Search

Abstract Background Current guidelines for osteoporosis diagnosis do not recommend forearm dual-energy X-ray absorptiometry (DXA) as a standard tool, except in specific cases. This systematic review and meta-analysis investigates the potential correlation between forearm BMD and BMD at the lumbar and/or hip sites. Methods The protocol was registered in PROSPERO (CRD42024568756), and the study adhered to the PRISMA guidelines. Major databases were systematically searched from their inception until August 2024 to identify studies evaluating the ability of forearm DXA scans to detect osteoporosis, particularly in comparison to central sites like the femoral neck and lumbar spine. A meta-analysis was conducted on studies that reported correlation coefficients between these measurements. Quality assessment was conducted independently by 3 reviewers following Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. Additionally, a narrative synthesis of the main findings across different patient groups was performed. Results Thirteen studies were included. Published between 1992 and 2023, these studies involved 5941 participants. Forearm scans exhibited strong correlations with lumbar and femoral sites (pooled effect size 0.603, 95%CI 0.579–0.627 and 0.641, 95%IC 0.600–0.680, respectively) demonstrating good predictive value for central osteoporosis. Despite some result variations, forearm DXA scanning emerged as a valid method, especially when lumbar and femoral measures are challenging. Conclusions A DXA scan of the distal forearm proves to be a valuable supplementary tool for identifying osteoporotic conditions. This could be particularly relevant in older patients, where conducting lumbar or hip scans is often challenging or not feasible.

Abstract Background About 50% of cutaneous melanoma (CM) harbors the activating BRAFV600 mutation which exerts most of the oncogenic effects through the MAPK signaling pathway. In the last years, a number of MAPK modulators have been identified, including Spry1. In this context, we have recently demonstrated that knockout of Spry1 (Spry1KO) in BRAFV600-mutant CM led to cell cycle arrest and apoptosis, repressed cell proliferation in vitro, and reduced tumor growth in vivo. Despite these findings, however, the precise molecular mechanism linking Spry1 to BRAFV600-mutant CM remains to be elucidated. Materials and methods Immunoprecipitation coupled to mass spectrometry was employed to gain insight into Spry1 interactome. Spry1 gene was knocked-out using the CRISPR strategy in the BRAF-mutant cell lines. Transmission electron microscopy was used to assess the relationship between Spry1 expression and mitochondrial morphology. By using in vitro and in vivo models, the effects of Spry1KO were investigated through RNA-sequencing, quantitative real-time PCR, Western blot, and immunofluorescence analyses. The Seahorse XF24 assay allowed real-time measurement of cellular metabolism in our model. Angiogenic potential was assessed through in vitro tube formation assays and in vivo CD31 staining. Results Spry1 was mainly located in mitochondria in BRAFV600-mutant CM cells where it interacted with key molecules involved in mitochondrial homeostasis. Spry1 loss resulted in mitochondrial shape alterations and dysfunction, which associated with increased reactive oxygen species production. In agreement, we found that nuclear hypoxia-inducible factor-1 alpha (HIF1α) protein levels were reduced in Spry1KO clones both in vitro and in vivo along with the expression of its glycolysis related genes. Accordingly, Ingenuity Pathway Analysis identified “HIF1α Signaling” as the most significant molecular and cellular function affected by Spry1 silencing, whereas the glycolytic function was significantly impaired in Spry1 depleted BRAFV600-mutant CM cells. In addition, our results indicated that the expression of the vascular endothelial growth factor A was down-regulated following Spry1KO, possibly as a result of mitochondrial dysfunction. Consistently, we observed a substantial impairment of angiogenesis, as assessed by the tube formation assay in vitro and the immunofluorescence staining of CD31 in vivo. Conclusions Altogether, these findings identify Spry1 as a potential regulator of mitochondrial homeostasis, and uncover a previously unrecognized role for Spry1 in regulating nuclear HIF1α expression and angiogenesis in BRAFV600-mutant CM. Significance Spry1KO profoundly impacts on mitochondria homeostasis, while concomitantly impairing HIF1α-dependent glycolysis and reducing angiogenesis in BRAF-mutant CM cells, thus providing a potential therapeutic target to improve BRAFV600-mutant CM treatment.

Abstract The COVIVAX study assessed the association between COVID-19 vaccination and the risk of common neurological disorders in a multicenter case-control design. Vaccination exposure was compared between individuals with a first diagnosis of a neurological disorder (cases) and age- and sex-matched controls. A total of 624 participants were enrolled, and after random 1:1 matching 265 cases and 265 matched controls (total 530 participants) were included in the analyses. The most frequent neurological diagnosis in cases were stroke (60.4%), multiple sclerosis (11.3%) and seizures (6.4%). The proportion of vaccinated participants was 72.1% among cases and 79.6% among controls. A protective role of vaccination on the risk of developing a new neurological disorder was detected in the unadjusted analysis (OR 0.50; 95% CI 0.29–0.86; p = 0.0114). After adjustment for confounders, the number of vaccination doses received was associated with a reduced risk of developing new neurological disorders for participants aged over 60 years ( p = 0.0472; OR 0.14, 95% CI 0.03–0.68), with pre-existing comorbidities (p = 0.0122; OR 0.04, 95% CI 0.01–0.99) and for stroke (p = 0.0232; OR 0.04, 95% CI 0.02–0.97). The COVIVAX study provided no warning sign regarding an increase in the risk of developing new neurological disorders following COVID-19 vaccination of any type or doses. A potentially protective effect of multiple doses of COVID-19 vaccines against the risk of stroke in people aged over 60 needs to be confirmed by further studies.

Abstract Introduction Predictors of coronavirus disease 2019 (COVID-19)-related rehospitalization remain underexplored. This study aims to identify the main risk factors associated with rehospitalizations due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections among residents of Lombardy, northern Italy. Methods A retrospective observational study was conducted using two linked administrative databases covering demographic data, comorbidities, hospital records, and COVID-19 data of Lombardy residents. The study population included patients hospitalized for COVID-19 between February 2020 and August 2021. Rehospitalization was defined as a second COVID-19-related hospitalization occurring at least 90 days after the first admission. The Fine–Gray subdistribution hazard model was used to identify risk factors, accounting for death as a competing risk. Results Out of 98,369 patients hospitalized for COVID-19 between February 1, 2020 and August 31, 2021, 72,593 were alive 90 days after admission and 610 of these (0.8%) were rehospitalized. A higher rehospitalization risk was observed in older male patients with multiple comorbidities. Renal failure, liver disease, and use of diuretics were significantly associated with rehospitalization risk, while female biological sex and the use of lipid-lowering drugs were associated with a lower risk. Conclusions This is the first study conducted on regional administrative databases to investigate COVID-19 rehospitalizations. Through the availability of a huge cohort, it provides a groundwork for optimizing care for individuals at higher risk for COVID-19-related rehospitalizations. It underlines the need for patient-management approaches that extend beyond the initial recovery. This stresses the importance of ongoing monitoring and personalized interventions for those at heightened risk not only of SARS-CoV-2 reinfection but also related rehospitalizations.

Line-waves are one-dimensional modes propagating at the interface between two planar complementary surfaces, characterized by tight transversal confinement of the field. Despite their unique guiding properties, their use in real microwave devices is still in the early stages, lacking a comprehensive design procedure and comparative analysis with conventional guiding structures. To fill this gap, here we report a simple and straightforward workflow for designing waveguides supporting 1D modes propagation. The design is based on the analytical relations existing between the surface impedance of the propagating modes and the sheet impedance of the metasurfaces, which allow quick retrieval of the geometrical parameters of the complementary metasurfaces sustaining the line-wave propagation. This approach is used to design several waveguiding layouts and compare their transmission performance through full-wave simulations accounting for dielectric and ohmic losses. Finally, experimental results for some selected designs in the microwave regime are provided, and a thoughtful comparison between a line-wave waveguide and an equivalent microstrip transmission line is carried out to assess the suitability of these devices for efficient high-frequency waveguiding.

Abstract Tumor dissemination to the central nervous system (CNS) is almost a rule in the treatment journey of advanced HER2+ breast cancer (BC). Recent results demonstrated high intracranial efficacy with Trastuzumab Deruxtecan (T-DXd). However, a real-world evidence is lacking in literature. We conducted a multicenter, observational, retrospective real-world analysis on 39 cases collected at 12 Italian Oncological Units. Patients with brain metastases (BMs) from HER2 + BC treated with T-DXd in various treatment lines were enrolled. Primary endpoint was the intracranial overall response rate (iORR). Secondary endpoints were intra- and global progression free survival (iPFS - gPFS); other secondary objectives were the intracranial disease control rate (iDCR), duration of response (iDoR), clinical benefit rate at 6 and 12 months (iCBr), overall survival, and safety. iORR was 59%, iPFS was 15.6 months, gPFS was 11.8 months. iDCR was 94.9%, iDoR was 11.9 months, and iCBr at 6 and 12 months were 69.2% and 59%, respectively. OS was not reached, with an overall rate of 77.9% of patients alive at 12 months. This study confirmed the high intracranial efficacy and manageable safety profile of T-DXd in this first-ever real world analysis.

Abstract In this study an in situ forming gel for curcumin and piperine delivery is investigated as a long-lasting strategy in the local treatment of inflammatory and degenerative joint disease, such as osteoarthritis and rheumatoid arthritis. Particularly glyceryl monooleate, in association with phosphatidylcholine and ethanol, were employed. Different ratios between excipients were tested, with the aim to obtain a liquid form suitable for subcutaneous injection, gaining a semisolid consistency in contact with biological fluids. A formulative study was conducted to assess the composition impact on the structural properties of the formulations, particularly focusing on injectability and phase transition. Curcumin and piperine were loaded, singularly or jointly, in selected in situ forming gels. Structural characterization, performed by X-ray scattering, revealed disordered reverse micellar phases, undergoing transition to hexagonal and cubic Pn3m phase upon hydration. In vitro dialysis release study demonstrated a sustained release of both drugs over 96 h, with a faster release in the case of jointly loaded drugs. Mechanistic analysis and water uptake studies indicated a drug release governed by both diffusion and swelling/erosion of the lipid supramolecular structure. Furthermore, an ex vivo release analysis performed using human skin explants suggested the formulation suitability for subcutaneous injection, indicating that the presence of piperine in the in situ formed gel allowed to double the curcumin release with respect to the simple curcumin loaded gel.

Abstract Background Insulin resistance (IR) and serum uric acid (SUA) are closely interconnected: SUA contributes to adversely affects the insulin signaling pathway and contributes to IR, while IR is a known predictor for the development of hyperuricemia. The triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio has been proposed as an easily obtainable marker for IR. This research aimed to investigate the interaction between IR and glomerular filtration rate (GFR)-adjusted uricemia (SUA/GFR ratio) in determining CV risk in a large population cohort study. Methods Data from 18,694 subjects were analyzed from Uric acid Right foR heArt Healt (URRAH) database. The study evaluated the association between TG/HDL-C ratio and SUA/GFR ratio, as well as their impact on the development of outcomes during the follow-up study period. The primary endpoint was CV mortality. Results After a mean follow-up of 124 ± 64 months, 2,665 (14.2%) CV deaths occurred. The incidence of fatal and non-fatal CV events increased in parallel with the increase of TG/HDL-C quintiles. TG/HDL-C ratio showed a positive association with increasing of SUA/GFR ratio, even in non-diabetic patients. Multivariate analysis showed that the TG/HDL-C ratio increases the mortality risk even after adjustment for potential confounding factors. Finally, IR and GFR-adjusted hyperuricemia showed an additive effect on CV mortality. Conclusions Both IR and SUA/GFR ratio independently predict CV mortality, regardless of age, gender, BMI, diabetes, hypertension and statin use. The joint effect of the TG/HDL-C ratio and the elevated SUA/GFR ratio was greater than the presence of each single risk factor on CV mortality. This highlights the importance of monitoring these markers to better assess cardiovascular risk.

Abstract Background Newborn screening (NBS) programs have significantly improved the health and outcomes of patients with inherited metabolic disorders (IMDs). Methods based on liquid chromatography/mass spectrometry (LC–MS/MS) analysis are viewed worldwide as the gold standard procedure for the expanded NBS programs for these disorders. Advanced molecular technologies point to genomic sequencing as an alternative and feasible strategy for the screening of genetic diseases, including IMDs. However, each of the two approaches has potential limitations when used as a first-tier analysis. In this study, we tested a workflow-based parallel biochemical and sequencing analyses to determine whether this approach could improve the diagnostic outcome. Results For each patient identified by LC–MS/MS as positive, we performed both the biochemical confirmatory tests and next-generation sequencing (NGS) procedures from the same Dried Blood Spot (DBS). NGS analysis was based on applying Exome Sequencing libraries, limiting the analysis to 105 actionable genes involved in IMDs. This allows overtaking the actual limitations of NBS on DBS, enhancing our capacity to identify variants that can drive a genetic disease. Through this approach, we could reach 100% of cases solved, with 37.9% of cases (41/108) for which the combination of the biochemical and NGS analysis was indispensable for a correct diagnosis. In total, we could identify 17 affected, 34 false positives, 12 individuals referred to us for maternal conditions. In 45 newborns the molecular analysis showed heterozygosity for mutations in one or more of the genes analyzed, with results compatible with the biochemical profile indicative of NBS positivity. Conclusions In this study, we validated the performance of the proposed workflow. The advantage of this approach is limiting molecular analysis only to positive newborns and using a restricted panel of 105 genes relevant for the expanded NBS, with a 100% rate of diagnosis and potential reduction of the costs related to NBS procedures and reduced impact on patients and families.

Abstract B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.

Abstract Although intense research effort is seeking to address which brain areas fire and connect to each other to produce complex behaviors in a few living primates, little is known about their evolution, and which brain areas or facets of cognition were favored by natural selection. By developing statistical tools to study the evolution of the brain cortex at the fine scale, we found that rapid cortical expansion in the prefrontal region took place early on during the evolution of primates. In anthropoids, fast-expanding cortical areas extended to the posterior parietal cortex. In Homo, further expansion affected the medial temporal lobe and the posteroinferior region of the parietal lobe. Collectively, the fast-expanding cortical areas in anthropoids are known to form a brain network producing mind reading abilities and other higher-order cognitive functions. These results indicate that pursuing complex cognition drove the evolution of Primate brains.

Abstract Background The coronavirus disease 2019 (COVID-19) emergency has represented a profound upheaval in the dynamics of infectious diseases transmission worldwide. This phenomenon has been at least in part driven by the introduction of non-pharmaceutical interventions (NPIs), implemented to counteract viral transmission. Our study aimed to assess the magnitude and the features of the impact of the COVID-19 pandemic on the incidence of notifiable infectious diseases (NIDs) in the Lazio region, Italy. Methods Data on NIDs in the Lazio Region with symptom onset date included in the time interval from 1 January 2017 to 31 December 2023 were collected from different surveillance system databases available at SERESMI/Lazio Region Unit and classified into five categories based on the main transmission route of the disease. Descriptive statistics were performed and interrupted time series (ITS) analysis was used to assess the effect of the COVID-19 pandemic and subsequent recovery period on monthly NIDs cases. Results Immediately after the start of the COVID-19 pandemic, a significant, sharp and immediate reduction in monthly cases was recorded for all NIDs (-86.73%), regardless of the transmission route. The decrease was particularly significant for vector-borne, food-borne and respiratory-transmitted diseases (RDs), and in general in females. During the COVID-19 recovery phase, monthly cases of all NIDs showed a significant positive level change, particularly significant for sexually transmitted/blood-borne diseases, contact diseases and RDs. Discussion The COVID-19 pandemic has been responsible for the disruption of all NIDs transmission patterns, while the magnitude and dynamics of its effects varied depending on the transmission route; furthermore, the impact of the pandemic wave was still noticeable during the post-COVID-19 era and the incidence trajectories of NIDs in this phase were peculiar for each disease category.

Abstract The present study aimed to investigate the causal relationships among cognitive impairment, psychopathology, and real-life functioning in a large sample of people with schizophrenia, using a data-driven causal discovery procedure based on partial ancestral graphs (PAGs). This method may provide additional insights for the identification of potential therapeutic targets to promote recovery in people with chronic schizophrenia. State-of-the-art instruments were used to assess the study variables. Two PAGs were generated at baseline and after 4 years of follow-up to model the nature of the causal relationships linking psychopathology, cognition, and functioning. The study sample was composed of more than 600 clinically stable patients with schizophrenia at two time points. The PAGs model indicated that working memory impairment is the first ancestor of the causal links, influencing all the other neurocognitive domains, social cognition, and functional capacity, which in turn affects everyday life functioning. From this domain of functioning a causal link is directed to disorganization and positive symptoms, and another to work skills and interpersonal relationships domains; the latter had a direct link to asociality and the other domains of negative symptoms. The structure of the PAGs did not differ significantly between baseline and follow-up, indicating the stability of the causal relationship model investigated cross-sectionally at both time points. The role of working memory impairment in the pathways to functional outcomes in schizophrenia highlights the importance of implementing integrated pharmacological and cognitive remediation interventions targeting neurocognition. The impact of everyday life and interpersonal functioning on the clinical presentation of schizophrenia suggests that integrated and personalized treatments, promoting relevant skills to improve these functional outcomes, may have a beneficial impact on clinical outcomes.

Abstract We explore the decay of bound neutrons in the JUNO liquid scintillator detector into invisible particles (e.g., $$n\rightarrow 3 \nu $$ n → 3 ν or $$nn \rightarrow 2 \nu $$ n n → 2 ν ), which do not produce an observable signal. The invisible decay includes two decay modes: $$ n \rightarrow { inv} $$ n → inv and $$ nn \rightarrow { inv} $$ n n → inv . The invisible decays of s-shell neutrons in $$^{12}\textrm{C}$$ 12 C will leave a highly excited residual nucleus. Subsequently, some de-excitation modes of the excited residual nuclei can produce a time- and space-correlated triple coincidence signal in the JUNO detector. Based on a full Monte Carlo simulation informed with the latest available data, we estimate all backgrounds, including inverse beta decay events of the reactor antineutrino $${\bar{\nu }}_e$$ ν ¯ e , natural radioactivity, cosmogenic isotopes and neutral current interactions of atmospheric neutrinos. Pulse shape discrimination and multivariate analysis techniques are employed to further suppress backgrounds. With two years of exposure, JUNO is expected to give an order of magnitude improvement compared to the current best limits. After 10 years of data taking, the JUNO expected sensitivities at a 90% confidence level are $$\tau /B( n \rightarrow { inv} ) > 5.0 \times 10^{31} \, \textrm{years}$$ τ / B ( n → inv ) > 5.0 × 10 31 years and $$\tau /B( nn \rightarrow { inv} ) > 1.4 \times 10^{32} \, \textrm{years}$$ τ / B ( n n → inv ) > 1.4 × 10 32 years .

Abstract: Elevated levels of the NAD+-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in multiple myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials because of the existence of alternative NAD+ production routes using NAD+ precursors other than nicotinamide. Here, by leveraging mathematical modeling approaches integrated with transcriptome data, we defined the specific NAD+ landscape of MM cells and established that the Preiss-Handler pathway for NAD+ biosynthesis, which uses nicotinic acid as a precursor, supports NAD+ synthesis in MM cells via its key enzyme nicotinate phosphoribosyltransferase (NAPRT). Accordingly, we found that NAPRT confers resistance to NAD+-depleting agents. Transcriptomic, metabolic, and bioenergetic profiling of NAPRT-knockout (KO) MM cells showed these to have weakened endogenous antioxidant defenses, increased propensity to oxidative stress, and enhanced genomic instability. Concomitant NAMPT inhibition further compounded the effects of NAPRT-KO, effectively sensitizing MM cells to the chemotherapeutic drug, melphalan; NAPRT added-back fully rescues these phenotypes. Overall, our results propose comprehensive NAD+ biosynthesis inhibition, through simultaneously targeting NAMPT and NAPRT, as a promising strategy to be tested in randomized clinical trials involving transplant-eligible patients with MM, especially those with more aggressive disease.

Abstract Background Patients with surgical outcomes of removal of oligodendrogliomas can present several clinical manifestations that could impact functioning, autonomy, and quality of life. Rehabilitation, employing various strategies, purposes to enhance patient capacity and performance. In this scenario, the International Classification of Functioning, Disability, and Health (ICF) Generic-30 Set might be useful to help physiatrists in the management of these patients. Therefore, by the present case report we aimed to investigate the impact of a rehabilitation plan including vibration therapy in reducing and improving functioning in a patient with surgical outcomes of removal of oligodendroglioma, according to a ICF approach. Case presentation A 39-year-old woman with surgical outcomes of removal of oligodendroglioma at 9 years old, undergone surgery. A tailored rehabilitation plan comprised including passive mobilization to counteract spasticity-related postures, vibratory therapy, trunk control exercises, and ambulation exercises was performed. The ICF Generic-30 Set was performed at the baseline (also useful to establish an adequate management) and at the end of the entire treatment. Outcome measures assessed were: spasticity, pain, trunk control, disability, and quality of life. Conclusions The patient experienced improvements in terms of functioning after a comprehensive rehabilitation plan including vibration therapy. The ICF Generic-30 Set showed to be a useful approach not only to tailor the intervention, but also to assess the effects of an individualized rehabilitation plan.

Abstract Background Temporomandibular disorders (TMD) are a set of musculoskeletal conditions involving the temporomandibular joint, masticatory muscles, and/or associated structures, characterized by symptoms as pain, joint stiffness with limited mouth opening, and joint sounds as crepitus. Rheumatic diseases (RD) are a heterogeneous group of conditions affecting the musculoskeletal system, including temporomandibular joint (TMJ). To date, there is a lack of systematic reviews that properly investigated the efficacy of conservative approaches in reducing pain in rheumatic patients affected by TMJ arthritis. Therefore, this systematic review aimed to evaluate the effectiveness of rehabilitative approaches in pain relief in rheumatic patients with TMJ arthritis. Methods PubMed, Scopus, and Web of Science were searched from inception until February 25th, 2024, to identify studies including patients with diagnosis of rheumatic disease affecting the temporomandibular joint who underwent specific rehabilitative approaches to reduce pain intensity. The risk of bias of studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Results Out of 479 search results, 115 duplicates were removed, and 364 studies were considered as eligible for inclusion and screened for title and abstract. Out of these, we included 19 papers for full-text screening. Then, 5 papers were included in the synthesis by this systematic review. Four studies assessed patients affected by rheumatoid arthritis, one systemic sclerodermia, and one included patients affected by ankylosing spondylitis, psoriatic arthritis, Sjogren’s syndrome, fibromyalgia, common variable immunodeficiency, and chronic polyarthritis. In the included studies, the interventions consisted of intraarticular TMJ injection of corticosteroids performed with or without anesthetics, or irrigation in three studies, dextrose subcutaneous TMJ perineural injection, and lower-level laser therapy (LLLT). Conclusions This systematic review showed that rehabilitative approaches (e.g., intra-articular injections and LLLT) might be effective in terms of pain relief in TMD RD-related. However, the heterogeneity of the rehabilitative approaches performed, and the low quality of the included studies do not allow to draw certain conclusions regarding the efficacy of these approaches. Further high-quality studies are mandatory to improve the robustness of the efficacy of the different rehabilitative techniques for pain relief in TMD patients affected by rheumatic diseases.

Abstract We describe a bibliometric network characterizing co-authorship collaborations in the entire Italian academic community. The network, consisting of 38,220 nodes and 507,050 edges, is built upon two distinct data sources: faculty information provided by the Italian Ministry of University and Research and publications available in Semantic Scholar. Both nodes and edges are associated with a large variety of semantic data, including gender, bibliometric indexes, authors’ and publications’ research fields, and temporal information. While linking data between the two original sources posed many challenges, the network has been carefully validated to assess its reliability and to understand its graph-theoretic characteristics. By resembling several features of social networks, our dataset can be profitably leveraged in experimental studies in the wide social network analytics domain as well as in more specific bibliometric contexts.

Abstract Background Grape production generates substantial agricultural waste, particularly grape pomace, a by-product rich in bioactive compounds. Moreover, its reuse is strongly recommended to prevent environmental issues from improper disposal. This study explores the feasibility of using exhausted grape pomace, alone and in combination with anaerobic digestate, as substrates for Pleurotus mushroom cultivation. Grape pomace is rich in fiber, lipids, sugars, proteins, and phenolic compounds, which makes it a promising substrate for this purpose. Results Elemental analyses of this substrate revealed high carbon (46%) and nitrogen (2.5%) contents, along with greater levels of macro and microelements (P, Ca, Mg, Fe) compared to conventional substrates. Fourier Transformed Infrared (FTIR) spectroscopy identified aliphatic groups from seed fatty acids and polysaccharide bands, typical of the seedless part of grape pomace. Fatty acid evaluation confirmed the presence of partial glycerides with linoleic acid content exceeding 62%, while phenolic composition analysis highlighted a predominance of bound phenols. These chemical characteristics significantly increased mushroom production, with statistically significant increases in fresh weights observed upon the addition of grape pomace, resulting in variations exceeding 130% in some instances. The mixture with digestate exhibited the most promising results, probably due to improved pH values. FTIR and Surface Enhanced Raman Scattering (SERS) spectra of mushrooms grown on different matrices were similar, but with some differences likely related to substrate composition. In addition, SERS analysis identified ergothioneine, a significant fungal amino acid, which was not detectable in the FTIR spectra. Conclusions This study highlights grape pomace as an effective and sustainable substrate for mushroom cultivation, offering a viable alternative to conventional growth mediums. The high yield and consistent quality of mushrooms grown on grape pomace, particularly when mixed with anaerobic digestate, demonstrate its potential for commercial mushroom production. The findings support the broader goals of sustainable agriculture by promoting the recycling of agricultural by-products, minimizing waste, and adding economic value. This innovative approach to utilizing grape pomace contributes to improved environmental management and opens new opportunities for enhancing the efficiency and sustainability of mushroom cultivation practices. Graphical Abstract

Abstract Background This study investigated sex differences in the associations between Alzheimer’s disease (AD) biomarkers, cognitive performance, and decline in memory clinic settings. Methods 249 participants (females/males:123/126), who underwent tau-PET, amyloid-PET, structural MRI, and plasma glial fibrillary acidic protein (GFAP) measurement were included from Geneva and Lausanne Memory Clinics. Mann-Whitney U tests investigated sex differences in clinical and biomarker data. Linear regression models estimated the moderating effect of sex on the relationship between biomarkers and cognitive performance and decline. Sex differences in cognitive decline were further evaluated using longitudinal linear mixed-effect models with three-way interaction effects. Results Women and men present similar clinical features, amyloid, and neurodegeneration. Women had higher tau load and plasma levels of GFAP than men (p

Abstract The soil health notion has been recently expanded to relate soil functions not only to soil fertility for a sustainable primary productivity, but also to the control of water cycling and of the soil carbon storage. Soil humus is fundamental to achieve the objectives of soil health, and it is therefore deemed necessary to enlarge the knowledge of its composition and dynamics, if a modern soil management was to be pursued. This review first describes the contemporary understanding of the supramolecular structure of soil humus and the derived modern method to identify the totality of humic components to an unprecedented extent in soils under different soil management and cropping systems. Then, it accounts on how humus, either native in soil or exogenous from sources rich in organic carbon such as lignite, compost, and lignocellulosic residues, improves the soil physical fertility, limits the risk of erosion, enhances the bioactivity of the rhizosphere microbiome, and directly stimulates plant growth. Moreover, it is highlighted the role played by humus in ecologically sound soil managements, such as in organic and biodynamic agricultural productions, which are progressively growing as alternative to conventional but environmentally unsafe practices. Graphical Abstract

Abstract The root-knot nematode Meloidogyne incognita is the most harmful and destructive nematode species due to its widespread distribution and its ability to destroy a wide range of agriculturally and economically important crops. Plant-derived essential oils (EO) are one of the promising strategies for nematode management showing high nematicidal potential. Very little is known about the molecular mechanisms activated by EOs in M. incognita. In our study, we assessed the effects of Cinnamomum zeylanicum, Citrus aurantium and the chemical nematicide Oxamyl on the mortality of M. incognita juveniles (J2) at different doses and exposure. The toxicity of C. zeylanicum and C. aurantium EOs to M. incognita J2 was largely different, peaking 94.7 and 26.7% mortality rates after a 24-hour exposure to 100 µg mL− 1 EO concentrations, respectively. The different nematicidal activity of the two EOs was also confirmed by their LC50 values, ranging between 0.1 and 399 mg mL− 1 concentrations for the 24-hour treatment, respectively. The sublethal dose (0.78 µg mL− 1), the concentration that does not cause mortality but still triggers physiological responses, was chosen for both EOs and Oxamyl to investigate the expression levels of Mi-ace-1, Mi-ace-2, and Mi-hsp90, involved in host finding processes, and Mi-far-1, involved in the cuticle protection, by using real time PCR. Our results reveal that C. zeylanicum is toxic at lower doses than C. aurantium. The different expression level of Mi-far-1 in J2s treated with C. zeylanicum suggests a different action mode compared to C. aurantium and Oxamyl. Understanding the action mode of these compounds at molecular level will help to develop more potent and effective nematicides safer for environment and humans.

Abstract Enterovirus D68 (EV-D68) is a non-polio enterovirus that causes respiratory illness and is linked to acute flaccid myelitis (AFM) in infants and children. Recent demonstration of association of EV-D68 with extracellular vesicles (EVs) released from infected cells in vitro suggests a role for these vesicles in non-lytic dissemination of virus beyond the respiratory tract. We previously reported the permissiveness of cotton rat (Sigmodon hispidus) to infection with different EV-D68 strains of clades A and B, but did not investigate the virus association with EVs. We present a model of acute respiratory infection with a clinical isolate of EV-D68 of clade B3 in immunocompetent cotton rats featuring systemic dissemination of the virus. EV-D68 was detected in circulation and organs outside of the respiratory tract with the inflammatory response accompanying dissemination. Further analysis demonstrated that the virus was associated with extracellular vesicles purified from plasma. We also present a model of intraperitoneal infection with EV-D68 in young cotton rats featuring dissemination of the virus to spinal cord and brain with associated clinical signs of neurologic disease. EV-D68-associated with EVs produced in cotton rat cells and injected intraperitoneally into young cotton rats also resulted in detection of virus in the CNS. Our results provide the first in vivo experimental support for the notion that respiratory infection with EV-D68 generates virus associated with extracellular vesicles that disseminate outside the respiratory tract. These models of infection could be used to investigate the role of EVs-associated EV-D68 in the pathogenesis of EV-D68 infection and to assess therapeutic interventions.

Abstract Recent studies have used big neuroimaging datasets to answer an important question: how many subjects are required for reproducible brain-wide association studies? These data-driven approaches could be considered a framework for testing the reproducibility of several neuroimaging models and measures. Here we test part of this framework, namely estimates of statistical errors of univariate brain-behaviour associations obtained from resampling large datasets with replacement. We demonstrate that reported estimates of statistical errors are largely a consequence of bias introduced by random effects when sampling with replacement close to the full sample size. We show that future meta-analyses can largely avoid these biases by only resampling up to 10% of the full sample size. We discuss implications that reproducing mass-univariate association studies requires tens-of-thousands of participants, urging researchers to adopt other methodological approaches.

Abstract This study aims to validate the Size Specific Dose Estimate (SSDE) provided by a modern Computed Tomography (CT) scanner and investigate its correlation with effective dose (E). SSDE is a size-specific dosimetric index addressing the limitations of the Computed Tomography Dose Index (CTDIvol). A set of 60 CT scans of anthropomorphic phantoms, including pediatric and obese models, were acquired and analyzed. SSDE values from the CT scanner were compared with those obtained through an independent Python-based calculation and Radimetrics, a dose monitor software. While the independent calculation and the one with Radimetrics were consistently in agreement, a systematic underestimation by the scanner up to 10% was seen, particularly in chest and abdominal exams. The underestimation, however, remained within the acceptable limits set by AAPM guidelines. Furthermore, a correlation between SSDE and effective dose was identified, suggesting SSDE’s potential for more accurate, size-specific radiation dose and risk assessments. These findings highlight the importance of SSDE in enhancing patient-specific dose management, though further validation using patient data is needed to confirm its clinical applicability.

Abstract Background SELENON-related myopathy is a rare autosomal recessive congenital neuromuscular disorder linked to defects in the selenoprotein N. The clinical onset typically occurs in infancy and axial weakness, rigid spine, and respiratory involvement are almost invariably present at early stages. Case presentation We report the case of a 44-year-old Italian woman who underwent intubation for acute respiratory failure, followed by weaning from invasive ventilation within 6 months. Her medical history was not significant, but a detailed medical history collection revealed slight motor limitations since childhood such as slow running, difficulty climbing high steps, early muscle exhaustion, and fatigue. The neurological examination showed a waddling gait and axial and proximal limb muscle weakness without rigid spine. The right quadriceps muscle biopsy showed nonspecific myopathic abnormalities. Clinical exome sequencing revealed the presence of the two heterozygous variants c.713DupA and c.803G > A in the SELENON gene. Conclusion This report focused on the clinical heterogeneity of SELENON-related myopathy. While we highlight that the absence of spinal rigidity and core pathology on muscle biopsy should not exclude the diagnostic suspicion, overall we stress the importance of respiratory failure as a possible late manifestation of the disease, even in middle-aged individuals.

Abstract Critical systems represent a valuable resource in quantum sensing and metrology. Critical quantum sensing (CQS) protocols can be realized using finite-component phase transitions, where criticality arises from the rescaling of system parameters rather than the thermodynamic limit. Here, we show that a collective quantum advantage can be achieved in a multipartite CQS protocol using a chain of parametrically coupled critical resonators in the weak-nonlinearity limit. We derive analytical solutions for the low-energy spectrum of this unconventional quantum many-body system, which is composed of locally critical elements. We then assess the scaling of the quantum Fisher information with respect to fundamental resources. We demonstrate that the coupled chain outperforms an equivalent ensemble of independent critical sensors, achieving quadratic scaling in the number of resonators. Finally, we show that even with finite Kerr nonlinearity or Markovian dissipation, the critical chain retains its advantage, making it relevant for implementing quantum sensors with current microwave superconducting technologies.

Abstract Background Celiac disease (CeD) is an autoimmune condition characterized by an aberrant immune response triggered by the ingestion of gluten, which damages epithelial cells lining the small intestine. Small intestinal epithelial cells (sIECs) play key roles in the enzymatic digestion and absorption of nutrients, maintaining gut barrier integrity, and regulating immune response. Chronic inflammation and tissue damage associated with CeD disrupt the intricate network of metabolic processes in sIECs that support these functions, impairing their ability to perform their essential roles. However, the specific disrupted metabolic processes underlying sIECs dysfunction in CeD remain largely undefined. Methods To address this knowledge gap, personalized, sex-specific genome-scale models of sIECs metabolism were constructed using transcriptional data from intestinal biopsies of 42 subjects with active CeD, CeD in remission (on a gluten-free diet), and non-CeD controls. These models were computationally simulated under relevant dietary conditions for each group of subjects to assess the activity of several metabolic tasks essential for sIECs function and to profile metabolite secretion into the bloodstream and intestinal lumen. Results Significant alterations in the activity of 28 essential metabolic tasks were observed in active CeD and remission CeD, impacting critical processes integral to sIECs function such as oxidative stress regulation, nucleotide synthesis and DNA repair, energy production, and polyamine and amino acid metabolism. Additionally, altered secretion profiles of several metabolites, encompassing amino acids, vitamins, polyamines, lipids, and fatty acids, into the bloodstream were detected in active CeD and remission CeD patients. These findings were partially supported by comparisons with independent external datasets and further corroborated through extensive review of existing literature. Furthermore, a drug target analysis was performed, identifying 22 FDA-approved drugs that target genes encoding impaired sIECs metabolic functions in CeD, potentially helping to restore their normal activity. Conclusions This study unveils new insights into the metabolic reprogramming of sIECs in CeD, highlighting specific dysregulated metabolic processes that compromise cellular functions essential for gut health. These findings offer a foundation for developing therapeutic interventions targeting impaired metabolic processes in CeD.

Abstract The need for a sensitive, selective, non-invasive and reversible fluorescent sensor for Zn2+ monitoring is addressed in this work. A novel guest-host system is developed, including a Zn2+ sensitive fluorescent probe, Zinpyr-1, embedded in a porous optically transparent hybrid film. The entrapped probe molecules are accessible and can interact with the external analyte. The immobilized Zinpyr-1 confirms its specificity and selectivity for Zn2+, as shown by sensing tests conducted in buffer solutions that mimic the ionic composition of biological media. The uniqueness of the developed sensor system lies in its reversibility, combined with a fast and selective response, allowing dynamic measurements of zinc concentrations in the 1 µM to 1 mM range within few tens of seconds. Unlike most Zn2+ sensors, this system is a film-based sensor, making it an interesting minimally invasive tool for future studies on how live cells cultured on it dynamically regulate the Zn2+ concentration under controlled physiological conditions.

Abstract Background The ability of machine learning (ML) to process and learn from large quantities of heterogeneous patient data is gaining attention in the precision oncology community. Some remarkable developments have taken place in the domain of image classification tasks in areas such as digital pathology and diagnostic radiology. The application of ML approaches to the analysis of DNA data, including tumor-derived genomic profiles, microRNAs, and cancer epigenetic signatures, while relatively more recent, has demonstrated some utility in identifying driver variants and molecular signatures with possible prognostic and therapeutic applications. Methods We conducted semi-structured interviews with academic and clinical experts to capture the status quo, challenges, opportunities, ethical implications, and future directions. Results Our participants agreed that machine learning in precision oncology is in infant stages, with clinical integration still rare. Overall, participants equated ongoing developments with better clinical workflows and improved treatment decisions for more cancer patients. They underscored the ability of machine learning to tackle the dynamic nature of cancer, break down the complexity of molecular data, and support decision-making. Our participants emphasized obstacles related to molecular data access, clinical utility, and guidelines. The availability of reliable and well-curated data to train and validate machine learning algorithms and integrate multiple data sources were described as constraints yet necessary for future clinical implementation. Frequently mentioned ethical challenges included privacy risks, equity, explainability, trust, and incidental findings, with privacy being the most polarizing. While participants recognized the issue of hype surrounding machine learning in precision oncology, they agreed that, in an assistive role, it represents the future of precision oncology. Conclusions Given the unique nature of medical AI, our findings highlight the field’s potential and remaining challenges. ML will continue to advance cancer research and provide opportunities for patient-centric, personalized, and efficient precision oncology. Yet, the field must move beyond hype and toward concrete efforts to overcome key obstacles, such as ensuring access to molecular data, establishing clinical utility, developing guidelines and regulations, and meaningfully addressing ethical challenges.

Abstract BK channels are large-conductance calcium (Ca2+)-activated potassium channels crucial for neuronal excitability, muscle contraction, and neurotransmitter release. The pore-forming (α) subunits co-assemble with auxiliary (β and γ) subunits that modulate their function. Previous studies demonstrated that the N-termini of β2-subunits can inactivate BK channels, but with no structural correlate. Here, we investigate BK β2-subunit inactivation using cryo-electron microscopy, electrophysiology and molecular dynamics simulations. We find that the β2 N-terminus occludes the pore only in the Ca2+-bound open state, via a ball-and-chain mechanism. The first three hydrophobic residues of β2 are crucial for occlusion, while the remainder of the N-terminus remains flexible. Neither the closed channel conformation obtained in the absence of Ca2+ nor an intermediate conformation found in the presence of Ca2+ show density for the N-terminus of the β2 subunit in their pore, likely due to narrower side access portals preventing their entry into the channel pore.

Abstract Brain metastases (BMs) are a common complication of advanced breast cancer (BC), and their management has significantly evolved. We evaluated the clinical impact of these changes dividing patients diagnosed with BCBMs at three Institutions according to year of BMs diagnosis: 2000-2007 (group A), 2008-2014 (group B) and 2015-2022 (group C). Stereotactic radiotherapy increased (p

Abstract Background Early detection of colorectal cancer (CRC) significantly improves its management and patients’ survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis. Methods In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples. Results Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p

Abstract Background Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options. To improve patients management and treatment, more precise stratification strategies are needed. This study aimed to characterize the phenogenomic landscapes of MPM and to understand their influence on patients clinical outcomes. Methods We conducted a phenogenomic analysis on 22 MPM patients using two high throughput approaches: imaging mass cytometry (IMC) with whole exome sequencing (WES). Resulting profiles were addressed for their clinical relevance to predict patients prognosis. Results IMC revealed a highly heterogeneous tumor microenvironment (TME) with distinct tumor cell subpopulations. Notably, we identified a novel sarcomatoid-like cellular cluster associated with poor prognosis. The TME was also infiltrated with immune cells including macrophages and CD4+ T lymphocytes, that were more abundant in patients with favorable clinical outcomes. WES identified a complex genomic landscape with limited prognostic value for individual genetic alterations. However, tumor mutational burden (TMB) emerged as a potential predictive biomarker, inversely correlating with immune cell infiltration, particularly macrophages and CD4+ T lymphocytes. Conclusions Our findings underscore the intricate interplay between the tumor genome, TME composition, and clinical outcomes in MPM. These data support the potential of integrating genomic and TME profiling to develop more precise patient stratification strategies and potentially optimize therapeutic approaches, including immunotherapy.

Abstract Background Noonan Syndrome (NS) is a rare multisystemic disorder with heterogeneous phenotypic manifestations. The aim of this study was to analyse rates of survival, hospitalisation, surgeries and prescriptions in children born with NS in the first 10 years of life. Methods This is a multi-centre population-based cohort study. Data on 175 liveborn children diagnosed with NS from 11 EUROCAT congenital anomaly registries were linked to healthcare databases. Each registry applied a common data model to standardise data and run common syntax scripts to produce aggregated results which were pooled using random effects meta-analyses. Results Mortality rates were high in the first year of life with 5.4% (95%CI 1.5%-10.1%) of children dying before the age of 1 year with a further 2% dying up to age 5. In the first year, 87.9% (95%CI 75.3%-94.3%) of children were hospitalized and the median Length Of hospital Stay (LOS) was 15.3 days (95%CI 9.3–21.2). After the first year, the proportion of children hospitalized remained higher than 70%, but the LOS decreased to 1.3 days per year. In the first 5 years, 65.2% of children underwent a median of two surgical procedures. The median age at first surgery was 29 weeks. The proportion of children with an antibiotic prescription increased from 53.6% at age 1 to 62.4% yearly until 4 years of age. Conclusions Children with NS have high mortality and morbidity not only in the first year of life but also up to five years of age. This study evaluated the health burden of NS and provided information for clinicians, health-care providers and families.

Abstract Background Third molar surgery is associated with various postoperative complications (PC). Different strategies, including the application of platelet-rich fibrin (PRF), have been implemented to reduce PC. Digital technologies have proven useful in objectively assessing postoperative facial swelling. This study aimed to evaluate the effect of PRF on reducing facial swelling after lower third molar surgery using a 3D face scanner. Methods A randomized split-mouth clinical trial was set up and 32 patients (18 to 32 years), requiring extraction of both mandibular third molars, were recruited at the Oral Surgery Clinic of the Magna Graecia University of Catanzaro. The primary predictive variable was the application or not of PRF plugs and membranes in the post-extraction socket. Primary outcome variable was facial swelling recorded with a face scanner preoperatively (T0), after three (T1) and seven (T2) days. Qualitative and quantitative data analysis were conducted following an automated and standardized imaging analysis workflow using the 3D Slicer software. Secondary outcome variables were trismus, recorded by measuring the maximum buccal opening with a caliper, pain, recorded using a visual analogue scale (VAS), and duration of the surgery. Descriptive and bivariate analysis were performed by setting the significance level $$\:\alpha\:$$ = 0.05. Results All patients exhibited a significant increase in facial swelling at T1, followed by a subsequent reduction from day 3 to day 7, with a slight persistence of edema observed on the seventh day. No significant data emerged from the statistical analysis conducted. Linear differences in PRF group reported improved values of postoperative swelling only in the T1-T2 and T0-T2 phases of analysis. Volumetric differences favored PRF group compared with control group in all phases. VAS was lower in PRF group only at T2, compared with control group. Conclusions Application of PRF in post-extraction sockets showed effectiveness in reducing facial swelling. Its advantages, including accessibility, cost-effectiveness, and absence of adverse reactions, make it an optimal treatment choice in reducing post-surgical sequelae.

Abstract Cancer cells adapt to harsh environmental conditions by inducing the Unfolded Protein Response (UPR), of which ERO1A is a mediator. ERO1A aids protein folding by acting as a protein disulfide oxidase, and under cancer-related hypoxia conditions, it favors the folding of angiogenic VEGFA, leading tumor cells to thrive and spread. The upregulation of ERO1A in cancer cells, oppositely to the dispensability of ERO1A activity in healthy cells, renders ERO1A a perfect target for cancer therapy. Here, we report the upregulation of ERO1A in a cohort of aggressive triple-negative breast cancer (TNBC) patients in which ERO1A levels correlate with a higher risk of breast tumor recurrence and metastatic spread. For ERO1A target validation and therapy in TNBC, we designed new ERO1A inhibitors in a structure-activity campaign of the prototype EN460. Cell-based screenings showed that the presence of the Micheal acceptor in the compound is necessary to engage the cysteine 397 of ERO1A but not sufficient to set out the inhibitory effect on ERO1A. Indeed, the ERO1 inhibitor must adopt a non-coplanar rearrangement within the ERO1A binding site. I2 and I3, two new EN460 analogs with different phenyl-substituted moieties, efficiently inhibited ERO1A, blunting VEGFA secretion. Accordingly, in vitro assays to measure ERO1A engagement and inhibition confirmed that I2 and I3 bind ERO1A and restrain its activity with a IC50 in a low micromolar range. EN460, I2 and I3 triggered breast cancer cytotoxicity while specifically inhibiting ERO1A in a dose-dependent manner. I2 more efficiently impaired cancer-relevant features such as VEGFA secretion and related cell migration. I2 also acted on the tumor microenvironment and viability of xenografts and syngeneic TNBC. Thus, small molecule-mediated ERO1A pharmacological inhibition is feasible and promises to lead to effective therapy for the still incurable TNBC.

Abstract Background Co-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival (OS) over conventional chemotherapy. The analysis by tumor histotype demonstrated greater efficacy of ICI therapy compared to standard chemotherapy in non-epithelioid (non-E) vs. epithelioid (E) PM, although some E PM patients also benefit from ICI treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Therefore, we utilized a panel of cultured PM cells of different histotype to provide preclinical evidence supporting the role of the tumor methylation landscape, along with its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients. Methods The methylome profile (EPIC array) of distinct E (n = 5) and non-E (n = 9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed (DE) and differentially methylated (DM) were then selected for gene ontology analysis. Results The CIMP index stratified PM cell lines into two distinct classes, CIMP (hyper-methylated; n = 7) and LOW (hypo-methylated; n = 7), regardless of their E or non-E histotype. Integrated methylome and transcriptome analyses revealed that CIMP PM cells exhibited a substantial number of hyper-methylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells. Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells. Conclusion The study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, independent of their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state highlights its potential for evaluation in phase I/II clinical trials investigating the efficacy of epigenetic-based ICI combinations to reverse cancer immune resistance mechanisms.

Abstract Background Decision-making in emergency settings is inherently complex, requiring surgeons to rapidly evaluate various clinical, diagnostic, and environmental factors. The primary objective is to assess a patient’s risk for adverse outcomes while balancing diagnoses, management strategies, and available resources. Recently, indocyanine green (ICG) fluorescence imaging has emerged as a valuable tool to enhance surgical vision, demonstrating proven benefits in elective surgeries. Aim This consensus paper provides evidence-based and expert opinion-based recommendations for the standardized use of ICG fluorescence imaging in emergency settings. Methods Using the PICO framework, the consensus coordinator identified key research areas, topics, and questions regarding the implementation of ICG fluorescence-guided surgery in emergencies. A systematic literature review was conducted, and evidence was evaluated using the GRADE criteria. A panel of expert surgeons reviewed and refined statements and recommendations through a Delphi consensus process, culminating in final approval. Results ICG fluorescence imaging, including angiography and cholangiography, improves intraoperative decision-making in emergency surgeries, potentially reducing procedure duration, complications, and hospital stays. Optimal use requires careful consideration of dosage and timing due to limited tissue penetration (5–10 mm) and variable performance in patients with significant inflammation, scarring, or obesity. ICG is contraindicated in patients with known allergies to iodine or iodine-based contrast agents. Successful implementation depends on appropriate training, availability of equipment, and careful patient selection. Conclusions Advanced technologies and intraoperative navigation techniques, such as ICG fluorescence-guided surgery, should be prioritized in emergency surgery to improve outcomes. This technology exemplifies precision surgery by enhancing minimally invasive approaches and providing superior real-time evaluation of bowel viability and biliary structures—areas traditionally reliant on the surgeon’s visual assessment. Its adoption in emergency settings requires proper training, equipment availability, and standardized protocols. Further research is needed to evaluate cost-effectiveness and expand its applications in urgent surgical procedures. Graphical abstract

Abstract Newborn chicks can solve complex numerical discriminations through a purely perceptual mechanism based on the possibility of creating all equal-sized subsets. The present work investigates whether this is a prerogative of precocial birds or whether an analogous mechanism can be found in humans. We familiarized 8-month-olds with sets of even numerosities (i.e., decomposable in equal-sized subsets), and then we tested them for their spontaneous preference between two novel sets, one that cannot be divided into equal-sized subsets (i.e., a prime numerosity) and one decomposable in equal-sized subsets (i.e., a non-prime odd numerosity). Infants were tested with either the 7vs.9 comparison (i.e., the prime being smaller) or the 9vs.11 comparison (i.e., the prime being larger). Infants oriented their gaze more often toward the prime set of elements, irrespective of whether it was smaller or larger in the comparison, similar to the preference observed in baby chicks. Overall, our results suggest an early-emerging perceptual mechanism that can support complex numerical discriminations, that might be shared between distantly related and ecologically different species.

Abstract The emergence of new public forums in the form of online social media has introduced unprecedented challenges to public discourse, including polarization, misinformation, and the rise of echo chambers. Existing research has extensively examined these topics by focusing on the active actions performed by users, without accounting for the share of individuals who consume content without actively interacting with it. In contrast, this study incorporates passive consumption data to investigate the prevalence of active participation in online discourse. We introduce a metric to quantify the share of active engagement and analyze over 17 million pieces of content linked to a polarized Twitter debate to understand its relationship with several features of online environments, such as echo chambers, coordinated behavior, political bias, and source reliability. Our findings reveal a significant proportion of users who consume content without active interactions, underscoring the importance of considering also passive consumption proxies in the analysis of online debates. Furthermore, we found that increased active participation is primarily correlated with the presence of multimedia content and unreliable news sources, rather than with the ideological stance of the content producer, suggesting that active engagement is independent of echo chambers. Our work highlights the significance of passive consumption proxies for quantifying active engagement, which influences platform feed algorithms and, consequently, the development of online discussions. Moreover, it highlights the factors that may encourage active participation, which can be utilized to design more effective communication campaigns.

Abstract An intense surge in the equatorial electron temperature (Te) at sunrise, known as the morning Te overshoot, has been one of the defining ionospheric features since its discovery early in the Space Age. Despite decades of study, the behavior of the morning overshoot during geomagnetic storms remains poorly understood. We report a two-stage response of the morning Te overshoot to geomagnetic activity, uncovered by a neural network model. Electron temperatures show an initial enhancement during the storm’s main phase, followed by a drastic depletion exceeding 1000 K and disappearance of the overshoot in the recovery phase. This two-phase change aligns with the early influence of westward prompt penetration electric field, overtaken by the development of the eastward disturbance dynamo later in the storm. These electric field changes affect vertical plasma drifts that redistribute electron densities, modifying ionospheric cooling rates. Our findings provide new insights into the dynamics of one of the most widely studied ionospheric features and showcase the potential of new-generation digital twin models of near-Earth space environment to reveal previously unrecognized physical patterns.

Abstract Targeting host proteins that are crucial for viral replication offers a promising antiviral strategy. We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporine A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells and have high specificity for CypA confirmed by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA-targeting PROTACs inhibit viral replication potently and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.

Abstract Hypervelocity impacts play a significant role in the evolution of asteroids, causing material to be ejected and partially reaccreted. However, the dynamics and evolution of ejected material in a binary asteroid system have never been observed directly. Observations of Double Asteroid Redirection Test (DART) impact on asteroid Dimorphos have revealed features on a scale of thousands of kilometers, including curved ejecta streams and a tail bifurcation originating from the Didymos system. Here we show that these features result naturally from the dynamical interaction of the ejecta with the binary system and solar radiation pressure. These mechanisms may be used to constrain the orbit of a secondary body, or to investigate the binary nature of an asteroid. Also, they may reveal breakup or fission events in active asteroids, and help determine the asteroid’s properties following an impact event. In the case of DART, our findings suggest that Dimorphos is a very weak, rubble-pile asteroid, with an ejecta mass estimated to be in the range of (1.1-5.5)×107 kg.

Abstract Kinetic deflection is a planetary defense technique delivering spacecraft momentum to a small body to deviate its course from Earth. The deflection efficiency depends on the impactor and target. Among them, the contribution of global curvature was poorly understood. The ejecta plume created by NASA’s Double Asteroid Redirection Test impact on its target asteroid, Dimorphos, exhibited an elliptical shape almost aligned along its north-south direction. Here, we identify that this elliptical ejecta plume resulted from the target’s curvature, reducing the momentum transfer to 44 ± 10% along the orbit track compared to an equivalent impact on a flat target. We also find lower kinetic deflection of impacts on smaller near-Earth objects due to higher curvature. A solution to mitigate low deflection efficiency is to apply multiple low-energy impactors rather than a single high-energy impactor. Rapid reconnaissance to acquire a target’s properties before deflection enables determining the proper locations and timing of impacts.

Abstract Defining the trajectory of cells during differentiation and disease is key for uncovering the mechanisms driving cell fate and identity. However, trajectories of human cells remain largely unexplored due to the challenges of studying them with human samples. In this study, we investigate the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identify RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for diHSCs’ commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we show that RORA is required for early differentiation and prevents diHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice have enhanced fibrosis, RORA agonists rescue multi-organ fibrosis in in vivo models. Notably, RORA expression correlates negatively with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, important for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease.

Abstract Background During the pandemic, the pneumology team at Bambino Gesù Children’s Hospital highlighted that telemedicine was a valuable tool for remotely managing the medical needs of children with medical complexity (CMC). Following the telemedicine experience during the emergency phase, a telemedicine service was established, and new tools were tested to optimize televisits and the overall eHealth approach for patients. In this context, the TytoHome™ device was tested for performing objective examinations remotely. This pilot study, conducted at our hospital, explored the management of CMC patients on long-term mechanical ventilation via the telemedicine platform and the TytoHome™ device. Methods This study involved the treatment of 10 pediatric patients over one year using this approach. The patients were already receiving care at our hospital and were undergoing long-term mechanical ventilation (LTV) at home—4 on invasive mechanical ventilation (IMV) and 6 on non-invasive ventilation (NIV). A database was developed to collect patient data, including personal details, vital parameters, objective examinations, audio quality, and patient satisfaction. A descriptive analysis was subsequently performed using the data collected during the earlier stages of the study. Results The utility of the TytoCare device for medically complex children was evaluated. The families were “satisfied” with the remote follow-up visits, and healthcare personnel rated the audio quality of the visits as “good.” Conclusions In conclusion, the remote management of these patients using the Tyto device offered several advantages. In our experience, Tyto proved to be a useful tool for the remote medical management of complex patients.