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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.

Reading and arithmetic are distinct academic skills that share similarities in skill acquisition and use. Previous research investigated the cognitive basis of associations and dissociations between reading and arithmetic by using either subtyping or dimensional approaches. In the current study, we aim to bridge the gap between these two approaches by investigating common and distinct predictors of reading and arithmetic at different performance levels with quantile regression models. This allowed us to look more closely at the lower tail of the ability distributions, and to test whether predictions for children with low reading and arithmetic fluency differed from the typical performance range. We analyzed longitudinal data of 357 children speaking English or German. Outcome variables were reading and arithmetic fluency assessed at the end of Grade 1, 2, and 3. Predictors were assessed in Grade 1. Results confirmed nonverbal IQ and working memory as domain-general predictors of reading and arithmetic. The association of reading and arithmetic was mainly explained by nonverbal IQ, phonological awareness, RAN and multi-digit transcoding. Across grades and performance levels, phonological awareness and RAN made a specific contribution to reading. Magnitude processing and multi-digit transcoding were specific predictors of arithmetic. Counting also made a specific prediction to arithmetic in Grade 3, but only in the low performance range. Our findings indicate partly distinct underlying cognitive mechanisms for reading and arithmetic. Shared predictors are involved in retrieval efficiency, language processing and cross-format integration. These results have important implications, as they suggest that most predictors are equally relevant for children with low, typical or even excellent reading and arithmetic fluency.

Tissue-engineered skin substitutes are promising tools to cover large and deep skin defects. However, the lack of a synergic and fast regeneration of the vascular network, nerves, and skin appendages limits complete skin healing and impairs functional recovery. It has been highlighted that an ideal skin substitute should mimic the structure of the native tissue to enhance clinical effectiveness. Here, we produced a pre-vascularized dermis (PVD) comprised of fibroblasts embedded in their own extracellular matrix (ECM) and a capillary-like network. Upon implantation in a mouse full-thickness skin defect model, we observed a very early innervation of the graft in 2 weeks. In addition, mouse capillaries and complete epithelialization were detectable as early as 1 week after implantation and, skin appendages developed in 2 weeks. These anatomical features underlie the interaction with the skin nerves, thus providing a further cue for reinnervation guidance. Further, the graft displays mechanical properties, collagen density, and assembly features very similar to the host tissue. Taken together our data show that the pre-existing ECM components of the PVD, physiologically organized and assembled similarly to the native tissue, support a rapid regeneration of dermal tissue. Therefore, our results suggest a promising potential for PVD in skin regeneration.

BackgroundSeveral systematic reviews (SRs) assessing the use of telemedicine for musculoskeletal conditions have been published in recent years. However, the landscape of evidence on multiple clinical outcomes remains unclear. ObjectiveWe aimed to summarize the available evidence from SRs on telemedicine for musculoskeletal disorders. MethodsWe conducted an umbrella review of SRs with and without meta-analysis by searching PubMed and EMBASE up to July 25, 2022, for SRs of randomized controlled trials assessing telemedicine. We collected any kind of patient-reported outcome measures (PROMs), patient-reported experience measures (PREMs), and objective measures, including direct and indirect costs. We assessed the methodological quality with the AMSTAR 2 tool (A Measurement Tool to Assess systematic Reviews 2). Findings were reported qualitatively. ResultsOverall, 35 SRs published between 2015 and 2022 were included. Most reviews (n=24, 69%) were rated as critically low quality by AMSTAR 2. The majority of reviews assessed “telerehabilitation” (n=29) in patients with osteoarthritis (n=13) using PROMs (n=142 outcomes mapped with n=60 meta-analyses). A substantive body of evidence from meta-analyses found telemedicine to be beneficial or equal in terms of PROMs compared to conventional care (n=57 meta-analyses). Meta-analyses showed no differences between groups in PREMs (n=4), while objectives measures (ie, “physical function”) were mainly in favor of telemedicine or showed no difference (9/13). All SRs showed notably lower costs for telemedicine compared to in-person visits. ConclusionsTelemedicine can provide more accessible health care with noninferior results for various clinical outcomes in comparison with conventional care. The assessment of telemedicine is largely represented by PROMs, with some gaps for PREMs, objective measures, and costs. Trial RegistrationPROSPERO CRD42022347366; https://osf.io/pxedm/

This research delves into the profound significance of the Science of Representation, demonstrating its pivotal role in crafting semantic and interoperable analysis. The adept application of these ‘mediums’ could represent a primary shift for future generations in how information is conceptualized, interpreted, represented, and communicated, ultimately fostering a deeper level of understanding and collaboration among professionals in the field. In this context, the convergence of digital representation, knowledge-driven semantic refinement, and techniques for intricate model conversion could assume a foundational role. Given these paramount considerations, the study emphasizes the urgency of establishing interoperable procedures and cultivating a comprehensive understanding of digital representation as a crucial informational medium.The results served as vessels for disseminating archaeological knowledge and as powerful tools for dissecting the structural intricacies of ancient environments. To achieve this, a highly specialized cognitive process was required to elucidate both the tangible and intangible elements within the ontological framework. The introduction of the interoperable approach at the archaeological site of Villa dei Quintili in Rome served as a prime example of the critical function of digital models able to interpret, disseminate, and preserve our cultural heritage accurately. It proved instrumental, both theoretically and practically, in transferring geometries and information for diverse analytical purposes, significantly enhancing their effectiveness through a thoughtfully selected range of exchange formats for preservation and structural analysis. Finally, the study introduces a methodology for translating digital models into advanced mediums, including extended reality (XR), pushing the boundaries of heritage preservation in the digital age.DOI: https://doi.org/10.20365/disegnarecon.30.2023.25

Eleonora Volpato,1,2 Paolo Banfi,2 Francesco Pagnini1,3 1Department of Psychology, Universita’ Cattolica del Sacro Cuore, Milan, Italy; 2IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy; 3Department of Psychology, Harvard University, Cambridge, MA, USACorrespondence: Eleonora Volpato, Department of Psychology, Università Cattolica Del Sacro Cuore, Via Nirone, 15 CAP. 20123, Milan, Italy, Email eleonora.volpato@unicatt.itIntroduction: The main aim was to gain insight into the experience of adult people with a diagnosis of at least 6-months of mild or moderate persistent asthma according to the Global Initiative for Asthma (GINA), and their emotions, beliefs, and expectations during the first wave of COVID-19.Methods: Qualitative semi-structured interviews using the Interpretative Phenomenological Analysis (IPA) were carried out by phone involving 31 people (mean age=58.2; SD=16.2). Interviews were audio recording, transcribed verbatim and analysed through thematic analysis.Results: Five superordinate themes and themes were dedicated to illness (symptoms of asthma; difficulties related to COVID-19), experienced emotions (lockdown period; medical changes; emotions COVID-19 related), beliefs (about asthma; about COVID-19), expectations (related to asthma; related to COVID-19) and behaviours (to protect; risk taken; adherence; contacts with General Practitioners; support). The prevalence of emotions such as fear, worry and anxiety emerged in the participants’ narratives. All are accompanied by a preference for action and problem solving. A sense of protection, connection to self and other, and commitment to life were revealed as central concepts for enhancing well-being even at a time of deterring.Discussion: The common threads of the presence of uncertainty and vulnerability open the outlook of a treatment that ensures greater continuity and ownership of care in the patient, preserving the sense of self-efficacy even in times of greater instability.Keywords: asthma, interpretative phenomenological analysis, COVID-19, clinical psychology

Matteo Briguglio,1 Claudio Cordani,2,3 Francesco Langella,4 Paolo Perazzo,5 Fabrizio Ernesto Pregliasco,6,7 Giuseppe Banfi,3,8 Thomas W Wainwright9,10 1Laboratory of Nutritional Sciences, IRCCS Orthopedic Institute Galeazzi, Milan, Italy; 2Department of Biomedical, Surgical, and Dental Sciences, University “La Statale”, Milan, Italy; 3Scientific Direction, IRCCS Orthopedic Institute Galeazzi, Milan, Italy; 4GSpine4, IRCCS Orthopedic Institute Galeazzi, Milan, Italy; 5Intensive Care Unit, IRCCS Orthopedic Institute Galeazzi, Milan, Italy; 6Health Management, IRCCS Orthopedic Institute Galeazzi, Milan, Italy; 7Department of Biomedical Sciences for Health, University of Milan, Milan, Italy; 8Faculty of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy; 9Orthopaedic Research Institute, Bournemouth University, Bournemouth, UK; 10Physiotherapy Department, University Hospitals Dorset NHS Foundation Trust, Bournemouth, UKCorrespondence: Matteo Briguglio, IRCCS Ospedale Galeazzi – Sant’Ambrogio, Via Cristina Belgioioso 173, Milan, 20157, Italy, Tel +0039 02 83502224, Email matteo.briguglio@grupposandonato.itAbstract: Individuals with severe cartilage degeneration of the hip or knee or collapsed vertebrae that cause spine deformities can suffer from joint and neuropathic pain in the back, disuse of the affected limb, and restriction of movements. Surgical intervention is the most widespread and successful solution to date. There is a general belief that eating healthy and staying physically and mentally active might have a preventive role against musculoskeletal disease occurrence, while instead, we are more certain of the benefits deriving from a healthy diet and exercise therapy after major orthopaedic procedures. These aspects are in fact vital components in enhanced recovery after surgery programmes. However, they are applied in hospital settings, are often centre-dependent, and lack primary and tertiary preventive efficacy since end once the patient is discharged. There is the lack of initiatives at the territorial level that ensure a continuum in the patient’s journey towards orthopaedic surgery, home transition, and a healthy and long-lasting life. The expert panel advocates the integration of an intermediate lifestyle clinic that promotes healthy eating, physical activity, and sleep hygiene. In this facility directed by professionals in enhancing recovery after surgery, patients can be referred after the surgical indication and before home discharge. Surgery is in fact a moment when individuals are more curious to do their best to heal and stay healthy, representing a timepoint and opportunity for educating patients on how lifestyle changes may optimise not only their surgical recovery but also long-term future health state.Keywords: access to health care, health care facilities, manpower, services, surgeries, orthopaedic rehabilitation, dietary habits, physical therapy modalities, good sleep habit

Abstract Background The risk of proximal femoral fractures increases with aging, causing significant morbidity, disability, mortality and socioeconomic pressure. The aims of the present work are (1) to investigate the epidemiology and incidence of these fractures among the elderly in the Region of Lombardy; (2) to identify the factors influencing survival; (3) to identify the factors influencing hospitalization and post-operative costs. Methods The Region of Lombardy provided anonymized datasets on hospitalized patients with a femoral neck fracture between 2011 and 2016, and anonymized datasets on extra-hospital treatments to track the patient history between 2008 and 2019. Statistical evaluations included descriptive statistics, survival analysis, Cox regression and multiple linear models. Results 71,920 older adults suffered a femoral fracture in Lombardy between 2011 and 2016. 76.3% of patients were females and the median age was 84. The raw incidence of fractures was stable from year 2011 to year 2016, while the age-adjusted incidence diminished. Pertrochanteric fractures were more spread than transcervical fractures. In patients treated with surgery, receiving treatment within 48 h reduced the hazard of death within the next 24 months. Combined surgical procedures led to increased hazard in comparison with arthroplasty alone, while no differences were observed between different arthroplasties and reduction or fixation. In patients treated conservatively, age and male gender were associated with higher hazard of death. All patients considered, the type of surgery was the main factor determining primary hospitalization costs. A higher number of surgeries performed by the index hospital in the previous year was associated with financial savings. The early intervention significantly correlated with minor costs. Conclusions The number of proximal femoral fractures is increasing even if the age-adjusted incidence is decreasing. This is possibly due to prevention policies focused on the oldest cohort of the population. Two policies proved to be significantly beneficial in clinical and financial terms: the centralization of patients in high-volume hospitals and a time limit of 48 h from fracture to surgery. Trial registration Non applicable.

Abstract Background and objective N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient’s hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods We analyzed blood samples of patients with HFrEF at baseline (before sacubitril/valsartan treatment), after 1, 2, and 3 months (respectively, after a month taking the 24/26 – 49/51 – 97/103 mg twice daily, or b.i.d., doses), and 6 months after the maximum-tolerated dose was reached (end study). Results We obtained samples from 72 patients with HFrEF (age 64.0 ± 10.5 years, 83% males). NT-proBNP and sST2 values progressively and significantly reduced to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p < 0.001). Specifically, NT-proBNP reduced from 1144 [593–2586] pg/mL to 743 [358–1524] pg/mL and sST2 from 27.3 [20.5–35.0] ng/mL to 23.1 [15.9–30.7] ng/mL, p for trend < 0.001 in both cases. The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP. No significant changes in renal function and potassium levels were recorded. Conclusion These findings suggest that, in patients with HF, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-fibrotic, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.

Abstract We present a new semi-numerical method to compute leading hadronisation corrections to two-jet event shapes in e + e − annihilation. The formalism we present utilises the dispersive approach, where the magnitude of power corrections is controlled by suitable moments of an effective strong coupling, but it can be adapted to other methods. We focus on observables where the interplay between perturbative and non-perturbative effects is crucial in determining the power corrections. A naive treatment of power corrections for some of these observables gives rise to an unphysical behaviour in the corresponding distributions for moderate observable values, thus considerably limiting the available range to fit the non-perturbative moments. We present a universal treatment to handle such observables, based on a suitable subtraction procedure, and compare our results to the analytic result in the case of total broadening. Finally, for the first time we present predictions for the thrust major, which cannot be handled with analytic methods.

Digital therapeutics refers to smartphone applications, software, and wearable devices that provide digital solutions to improve healthcare delivery. We developed a digital platform to support the GYM (Grow Your Muscle) study, an ongoing 48-week randomized, controlled trial on reduction of sarcopenia through a home-based, app-monitored physical exercise intervention. The GYM platform consists of a smartphone application including the exercise program and video tutorials of body-weight exercises, a wearable device to monitor heart rate during training, and a website for downloading training data to remotely monitor the exercise. The aim of this paper is to describe the platform in detail and to discuss the technical issues emerging during the study and those related to usability of the smartphone application through a retrospective survey. The main technical issue concerned the API level 33 upgrade, which did not enable participants using the Android operating systems to use the wearable device. The survey revealed some problems with viewing the video tutorials and with internet or smartphone connection. On the other hand, the smartphone application was reported to be easy to use and helpful to guide home exercising. Despite the issues encountered during the study, this digital-supported physical exercise intervention could provide useful to improve muscle measures of sarcopenia.

Background: Different specific surfactant proteins (SPs) have been associated with various pathological conditions, not only of the respiratory system, but also more recently with cardiovascular diseases, such as heart failure. The aim of the present study was to evaluate the role of SP-A, SP-D, and the precursor protein of SP-B (proSP-B) in the pathogenesis of cardiovascular damage in patients affected by type 2 diabetes (T2D). Methods: The study considered 31 patients with T2D (DN group), 34 patients with both T2D and coronary heart disease (CHD) (DC group), and 30 patients without diabetes but with a diagnosis of CHD (NC group). SP-A, SP-D, and proSP-B concentrations were determined in plasma samples, and were statistically compared using parametric and multivariate methods. Results: Higher plasma concentrations of SP-D and proSP-B were found in patients affected by both T2D and CHD (DC group), and in patients with CHD without diabetes (NC group), in comparison to T2D patients (DN group). A significant correlation, both with linear regression (r = 0.3565, p = 0.001) and Principal Component Analysis (PCA), was found between the plasma levels of SP-D and proSP-B in the overall cohort of patients. No differences in SP-A were observed among the three groups of subjects. Conclusion: The present study extends the knowledge on the role of plasma SPs’ levels as possible indicators of the risk of CHD being linked to T2D disease progression.

The rapid spread of SARS-COV-2 and the millions of worldwide deaths and hospitalizations have prompted an urgent need for the development of screening tests capable of rapidly and accurately detecting the virus, even in asymptomatic people. The easy collection and the biomarker content of saliva, together with the label-free and informative power of surface-enhanced Raman spectroscopy (SERS) analysis have driven the creation of point-of-care platforms capable of identifying people with COVID-19. Indeed, different salivary fingerprints were observed between uninfected and infected people. Hence, we performed a retrospective analysis of SERS spectra from salivary samples of COVID-19-infected and -vaccinated subjects to understand if viral components and/or the immune response are implicated in spectral variations. The high sensitivity of the proposed SERS-based method highlighted the persistence of molecular alterations in saliva up to one month after the first positive swab, even when the subject tested negative for the rapid antigenic test. Nevertheless, no specific spectral patterns attributable to some viral proteins and immunoglobulins involved in COVID-19 infection and its progression were found, even if differences in peak intensity, presence, and position were observed in the salivary SERS fingerprint.

Valvular disease is a complex pathological condition that impacts countless individuals around the globe. Due to limited treatments, it is crucial to understand its mechanisms to identify new targets. Valve disease may result in pulmonary venous hypertension, which is linked to compromised functioning of the alveolar and capillary membranes and hindered gas exchange. Nonetheless, the correlation between surfactant proteins (SPs) and valve disease remains unexplored. A total of 44 patients were enrolled in this study, with 36 undergoing aortic valve replacement and 8 needing a second aortic valve substitution due to bioprosthetic valve degeneration. Ten healthy subjects were also included. The results showed that patients who underwent both the first valve replacement and the second surgery had significantly higher levels of immature SP-B (proSP-B) compared to control subjects. The levels of the extra-lung collectin SP-D were higher in patients who needed a second surgery due to bioprosthetic valve degeneration, while SP-A levels remained unchanged. The research also showed that there was no reciprocal relationship between inflammation and SP-D as the levels of inflammatory mediators did not differ between groups. The present study demonstrates that circulating proSP-B serves as a reliable marker of alveolar–capillary membrane damage in patients with valvular heart disease.