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Benedetta Maria Bonora, Angelo Avogaro, Gian Paolo Fadini Department of Medicine, University of Padova, Padova 35128, ItalyCorrespondence: Gian Paolo FadiniDepartment of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, ItalyTel +39 49 8214318Fax +29 49 8212184Email gianpaolo.fadini@unipd.itAbstract: Patients with type 2 diabetes (T2D) are often overweight/obese and affected by arterial hypertension, dyslipidaemia, and have high serum levels of uric acid. Moreover, T2D patient have a higher risk of developing cardiovascular or renal complications, which are leading causes of morbidity and mortality in this population. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering medications that block the reabsorption of glucose in the kidney, thereby increasing urinary glucose excretion, and lowering blood glucose levels. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, and include improvement in blood pressure, body weight, uric acid concentrations, liver steatosis, oxidative stress, and inflammation. In dedicated cardiovascular outcome trials, SGLT2i treatment was associated with a significant reduction in the rate of cardiovascular events and renal endpoints. In this review, we summarize the evidence for extra-glycemic effects of SGLT2i and the potential mechanisms driving cardiorenal protection exerted by this class of medications.Keywords: type 2 diabetes, sodium-glucose cotransporter-2 inhibitors, cardiovascular effects, renal effects, review

Breast cancer is the top cause of cancer mortality among women in the world and the second in Africa. The aims of this study were to: i) identify women with breast nodules suspected of having breast cancer ii) sequence the BRCA1 and BRCA2 genes and iii) screen mutations. From 2015 to 2016, 112 women aged from 35 to 44 years, who had come for consultation in the gynecology/obstetrics and the oncology department of the University Hospital Yalgado Ouedraogo, voluntarily agreed to participate to this study. Whole blood was collected from those with mammary nodules. The genomic DNA was extracted using Qiagen kit. FAST KAPA was used for genomic DNA amplification and the purified PCR products were analyzed by direct sequencing using Big Dye v1.1 and ABI 3730 automated sequencer. Nucleotides substitutions were determined. We identified BRCA1 SNPs rs1799966, rs799917, rs16942, rs16941, rs2227945, and BRCA2 SNPs rs169547, rs4986860. These identified variants are found mostly in cases of benign tumors of breast or ovarian cancer with familial history of breast cancer. This study in Burkina-Faso, is the basis for improved and more specific genetic testing, and suggests that additional genes contributing to an increased risk of breast cancer should be analyzed.

Background: The usual history of chronic heart failure (HF) is characterized by frequent episodes of acute decompensation (ADHF), needing urgent management in the emergency department (ED). Since the diagnostic accuracy of routine laboratory tests remains quite limited for predicting short-term mortality in ADHF this retrospective study investigated the potential significance of combining red blood cell distribution width (RDW) with other conventional tests for prognosticating ADHF upon ED admission. Methods: We conducted a retrospective study including visits for episodes of ADHF recorded in the ED of the University Hospital of Verona throughout a 4-year period. Demographic and clinical features were recorded upon patient presentation. All patients were subjected to standard Chest X-ray, electrocardiogram (ECG) and laboratory testing in - cluding creatinine, blood urea nitrogen, B-type natriuretic peptide (BNP), complete blood cell count (CBC), sodium, chloride, potassium and RDW. The 30-day overall mortality after ED presentation was defined as primary endpoint. Results: The values of sodium, creatinine, BNP and RDW were higher in patients who died than in those who survived, whilst hypochloremia was more frequent in patients who died than in those who survived. The multivariate model, incorporating these parameters, displayed a modest efficiency for predicting 30-day mortality after ED admission (AUC, 0.701; 95% CI, 0 .6 6 2 -0 .7 3 8 ; p= 0.001). Notably, the inclusion of RDW in the model significantly enhanced prediction efficiency, with an AUC of 0.723 (95% CI, 0 .6 9 3 -0 .7 6 3 ; p< 0.001). These results were confirmed with net reclassification improvement (NRI) analysis, showing that combination of RDW with conventional laboratory tests resulted in a much better prediction performance (net reclassification index, 0.222; p= 0.001). Conclusions: The results of our study show that prognostic assessment of ADHF patients in the ED can be significantly improved by combining RDW with other conventional laboratory tests.

In this work, nanoparticles of ZnO and zero-valent Fe were sonochemically synthesised using a solution produced from electric arc furnace dust leaching as raw material. The leaching was previously carried out using ultrasound with various concentrations of sulphuric acid. The resulting solutions contained, in addition to varying amounts of Zn and Fe, elements such as Cr, Mn, Mg, Ca, and Si. Two methods were developed, one for Fe and one for ZnO, to obtain the nanoparticles and to avoid the precipitation of the additional elements during the nanoparticle production. The synthesis of ZnO nanoparticles was performed through the formation of a precursor by sonochemical reaction with NaOH, and the thermal decomposition of this precursor by heating in furnace. The production of Fe nanoparticles involved the precipitation of FeOOH, the dissolution of FeOOH in HCl solution, and the ultrasound-assisted reduction of the iron ions with NaBH4. The nanoparticles were characterised by scanning and transmission electron microscopy, X-ray diffraction, X-ray fluorescence, and UV spectroscopy. The nanoparticles of Fe had a particle size of 6 nm and resulted in zero-valent Fe, whereas the ZnO nanoparticles were between 30 and 50 nm.

Background: Universally accepted and validated instruments for predicting the outcome of patients presenting to the emergency department (ED) with severe dyspnoea do not exist so far, nor are they regularly used by the emergency physicians. This study hence aimed to establish whether red blood cell distribution width (RDW) may be a predictive parameter of 1-year mortality in a population of patients admitted to the ED with severe dyspnoea attributable to different underlying disorders. Methods: We retrospectively evaluated all the patients undergoing arterial blood gas analysis for severe dyspnoea (irrespective of the cause) during admission to ED of University Hospital of Verona from September 1, 2014 to November 31, 2014. Results: The final study population consisted of 287 patients for whom complete clinical and laboratory information was available. Overall, 36 patients (12.5%) died after a 1-year follow-up. The RDW value was found to be considerably increased in patients who deceased during the follow-up compared to those who survived (17.2% versus 14.8%; p 15.0% displayed a 72% increased risk of 1-year mortality after multiple adjustments. Conclusions: The measurement of RDW, a very simple and inexpensive laboratory parameter, may represent an important factor for predicting medium-term mortality in patients presenting to the ED with severe dyspnoea.

Abstract Background A Chronic Kidney Disease (CKD) Epidemiology Collaboration (EPI) formula not including a Black race coefficient has been recently developed and is now recommended in the US. The new (2021) equation was shown to yield higher estimated glomerular filtration rate (eGFR) values than the old (2009) one in a non-Black general population sample, thus reclassifying a significant number of individuals to a better eGFR category. However, reclassified individuals were previously shown to have a lower risk of progression to end-stage kidney disease, but higher adjusted risks for all-cause death and morbidity and mortality from cardiovascular disease than those not reclassified. This study evaluated the prognostic impact of switching from the 2009 to the 2021 CKD-EPI equation in non-Black individuals with type 2 diabetes. Methods The Renal Insufficiency And Cardiovascular Events (RIACE) was a prospective cohort study enrolling 15,773 Caucasian patients in 19 Italian centers in 2006–2008. Cardiometabolic risk profile, treatments, complications, and comorbidities were assessed at baseline and eGFR was calculated with the two equations. Vital status was retrieved on 31 October 2015 for 15,656 participants (99.3%). Results With the 2021 equation, the eGFR value increased in all patients, except for 293 individuals with a 2009 eGFR ≥ 105 ml·min− 1·1.73 m− 2. The median difference was 4.10 ml·min− 1·1.73 m− 2 and was higher in males, older individuals and those in the G2 category. Reclassification decreased the percentage of patients with reduced eGFR from 17.28 to 13.96% and with any CKD from 36.23 to 34.03%. Reclassified individuals had better cardiometabolic risk profile and lower prevalence of complications and use of medications than non-reclassified individuals. Risk of death versus the 2009 G1 category was lower for reclassified than non-reclassified participants in all eGFR categories and, particularly, in each 2009 eGFR category, though difference was significant only in the G4-G5 category. The Receiver Operator Characteristic curves were statistically, but not clinically different with the two equations. Conclusion Changing from the 2009 to the 2021 CKD-EPI equation results in higher eGFR and lower CKD prevalence, with a lower risk of death in reclassified patients with an eGFR

Abstract In this work, we investigated the effects of alloying elements on plastic deformation and microstructure evolution in polycrystalline copper (Cu) and Cu alloyed with 1 wt. $$\%$$ % lead (Cu-1 $$\%$$ % Pb). These materials were selected due to the size mismatch between Cu and Pb, with the latter forming precipitates at grain boundaries. Multi-modal characterization techniques, including neutron diffraction, electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM), along with finite element simulations were employed to study the deformation behavior across multiple length scales. While both Cu and Cu-1 $$\%$$ % Pb exhibited similar macroscale response and final deformation textures, both dislocation line profile analysis and TEM revealed increased dislocation density in deformed Cu-1 $$\%$$ % Pb specimens. The presence of lead precipitates also significantly affected local plastic deformation during compression, with their influence diminishing with increasing strain. These results demonstrate the complex relationships between alloying elements, plastic deformation, microstructural evolution, and material behavior under load. The insights gained from this multi-scale and multi-technique approach contribute to the fundamental understanding of microstructural evolution in immiscible alloys and are valuable for tailoring the properties of structural materials for specific engineering applications.

Abstract Background Childhood trauma history has frequently been linked to eating disorders (EDs); nevertheless, the scientific literature calls for extending knowledge regarding mediators between EDs and childhood trauma. This study explored whether ED symptoms and early maladaptive schemas were more severe in ED patients with severe childhood trauma than in ED patients with no/mild childhood trauma and whether early maladaptive schemas mediated the relationship between childhood trauma and ED symptom severity. Methods Data were extracted from the Regional Centre for Eating Disorders registry at the University Hospital of Verona. The extracted data included self-reported data, including the Eating Disorder Inventory-3 score, Young Schema Questionnaire score, Childhood Experience and Experience of Care and Abuse Questionnaire score, and sociodemographic and clinical information on the ED outpatients seeking care. A mediation analysis using the structural equation modeling procedure was conducted. Results Forty-two outpatients, 31% of whom exhibited severe childhood trauma, satisfied the criteria for registry data extraction. The severity of ED symptoms, as well as the early maladaptive schemas’ scores for emotional deprivation, defectiveness, failure, vulnerability, insufficient self-control, and negativity, were greater in ED outpatients with severe childhood trauma. Furthermore, early maladaptive schemas related to defectiveness, failure, and negativity had a mediating role in the relationship between severe childhood trauma and ED symptom severity. Conclusions This exploratory study provides preliminary evidence about the importance of early maladaptive schemas in the relationship between trauma history and ED psychopathology. In addition, ED symptoms may represent a dysfunctional attempt to avoid unpleasant emotions associated with schema activation. The results support the need to consider early maladaptive schemas in the treatment of traumatized patients with ED symptoms. Study limitations, research and clinical implications are discussed.

The ALICE experiment at the CERN LHC will feature several upgrades for Run 3, one of which is a new Inner Tracking System (ITS). The ITS upgrade is currently under development and commissioning, and will be installed during the ongoing long shutdown 2. A number of factors will have an impact on the performance and readout efficiency of the ITS in run 3, and to that end, a simulation model of the readout logic in the ALPIDE pixel sensor chips for the ITS was developed, using the SystemC library for system level modeling in C++. This simulation model is three orders of magnitude faster than a normal HDL simulation of the chip and facilitates simulations of an increased number of events for a large portion of the detector. In this paper, we present simulation results, where we have been able to quantify detector performance under different running conditions. The results are used for system configuration as well as for the ongoing development of the readout electronics.

Abstract Background Clozapine is the only recommended antipsychotic medication for individuals diagnosed with treatment-resistant schizophrenia. Unfortunately, its wider use is hindered by several possible adverse effects, some of which are rare but potentially life threatening. As such, there is a growing interest in studying clozapine use and safety in routinely collected healthcare data. However, previous attempts to characterise clozapine treatment have had low accuracy. Aim To develop a methodology for identifying clozapine treatment dates by combining several data sources and implement this on a large clinical database. Methods Non-identifiable electronic health records from a large mental health provider in London and a linked database from a national clozapine blood monitoring service were used to obtain information regarding patients' clozapine treatment status, blood tests and pharmacy dispensing records. A rule-based algorithm was developed to determine the dates of starting and stopping treatment based on these data, and more than 10% of the outcomes were validated by manual review of de-identified case note text. Results A total of 3,212 possible clozapine treatment periods were identified, of which 425 (13.2%) were excluded due to insufficient data to verify clozapine administration. Of the 2,787 treatments remaining, 1,902 (68.2%) had an identified start-date. On evaluation, the algorithm identified treatments with 96.4% accuracy; start dates were 96.2% accurate within 15 days, and end dates were 85.1% accurate within 30 days. Conclusions The algorithm produced a reliable database of clozapine treatment periods. Beyond underpinning future observational clozapine studies, we envisage it will facilitate similar implementations on additional large clinical databases worldwide.

Urinary tract infections (UTIs) are the most common bacterial infections in children, occurring both in children with normal urinary tracts and in ones with urinary tract abnormalities. Children with UTIs can present relevant clinical symptoms and risk long-term consequences. Current recommended preventive measures include chemoprophylaxis and dietary supplements such as cranberry, probiotics and vitamins A and E. Although chemoprophylaxis still represents the gold standard, it raises concerns about antimicrobial resistance. N-acetylcysteine (NAC), a precursor of the antioxidant glutathione, has been proven both to inhibit biofilm formation and to destroy developed biofilms. In adults, NAC has been demonstrated to prevent UTIs and to improve the effect of antibiotics, but so far it has not been analyzed as an antimicrobial option for pediatric UTIs. In this work, we aim to discuss the current applications of NAC in adult urology and its future possible evolutions in pediatric urology.

Teaching experience in geomatics heavily relies on hands-on activities, but field surveys for educational purposes are usually conducted in controlled environments without proper connection to real-world scenarios. Combining the widespread availability of low-cost equipment with the potential of Free and Open Source Software for Geospatial (FOSS4G) in innovative teaching programmes can fill the gap in preparing young professionals in geomatics and surveying for real-world problems and global challenges, including climate change. This paper presents the active learning experience of the Belvedere Glacier Summer School organized annually by the Department of Civil and Environmental Engineering of Politecnico di Milano in the Italian Alps. During the week-long programme of theoretical and practical sessions, students from different backgrounds, ranging from Engineering to Architecture and Geoinformatics, transform knowledge into skills by designing and carrying out surveys focused on monitoring the evolution of the glacier volume, using GNSS and UAV photogrammetry, and familiarising with 2D and 3D data processing. In a peer-led environment, participants also contribute to the production of open data (orthophotos, DSM and point measurements) published in Zenodo, fostering teamwork and collaboration not only internally but also with the wider research community.

Abstract One open question in the biology of growth factor receptors is how a quantitative input (i.e., ligand concentration) is decoded by the cell to produce specific response(s). Here, we show that an EGFR endocytic mechanism, non-clathrin endocytosis (NCE), which is activated only at high ligand concentrations and targets receptor to degradation, requires a tripartite organelle platform involving the plasma membrane (PM), endoplasmic reticulum (ER) and mitochondria. At these contact sites, EGFR-dependent, ER-generated Ca2+ oscillations are sensed by mitochondria, leading to increased metabolism and ATP production. Locally released ATP is required for cortical actin remodeling and EGFR-NCE vesicle fission. The same biochemical circuitry is also needed for an effector function of EGFR, i.e., collective motility. The multiorganelle signaling platform herein described mediates direct communication between EGFR signaling and mitochondrial metabolism, and is predicted to have a broad impact on cell physiology as it is activated by another growth factor receptor, HGFR/MET.

We review the recent results on the Pontryagin trace anomaly in QFT's with free Weyl fermion in curved four-dimensional spacetime.

Optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) are imaging technologies invented in the 1980s that have revolutionized the field of in vivo retinal diagnostics and are now commonly used in ophthalmology clinics as well as in vision science research. Adaptive optics (AO) technology enables high-fidelity correction of ocular aberrations, resulting in improved resolution and sensitivity for both SLO and OCT systems. The potential of gathering multi-modal cellular-resolution information in a single instrument is of great interest to the ophthalmic imaging community. Although similar instruments have been developed for imaging the human retina, developing such a system for mice will benefit basic science research and should help with further dissemination of AO technology. Here, we present our work integrating OCT into an existing mouse retinal AO-SLO system, resulting in a multi-modal AO-enhanced imaging system of the living mouse eye. The new system allows either independent or simultaneous data acquisition of AO-SLO and AO-OCT, depending on the requirements of specific scientific experiments. The system allows a data acquisition speed of 200 kHz A-scans/pixel rate for OCT and SLO, respectively. It offers ∼6 µm axial resolution for AO-OCT and a ∼1 µm lateral resolution for AO-SLO-OCT imaging.

The chemical modification of synthetic oligonucleotides has recently been investigated to improve their pharmacological utilization. In addition to chemical alterations of the backbone and of the heterocyclic bases, their conjugation with amphiphylic moieties, such as the polyethylene glycol has been proposed. The large scale production of these molecules as demanded for commercial purposes is hampered by the heterogeneity of the solid-phase processes and by the low reactivity of high-molecular weight PEGs in solution. A new synthetic procedure based on the recently developed liquid-phase method (HELP), has been set up to overcome these limitations.

Abstract Background Plant-derived nanovesicles (PDNVs) are a novelty in medical and agrifood environments, with several studies exploring their functions and potential applications. Among fruits, apples (sp. Malus domestica) have great potential as PDNVs source, given their widespread consumption, substantial waste production, and recognized health benefits. Notably, apple-derived nanovesicles (ADNVs) can interact with human cell lines, triggering anti-inflammatory and antioxidant responses. This work is dedicated to the comprehensive biochemical characterization of apple-derived nanovesicles (ADNVs) through proteomic and lipidomic analysis, and small RNAs sequencing. This research also aims to shed light on the underlying mechanism of action (MOA) when ADNVs interface with human cells, through observation of intracellular calcium signalling in human fibroblasts, and to tackles differences in ADNVs content when isolated from fruits derived from integrated and organic production methods cultivars. Results The ADNVs fraction is mainly composed of exocyst-positive organelles (EXPOs) and MVB-derived exosomes, identified through size and molecular markers (Exo70 and TET-3-like proteins). ADNVs’ protein cargo is heterogeneous and exhibits a diverse array of functions, especially in plant's protection (favouring ABA stress-induced signalling, pathogen resistance and Reactive Oxygen Species (ROS) metabolism). Noteworthy plant miRNAs also contribute to phytoprotection. In relation with human cells lines, ADNVs elicit spikes of intracellular Ca2+ levels, utilizing the cation as second messenger, and produce an antioxidant effect. Lastly, organic samples yield a substantial increase in ADNV production and are particularly enriched in bioactive lysophospholipids. Conclusions We have conclusively demonstrated that ADNVs confer an antioxidant effect upon human cells, through the initiation of a molecular pathway triggered by Ca2+ signalling. Within ADNVs, a plethora of bioactive proteins, small RNAs, and lipids have been identified, each possessing well-established functions within the realm of plant biology. While ADNVs predominantly function in plants, to safeguard against pathogenic agents and abiotic stressors, it is noteworthy that proteins with antioxidant power might act as antioxidants within human cells. Graphical Abstract

The paper explores the integration of Geomatics and architectural surveying into the educational context of Geomatic for Built Heritage Conservation course within the Master on Architectural Design, in which a multidisciplinary teaching approach is applied, emphasizing the importance of holistic knowledge encompassing historical, geometric, material, and structural aspects for the conservation and restoration of architectural heritage.A central theme is the role of Geomatics and 3D modelling in historical built heritage documentation, assuming the creation of three-dimensional models as a foundation for integrating various thematic data, enabling interdisciplinary studies, and facilitating knowledge representation and communication.The paper delves into the challenges and strategies of semantic 3D modelling. It discusses the necessity for a flexible and layered informational model, integrating spatial, geometric, and semantic data. The complexity of semantic annotation is explored, considering the subjectivity and cultural context inherent in identifying and describing architectural elements. The educational approach employed in fostering critical thinking among students, particularly in interpreting cultural heritage issues related to documentation and recording, is presented.A case study involving Pitti Palace in Florence is considered. An attempt to implement the Getty Vocabulary on Art & Architecture Thesaurus for semantic annotation is described, emphasizing the need for a coherent alignment between the 3D model and controlled vocabulary hierarchy. The study concludes with insights from the student's experience, highlighting the difficulties in aligning spatial and semantic elements within existing controlled vocabularies and suggesting avenues for future developments in refining these vocabularies for enhanced spatial-semantic coherence in 3D modelling applications.

The increasing demand for 3D digital models has spurred the rapid evolution of technologies to acquire, process, and disseminate 3D data of physical artifacts. Current scanners meet building surveying needs, prompting the exploration of closed systems with multiple sensors, custom accessories, control systems, and varied data processing approaches. While efficient in specific conditions, these systems require careful consideration of factors like technical requirements, environmental conditions, and the intended use of the final model. This article compares a static terrestrial laser scanner (TLS) and a portable mobile mapping system (PMMS) for documenting built heritage, focusing on the City Hall of Montecatini Terme in Italy. The Leica Geosystems RTC360 scanner provides quick scanning times and pre-alignment during fieldwork, reducing post-processing efforts. The Leica BLK2GO, belonging to the PMMS family, utilizes laser SLAM, visual SLAM, and inertial IMU measurements for rapid large-area documentation. The comparison assesses accuracy, completeness, and detail recognition, revealing that both systems are suitable for heritage documentation requiring centimetre-level accuracy. However, differences in point density and roughness indicate that the RTC360 may be better for intricate details. The BLK2GO excels in efficiency but is more oriented toward general representations at the architectural scale. This study emphasizes the importance of evaluating different methodologies based on project objectives and desired levels of detail, providing insights into the strengths and limitations of each system for diverse applications in heritage documentation.

Abstract Background Foot ulcers and/or infections are common long-term complications of diabetes and are associated with increased mortality, especially from cardiovascular disease, though only a few studies have investigated the independent contribution of these events to risk of death. This study aimed at assessing the association of history of diabetic foot with all-cause mortality in individuals with type 2 diabetes, independent of cardiovascular risk factors, other complications, and comorbidities. Methods This prospective cohort study enrolled 15,773 Caucasian patients in 19 Italian centers in the years 2006–2008. Prior lower extremity, coronary, and cerebrovascular events and major comorbidities were ascertained by medical records, diabetic retinopathy by fundoscopy, diabetic kidney disease by albuminuria and estimated glomerular filtration rate, cardiovascular risk factors by standard methods. All-cause mortality was retrieved for 15,656 patients on 31 October 2015. Results At baseline, 892 patients (5.7%) had a history of diabetic foot, including ulcer/gangrene and/or amputation (n = 565; 3.58%), with (n = 126; 0.80%) or without (n = 439; 2.78%) lower limb revascularization, and revascularization alone (n = 330; 2.09%). History of diabetic foot was associated with all-cause death over a 7.42-year follow-up (adjusted hazard ratio, 1.502 [95% confidence interval, 1.346–1.676], p