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Abstract Computer-driven molecular design combines the principles of chemistry, physics, and artificial intelligence to identify chemical compounds with tailored properties. While quantum-mechanical (QM) methods, coupled with machine learning, already offer a direct mapping from 3D molecular structures to their properties, effective methodologies for the inverse mapping in chemical space remain elusive. We address this challenge by demonstrating the possibility of parametrizing a chemical space with a finite set of QM properties. Our proof-of-concept implementation achieves an approximate property-to-structure mapping, the QIM model (which stands for “Quantum Inverse Mapping”), by forcing a variational auto-encoder with a property encoder to obtain a common internal representation for both structures and properties. After validating this mapping for small drug-like molecules, we illustrate its capabilities with an explainability study as well as by the generation of de novo molecular structures with targeted properties and transition pathways between conformational isomers. Our findings thus provide a proof-of-principle demonstration aiming to enable the inverse property-to-structure design in diverse chemical spaces.

Abstract Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score

Abstract We propose a compartmental model for investigating smoking dynamics in an Italian region (Tuscany). Calibrating the model on local data from 1993 to 2019, we estimate the probabilities of starting and quitting smoking and the probability of smoking relapse. Then, we forecast the evolution of smoking prevalence until 2043 and assess the impact on mortality in terms of attributable deaths. We introduce elements of novelty with respect to previous studies in this field, including a formal definition of the equations governing the model dynamics and a flexible modelling of smoking probabilities based on cubic regression splines. We estimate model parameters by defining a two-step procedure and quantify the sampling variability via a parametric bootstrap. We propose the implementation of cross-validation on a rolling basis and variance-based Global Sensitivity Analysis to check the robustness of the results and support our findings. Our results suggest a decrease in smoking prevalence among males and stability among females, over the next two decades. We estimate that, in 2023, 18% of deaths among males and 8% among females are due to smoking. We test the use of the model in assessing the impact on smoking prevalence and mortality of different tobacco control policies, including the tobacco-free generation ban recently introduced in New Zealand.

Abstract The temperature measurement of material inside of an object is one of the key technologies for control of dynamical processes. For this purpose, various techniques such as laser-based thermography and phase-contrast imaging thermography have been studied. However, it is, in principle, impossible to measure the temperature of an element inside of an object using these techniques. One of the possible solutions is measurements of Doppler brooding effect in neutron resonance absorption (NRA). Here we present a method to measure the temperature of an element or an isotope inside of an object using NRA with a single neutron pulse of approximately 100 ns width provided from a high-power laser. We demonstrate temperature measurements of a tantalum (Ta) metallic foil heated from the room temperature up to 617 K. Although the neutron energy resolution is fluctuated from shot to shot, we obtain the temperature dependence of resonance Doppler broadening using a reference of a silver (Ag) foil kept to the room temperature. A free gas model well reproduces the results. This method enables element(isotope)-sensitive thermometry to detect the instantaneous temperature rise in dynamical processes.

Abstract We here introduce the Aquamarine (AQM) dataset, an extensive quantum-mechanical (QM) dataset that contains the structural and electronic information of 59,783 low-and high-energy conformers of 1,653 molecules with a total number of atoms ranging from 2 to 92 (mean: 50.9), and containing up to 54 (mean: 28.2) non-hydrogen atoms. To gain insights into the solvent effects as well as collective dispersion interactions for drug-like molecules, we have performed QM calculations supplemented with a treatment of many-body dispersion (MBD) interactions of structures and properties in the gas phase and implicit water. Thus, AQM contains over 40 global and local physicochemical properties (including ground-state and response properties) per conformer computed at the tightly converged PBE0+MBD level of theory for gas-phase molecules, whereas PBE0+MBD with the modified Poisson-Boltzmann (MPB) model of water was used for solvated molecules. By addressing both molecule-solvent and dispersion interactions, AQM dataset can serve as a challenging benchmark for state-of-the-art machine learning methods for property modeling and de novo generation of large (solvated) molecules with pharmaceutical and biological relevance.

Background. This study evaluated the gingival crevicular fluid (GCF) and Peri- implant crevicular fluid (PICF) concentrations of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and active metalloproteinase-8 (a-MMP-8) in sites with healthy conditions vs. sites affected by periodontitis (PER) and peri-implantitis (PIM). Methods. Periodontally healthy (PH) sites with PER, sites with peri-implant health (PIH), and sites with PIM were investigated intra-individually, according to the inclusion criteria of each group. Probing pocket depth (PPD), plaque index, gingival index, and the presence or absence of bleeding on probing (BoP) were evaluated. In GCF and PICF samples, IL-1β, IL-6, and TNF-α were quantified by ELISA Duoset® kit in combination with Ultramark® micro-ELISA digital reader; a-MMP8 concentration was analyzed by a chairside test (Perio/ImplantSafe®) in combination with a digital reader (ORALyzer®). Results. The concentrations of IL-6 and IL-1β, TNF-α, and a-MMP-8 were significantly higher in the PIM and PER sites compared to healthy sites (P0.05). Conclusion. aMMP-8, IL-6, IL-1β, and TNF-α presented higher GCF/PICF concentrations in diseased periodontal and peri-implant sites. However, only the concentrations of IL-1β and a-MMP-8 were significantly higher in PIM than in PER sites.

Many industrial sectors exploit fossil sources to develop useful and necessary materials for our needs, such as bituminous paving materials. Bitumen, a key component of asphalt mixtures, is derived from oil refining and its properties are influenced by the crude oil source and refining process, resulting in a significant carbon footprint. With growing awareness of resource depletion and environmental concerns, pavement researchers are exploring sustainable alternatives to reduce dependence on fossil sources. This includes a rising trend in using renewable materials like biomasses to produce bio-based binders as substitutes for bitumen, aiming for a more sustainable approach. Biomasses, including vegetal and animal wastes, and waste cooking oils, as substitutes for crude oil in the production of bio-binders. Through thermochemical conversion (TCC), such as pyrolysis, biomasses can be converted into bio-char and bio-oils, which can replace fossil-based components in binders. Researchers have utilized these bio-products to reduce the dependency on fossil fuels in binders. However, there are no set minimum requirements for bio-components in bio-based binders. As the percentage of replaced bitumen increases, various types of binders are produced, including modified bitumen, extended bitumen, and alternative binders, where the fossil replacement is gradual. Overall rheological tests on bio-binders, reveal that those containing bio-char exhibit increased viscosity, stiffness, rutting resistance, and sometimes antioxidant properties. Conversely, bio-binders with bio-oils as bitumen substitutes show poorer performance at high temperatures but improved behavior at low temperatures. These results suggest that bio-binders could provide versatile solutions for various climatic and loading conditions in road construction. However, the development of pavement mixtures based on bio-binders has not been studied in depth and requires further attention to unlock its full potential. As sustainability considerations, including life cycle assessments (LCA) and life cycle cost analyses (LCC), are crucial aspects for future studies. It is essential not only to collect data on the performance characteristics of bio-binders but also to understand their environmental impact and recyclability. In-depth evaluations using methods such as LCA and LCC will provide valuable insights into the overall sustainability and long-term viability of these products.

Abstract Background Health professionals from different specialties in medical and psychological areas play an important role in diagnosis and treatment of eating disorders (EDs). This study aimed to identify gaps in knowledge about the diagnosis, etiology, and management of EDs and to assess health professionals’ attitudes towards these illnesses. Methods A new questionnaire was developed and validated. Residents and consultants working in disciplines involved in the management of EDs (namely, internal medicine, general practitioners, psychiatric area, psychological area, and surgical area) completed the questionnaire. Knowledge and attitudes were compared among the study groups through one-way ANCOVA and chi-square tests. Results The final version of the questionnaire consisted of 54 items assessing the following areas: stigma, treatment, physical complications, diagnosis, and aetiopathogenesis of EDs. For all health professionals the area of most deficiency was the aetiopathogenesis, while the best one was the management of physical complications. All medical professionals showed less knowledge than psychiatrists in terms of etiology, diagnosis, and treatment of EDs. A lack of knowledge about evidence-based psychotherapies, general psychopathology, and family members’ role in the management of EDs emerged among all health professionals. Stigma was found among non-mental health professionals who considered these patients to be different from others and responsible for their abnormal eating behaviors. Conclusions Clarifying the health professionals’ specific gaps occurring in the knowledge of EDs and in the attitudes towards these individuals may inform educational programs to improve early detection and management of EDs.

Abstract Background Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium’s clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations. Content This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors’ preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections. Conclusions Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium’s ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.

Abstract Background Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. Methods The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile. Discussion Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity. Trial Registration CESC IOV 2023-78.

Abstract Background An intronic deletion within intron 2 of the DCDC2 gene encompassing the entire READ1 (hereafter, READ1d) has been associated in both children with developmental dyslexia (DD) and typical readers (TRs), with interindividual variation in reading performance and motion perception as well as with structural and functional brain alterations. Visual motion perception -- specifically processed by the magnocellular (M) stream -- has been reported to be a solid and reliable endophenotype of DD. Hence, we predicted that READ1d should affect neural activations in brain regions sensitive to M stream demands as reading proficiency changes. Methods We investigated neural activations during two M-eliciting fMRI visual tasks (full-field sinusoidal gratings controlled for spatial and temporal frequencies and luminance contrast, and sensitivity to motion coherence at 6%, 15% and 40% dot coherence levels) in four subject groups: children with DD with/without READ1d, and TRs with/without READ1d. Results At the Bonferroni-corrected level of significance, reading skills showed a significant effect in the right polar frontal cortex during the full-field sinusoidal gratings-M task. Regardless of the presence/absence of the READ1d, subjects with poor reading proficiency showed hyperactivation in this region of interest (ROI) compared to subjects with better reading scores. Moreover, a significant interaction was found between READ1d and reading performance in the left frontal opercular area 4 during the 15% coherent motion sensitivity task. Among subjects with poor reading performance, neural activation in this ROI during this specific task was higher for subjects without READ1d than for READ1d carriers. The difference vanished as reading skills increased. Conclusions Our findings showed a READ1d-moderated genetic vulnerability to alterations in neural activation in the ventral attentive and salient networks during the processing of relevant stimuli in subjects with poor reading proficiency.

Abstract The paper analyzes the cryptocurrency ecosystem at both the aggregate and individual levels to understand the factors that impact future volatility. The study uses high-frequency panel data from 2020 to 2022 to examine the relationship between several market volatility drivers, such as daily leverage, signed volatility and jumps. Several known autoregressive model specifications are estimated over different market regimes, and results are compared to equity data as a reference benchmark of a more mature asset class. The panel estimations show that the positive market returns at the high-frequency level increase price volatility, contrary to what is expected from the classical financial literature. We attributed this effect to the price dynamics over the last year of the dataset (2022) by repeating the estimation on different time spans. Moreover, the positive signed volatility and negative daily leverage positively impact the cryptocurrencies’ future volatility, unlike what emerges from the same study on a cross-section of stocks. This result signals a structural difference in a nascent cryptocurrency market that has to mature yet. Further individual-level analysis confirms the findings of the panel analysis and highlights that these effects are statistically significant and commonly shared among many components in the selected universe.

In this contribution, new chromosome data obtained on material collected in Italy are presented. It includes the first counts for four subspecies of the Italian endemic Centaurea aplolepa Moretti, i.e. C. aplolepa subsp. aplolepa, C. aplolepa subsp. bertolonii, C. aplolepa subsp. levantina, and C. aplolepa subsp. parvula. In addition, the first chromosome count for an Italian population of Silene canescens (Caryophyllaceae) is provided.

Intrigante e complesso, il rapporto tra aristocrazia e crimine compare da sempre sulle pagine della letteratura e della cronaca. Una contaminazione che unisce due mondi apparentemente opposti o quantomeno lontani ma, spesso, intimamente interconnessi, vittime di una controversa fascinazione reciproca. Scandagliando il fondale della cultura popolare, letteraria, cinematografica e facendo lo stesso con quello ancor più profondo della storiografia, emergono verità e leggende testimoni di questo costante intreccio. Racconti dove il potere, per essere ottenuto o mantenuto, richiede prezzi altissimi che persone e personaggi pagano sacrificando anima e corpo, oltre alle anime e ai corpi delle persone e i personaggi a loro vicini. In questa curiosa dinamica di coppia, Taormina, quantomeno dall’Ottocento, sembra essere stata palcoscenico inconsapevole e accondiscendente

While the spreading of the Internet of Things continues beyond expectations, the security of networking technologies used in this context remains an open issue. This paper provides a comprehensive overview of the state of the art on the security of Low Power Wide Area Networks (LPWANs), with a focus on Sigfox, LoRaWAN, and Narrowband Internet of Things. The paper covers five main areas: (1) security requirements and their implementation in these networks, such as authentication, encryption, access control, and key management; (2) categorization of attacks and threat modeling, with the identification of the attack vectors and the presentation of an attack categorization and analysis; (3) a detailed explanation of attacks documented on Sigfox, LoRaWAN, and Narrowband Internet of Things, examining the underlying vulnerabilities exploited, outlining potential consequences, and discussing countermeasures proposed to mitigate these attacks; (4) security enhancements proposed to address vulnerabilities in each network; (5) the integration of LPWANs with 5G and the consequent security challenges. This survey constitutes an important and missing resource for the study and the development of secure Internet of Things solutions based on Low Power Wide Area Networks, raising awareness of potential threats, and guiding future research efforts towards strengthening the security of these networks and of the broader IoT landscape.

Abstract Purpose Although insecure attachment and interpersonal problems have been acknowledged as risk and maintaining factors of eating disorders (EDs), the mediating role of interpersonal problems between attachment style and ED psychopathology has been poorly explored. The purpose of this study was to investigate the mediating role of interpersonal problems between insecure attachment and ED psychopathology. Methods One-hundred-nine women with anorexia nervosa and 157 women with bulimia nervosa filled in the Eating Disorder Inventory-2 (EDI-2) and the Experiences in Close Relationships (ECR) revised scale to assess ED core symptoms and attachment styles, respectively. Interpersonal difficulties were evaluated by the Inventory of Interpersonal Problems (IIP-32). A mediator’s path model was conducted with anxious and avoidant attachment subscores as independent variables, ED core symptoms as dependent variables and interpersonal difficulties as mediators. The diagnosis was entered in the model as a confounding factor. Results The socially inhibited/avoidant interpersonal dimension was a mediator between avoidant attachment and the drive to thinness as well as between avoidant attachment and body dissatisfaction. An indirect connection was found between attachment-related anxiety and bulimic symptoms through the mediation of intrusive/needy score. Conclusions Social avoidance and intrusiveness mediate the relationships between avoidant and anxious attachment styles and ED psychopathology. These interpersonal problems may represent specific targets for psychotherapeutic treatments in individuals with EDs and insecure attachment. Level of evidence Level III: Evidence obtained from well-designed cohort or case–control analytic studies.

Abstract Background Post-tooth extraction, dry socket is a frequently encountered complication, causing substantial pain and hindering the healing process. Conventional approaches to manage this condition have traditionally involved the use of antiseptic dressings to diminish bacterial presence and facilitate healing. This study aims to assess the efficacy of laser therapy in the symptomatic treatment of alveolitis. Methods A literature search was conducted on PubMed, Embase, Scopus, Google Scholar, Web of Science, focusing on publications from 1998 to 31/01/2024 using relevant keywords. The combination of “laser” and “dry socket” was executed through the boolean connection AND. Results At the conclusion of the study, a total of 50 studies were identified across the three search engines, with only three selected for the current systematic study and meta-analysis. The meta-analysis indicated that laser treatment proves effective in addressing alveolitis compared to Alvogyl. However, the correlation between the two was not highly significant. Conclusion These findings suggest that laser therapy may serve as a viable alternative to traditional treatments for dry socket. This minimally invasive procedure has the potential to alleviate pain and promote healing with fewer associated side effects.”

Abstract Objective Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non‐invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE‐ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non‐demented older adults. Methods Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid β1‐42 and p‐Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow‐up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed‐effects model for each tract. Results AD pathology, APOE‐ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE‐ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect. Interpretation Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.

Abstract Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Abstract Intra-abdominal infections (IAIs) are common surgical emergencies and are an important cause of morbidity and mortality in hospital settings, particularly if poorly managed. The cornerstones of effective IAIs management include early diagnosis, adequate source control, appropriate antimicrobial therapy, and early physiologic stabilization using intravenous fluids and vasopressor agents in critically ill patients. Adequate empiric antimicrobial therapy in patients with IAIs is of paramount importance because inappropriate antimicrobial therapy is associated with poor outcomes. Optimizing antimicrobial prescriptions improves treatment effectiveness, increases patients’ safety, and minimizes the risk of opportunistic infections (such as Clostridioides difficile) and antimicrobial resistance selection. The growing emergence of multi-drug resistant organisms has caused an impending crisis with alarming implications, especially regarding Gram-negative bacteria. The Multidisciplinary and Intersociety Italian Council for the Optimization of Antimicrobial Use promoted a consensus conference on the antimicrobial management of IAIs, including emergency medicine specialists, radiologists, surgeons, intensivists, infectious disease specialists, clinical pharmacologists, hospital pharmacists, microbiologists and public health specialists. Relevant clinical questions were constructed by the Organizational Committee in order to investigate the topic. The expert panel produced recommendation statements based on the best scientific evidence from PubMed and EMBASE Library and experts’ opinions. The statements were planned and graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence. On November 10, 2023, the experts met in Mestre (Italy) to debate the statements. After the approval of the statements, the expert panel met via email and virtual meetings to prepare and revise the definitive document. This document represents the executive summary of the consensus conference and comprises three sections. The first section focuses on the general principles of diagnosis and treatment of IAIs. The second section provides twenty-three evidence-based recommendations for the antimicrobial therapy of IAIs. The third section presents eight clinical diagnostic-therapeutic pathways for the most common IAIs. The document has been endorsed by the Italian Society of Surgery.

Abstract Valence (positive and negative) and content (embodied vs non-embodied) characteristics of visual stimuli have been shown to influence motor readiness, as tested with response time paradigms. Both embodiment and emotional processing are affected in Parkinson’s disease (PD) due to basal ganglia dysfunction. Here we aimed to investigate, using a two-choice response time paradigm, motor readiness when processing embodied (emotional body language [EBL] and emotional facial expressions [FACS]) vs non-embodied (emotional scenes [IAPS]) stimuli with neutral, happy, and fearful content. We enrolled twenty-five patients with early-stage PD and twenty-five age matched healthy participants. Motor response during emotional processing was assessed by measuring response times (RTs) in a home-based, forced two-choice discrimination task where participants were asked to discriminate the emotional stimulus from the neutral one. Rating of valence and arousal was also performed. A clinical and neuropsychological evaluation was performed on PD patients. Results showed that RTs for PD patients were longer for all conditions compared to HC and that RTs were generally longer in both groups for EBL compared to FACS and IAPS, with the sole exception retrieved for PD, where in discriminating fearful stimuli, RTs for EBL were longer compared to FACS but not to IAPS. Furthermore, in PD only, when discriminating fearful respect to neutral stimuli, RTs were shorter when discriminating FACS compared to IAPS. This study shows that PD patients were faster in discriminating fearful embodied stimuli, allowing us to speculate on mechanisms involving an alternative, compensatory, emotional motor pathway for PD patients undergoing fear processing.

Abstract Background Various blood metabolites are known to be useful indicators of health status in dairy cattle, but their routine assessment is time-consuming, expensive, and stressful for the cows at the herd level. Thus, we evaluated the effectiveness of combining in-line near infrared (NIR) milk spectra with on-farm (days in milk [DIM] and parity) and genetic markers for predicting blood metabolites in Holstein cattle. Data were obtained from 388 Holstein cows from a farm with an AfiLab system. NIR spectra, on-farm information, and single nucleotide polymorphisms (SNP) markers were blended to develop calibration equations for blood metabolites using the elastic net (ENet) approach, considering 3 models: (1) Model 1 (M1) including only NIR information, (2) Model 2 (M2) with both NIR and on-farm information, and (3) Model 3 (M3) combining NIR, on-farm and genomic information. Dimension reduction was considered for M3 by preselecting SNP markers from genome-wide association study (GWAS) results. Results Results indicate that M2 improved the predictive ability by an average of 19% for energy-related metabolites (glucose, cholesterol, NEFA, BHB, urea, and creatinine), 20% for liver function/hepatic damage, 7% for inflammation/innate immunity, 24% for oxidative stress metabolites, and 23% for minerals compared to M1. Meanwhile, M3 further enhanced the predictive ability by 34% for energy-related metabolites, 32% for liver function/hepatic damage, 22% for inflammation/innate immunity, 42.1% for oxidative stress metabolites, and 41% for minerals, compared to M1. We found improved predictive ability of M3 using selected SNP markers from GWAS results using a threshold of > 2.0 by 5% for energy-related metabolites, 9% for liver function/hepatic damage, 8% for inflammation/innate immunity, 22% for oxidative stress metabolites, and 9% for minerals. Slight reductions were observed for phosphorus (2%), ferric-reducing antioxidant power (1%), and glucose (3%). Furthermore, it was found that prediction accuracies are influenced by using more restrictive thresholds (−log10(P-value) > 2.5 and 3.0), with a lower increase in the predictive ability. Conclusion Our results highlighted the potential of combining several sources of information, such as genetic markers, on-farm information, and in-line NIR infrared data improves the predictive ability of blood metabolites in dairy cattle, representing an effective strategy for large-scale in-line health monitoring in commercial herds.

Abstract Advanced methods such as REACT have allowed the integration of fMRI with the brain’s receptor landscape, providing novel insights transcending the multiscale organisation of the brain. Similarly, normative modelling has allowed translational neuroscience to move beyond group-average differences and characterise deviations from health at an individual level. Here, we bring these methods together for the first time. We used REACT to create functional networks enriched with the main modulatory, inhibitory, and excitatory neurotransmitter systems and generated normative models of these networks to capture functional connectivity deviations in patients with schizophrenia, bipolar disorder (BPD), and ADHD. Substantial overlap was seen in symptomatology and deviations from normality across groups, but these could be mapped into a common space linking constellations of symptoms through to underlying neurobiology transdiagnostically. This work provides impetus for developing novel biomarkers that characterise molecular- and systems-level dysfunction at the individual level, facilitating the transition towards mechanistically targeted treatments.

Abstract Technological advances in massively parallel sequencing have led to an exponential growth in the number of known protein sequences. Much of this growth originates from metagenomic projects producing new sequences from environmental and clinical samples. The Unified Human Gastrointestinal Proteome (UHGP) catalogue is one of the most relevant metagenomic datasets with applications ranging from medicine to biology. However, the low levels of sequence annotation may impair its usability. This work aims to produce a family classification of UHGP sequences to facilitate downstream structural and functional annotation. This is achieved through the release of the DPCfam-UHGP50 dataset containing 10,778 putative protein families generated using DPCfam clustering, an unsupervised pipeline grouping sequences into single or multi-domain architectures. DPCfam-UHGP50 considerably improves family coverage at protein and residue levels compared to the manually curated repository Pfam. In the hope that DPCfam-UHGP50 will foster future discoveries in the field of metagenomics of the human gut, we release a FAIR-compliant database of our results that is easily accessible via a searchable web server and Zenodo repository.

In response to the uncertainty and volatility arising from renewable sources, there is a growing need for enhanced flexibility within the energy system to maintain a continuous balance between power generation and demand. In this context, interest is growing around the so-called Multi-Energy Systems (MES) where different energy vectors coexist and optimally interact through conversion technologies and energy networks, creating additional flexibility opportunities. Nevertheless, there exists a gap in research regarding the impact of the network on flexibility availability. Typically, these complex systems are treated as power nodes or energy hubs without comprehensive network considerations. For this reason, the paper aims to propose a methodology and a tool to evaluate flexibility in a Multi-Energy System, considering not only the individual devices in place and the users' demands but also their interactions with the physical energy network. In detail, a simulation-based methodology is developed and described, and finally tested on a Case Study. As a result, both the physical and operational flexibilities (UP-flex and DOWN-flex) of the system regarding the electrical vector were obtained analytically and graphically. Particular attention was given to the evolution of key temperatures within the district heating network and the thermal power produced by the central unit in various flexibility scenarios. The outcomes demonstrate the utility of this tool for defining flexibility boundaries and profiles, as well as for assessing whether the flexibility demanded by grid operators aligns with the physical constraints of the network.

Abstract Assessment of current and future growth in the global rooftop area is important for understanding and planning for a robust and sustainable decentralised energy system. These estimates are also important for urban planning studies and designing sustainable cities thereby forwarding the ethos of the Sustainable Development Goals 7 (clean energy), 11 (sustainable cities), 13 (climate action) and 15 (life on land). Here, we develop a machine learning framework that trains on big data containing ~700 million open-source building footprints, global land cover, road, and population datasets to generate globally harmonised estimates of growth in rooftop area for five different future growth narratives covered by Shared Socioeconomic Pathways. The dataset provides estimates for ~3.5 million fishnet tiles of 1/8 degree spatial resolution with data on gross rooftop area for five growth narratives covering years 2020–2050 in decadal time steps. This single harmonised global dataset can be used for climate change, energy transition, biodiversity, urban planning, and disaster risk management studies covering continental to conurbation geospatial levels.

Abstract Localised fruit thinning strategies must be investigated to improve precision crop load management in narrow-canopy, multileader apple trees. This study aimed to determine the effects of within-leader and tree total crop load on leaders’ and trunk’s growth, fruit set, yield, and fruit quality in ‘Ruby Matilda’ apples (marketed as Pink Lady®) over three years. Different crop loads were imposed on two leaders (primary and secondary) of bi-axis trees. Leader and trunk relative growth rate, return fruit set, yield, and fruit quality parameters at harvest were measured. High within-leader crop loads led to a significant increase in yield and reductions in trunk growth, return fruit set, and deterioration of fruit quality parameters except for flesh firmness and starch index. Similar trends were observed in whole-tree relationships. High crop load in secondary leaders had moderate negative effects on trunk growth, yield, and fruit mass of primary leaders; it only marginally affected their return fruit set and had no significant effect (p > 0.05) on their fruit quality. A crop load of 6.8 fruit no. cm−2 of leader cross-sectional area was estimated to achieve a relatively consistent return fruit set within the same leader. At a whole-tree level, a similar crop load (6.9 fruit no. cm−2 of trunk cross-sectional area) produced a consistent return fruit set despite its higher variability. These crop loads produced high yields (120 and 111 t ha−1, respectively) and good quality fruit. Using individual leaders as management units is recommended to simplify operations and reduce variability.

Abstract Magma ascending through Earth’s crust undergoes complex chemical and physical changes that may induce crystallization, a process that contributes to lead the magmatic system toward a thermodynamic state of equilibrium. The diverse cooling and deformative regimes suffered by magmas heavily influence crystallization rates, solidification timescales, and consequently, the rheological evolution of magma. This, in turn, significantly impacts the dynamics of volcanic plumbing systems and the associated eruptive styles. Here, we investigate the rheological changes in Stromboli magma (Italy) during disequilibrium crystallization under non-isothermal subliquidus conditions. By systematically varying the cooling rate (1-10 °C/min) and the shear rate (1-10 s−1), we find that cooling rates significantly influence the solidification path of the basalt, whereas shear rates have a subordinate effect. By comparing our results with literature data on basalts from Mt. Etna (Italy), characterized by higher TiO2 and FeOtot contents, we observed distinct timescales and rates of solidification, contributing to unique eruptive dynamics in these volcanic plumbing systems.

Abstract Background This study explores the biosynthesis, characteristics, and functional properties of exopolysaccharide produced by the strain Liquorilactobacillus mali T6-52. The strain demonstrated significant EPS production with a non-ropy phenotype. Results The genomic analysis unveiled genes associated with EPS biosynthesis, shedding light on the mechanism behind EPS production. These genes suggest a robust EPS production mechanism, providing insights into the strain’s adaptability and ecological niche. Chemical composition analysis identified the EPS as a homopolysaccharide primarily composed of glucose, confirming its dextran nature. Furthermore, it demonstrated notable functional properties, including antioxidant activity, fat absorption capacity, and emulsifying activity. Moreover, the EPS displayed promising cryoprotective activities, showing notable performance comparable to standard cryoprotective agents. The EPS concentration also demonstrated significant freeze-drying protective effects, presenting it as a potential alternative cryoprotectant for bacterial storage. Conclusions The functional properties of L. mali T6-52 EPS reveal promising opportunities across various industrial domains. The strain’s safety profile, antioxidant prowess, and exceptional cryoprotective and freeze-drying characteristics position it as an asset in food processing and pharmaceuticals.

Recently, the development of targeted therapy approaches such as those based on tyrosine kinase inhibitor (TKI) greatly improved the clinical outcomes of patients affected by oncogene addicted advanced non-small cell lung cancer (NSCLC). Similarly, the improvement of radiation therapy techniques has permitted to deliver high radiation doses to a limited number of metastatic target lesions (oligopersistent or oligoprogressive), with limited high-dose normal tissue exposure that leads to low severe toxicity rates. The aim of this narrative review was to provide an overview of the currently established definition of oligometastatic and oligoprogressive disease, to define first line and subsequent lines targeted therapies and the role of consolidative non-invasive local ablative treatments (LATs) in these settings. The potential benefit of local treatment (LT) such as radiotherapy (RT) or surgery might be represented by an overall reduction of switching to subsequent systemic treatments lowering the risk of further systemic dissemination. Further randomized clinical trials will clarify the role of LT and their correct timing in relation to systemic targeted therapies.

Abstract Tauopathies, including Alzheimer’s disease and Frontotemporal Dementia, are debilitating neurodegenerative disorders marked by cognitive decline. Despite extensive research, achieving effective treatments and significant symptom management remains challenging. Accurate diagnosis is crucial for developing effective therapeutic strategies, with hyperphosphorylated protein units and tau oligomers serving as reliable biomarkers for these conditions. This study introduces a novel approach using nanotechnology to enhance the diagnostic process for tauopathies. We developed humanized ferritin nanocages, a novel nanoscale delivery system, designed to encapsulate and transport a tau-specific fluorophore, BT1, into human retinal cells for detecting neurofibrillary tangles in retinal tissue, a key marker of tauopathies. The delivery of BT1 into living cells was successfully achieved through these nanocages, demonstrating efficient encapsulation and delivery into retinal cells derived from human induced pluripotent stem cells. Our experiments confirmed the colocalization of BT1 with pathological forms of tau in living retinal cells, highlighting the method’s potential in identifying tauopathies. Using ferritin nanocages for BT1 delivery represents a significant contribution to nanobiotechnology, particularly in neurodegenerative disease diagnostics. This method offers a promising tool for the early detection of tau tangles in retinal tissue, with significant implications for improving the diagnosis and management of tauopathies. This study exemplifies the integration of nanotechnology with biomedical science, expanding the frontiers of nanomedicine and diagnostic techniques.

Abstract The subcontinental lithospheric mantle (SCLM) beneath Phanerozoic regions is mostly constituted by fertile lherzolites, which sharply contrast with cratonic mantle made of highly-depleted peridotites. The question of whether this chemical difference results from lower degrees of melting associated with the formation of Phanerozoic SCLM or from the refertilization of ancient depleted SCLM remains a subject of debate. Additionally, the timing and geodynamic environment of accretion of the fertile SCLM in many Phanerozoic regions are poorly constrained. We here document new geochemical and Nd-Hf isotopic data for orogenic lherzolite massifs from the Ivrea-Verbano Zone (IVZ), Southern Alps. Even though a few Proterozoic Re depletion ages are locally preserved in these mantle bodies, our data reveal that the IVZ lherzolitic massifs were “recently” accreted to the SCLM in the Upper Devonian (ca. 370 Ma) during Pangea amalgamation, with a petrochemical evolution characterized by low-degree (~ 5–12%) depletion and nearly contemporaneous pervasive to focused melt migration. The lithospheric accretion putatively took place through asthenospheric upwelling triggered by Variscan intra-continental extension in a back-arc setting related to the subduction of the Rheic Ocean. We thus conclude that the fertile sections of Phanerozoic SCLM can be accreted during “recent” events of back-arc continental extension, even where Os isotopes preserve memories of melting events in much older times.

Abstract Background The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing The Cancer Genome Atlas MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner.

Abstract Several lines of evidence demonstrate that the brain histaminergic system is fundamental for cognitive processes and the expression of memories. Here, we investigated the effect of acute silencing or activation of histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMNHA neurons) in vivo in both sexes in an attempt to provide direct and causal evidence of the necessary role of these neurons in recognition memory formation and retrieval. To this end, we compared the performance of mice in two non-aversive and non-rewarded memory tests, the social and object recognition memory tasks, which are known to recruit different brain circuitries. To directly establish the impact of inactivation or activation of TMNHA neurons, we examined the effect of specific chemogenetic manipulations during the formation (acquisition/consolidation) or retrieval of recognition memories. We consistently found that acute chemogenetic silencing of TMNHA neurons disrupts the formation or retrieval of both social and object recognition memory in males and females. Conversely, acute chemogenetic activation of TMNHA neurons during training or retrieval extended social memory in both sexes and object memory in a sex-specific fashion. These results suggest that the formation or retrieval of recognition memory requires the tonic activity of histaminergic neurons and strengthen the concept that boosting the brain histaminergic system can promote the retrieval of apparently lost memories.

Abstract The European Association of Urology (EAU) has proposed a risk stratification for patients harboring biochemical recurrence (BCR) after radical prostatectomy: ISUP 12 months for low risk, and ISUP ≥ 4 or PSAdt ≤ 12 months for high risk. This dual-center retrospective study aims to investigate the correlation between the EAU risk stratification for BCR following radical prostatectomy and the detection rate of lesions using 18F-PSMA-1007 PET/CT. Among the 71 included patients (58 high-risk, 13 low-risk), with a median PSA level of 1.43 ng/ml, PET/CT demonstrated a significantly higher positivity in the high-risk group compared to the low-risk group (72.4% vs. 38.0%, p = 0.026). Analysis of recurrence sites revealed a similar proportion of pelvic-confined disease in both groups (24.1% vs. 23.1%, p = 0.935), but a significantly higher incidence of metastatic disease in the high-risk group (51.7% vs. 15.4%, p = 0.017), with detailed findings indicating an increased prevalence of bone metastases in the high-risk BCR group (37.8% vs. 7.7%, p = 0.048). Therefore, PSMA PET/CT offers valuable insights for treatment decisions, aligning with the evolving landscape of prostate cancer management.

Abstract Background The European-funded Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy in Pediatrics (HARMONIC) project aims to improve knowledge on the effects of medical exposure to ionizing radiation (IR) received during childhood. One of its objectives is to build a consolidated European cohort of pediatric patients who have undergone cardiac catheterization (Cath) procedures, with the goal of enhancing the assessment of long-term radiation-associated cancer risk. The purpose of our study is to provide a detailed description of the Italian cohort contributing to the HARMONIC project, including an analysis of cumulative IR exposure, reduction trend over the years and an overview of the prospective collection of biological samples for research in this vulnerable population. Methods In a single-center retrospective cohort study, a total of 584 patients (323 males) with a median age of 6 (2–13) years, referred at the Pediatric Cardiology in Niguarda Hospital from January 2015 to October 2023, were included. Biological specimens from a subset of 60 patients were prospectively collected for biobanking at baseline, immediately post-procedure and after 12 months. Results Two hundred fifty-nine (44%) patients were under 1 year old at their first procedure. The median KAP/weight was 0.09 Gy·cm2/kg (IQR: 0.03–0.20), and the median fluoroscopy time was 8.10 min (IQR: 4.00–16.25). KAP/weight ratio showed a positive correlation with the fluoroscopy time (Spearman’s rho = 0.679, p

Abstract According to textbooks, no physical observable can be discerned allowing to distinguish a liquid from a gas beyond the critical point. Yet, several proposals have been put forward challenging this view and various transition boundaries between a gas-like and a liquid-like behaviour, including the so-called Widom and Frenkel lines, and percolation line, have been suggested to delineate the supercritical state space. Here we report observation of a crossover from gas-like (Gaussian) to liquid-like (Lorentzian) self-dynamic structure factor by incoherent quasi-elastic neutron scattering measurements on supercritical fluid methane as a function of pressure, along the 200 K isotherm. The molecular self-diffusion coefficient was derived from the best Gaussian (at low pressures) or Lorentzian (at high pressures) fits to the neutron spectra. The Gaussian-to-Lorentzian crossover is progressive and takes place at about the Widom line intercept (59 bar). At considerably higher pressures, a liquid-like jump diffusion mechanism properly describes the supercritical fluid on both sides of the Frenkel line. The present observation of a gas-like to liquid-like crossover in the self dynamics of a simple supercritical fluid confirms emerging views on the unexpectedly complex physics of the supercritical state, and could have planet-wide implications and possible industrial applications in green chemistry.

Abstract Purpose Bariatric surgery (BS), an effective treatment for severe obesity and its comorbidities, may result in micronutrient and vitamin deficiencies. This monocentric prospective observational study aimed at evaluating the efficacy of a specifically designed vitamin/mineral formula (Bariatrifast, BIOITALIA S.r.l., Italy) for preventing and treating micronutrient deficiencies in patients submitted to BS. Methods Twenty patients with severe obesity (mean weight and BMI: 123.5 kg (range 88–174) and 43.3 kg/m2 (range 37–54) respectively) underwent BS (10 vertical sleeve gastrectomy VSG, 10 Roux-en-Y gastric bypass, RYGB). The mean age was 49.9 years (range 27–68). After a presurgical visit (V0), follow-up visits were performed at 1, 3, 6 and 12 months after surgery (V1–V4). Recorded data included weight, height and BMI. A complete blood count, measurement of ferritin, folic acid, vitamin B12, ionized calcium, 25 OH vitamin D, parathyroid hormone (PTH) were obtained. Following BS, patients started the daily oral multivitamin and mineral supplement. Results All patients achieved a significant weight loss (mean − 34.7 ± 11.8 kg). No deficiencies of various vitamins/micronutrients were detected during the entire study period. The serum concentrations of vitamin B12, 25-OH Vitamin D and folic acid increased over the follow-up period compared with V0 (mean increase 243 ng/L, 23 µg /L, 8 µg/L, respectively). Compared to RYGB, patients who underwent sleeve gastrectomy showed higher levels of 25-OH vitamin D at V2, V3 and V4 (all p

Abstract The unique dimension-5 effective operator, LLHH, known as the Weinberg operator, generates tiny Majorana masses for neutrinos after electroweak spontaneous symmetry breaking. If there are new scalar multiplets that take vacuum expectation values (VEVs), they should not be far from the electroweak scale. Consequently, they may generate new dimension-5 Weinberg-like operators which in turn also contribute to Majorana neutrino masses. In this study, we consider scenarios with one or two new scalars up to quintuplet SU(2) representations. We analyse the scalar potentials, studying whether the new VEVs can be induced and therefore are naturally suppressed, as well as the potential existence of pseudo-Nambu-Goldstone bosons. Additionally, we also obtain general limits on the new scalar multiplets from direct searches at colliders, loop corrections to electroweak precision tests and the W-boson mass.

Abstract This article looks at the key factors affecting the connection between peasant family size and farm size in Italy in 1930–1931. The association between farm size and family size was analyzed using a new dataset merging data drawn from both the Population Census of 1931 and the Census of Agriculture of 1930. We found a strict association between peasant family size, here considered as a production unit, and the surface area of the farm. The results seem to correspond to different causal relationship between family size and farm size according to access to land, and form of tenure. In some contexts, where sharecropping was widespread, farm size defines the size of the family. In others where small land ownership prevailed, it seems that family size shapes the size of the farm. In this study we propose a new explanation for peasant family size in the Fascist period. This is done adopting a cross-sectional perspective, providing a geographical analysis based on the 786 agrarian areas that formed the national territory in that period.

Abstract Without the protective shielding of Earth’s atmosphere, astronauts face higher doses of ionizing radiation in space, causing serious health concerns. Highly charged and high energy (HZE) particles are particularly effective in causing complex and difficult-to-repair DNA double-strand breaks compared to low linear energy transfer. Additionally, chronic cortisol exposure during spaceflight raises further concerns, although its specific impact on DNA damage and repair remains unknown. This study explorers the effect of different radiation qualities (photons, protons, carbon, and iron ions) on the DNA damage and repair of cortisol-conditioned primary human dermal fibroblasts. Besides, we introduce a new measure, the Foci-Integrated Damage Complexity Score (FIDCS), to assess DNA damage complexity by analyzing focus area and fluorescent intensity. Our results show that the FIDCS captured the DNA damage induced by different radiation qualities better than counting the number of foci, as traditionally done. Besides, using this measure, we were able to identify differences in DNA damage between cortisol-exposed cells and controls. This suggests that, besides measuring the total number of foci, considering the complexity of the DNA damage by means of the FIDCS can provide additional and, in our case, improved information when comparing different radiation qualities.

Abstract The characterization of a quantum device is a crucial step in the development of quantum experiments. This is accomplished via Quantum Process Tomography, which combines the outcomes of different projective measurements to deliver a possible reconstruction of the underlying process. The tomography is typically performed by processing an overcomplete set of measurements and extracting the process matrix from maximum-likelihood estimation. Here, we introduce Fourier Quantum Process Tomography, a technique which requires a reduced number of measurements, and benchmark its performance against the standard maximum-likelihood approach. Fourier Quantum Process Tomography is based on measuring probability distributions in two conjugate spaces for different state preparations and projections. Exploiting the concept of phase retrieval, our scheme achieves a complete and robust characterization of the setup by processing a near-minimal set of measurements. We experimentally test the technique on different space-dependent polarization transformations, reporting average fidelities higher than 90% and significant computational advantage.

Abstract Richter’s syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade B-cell malignancy. Molecular and functional studies have pointed out that CLL cells are close to the apoptotic threshold and dependent on BCL-2 for survival. However, it remains undefined how evasion from apoptosis evolves during disease transformation. Here, we employed functional and static approaches to compare the regulation of mitochondrial apoptosis in CLL and RS. BH3 profiling of 17 CLL and 9 RS samples demonstrated that RS cells had reduced apoptotic priming and lower BCL-2 dependence than CLL cells. While a subset of RS was dependent on alternative anti-apoptotic proteins and was sensitive to specific BH3 mimetics, other RS cases harbored no specific anti-apoptotic addiction. Transcriptomics of paired CLL/RS samples revealed downregulation of pro-apoptotic sensitizers during disease transformation. Albeit expressed, effector and activator members were less likely to colocalize with mitochondria in RS compared to CLL. Electron microscopy highlighted reduced cristae width in RS mitochondria, a condition further promoting apoptosis resistance. Collectively, our data suggest that RS cells evolve multiple mechanisms that lower the apoptotic priming and shift the anti-apoptotic dependencies away from BCL-2, making direct targeting of mitochondrial apoptosis more challenging after disease transformation.

Abstract The concept of synthetic dimensions works particularly well in atomic physics, quantum optics, and photonics, where the internal degrees of freedom (Zeeman sublevels of the ground state, metastable excited states, or motional states for atoms, and angular momentum states or transverse modes for photons) provide the synthetic space. In this Perspective article we report on recent progress on studies of synthetic dimensions, mostly, but not only, based on the research realized around the Barcelona groups (ICFO, UAB), Donostia (DIPC), Poznan (UAM), Kraków (UJ), and Allahabad (HRI). We describe our attempts to design quantum simulators with synthetic dimensions, to mimic curved spaces, artificial gauge fields, lattice gauge theories, twistronics, quantum random walks, and more.

Abstract Large Language Models (LLMs) are characterized by their inherent memory inefficiency and compute-intensive nature, making them impractical to run on low-resource devices and hindering their applicability in edge AI contexts. To address this issue, Knowledge Distillation approaches have been adopted to transfer knowledge from a complex model, referred to as the teacher, to a more compact, computationally efficient one, known as the student. The aim is to retain the performance of the original model while substantially reducing computational requirements. However, traditional knowledge distillation methods may struggle to effectively transfer crucial explainable knowledge from an LLM teacher to the student, potentially leading to explanation inconsistencies and decreased performance. This paper presents DiXtill, a method based on a novel approach to distilling knowledge from LLMs into lightweight neural architectures. The main idea is to leverage local explanations provided by an eXplainable Artificial Intelligence (XAI) method to guide the cross-architecture distillation of a teacher LLM into a self-explainable student, specifically a bi-directional LSTM network.Experimental results show that our XAI-driven distillation method allows the teacher explanations to be effectively transferred to the student, resulting in better agreement compared to classical distillation methods,thus enhancing the student interpretability. Furthermore, it enables the student to achieve comparable performance to the teacher LLM while also delivering a significantly higher compression ratio and speedup compared to other techniques such as post-training quantization and pruning, which paves the way for more efficient and sustainable edge AI applications

Abstract Metal-organic frameworks (MOF) are an attractive class of porous materials due to their immense design space, allowing for application-tailored properties. Properties of interest, such as gas sorption, can be predicted in silico with molecular mechanics simulations. However, the accuracy is limited by the available empirical force field and partial charge estimation scheme. In this work, we train a graph neural network for partial charge prediction via active learning based on Dropout Monte Carlo. We show that active learning significantly reduces the required amount of labeled MOFs to reach a target accuracy. The obtained model generalizes well to different distributions of MOFs and Zeolites. In addition, the uncertainty predictions of Dropout Monte Carlo enable reliable estimation of the mean absolute error for unseen MOFs. This work paves the way towards accurate molecular modeling of MOFs via next-generation potentials with machine learning predicted partial charges, supporting in-silico material design.

Abstract Background Multisystem inflammatory syndrome in children (MIS-C) shows a significant overlap of symptoms with other hyper-inflammatory diseases such as Kawasaki disease (KD), but the real difference of the two conditions is still matter of debate. Coronary artery lesions (CAL) are the most relevant complication in KD. Nonetheless, CAL, myocarditis, pericarditis, arrhythmia are the main cardiovascular complications in MIS-C. A close clinical assessment is mandatory, both at the diagnosis and during the follow-up, by ECG and echocardiography. Cardiac magnetic resonance (MRI) adds important data to ultrasound findings. However, cardiac MRI studies in MIS-C are limited to a small number of cohorts. Methods We enrolled 20 children (age:1–16 years; 11 F; 9 M) with cardiac involvement secondary to MIS-C, all evaluated by cardiac MRI. Results 8 children showed pathological cardiac MRI: 2 showed pericardial effusion; 2 showed myocardial oedema; 1 showed aortic insufficiency; 3 showed delayed enhancement (one for acute myocarditis with oedema; 2 for myocardial fibrosis). Delayed enhancement was reduced significantly 5.6-9 months after the first MRI evaluation. 25% of patients with pathological MRI had CAL associated with valvular insufficiency of 2 valves. 17% of patients with normal MRI had CAL, associated with valvular insufficiency of 1 valve in 1 patient. The correlations between haematological, clinical, cardiologic parameters, treatment, did not reach the statistical significance. 4 patients were treated with anakinra. Among those, 2 patients showed a normal cardiac MRI. Cardiac lesions resolved in all the patients during the follow-up. Some patients with pathological cardiac MRI could not underwent a control with MRI, for the low compliance. However, echocardiography and ECG, documented the resolution of the pathological data in these cases. Conclusions A higher risk of CAL was documented in patients with an association of other cardiac lesions. Cardiac MRI is difficult to perform routinely; however, it is useful for evaluating the acute myocardial damage and the outcome of patients with MIS-C.

Abstract Introduction Oral chlorhexidine has been widely used for ventilator-associated pneumonia prevention in the critical care setting; however, previous studies and evidence synthesis have generated inconsistent findings. Our study aims to investigate if different concentrations of oral chlorhexidine may be effective in preventing such complication in intensive care unit patients. Methods After pre-registration (Open Science Framework: 8CUKF), we conducted a network meta-analysis with the following PICOS: adult patients (age > 18 years old) undergoing invasive mechanical ventilation admitted in ICU (P); any concentration of chlorhexidine used for oral hygiene (I); placebo, sham intervention, usual care, or no intervention (C); rate of VAP (primary outcome), mechanical ventilation length, ICU length of stay (LOS), hospital LOS, mortality (secondary outcomes) (O); randomized controlled trials (S). We used the following database: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and EMBASE without any limitation in publication date or language. Results Chlorhexidine did not demonstrate any significant advantage over the control group in preventing ventilator-associated pneumonia or reducing mortality, duration of mechanical ventilation, length of stay in the intensive care unit, or overall mortality. Conclusions Chlorhexidine oral decontamination does not reduce the rate of ventilator-associated pneumonia in critically ill adult patients and its routine use could not be recommended. Trial registration Registration number: Open Science Framework: 8CUKF.

The immunization of mice with the sterile culture medium supernatants of Mycobacterium tuberculosis (Mtb) H37Rv permitted the production of several monoclonal antibodies (mAbs) specific for secreted and/or released antigens. Two mAbs bound and immunoprecipitated an 80-kDa protein that was identified by mass spectrometry as Rv1133c, the methionine synthase MetE. The protein MetE is ubiquitous among prokaryota and shows a significant sequence homology in many bacteria. We produced both the full-length recombinant MetE and its N-terminal fragment, whose sequence is more conserved among mycobacteria, to select mAbs recognizing an Mtb-specific region of MetE. Finally, we produced and selected eight mAbs that specifically detect the MetE protein in the supernatant and cell lysate of Mtb and BCG, but not other bacteria such as non-tuberculous mycobacteria (NTM), Streptococcus pneumoniae, Staphylococcus aureus, Acinetobacter baumanii, or Escherichia coli. Taking advantage of our mAbs, we studied (i) the vitamin B12 dependence for the synthesis of MetE in Mtb and NTM and (ii) the kinetics of MetE production and secretion in supernatants during the in vitro reproduced replicative, dormant, and resuscitation cycle of Mtb. Our data demonstrate that dormant Mtb, which are assumed to be prevalent in latent infections, as well as NTM do not produce and secrete MetE. Results indicate an unexpected specificity for Mtb of our anti-MetE mAbs and encourage the use of rMetE and our mAbs as tools for the immunodiagnosis of TB and its stages.