Search

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Recently, Virtual Reality (VR) has witnessed remarkable growth across various fields, such as education, gaming, and entertainment. In the cultural heritage domain, VR has demonstrated its significance by enabling digital reconstructions of buildings and objects. It allows the public to access virtual representations, interpreting and disseminating cultural heritage through virtual visual storytelling experiences. Despite its potential, VR remains underutilized in the cultural field. By leveraging VR’s extensive capabilities alongside on-site experiences, it offers a comprehensive exploration of architectural and museum environments, becoming a versatile tool for interpretation, learning, and knowledge dissemination. VR introduces innovative paradigms like proxemics, interactivity, and immersion in entirely new digital worlds. The study conducts an in-depth analysis of this ever-evolving technology, with a focus on its applications in two significant case studies: the Museo Egizio of Torino and the Basilica of Sant’Ambrogio in Milano. The investigation critically assess VR’s effectiveness, highlighting its potential to implement visitors’ experience and improve knowledge dissemination of both tangible and intangible aspects embedded in museums’ collections and historical buildings.

Abstract We present a next-to-leading-order (NLO) study of the process pp (→ {h 1, h 2}) → t t ¯ $$ t\overline{t} $$ + X in the 1-Higgs-singlet extension of the Standard Model with an additional heavy Higgs boson h 2 that mixes with the light Higgs boson h 1. This process is subject to large interference effects between loop-induced Higgs-mediated amplitudes and the QCD continuum background which tend to overcompensate any resonance contributions. A reliable modelling of the resulting top-pair invariant mass shapes requires the inclusion of higher-order QCD corrections, which are presented here. The computation of these NLO corrections is exact in all contributions but in the class of non-factorisable two-loop diagrams which are included in an approximate way such that all infrared singular limits are preserved. We present numerical results for several benchmark points with heavy Higgs masses in the range 700–3000 GeV considering the production of stable top quarks. We find that the interference effects dominate the BSM signal yielding sharp dip structures instead of resonance peaks. The significance and excludability of the BSM effect is explored for the LHC Run 2, Run 3 and HL-LHC.

Landslides are complex phenomena that cause important impacts in vulnerable areas, including the destruction of infrastructure, environmental damage, and loss of life. The occurrence of landslide events is often triggered by rainfall episodes, single and intense ones or multiple ones occurring in sequence, i.e., clustered in time. Landslide prediction is typically obtained via process-based or empirical thresholds. Here, we develop a new approach that uses information on the temporal clustering of rainfall to detect landslide events and compare it with the use of classical empirical rainfall thresholds. In addition, we evaluate the performance of the two approaches combined together as a case study in the region of Lisbon in Portugal. We consider a dataset that categorizes landslides into shallow and deep events and a review of empirical rainfall thresholds that makes a good benchmark for testing our novel method. We show that the new approach based on temporal clustering overall has a good power of detecting landslide events but has a skill comparable with the classic rainfall threshold method. While there is no clear outperformance of one method, the novel clustering-based method has a higher sensitivity despite a lower precision than the threshold-based method. For all approaches, the potential detection is better for deep landslides than for shallow ones. The results of this study could help to improve the prediction of rainfall-triggered landslides.

Umberto Restelli,1 Jacopo Vitale,2 Edoardo Croce,3 Susan Bernareggi,3 Stefania Guida,3 Sofia Silvola,1,4 Giuseppe Banfi,3,5 Luigi Zagra3 1LIUC University, Castellanza, Italy; 2Schulthess Klinik, Zürich, Switzerland; 3IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 4Department of Public Health Medicine, School of Health System & Public Health, Faculty of Health Science, University of Pretoria, Pretoria, South Africa; 5Vita-Salute San Raffaele University, Milan, ItalyCorrespondence: Umberto Restelli, Email urestelli@liuc.itObjective: The objective of the analysis presented is to assess the efficacy of a fast-track pathway for elective hip and knee arthroplasty, compared to the traditional approach, adopted within a research hospital located in Milan (Italy), in terms of length of stay reduction and related direct medical costs.Methods: A monocentric observational retrospective study was implemented considering adult subjects who underwent elective primary total hip or knee replacement, with a diagnosis of primary or secondary osteoarthritis. Exclusion criteria were subjects admitted via emergency department, subjects undergoing knee or hip replacement because of fractures or prosthesis revision. The analysis compared the length of stay and the direct medical costs, assuming the hospital perspective, of subjects admitted in the pre-fast-track period (years 2016/2017) and during the fast-track period (years 2018/2019).Results: Knee replacement mean costs are 5,599 € (± 1,158.3 €) in the pre-fast-track period and 4,487 € (± 978.4 €) in the fast-track period (− 1,112 €; − 19.9%). Hip replacement mean costs in the pre-fast-track period are 5,364 € (± 1,037.2 €) and 4,450 € (± 843.7 €) in the fast-track period (− 914 €; − 17.0%). The adoption of fast-track pathway led to a statistically significant decrease of days of hospitalization of − 2.8 (− 37.6%) in knee replacement and of − 2.9 (− 39.2%) in hip replacement.Conclusion: The fast-track pathway adopted proved to be effective, reducing patients’ length of stay, and sustainable and efficient, reducing direct medical costs, for both elective hip and knee replacement surgeries.Keywords: health economics, direct medical costs, observational, hip replacement, knee replacement

In recent years, the field of reality-based 3D model generation has undergone a profound transformation, impacting disciplines such as preservation, archaeology, anthropology, and virtual museums by introducing concepts like virtual heritage and extended reality (XR). The integration of digital models and 3D survey data has become pivotal, enabling immersive experiences and providing unprecedented access to previously inaccessible archaeological sites.In 2022, the Soprintendenza Archeologia, Belle Arti e Paesaggio - Città Metropolitana di Bari embarked on a groundbreaking project to explore Lamalunga cave. This cave, housing a 172,000-130,000-year-old Neanderthal skeleton and 500 faunal remnants, became the focus of an interdisciplinary effort aimed at comprehensively documenting its morphological and typological details alongside the Neanderthal remains. Over a meticulous two-year period, the project meticulously recorded 28 previously undiscovered faunal remains using precise scanning, topographic surveying, and close-range photogrammetry. Central to this endeavor is the Science of Representation, employing advanced 3D modelling techniques such as NURBS algorithms and mesh retopology. These methods facilitated the creation of highly detailed and accurate digital replicas, capturing not only the cave’s intricate physical features but also preserving the contextual integrity necessary for detailed analysis and interpretation of the archaeological findings. This study provides an overview of the digitisation process, examining both the capabilities and limitations of digital models for XR applications. By leveraging cutting-edge technology, this approach enhances preservation, accessibility, inclusivity, and global engagement with one of the world’s most significant Neanderthal sites.DOI: https://doi.org/ 10.20365/disegnarecon.32.2024.6

Abstract Background The frequency of hip and knee arthroplasty surgeries has been rising steadily in recent decades. This trend is attributed to an aging population, leading to increased demands on healthcare systems. Fast Track (FT) surgical protocols, perioperative procedures designed to expedite patient recovery and early mobilization, have demonstrated efficacy in reducing hospital stays, convalescence periods, and associated costs. However, the criteria for selecting patients for FT procedures have not fully capitalized on the available patient data, including patient-reported outcome measures (PROMs). Methods Our study focused on developing machine learning (ML) models to support decision making in assigning patients to FT procedures, utilizing data from patients’ self-reported health status. These models are specifically designed to predict the potential health status improvement in patients initially selected for FT. Our approach focused on techniques inspired by the concept of controllable AI. This includes eXplainable AI (XAI), which aims to make the model’s recommendations comprehensible to clinicians, and cautious prediction, a method used to alert clinicians about potential control losses, thereby enhancing the models’ trustworthiness and reliability. Results Our models were trained and tested using a dataset comprising 899 records from individual patients admitted to the FT program at IRCCS Ospedale Galeazzi-Sant’Ambrogio. After training and selecting hyper-parameters, the models were assessed using a separate internal test set. The interpretable models demonstrated performance on par or even better than the most effective ‘black-box’ model (Random Forest). These models achieved sensitivity, specificity, and positive predictive value (PPV) exceeding 70%, with an area under the curve (AUC) greater than 80%. The cautious prediction models exhibited enhanced performance while maintaining satisfactory coverage (over 50%). Further, when externally validated on a separate cohort from the same hospital-comprising patients from a subsequent time period-the models showed no pragmatically notable decline in performance. Conclusions Our results demonstrate the effectiveness of utilizing PROMs as basis to develop ML models for planning assignments to FT procedures. Notably, the application of controllable AI techniques, particularly those based on XAI and cautious prediction, emerges as a promising approach. These techniques provide reliable and interpretable support, essential for informed decision-making in clinical processes.

BackgroundNeurodevelopmental disorders (NDDs) are heterogeneous conditions due to alterations of a variety of molecular mechanisms and cell dysfunctions. SETD5 haploinsufficiency leads to NDDs due to chromatin defects. Epigenetic basis of NDDs has been reported in an increasing number of cases while mitochondrial dysfunctions are more common within NDD patients than in the general population.MethodsWe investigated in vitro neural stem cells as well as the brain of the Setd5 haploinsufficiency mouse model interrogating its transcriptome, analyzing mitochondrial structure, biochemical composition, and dynamics, as well as mitochondrial functionality.ResultsMitochondrial impairment is facilitated by transcriptional aberrations originated by the decrease of the SETD5 enzyme. Low levels of SETD5 resulted in fragmented mitochondria, reduced mitochondrial membrane potential, and ATP production both in neural precursors and neurons. Mitochondria were also mislocalized in mutant neurons, with reduced organelles within neurites and synapses.LimitationsWe found several defects in the mitochondrial compartment; however, we can only speculate about their position in the hierarchy of the pathological mechanisms at the basis of the disease.ConclusionsOur study explores the interplay between chromatin regulation and mitochondria functions as a possible important aspect of SETD5-associated NDD pathophysiology. Our data, if confirmed in patient context, suggest that the mitochondrial activity and dynamics may represent new therapeutic targets for disorders associated with the loss of SETD5.

Introduction: Pregnant women can choose from different prenatal genetic tests throughout their maternity journey. We aim to investigate the clinical, societal, and economic determinants influencing the selection of different options (non-invasive, invasive, or both). Methods: A systematic survey focusing on maternity pathways was launched by the Region of Tuscany, Italy, to collect data on pregnant women’s experience, outcomes and satisfaction levels. Drawing from this survey, we retrospectively analyzed data on women who filled out the second-trimester questionnaire between March 2019 and February 2023 (n = 27,337), providing complete data on relevant variables. Logistic regression models were applied to identify the factors contributing to a higher likelihood of opting for non-invasive prenatal testing (NIPT) and invasive testing. Results: Among the participants, 42.7 % chose only NIPT, 3.8 % opted for invasive tests exclusively, 1.3 % underwent both tests, and 52.2 % did not pursue any genetic testing. NIPT was more often chosen by older, Italian, highly educated, nulliparous women, who perceived better health, were employed (versus unemployed), had higher economic status, planned pregnancy, received hospital-based care (versus counseling center), under gynecologist supervision (versus midwife), not opted for combined testing and received pregnancy vaccinations. Conversely, invasive testing was more prevalent among older women but less common among those who were nulliparous, had Italian nationality, and had a perceived better health status. This group also tended to experience unplanned and high-risk pregnancy, did not take folate during pregnancy, received public hospital-based assistance, less frequently chose combined tests or NIPT, and had frequent delays in examinations. Conclusions: Various factors beyond clinical considerations influence the selection of a prenatal test. Therefore, NIPT pathways should include balanced, high-quality information about benefits and limitations, ensuring laboratory specialists' active and integrated involvement in decision-making.

IntroductionThe stromal vascular fraction (SVF) of human adipose tissue is an attractive cell source for engineering grafts with intrinsic vascularization potential, as it is rich in vasculogenic progenitors. However, in order to maintain their functional perfusion it is important to promote the in vivo stabilization of newly assembled microvascular networks. We previously found that Semaphorin 3A (Sema3A) promotes the rapid stabilization of new blood vessels induced by VEGF overexpression in skeletal muscle. Here we investigated whether Sema3A could promote the assembly, connection to circulation and persistence of human SVF-derived microvascular networks in engineered grafts.MethodsRecombinant Sema3A was engineered with a transglutaminase substrate sequence (TG-Sema3A) to allow cross-linking into fibrin hydrogels. Grafts were prepared with freshly isolated human SVF cells in fibrin hydrogels decorated with 0, 0.1 or 100 μg/ml TG-Sema3A and implanted subcutaneously in immune-deficient mice.ResultsAfter 1 week in vivo, the assembly of human-derived networks was similar in all conditions. The outer part of the grafts was populated by blood vessels of both human and mouse origin, which formed abundant hybrid structures within a common basal lamina. About 90% of human-derived blood vessels were functionally connected to the host circulation in all conditions. However, in the control samples human vessels were unstable. In fact, they significantly regressed by 6 weeks and could no longer be found by 12 weeks. In contrast, a low Sema3A dose (0.1 μg/ml) promoted further human vascular expansion by about 2-fold at 6 weeks and protected them from regression until 12 weeks. From a mechanistic point of view, the stabilization of SVF-derived vessels by 0.1 μg/ml of Sema3A correlated with the recruitment of a specific population of monocytes expressing its receptor Neuropilin-1.DiscussionIn conclusion, Sema3A is a potent stimulator of in vivo long-term persistence of microvascular networks derived from human SVF. Therefore, decoration of matrices with Sema3a can be envisioned to promote the functional support of tissue engineered grafts.

Abstract Background Skeletal muscle mass wasting almost invariably accompanies bone loss in elderly, and the coexistence of these two conditions depends on the tight endocrine crosstalk existing between the two organs, other than the biomechanical coupling. Since the current diagnostics limitation in this field, and given the progressive population aging, more effective tools are needed. The aim of this study was to identify circulating microRNAs (miRNAs) as potential biomarkers for muscle mass wasting in post‐menopausal osteoporotic women. Methods One hundred seventy‐nine miRNAs were assayed by quantitative real‐time polymerase chain reaction in plasma samples from 28 otherwise healthy post‐menopausal osteoporotic women (73.4 ± 6.6 years old). The cohort was divided in tertiles based on appendicular skeletal muscle mass index (ASMMI) to better highlight the differences on skeletal muscle mass (first tertile: n = 9, ASMMI = 4.88 ± 0.40 kg·m−2; second tertile: n = 10, ASMMI = 5.73 ± 0.23 kg·m−2; third tertile: n = 9, ASMMI = 6.40 ± 0.22 kg·m−2). Receiver operating characteristic (ROC) curves were calculated to estimate the diagnostic potential of miRNAs. miRNAs displaying a statistically significant fold change ≥ ±1.5 and area under the curve (AUC) > 0.800 (P 0.8 (P

Abstract We present a new event generator for the simulation of both neutral- and charged-current deep inelastic scattering (DIS) at next-to-leading order in QCD matched to parton showers using the POWHEG method. Our implementation builds on the existing POWHEG BOX framework originally designed for hadron-hadron collisions, supplemented by considerable extensions to account for the genuinely different kinematics inherent to lepton-hadron collisions. In particular, we present new momentum mappings that conserve the special kinematics found in DIS, which we use to modify the POWHEG BOX implementation of the Frixione-Kunszt-Signer subtraction mechanism. We compare our predictions to fixed-order and resummed predictions, as well as to data from the HERA ep collider. Finally we study a few representative distributions for the upcoming Electron Ion Collider.

Abstract Background Post COVID-19 syndrome is characterized by several cardiorespiratory symptoms but the origin of patients’ reported symptomatology is still unclear. Methods Consecutive post COVID-19 patients were included. Patients underwent full clinical evaluation, symptoms dedicated questionnaires, blood tests, echocardiography, thoracic computer tomography (CT), spirometry including alveolar capillary membrane diffusion (DM) and capillary volume (Vcap) assessment by combined carbon dioxide and nitric oxide lung diffusion (DLCO/DLNO) and cardiopulmonary exercise test. We measured surfactant derive protein B (immature form) as blood marker of alveolar cell function. Results We evaluated 204 consecutive post COVID-19 patients (56.5 ± 14.5 years, 89 females) 171 ± 85 days after the end of acute COVID-19 infection. We measured: forced expiratory volume (FEV1) 99 ± 17%pred, FVC 99 ± 17%pred, DLCO 82 ± 19%, DM 47.6 ± 14.8 mL/min/mmHg, Vcap 59 ± 17 mL, residual parenchymal damage at CT 7.2 ± 3.2% of lung tissue, peakVO2 84 ± 18%pred, VE/VCO2 slope 112 [102–123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV1, Vcap and high VE/VCO2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO2 slope and low PeakVO2 and FEV1 while fatigability with high VE/VCO2 slope. SPB was fivefold higher in post COVID-19 than in normal subjects, but not associated to any of the referred symptoms. SPB was negatively associated to Vcap. Conclusions In patients with post COVID-19, cardiorespiratory symptoms are linked to VE/VCO2 slope. In these patients the alveolar cells are dysregulated as shown by the very high SPB. The Vcap is low likely due to post COVID-19 pulmonary endothelial/vasculature damage but DLCO is only minimally impaired being DM preserved.

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Abstract Melanism, the process of heavier melanin deposition, can interact with climate variation at both micro and macro scales, ultimately influencing color evolution in organisms. While the ecological processes regulating melanin production in relation to climate have been extensively studied, intraspecific variations of melanism are seldom considered. Such scientific gap hampers our understanding of how species adapt to rapidly changing climates. For example, dark coloration may lead to higher heat absorption and be advantageous in cool climates, but also in hot environments as a UV or antimicrobial protection mechanism. To disentangle such opposing predictions, here we examined the effect of climate on shaping melanism variation in 150 barred grass snakes (Natrix helvetica) and 383 green whip snakes (Hierophis viridiflavus) across Italy. By utilizing melanistic morphs (charcoal and picturata in N. helvetica, charcoal and abundistic in H. viridiflavus) and compiling observations from 2002 to 2021, we predicted that charcoal morphs in H. viridiflavus would optimize heat absorption in cold environments, while offering protection from excessive UV radiation in N. helvetica within warm habitats; whereas picturata and abundistic morphs would thrive in humid environments, which naturally have a denser vegetation and wetter substrates producing darker ambient light, thus providing concealment advantages. While picturata and abundistic morphs did not align with our initial humidity expectations, the charcoal morph in N. helvetica is associated with UV environments, suggesting protection mechanisms against damaging solar radiation. H. viridiflavus is associated with high precipitations, which might offer antimicrobial protection. Overall, our results provide insights into the correlations between melanin‐based color morphs and climate variables in snake populations. While suggestive of potential adaptive responses, future research should delve deeper into the underlying mechanisms regulating this relationship.

If we focus on the wild plants described by Alessandro Manzoni in the novel I Promessi Sposi, it is possible to explore two important dimensions that have received little attention, namely the imaginary but realistic reconstruction of a 17th-century plant landscape and the writer's knowledge of wild flora. Manzoni's botanical expertise was enhanced in the management of the estate in Brusuglio (Milan), where his duties as a farmer put him in daily contact with plants and weeds of all kinds, good or bad for the progress of the estate, which the writer observed with curiosity and attention. Benefiting from this experience, the writer transposed 22 of the different wild species known to him into his novel to give each of them a setting and landscape role in the scenarios of the story's events. Today, these plants tell us about him. [Article in Italian]

Summary: Inherited retinal diseases (IRDs) are a group of rare monogenic diseases with high genetic heterogeneity (pathogenic variants identified in over 280 causative genes). The genetic diagnostic rate for IRDs is around 60%, mainly thanks to the routine application of next-generation sequencing (NGS) approaches such as extensive gene panels or whole exome analyses. Whole-genome sequencing (WGS) has been reported to improve this diagnostic rate by revealing elusive variants, such as structural variants (SVs) and deep intronic variants (DIVs).We performed WGS on 33 unsolved cases with suspected autosomal recessive IRD, aiming to identify causative genetic variants in non-coding regions or to detect SVs that were unexplored in the initial screening. Most of the selected cases (30 of 33, 90.9%) carried monoallelic pathogenic variants in genes associated with their clinical presentation, hence we first analyzed the non-coding regions of these candidate genes. Whenever additional pathogenic variants were not identified with this approach, we extended the search for SVs and DIVs to all IRD-associated genes.Overall, we identified the missing causative variants in 11 patients (11 of 33, 33.3%). These included three DIVs in ABCA4, CEP290 and RPGRIP1; one non-canonical splice site (NCSS) variant in PROM1 and three SVs (large deletions) in EYS, PCDH15 and USH2A. For the previously unreported DIV in CEP290 and for the NCCS variant in PROM1, we confirmed the effect on splicing by reverse transcription (RT)-PCR on patient-derived RNA.This study demonstrates the power and clinical utility of WGS as an all-in-one test to identify disease-causing variants missed by standard NGS diagnostic methodologies.

Abstract The occurrence of multiple precipitation events not‐independent in time, that is, a temporal clustering, is an example of a temporal compounding event. This type of forcing is of great relevance for the occurrence of different natural hazards, like floods and deep‐seated landslides, for which previous soil saturation plays an important role in shaping the associated hazard. Using ERA5‐Land data set and E‐OBS, we firstly investigate the spatial and temporal characteristics of temporal clustering of precipitation over the Italian territory, and we relate it with two oscillation patterns, namely North Atlantic Oscillation (NAO) and Mediterranean Oscillation Index (MOI), and with common synoptic conditions. Then, we explore the role of temporal compounding of precipitation in the generation of different movement types (complex, debris flow, fall, flow, and sliding) using the database of landslides from the Aree Vulnerate Italiane project (in Italian AVI, meaning Areas Affected by Landslides or Floods). From this study it emerges that below average values of NAO and MOI increase the probability of having clustered precipitation events. For all types of landslides, except rock falls, we observed that the majority of the events are preceded by a temporal clustering of precipitation, over longer time windows for complex events, shorter for debris flows. For rock falls, we found also a link with low minimum temperature and freeze‐thaw cycles for winter events and high maximum temperature for summer events. This work contributes to the investigation of temporal clustering of precipitation in connection with natural hazards characterized by a mechanism of saturation.

Abstract Background Type 2 diabetes mellitus (T2DM) increases the risk of coronary heart disease (CHD) by 2–4 fold, and is associated with endothelial dysfunction, dyslipidaemia, insulin resistance, and chronic hyperglycaemia. The aim of this investigation was to assess, by a multimarker mass spectrometry approach, the predictive role of circulating proteins as biomarkers of cardiovascular damage progression associated with diabetes mellitus. Methods The study considered 34 patients with both T2DM and CHD, 31 patients with T2DM and without CHD, and 30 patients without diabetes with a diagnosis of CHD. Plasma samples of subjects were analysed through a multiplexed targeted liquid chromatography mass spectrometry (LC-MS)-based assay, namely Multiple Reaction Monitoring (MRM), allowing the simultaneous detection of peptides derived from a protein of interest. Gene Ontology (GO) Analysis was employed to identify enriched GO terms in the biological process, molecular function, or cellular component categories. Non-parametric multivariate methods were used to classify samples from patients and evaluate the relevance of the analysed proteins’ panel. Results A total of 81 proteins were successfully quantified in the human plasma samples. Gene Ontology analysis assessed terms related to blood microparticles, extracellular exosomes and collagen-containing extracellular matrix. Preliminary evaluation using analysis of variance (ANOVA) of the differences in the proteomic profile among patient groups identified 13 out of the 81 proteins as significantly different. Multivariate analysis, including cluster analysis and principal component analysis, identified relevant grouping of the 13 proteins. The first main cluster comprises apolipoprotein C-III, apolipoprotein C-II, apolipoprotein A-IV, retinol-binding protein 4, lysozyme C and cystatin-C; the second one includes, albeit with sub-grouping, alpha 2 macroglobulin, afamin, kininogen 1, vitronectin, vitamin K-dependent protein S, complement factor B and mannan-binding lectin serine protease 2. Receiver operating characteristic (ROC) curves obtained with the 13 selected proteins using a nominal logistic regression indicated a significant overall distinction (p

Urban-Building Energy Modelling (UBEM) tools play a crucial role in analysing and optimizing energy use within cities. Among the available approaches, the bottom-up physics-based one is the most versatile for urban development and management applications. However, their accuracy is often limited by the inability to capture the dynamic impact of occupants’ presence and actions (i.e., Occupant Behaviour) on building energy use patterns. While recent research has explored advanced Occupant Behaviour (OB) modelling techniques that incorporate stochasticity and contextual influences, current UBEM practices primarily rely on static occupant profiles, due to limitations in the software itself. This paper addresses this topic by conducting a thorough literature review to examine existing OB modelling techniques, data sources, key features and detailed information that could enhance UBEM simulations. Furthermore, the flexibility of available UBEM tools for integrating advanced OB models will be assessed, along with the identification of areas for improvement. The findings of this review are intended to guide researchers and tool developers towards creating more robust and occupant-centric urban energy simulations.

The aim of this work was to develop an experimental protocol for the infection of Galleria mellonella with Gram-positive bacteria. Some physiological characteristics of these insects are comparable to those of vertebrates, therefore allowing the replacement of mammals in the preclinical phases of drug development. G. mellonella Linnaeus 1758 (Lepidoptera: Pyralidae) is accepted as an alternative model for the study of infectious diseases. Since data on infection procedures with different bacterial strains are scarce and sometimes conflicting, also due to different and non-uniform protocols, we developed an experimental protocol that would allow for controlled and repeatable infections, using the Gram-positive bacterium GRAS (Generally Regarded As Safe) Micrococcus luteus. After analyzing the morphology and defining the growth rate of M. luteus, doses of between 101 and 106 CFU/larvae were administered to late-stage larvae. The survival rate of the larvae was monitored up to 7 days and the LD50 determined. The bacterial clearance capacity of the larvae after injection with 103 and 105 CFU/larvae was assessed by hemolymph bacterial load analysis. The results made it possible to define the growth curve of M. luteus correlated with the CFU count; based on the LD50 (103.8 CFU/larvae) calculated on the survival of G. mellonella, infections were carried out to evaluate the immune efficiency of the larvae in bacterial clearance. This protocol, standardized on G. mellonella larvae, could provide a functional tool to study the course of bacterial infections.