mechanisms, optimize treatment protocols, explore potential synergies, and decipher the parameters influencing the abscopal effect. As the field advances, the integration of ECT’s potential immunomodulatory aspects into clinical practice will need careful evaluation and collaboration among clinical practitioners, researchers, and policymakers.

Abstract PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer.

ABSTRACT Background Biallelic pathogenic variants in the FUCA1 gene are associated with fucosidosis. This report describes a 4‐year‐old boy presenting with psychomotor regression, spasticity, and dystonic postures. Methods and Results Trio‐based whole exome sequencing revealed two previously unreported loss‐of‐function variants in the FUCA1 gene. Brain magnetic resonance imaging (MRI) findings included corpus callosum hypoplasia, white matter hypomyelination, and alterations in the globus pallidi, alongside markedly reduced cortical thickness. Conclusions These findings suggest that cortical atrophy may occur in the early stages of fucosidosis. Early diagnosis is imperative for genetic counseling, timely investigations, and initiating early therapeutic interventions to potentially mitigate more extensive brain involvement.

High-grade serous ovarian carcinoma (HGSOC) is one of the deadliest malignancies in female population and the cause of 70% of all ovarian cancer-related deaths. Among its hallmarks, the fluid accumulation in the peritoneal cavity, or ascites, is a peculiar pathological sign during late stages and in recurrent patients. Besides cancer cells, ascitic fluids contain a heterogeneous cellular composition, representing a precious source to dissect molecular mechanisms underlying invasion and metastatization or find new biomarkers to predict therapy response. However, malignant cells are often a minority population in ascites making the detection and analysis of cancer cells a challenge. Here we propose a combinatorial approach for the detection of malignant cells in OC ascites based on TP53 deep sequencing and PAX8 cytological staining. In addition, we improve the procedure by implementing a cancer cell enrichment step, increasing the sensitivity in the detection of neoplastic fraction and potentiating downstream research and diagnostics applications.

The aim of this study was to evaluate the influence of different pressures of homogenization on whole milk powder with crystallized lactose on free fat content and particle size. Three homogenization pressure levels were applied. The powder produced at homogenization pressure of 75/5 MPa presented a smaller number of particles in the region < 1 μm (39.28%) and higher free fat content (13.78%) when compared to the powder produced at conventional homogenization pressure (15/5 MPa), which presented 59.40% particles in the region < 1 μm and 5.03% of free fat. Milk powder produced at 0/0 MPa presented the lowest number of particles in the region < 1 μm (24.60%) and the highest free fat content (19.39%). This study showed that the powder produced at a homogenization pressure of 15/5 MPa, which is commonly used in the industry, produces a crystallized milk powder with less suitable properties than the one obtained without homogenization.

Summary: Background: Heart Failure (HF) quality of care (QoC) is associated with clinical outcomes. Therefore, we investigated differences in HF QoC across worldwide regions (with differing national income) and the association of quality indicators with outcomes. Methods: We examined the quality of care (QoC) in acute heart failure (HF) patients across different regions using quality indicators (QIs) from the European Society of Cardiology (ESC) and the American Heart Association (AHA) to evaluate QoC. The analysis included 17,632 patients enrolled from 358 medical centres in 44 countries between 23 July 2014 and 24 March 2017, all part of the prospective REPORT-HF cohort study. We investigated how QoC varied by region and its relationship with mortality rates at 30 days and 1 year after hospital discharge. For each QI, percentage attainment of QI among eligible patients was calculated and compared across regions. Findings: Among 17,632 patients (median age: 67 years; 61% women) followed up for a median of two years, we assessed 16 QIs. QIs that were least often achieved included measurement of natriuretic peptides, performance of echocardiography, treatment with guideline medical therapy, and a scheduled follow-up consultation after discharge. QI achievement was significantly lower in lower-than higher-income countries. Higher (≥50% vs.

AIM: This analysis investigated the population with Myasthenia Gravis (MG) in Italy, to describe epidemiology, mortality, patients’ characteristics, comorbidity profile, therapeutic management, and healthcare consumption and related costs. METHODS: From 2012 to 2021, MG patients were identified in administrative flows of healthcare entities through hospitalization discharge diagnosis or exemption code for MG or a pyridostigmine prescription. Medications and comorbidities were searched before inclusion and healthcare costs were analysed at 1-year follow-up. Epidemiology estimates were reported as cases/100,000 people, and mortality rates, stratified by age classes and gender, were assessed during 2019. MG patients were compared with age- and gender-matched subjects without MG. RESULTS: At the end of 2021, MG prevalence was 35.1/100,000 and incidence 4.7/100,000 people. Mortality in 2019 was 3.2% in overall MG sample, and tended to rise in males and elderly patients. About 90% received MG-related treatments, namely pyridostigmine, corticosteroids and immunosuppressants (81.3%, 76.9% and 26.1% of patients respectively). Unsurprisingly, the yearly healthcare resource consumption/patient was higher in MG patients than in non-MG subjects (p

EVALUATION AND COMPARISON OF COLOIDAL SYSTEMS OF UHT MILK MARKETED IN THE SOUTH AND SOUTHEAST REGIONS OF BRAZIL. Ultra high temperature (UHT) milk has great relevance in the Brazilian dairy market. Thermal processing, physical-chemical and compositional properties have relevant impact on the quality of milk processed via UHT. The emergence of new categories of this product makes the production scenario even more challenging. The aim of this study was to investigate UHT milk and the effect of food additives on it, from a colloidal perspective, in the main consumer regions. The colloidal systems of samples with or without addition of stabilizers and with or without addition of tricalcium phosphate were evaluated based on analyses of ionic calcium concentration, pH, sedimentation, HCT (heat coagulation time), ethanol stability, particle size (D90) and zeta potential. The results indicated a relevant colloidal stability for this type of matrix, in addition to an efficient industrial homogenization process. The samples that received stabilizers addition showed lower ionic calcium, higher HCT and greater ethanol stability. There was no significant difference in sediment mass and pH. The samples that received Ca3(PO4)2 addition showed higher sedimentation and lower stability to ethanol. There were no significant differences regarding ionic calcium, pH and HCT.

ABSTRACT: Wine industry by-product (WIBP) encapsulated in alginate beads were incorporated to beer to increase antioxidant properties. The phenolic profile, in vitro bioaccessibility and gut metabolism were assessed. Scanning electron micrographs of the beads with WIBP revealed a relatively rough surface with large pores with craters, but without cracks, which ensures the protection of the encapsulated compounds. X-ray diffraction profiles showed the attenuated of the crystalline peaks, indicating the interactions between alginate and Ca2+. The WIPB antioxidant activity was assessed by FRAP (0.13 mmol Fe2+/g WIBP) and TEAC (0.078 mmol Trolox/g WIBP). The phenolic profile of the craft beer was not altered after the immersion of the beads for 60 days, maintaining its six free phenolic compounds (gallic, 3,4-dihydroxyphenylacetic, 4-hydroxybenzoic, 2,4-dihydroxybenzoic, ferulic, and salicylic acids). The phenolic compounds observed in WIBP and not in the craft beer (quercetin, rutin and syringic acids) were only detected after simulated digestion of WIBP beads that had been immersed in the beer, showing that the encapsulation of WIBP with calcium alginate beads protected the phenolic compounds until consumption. Total phenolic content increased after simulated digestion, and after gut fermentation. During this process the phenolic compounds diversity in each digestion step also increased. Therefore, the enrichment of beer with alginate beads containing the WIBP not only increases the content of phenolic compounds ingested by the consumer, but also the bioaccessibility of those compounds in relation to beer without the beads.

DNAJC15 is a mitochondrial TIMM23-related co-chaperonin known for its role in regulating oxidative phosphorylation efficiency, oxidative stress response and lipid metabolism. Recently, it has been proposed that the loss of DNAJC15 correlates with cisplatin (CDDP)-resistance onset in ovarian cancer (OC), suggesting this protein as a potential prognostic factor during OC progression. However, the molecular mechanisms through which DNAJC15 contributes to CDDP response remains poorly investigated. Here, we show that high levels of DNAJC15 are associated with accumulation of lipid droplets, decreased tumorigenic features and increased sensitivity to CDDP in OC cells. When overexpressed, DNAJC15 induced a phenotype displaying increased lipid peroxidation and subsequent ferroptosis induction. To prove a role for DNAJC15-induced ferroptosis in promoting sensitivity to CDDP, we reduced lipid peroxidation upon Ferrostatin 1 treatment, which decreased cells’ vulnerability to ferroptosis ultimately recovering their CDDP-resistant phenotype. In conclusion, our study uncovers the role of DNAJC15 in modulating ferroptosis activation and in the onset of CDDP resistance in OC cells.

In this study, we focused on the computational analysis of a selected single-point mutation identified by a NGS screening panel in the TET2 enzyme classified as “variant of uncertain clinical significance.” The mutation, namely Q1084P, occurs at the interface between TET2, an important epigenetic regulator, and NANOG, a transcription factor fundamental for hematopoietic cells differentiation. Notably, the mutation occurs in a protein region distant from the active site; moreover, the experimental structures of the interacting region of both proteins are unknown, making it difficult to validate the impact of TET2 mutation on its binding with NANOG. To address these challenges, we employed an integrated computational approach combining molecular docking, molecular dynamics simulations and protein-protein interaction prediction. Our findings indicate that the single-point mutation might effectively reduce the TET2-NANOG interaction, which would consequently impair cells differentiation and hematopoiesis process, consistent with the clinical presentation of pure red cell aplastic anemia. These results, along with the proposed computational method, provide insights for establishing clinical correlations between variants of uncertain significance and anemias in general, comprising common hematological problems widespread in the world population and for which dedicated NGS panels are still not available.

BackgroundThe increasing use of social media to share lived and living experiences of substance use presents a unique opportunity to obtain information on side effects, use patterns, and opinions on novel psychoactive substances. However, due to the large volume of data, obtaining useful insights through natural language processing technologies such as large language models is challenging. ObjectiveThis paper aims to develop a retrieval-augmented generation (RAG) architecture for medical question answering pertaining to clinicians’ queries on emerging issues associated with health-related topics, using user-generated medical information on social media. MethodsWe proposed a two-layer RAG framework for query-focused answer generation and evaluated a proof of concept for the framework in the context of query-focused summary generation from social media forums, focusing on emerging drug-related information. Our modular framework generates individual summaries followed by an aggregated summary to answer medical queries from large amounts of user-generated social media data in an efficient manner. We compared the performance of a quantized large language model (Nous-Hermes-2-7B-DPO), deployable in low-resource settings, with GPT-4. For this proof-of-concept study, we used user-generated data from Reddit to answer clinicians’ questions on the use of xylazine and ketamine. ResultsOur framework achieves comparable median scores in terms of relevance, length, hallucination, coverage, and coherence when evaluated using GPT-4 and Nous-Hermes-2-7B-DPO, evaluated for 20 queries with 76 samples. There was no statistically significant difference between GPT-4 and Nous-Hermes-2-7B-DPO for coverage (Mann-Whitney U=733.0; n1=37; n2=39; P=.89 two-tailed), coherence (U=670.0; n1=37; n2=39; P=.49 two-tailed), relevance (U=662.0; n1=37; n2=39; P=.15 two-tailed), length (U=672.0; n1=37; n2=39; P=.55 two-tailed), and hallucination (U=859.0; n1=37; n2=39; P=.01 two-tailed). A statistically significant difference was noted for the Coleman-Liau Index (U=307.5; n1=20; n2=16; P

Not available.

Food waste management is a growing global concern, driven by the imperative to address environmental sustainability, resource conservation, and global hunger. This article aims to provide a theoretical analysis of the historical evolution of food waste management, delving into the definition of the term and its international relevance. Additionally, it critically examines the need for sustainable approaches. The methodology comprises a comprehensive literature review from 2013 to 2023, utilizing keywords related to food waste, sustainability, and the circular economy. The databases used include Science Direct and MDPI. Findings reveal a shift from individual to institutional food waste sources, underscoring the necessity for alternative approaches. Environmental analysis highlights the adverse impacts of conventional practices, while strategies such as food rescue, fermentation, and anaerobic digestion emerge as promising solutions. Understanding consumer behavior is crucial, and smart labels are introduced as potential tools to reduce food waste. The article identifies the challenges and limitations of current food waste management practices, emphasizing the need for sustainable treatments. Sustainable approaches in managing food industry residues, including food rescue, fermentation, and anaerobic digestion, are discussed as alternatives to conventional methods. The article concludes by proposing future research directions, emphasizing the importance of understanding consumer behavior, exploring the potential of smart labels, and addressing gaps in current knowledge to achieve a more sustainable and responsible approach to food consumption and waste management.

Abstract Background Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann’s procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P

La formazione della coppia è un processo in continua evoluzione, negli ultimi anni le richieste d’aiuto per la psicoterapia di coppia sono sempre più in aumento. I motivi sembrano riguardare il presente, ma spesso sono legati ad un malessere radicato nel tempo. Attraverso la lente dello psicoterapeuta della Gestalt abbiamo analizzato prevalentemente gli studi della teoria dell’attaccamento riferiti al lavoro con le coppie attraverso un’integrazione di approcci, teorie e pratiche, in particolare la terapia di coppia focalizzata sulle emozioni. Secondo la teoria dell’attaccamento gli stili relazionali degli adulti con i propri partner sono paralleli alle relazioni bambino-caregiver, caratterizzandosi perciò per la ricerca di determinate caratteristiche nell’altra persona. Il lavoro psicoterapeutico con le coppie ha tra i propri obiettivi quello di modificare i modelli operativi interni di attaccamento dei pazienti. La terapia di coppia focalizzata sulle emozioni si basa sulla risposta emotiva e su quello che i partner sentono all’interno di una relazione supportante. Consente un’esperienza emotiva risanatrice, trasformando i cicli di interazione negativa presenti nella relazione e sperimentati con i caregiver primari. La psicoterapia della Gestalt ci aiuta a osservare come i partner della coppia realizzano o bloccano la loro intenzionalità di raggiungere e farsi raggiungere dall'altro. Lo scopo della ricerca è stato esaminare i correlati tra teoria dell’attaccamento, terapia focalizzata sulle emozioni e terapia della Gestalt, in vista di ulteriori studi che permettano un maggior approfondimento delle dinamiche di coppia in terapia.

Background: JAK2 V617F is a somatic mutation associated with myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In MPNs, this mutation is associated with the germline GGCC (46/1) haplotype. Several studies associated JAK2 haplotype GGCC_46/1 with some MPNs clinical parameters, but not one explore the link between JAK2 haplotype GGCC_46/1 and onco-drug resistance. Thus, we assessed for the JAK2 46/1 haplotype’s correlation with therapy response in JAK2 V617F-positive patients. Methods: Patients with MPN, selected by the Hematology Laboratory of “V. Fazzi” Hospital (LE), were analyzed with RLFP-PCR assay with rs10974944 SNP. Results: Results show how the majority of patients had PV (63%) or PMF (61%) and that 58% of patients who developed drug resistance had the C/G genotype, while only 11% had the G/G allele. While no direct correlation between JAK2 46/1 haplotype variants and drug resistance was found, the G/G allele was associated with disease progression to myelofibrosis and certain resistance-related clinical parameters (p = 0.002449, odds ratio = 3.701209). Conclusions: Although other analyses are required, due to the narrow cardinality of sample, our findings suggest how the G/G allele could be useful for MPNs diagnosis and for the prediction of the disease outcome.

Pleurotus spp. compõem o segundo grupo dos cogumelos mais cultivados no mundo. A elaboração de farinha a partir da biomassa desses macrofungos constitui uma alternativa tecnológica para a formulação de produtos alimentícios funcionais. O objetivo desta pesquisa foi caracterizar a farinha de Pleurotus djamor cultivado em resíduo lignocelulósico da floresta amazônica. P. djamor, cedido pela coleção de culturas DPUA, da Universidade Federal do Amazonas, foi cultivado em ágar batata dextrose + extrato de levedura 0,5% (p/v). Para obtenção do inóculo, P. djamor foi cultivado em ágar Sabouraud + extrato de levedura 0,5% (p/v). A produção do cogumelo foi realizada em exocarpo de cupuaçu (Theobroma grandiflorum) suplementado com farelo de arroz. Em seguida, foram avaliados os parâmetros de produção e os basidiomas obtidos foram utilizados para elaboração da farinha. Neste produto alimentício foram determinadas a composição centesimal, análise microbiológica e as propriedades tecnológicas. Os parâmetros produtivos evidenciaram que adaptação da espécie e o potencial de resíduos Amazônicos foram significativos, pois apresentaram eficiência biológica 137,91%, taxa de produção 8,11 g/dia, produtividade 21,81% e perda de matéria orgânica 31,86%. O tamanho médio dos basidiomas foi de 12,2 x 7,5cm, estipe 2,5cm. A farinha demonstrou ser fonte de nutrientes como proteínas (13,68%) e fibras (9,84%). O índice de absorção de água, índice de solubilidade em água e capacidade de capacidade de intumescimento foram 6,29 g/g, 52% e CI 5,68 g/g, respectivamente. A farinha de cogumelo ostra cultivado em resíduos agroflorestais amazônicos constitui uma alternativa inovadora para a elaboração de alimentos funcionais saudáveis.

Abstract Background Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods In this study, 382 infants born at 24+0–27+6 weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. The secondary outcomes are BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0–27+6 weeks’ gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks’ postmenstrual age of life. Trial registration ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Our objectives were to develop a blend of heat-extracted jaboticaba juice and apple juice, and to investigate the protective effect of the addition of metallic cations on the stability of its anthocyanins during storage at 25 °C, 45 °C and 80 °C. Jaboticaba juice yields were similar when extracted at 70 °C and 90 °C. However, juice extracted at the higher temperature exhibited higher ideal proportions of apple juice for the attributes “sweetness” and “color” compared to that extracted at the lower temperature. The blended juice containing 55 % of jaboticaba juice extracted at 90 °C was sensory well-accepted (overall acceptance score of 7.1 in a 9-point scale), but the addition of apple juice resulted in 10 % higher losses in total anthocyanins contents after 30 days at 25 °C. The addition of Ca2+, Mg2+, Fe2+ and Fe3+ led to a less fast degradation of anthocyanins of jaboticaba juice only at 80 °C. At 45 °C, Zn2+ was the sole metallic cation which addition reduced total anthocyanins degradation of JAJ, while the other cations increased anthocyanins degradation. At 25 °C, Zn2+addition delayed anthocyanins degradation of both jaboticaba and blended juices, but better in the absence of apple juice. Although the use of apple juice instead of sucrose as a sweetener was detrimental to anthocyanins protection, it should be considered from the nutritional point of view.

ABSTRACT Background The identification of actionable molecular targets of pancreatic cancer (PAC) is key to improving patient outcomes. We hypothesized O6‐methylguanine‐DNA methyltransferase (MGMT) silencing may occur in a subset of PAC tumors, with unexplored clinical and molecular correlates. Experimental Design We leveraged sequencing data from The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium 3 (CPTAC‐3), and the (Australian Pancreatic Cancer Genome Initiative) PACA‐AU cohorts to characterize MGMT‐silenced PAC. Genomic, transcriptomic, methylation, and clinical data were investigated, and findings were validated in silico using methylation, transcriptomic and drug sensitivity data from Cancer Cell Line Encyclopedia (CCLE) project, and in a real‐world cohort of PAC patients profiled for MGMT status at Istituto Nazionale Tumori of Milan (INT). Results On the basis of Human Methylation 450k data, MGMT silencing was identified in ~6% of PAC cases and was enriched in tumors with non‐ductal histology, with a trend toward longer overall survival. MGMT‐silenced tumors were associated with a lower frequency of KRAS mutations and showed features of immune exclusion. In the INT cohort, MGMT‐silencing was confirmed in ~7% of cases and prevalent in KRAS wild type tumors, with a favorable prognostic impact. In silico analysis suggested a higher sensitivity to alkylating and DNA damaging agents in MGMT‐silenced PAC cell lines. Conclusions MGMT silencing occurs in a small subgroup of PACs and is enriched in KRAS wild type cases, with a favorable prognostic impact. Our findings provide the rationale to explore combinations of alkylating with DNA damaging agents in MGMT‐silenced PAC.

Vulvodynia is a chronic pain condition that affects the vulvar area, often resulting in significant discomfort and a reduced quality of life. Current treatments for vulvodynia are limited, and there is a need for more effective therapeutic options. Acmella oleracea, known for its spilanthol content, and Boswellia serrata, rich in boswellic acids, have been explored for their potential analgesic properties in pain management. In this study, vulvodynia-like symptoms were induced in female mice using Complete Freund’s adjuvant (CFA). After the induction of symptoms, the mice were treated with a combination of Acmella oleracea and Boswellia serrata extracts (AO + BS). Behavioral pain assessments were conducted to monitor the effects of the treatment. Additionally, biochemical and functional evaluations were performed to measure spinal microgliosis and neuronal overexcitation. The combination of Acmella oleracea and Boswellia serrata (AO + BS) resulted in a significant reduction of vulvar hypersensitivity in mice. Besides alleviating pain, AO + BS therapy also reduced spinal microgliosis and neuronal overexcitation in mice with vulvodynia. The findings suggest that the AO + BS combination has the potential to alleviate vulvodynia associated pain through mechanisms involving the reduction of spinal microgliosis and neuronal overexcitation. These results point to the therapeutic promise of these plant extracts for chronic pain conditions like vulvodynia. The combination of Acmella oleracea and Boswellia serrata shows potential as a treatment for vulvodynia. However, further studies are needed to explore the underlying mechanisms and to optimize the dosage for clinical use.

Chikungunya virus (CHIKV) has emerged as a significant public health concern due to its rapid spread and potential for causing debilitating epidemics. In Argentina, the virus has garnered attention since its introduction to the Americas in 2013, due to its growing incidence and impact in neighbouring countries. Here we present a comprehensive analysis of the spatiotemporal dynamics of CHIKV in Argentina, focusing on the evolutionary trajectory of its genetic variants. Through a combination of active surveillance, screening of historical and recent samples, and whole-genome sequencing, we traced the evolutionary history of CHIKV lineages circulating within the country. Our results reveal that two distinct genotypes circulated in Argentina: The Asian lineage during the 2016 epidemic and the ECSA lineage in 2023. This distribution reflects the dominance of particular variants across Latin America. Since 2023, the ECSA lineage has led to a surge in cases throughout the Americas, marking a significant shift. The replacement of lineages in the American region constitutes a major epidemiological event, potentially affecting the dynamics of virus transmission and the clinical outcomes in impacted populations. The spatiotemporal analysis highlights CHIKV's distribution across Argentina and underscores the significant role of human mobility, especially when considering recent epidemics in neighbouring countries such as Paraguay and Uruguay, which have facilitated the spread and introduction of the viral strain into different districts. By integrating epidemiological data with genomic insights, we elucidate the patterns of virus dissemination, highlighting key areas of transmission and potential factors contributing to its spread.

Objective Lynch syndrome (LS) is a hereditary condition associated with an increased risk of colorectal and endometrial cancer. This study aimed to assess the knowledge, attitudes, and beliefs of women with LS regarding combined hormonal contraceptive (CHC) use compared to a control group of healthy women.Methods Pre-menopausal women with LS (n = 43) and an age-matched control group of healthy women (n = 128) participated in this prospective, cross-sectional study (NCT05909410). Participants completed an electronic questionnaire evaluating perceptions of CHC use and its impact on various cancers, medical conditions, and symptoms. Statistical analysis compared responses between the two groups, with reported p-values.Results Women with LS were less likely to use CHCs compared to the control group (p = 0.03) and had a more negative perception of CHCs’ impact on colorectal cancer (p = 0.023) and endometrial cancer (p = 0.028). Limited knowledge was observed in both groups regarding the protective effects of CHCs against colorectal and ovarian cancer. Perceptions of CHC use and its impact on symptoms and chronic diseases did not significantly differ between the groups (p > 0.05). CHC use was not associated with greater awareness of the protective effect against colorectal (p = 0.89) and endometrial cancer (p = 0.47), but it was associated with a desire for contraception (OR 21.25; 95% CI 1.16 to 388.21; p = 0.039).Conclusion This study highlights contrasting perceptions of CHCs and their implications in oncology between women with LS and healthy women. Tailored counselling and support strategies are crucial for empowering women with LS to make informed decisions about their gynaecologic health.

Opioid use disorder (OUD) is associated with a history of early-life adversity (ELA), an association that is particularly strong in women. In a rodent model, we previously found that ELA enhances risk for opioid addiction selectively in females, but the mechanisms for this effect are unclear. Here, we show that ELA robustly alters cFos responses to opioid drugs in females’ nucleus accumbens (NAc) and basolateral amygdala (BLA), but not elsewhere. We further identify delta opioid receptors (DOR), which mature in the first week of life and thus later than kappa or mu opioid receptors, as a potential mediator of ELA's impacts on reward circuit functions. Accordingly, DOR mRNA in NAc was persistently reduced in adult females with ELA history. Moreover, pharmacological stimulation of NAc DORs increased opioid demand in control females (recapitulating the ELA phenotype), while blocking DORs in ELA females conversely reduced high-effort drug consumption, simulating the control rearing phenotype. These findings support a role for NAc DORs in mediating ELA-induced opioid vulnerability. In contrast, BLA neurons expressing DOR protein do not overlap heroin- responsive cells in ELA rats, arguing against a direct relationship of BLA DORs to heroin's addiction-relevant actions in the brain. Together, these results suggest a novel and selective role for NAc DORs in contributing to enduring, ELA-provoked vulnerability to OUD.

In this work, we present the detection of proteins expressed by poxvirus with fiber-optic probes based on a semi-distributed interferometer (SDI) assisted by a fiber Bragg grating (FBG), performing the measurement directly into a wastewater sample. Modern biosafety applications benefit from real-time, dynamic-sensing technologies that can perform diagnostic tasks into a wide set of analytes, with a particular emphasis on wastewater, which appears to collect a significant number of viral titers in urban and indoor environments. The SDI/FBG probe can perform substantial progress in this field, as it embeds a dual sensitivity mechanism to refractive index changes (sensitivity up to 266.1 dB/RIU (refractive index units)) that can be exploited in biosensing, while simultaneously having the capability to measure the temperature (sensitivity 9.888 pm/°C), thus providing an intrinsic cross-sensitivity compensation. In addition, a standard FBG analyzer can be used as an interrogator, improving affordability and real-time detection over previous works. The probes have been functionalized with antibodies specific for L1, A27 and A33 vaccinia virus proteins, performing detection of a protein concentration in a scenario compatible with online viral threat detection. Direct detection of wastewater samples shows that the L1-functionalized sensor has a higher response, 9.1–11.3 times higher than A33 and A27, respectively, with a maximum response of up to 1.99 dB and excellent specificity. Dynamic detection in wastewater shows that the sensors have a response over multiple detection cycles, with a sensitivity of 0.024–0.153 dB for each 10-fold increase of concentration.

We provide a simple proof of why the Love number vanishes for extremal Reissner-Nordstrøm and Kerr-Newman black holes. The argument is based on a conformal inversion isometry of the spacetime connecting the horizon with large distances.

To date, no retrospective or real-world studies have comprehensively examined the interactions between direct-acting antivirals (DAAs) and widely used medications such as novel oral anticoagulant, statins, and antihypertensive agents. However, clinical experience from key opinion leaders may guide physicians in managing these interactions in patients undergoing DAA treatment. This study aims to elucidate the interactions between DAAs and commonly prescribed drugs in patients with prevalent comorbidities (e.g., type II diabetes, hypertension, and dyslipidemia), with a particular focus on those receiving polytherapy with cardiovascular drugs while undergoing DAA treatment for hepatitis C. The clinicians’ experience was combined with input from a qualified expert panel using a Consensus Delphi approach. The findings of this study offer essential and practical recommendations that can be readily applied in everyday clinical practice, helping physicians in managing hepatitis C virus patients undergoing DAA therapy.

Patients’ self-reporting is increasingly considered essential to measure quality-of-life and treatment-related side-effects. However, if multiple patient-reported instruments are used, redundancy may represent an overload for patients.Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) are a tool allowing direct patients’ reporting of side-effects.We tested psychometric properties of a selected list of PRO-CTCAE items, in a cohort of 303 breast cancer patients, using validated instruments for quality of life assessment as anchors.The analysis of convergent validity with HADS (Hospital Anxiety and Depression Scale) and EORTC BR-23 sub-scales, and the analysis of responsiveness with the PGIC (Patients Global Impression of Change) score supported that a selected list of PRO-CTCAE symptoms might represent a standardized, agile tool for both research and practice settings to reduce patient burden without missing relevant information on patient perceptions.Among patients using digital devices, those with a higher education levels required shorter time to fulfil questionnaires.In conclusion, a selected list of PRO-CTCAE items can be considered as a standardized, agile tool for capturing crucial domains of side-effects and quality of life in patients with breast cancer.The study is registered on clinicaltrials.gov (NCT04416672).

IntroductionEwing Sarcoma (EWS) has been reported in seven children with Down syndrome (DS). To date, a detailed assessment of this solid tumour in DS patients is yet to be made.MethodsHere, we characterise a chemo-resistant mediastinal EWS in a 2-year-old DS child, the youngest ever reported case, by exploiting sequencing approaches.ResultsThe tumour showed a neuroectodermal development driven by the EWSR1-FLI1 fusion. The inherited myeloperoxidase deficiency of the patient caused failure of neutrophil-mediated cell death and promoted genomic instability.DiscussionIn this context, the tumour underwent genome-wide near haploidisation resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered rapid evolution of this EWS.

Abstract Phycocyanin (PC) is commercially exploited in various commercial sectors, as novel applications are developed rapidly. However, the state-of-the-art is difficult to define, given the extremely heterogeneous information available. Hence, this study aimed to perform a technological and scientific review on PC production from Spirulina (Arthrospira spp.), based on a bibliometric analysis of patents and research articles deposited from 2015 to 2023. To close the knowledge gap evidenced by the prospection, we optimized the instrumental conditions of microalgae cultivation, i.e., orbital agitation, culture volume, and cultivation time, for the production of PC. We assessed the color parameters and stability of the PC used as an ice cream colorant. The prospection highlighted rather diverse points of view between academia and the industry regarding PC production methods. The optimization showed a substantial impact of cultivation time on PC yield and purity. A purification step via precipitation was note necessary to obtain food-grade PC (purity > 0.7). Optimal experimental conditions were 180 rpm, 250 mL, and 14 days of cultivation. The ice cream colored using PC from the optimized cultivation conditions showed concentration-dependent color variations, without significant color losses for 90 days.

The damage observed during past earthquakes demonstrated the need for the seismic vulnerability assessment of industrial plants to reduce the risk of major accidents and to develop detailing for risk mitigation. If damaged by a seismic event, industrial plants might be affected by a domino effect with the consequent interruption of plant serviceability and severe economic losses; at the same time, toxic substances could be released due to the damage of pipelines and tanks, causing environmental damages and loss of lives. This preliminary study investigates the influence of the dynamic properties of pressurised tanks on the industrial plant seismic vulnerability, focusing on the possible issues to which the pipelines connecting the tanks are prone. To this purpose, numerical analyses are conducted aimed at identifying the most critical conditions in terms of displacements and stress state to which the pipelines are subjected. At the same time, a framework for the definition of fragility functions including the damage states related to piping connections, is also presented.

Introdução: Os serviços de saúde são criados para darem resolutividade ao processo saúde-doença e, se não buscarem qualidade, o efeito para o usuário pode significar riscos. Assim, ao pensarmos em qualidade, necessitamos identificar nosso cliente e pensar em quais requisitos ele espera para o nosso serviço. O Transplante de Medula Óssea (TMO), apesar de ser considerado seguro e de alta especialidade, também é complexo e exige cuidados efetivos da equipe multiprofissional, em todas as suas fases. Objetivo: Relatar os benefícios da inserção no Programa Mais TMO/PROADI-SUS para o serviço de TMO de um hospital universitário. Método: Após inserção, equipe do Hospital da Beneficência Portuguesa, vinculada ao programa, realizou visita diagnóstica no centro de transplante de medula óssea de um hospital universitário; reuniões periódicas, por videoconferência, para monitoramento das ações de melhoria de processos gerenciais propostas; imersões semanais “in loco”de cinco equipes multiprofissionais do centro de TMO; realização de curso em plataforma on-line sobre TMO. Resultados: A inserção no programa propiciou a revisão dos processos internos do centro de TMO; identificação de fragilidades a partir do diagnóstico situacional; elaboração de planos de ação com metas e execução monitoradas quinzenalmente, criação de indicadores setoriais, capacitação profissional, que oportunizaram reflexões internas, fomentaram mudança organizacional visando a segurança e a melhoria da qualidade da assistência prestada. Conclusão: A realização de capacitação e revisão dos processos internos fomentam mudança organizacional, aumentam as interações entre os processos relacionados e tendem a melhorar a qualidade e a segurança da assistência prestada.

Se formula una propuesta hermenéutica referente a la regulación de los proyectos de inversión con efectos o potenciales efectos sobre comunidades indígenas. Esta propuesta sistematiza estándares de cumplimiento y enfoques culturalmente pertinentes, conforme el derecho humano al medio ambiente sano y el derecho humano a la identidad cultural, articulando las fuentes desde los niveles internacional y regional interamericano, para la protección de comunidades indígenas y respectivos territorios ambientalmente relevantes. Con base en dicha propuesta, se realiza un análisis crítico de jurisprudencia chilena en materia ambiental (competencia técnica ambiental o constitucional). Luego, se identifican brechas de cumplimiento, de origen regulatorio o interpretativo judicial, en la protección de comunidades indígenas, frente a los proyectos de inversión, conforme los referidos a estándares de contenidos en la propuesta. El estudio se focaliza en proyectos de inversión y sus efectos sobre los “intangibles culturales indígenas”, como bienes jurídicos protegidos a la luz de los derechos humanos indicados. Así, en el epígrafe 1), se estudia el derecho humano a la identidad cultural y el derecho humano al medio ambiente sano; en el epígrafe 2) se revisa el marco normativo doméstico pertinente a la evaluación ambiental; en el epígrafe 3) se formula una propuesta hermenéutica cautelar ambiental e intercultural; en el 4) se estudia críticamente la jurisprudencia ambiental local a partir de la propuesta formulada.

Abstract Filtering approaches on Global Ecosystem Dynamics Investigation (GEDI) data differ considerably across existing studies and it is yet unclear which method is the most effective. We conducted an in‐depth analysis of GEDI's vertical accuracy in mapping terrain and canopy heights across three study sites in temperate forests and grasslands in Spain, California, and New Zealand. We started with unfiltered data (2,081,108 footprints) and describe a workflow for data filtering using Level 2A parameters and for geolocation error mitigation. We found that retaining observations with at least one detected mode eliminates noise more effectively than sensitivity. The accuracy of terrain and canopy height observations depended considerably on the number of modes, beam sensitivity, landcover, and terrain slope. In dense forests, a minimum sensitivity of 0.9 was required, while in areas with sparse vegetation, sensitivity of 0.5 sufficed. Sensitivity greater than 0.9 resulted in an overestimation of canopy height in grasslands, especially on steep slopes, where high sensitivity led to the detection of multiple modes. We suggest excluding observations with more than five modes in grasslands. We found that the most effective strategy for filtering low‐quality observations was to combine the quality flag and difference from TanDEM‐X, striking an optimal balance between eliminating poor‐quality data and preserving a maximum number of high‐quality observations. Positional shifts improved the accuracy of GEDI terrain estimates but not of vegetation height estimates. Our findings guide users to an easy way of processing of GEDI footprints, enabling the use of the most accurate data and leading to more reliable applications.

Abstract Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a ‘control group’ consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor.

This article considers a subset of lawsuits in which emancipated people sued to have their enslavers’ bequests to them honored. It contends that we should see these suits as contests over reparations. By exploring this unappreciated history, this article argues that enslavers themselves believed reparations were due and were willing to pay them, that there was a general agreement between enslaved and enslaver about the form reparations should take, and that there was a similar understanding that reparations should be generational. The article further suggests the promise of additional inquiry into historical testamentary records. Such a novel archive would add to contemporary arguments in favor of reparations by identifying an unacknowledged effort to provide compensation to formerly enslaved people.

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 β (IL-1β) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1β production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.

Abstract The evaluation of cognitive functions interactions has become increasingly implemented in the cognition exploration. In the present study, we propose to examine the organization of the cognitive network in healthy participants through the analysis of behavioral performances in several cognitive domains. Specifically, we aim to explore cognitive interactions profiles, in terms of cognitive network, and as a function of participants’ handedness. To this end, we proposed several behavioral tasks evaluating language, memory, executive functions, and social cognition performances in 175 young healthy right-handed and left-handed participants and we analyzed cognitive scores, from a network perspective, using graph theory. Our results highlight the existence of intricate interactions between cognitive functions both within and beyond the same cognitive domain. Language functions are interrelated with executive functions and memory in healthy cognitive functioning and assume a central role in the cognitive network. Interestingly, for similar high performance, our findings unveiled differential organizations within the cognitive network between right-handed and left-handed participants, with variations observed both at a global and nodal level. This original integrative network approach to the study of cognition provides new insights into cognitive interactions and modulations. It allows a more global understanding and consideration of cognitive functioning, from which complex behaviors emerge.