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The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.The lysine-specific histone demethylase 1 A (LSD1) can regulate cytotoxic CD8 T cell (CTL) responses and anti-tumor immunity. Here the authors show that ex vivo epigenetic reprogramming with a LSD1 inhibitor enhances cell persistence and anti-tumor activity of adoptively transferred CD8 T cells in preclinical tumor models. [ABSTRACT FROM AUTHOR]

Early diagnosis is crucial for Autism spectrum disorder (ASD) and is achieved through a screening of developmental indicators to recognise children who are at risk of autism. One of the most widely used instruments in clinical practice for assessing child development is the Griffiths Mental Development Scale (GMDS). We sought (a) to assess longitudinally whether children diagnosed with ASD, with a mean age of 33.50 months (SD 7.69 months), show a developmental delay of abilities measured by the GMDS over time and (b) to analyse which skills of the GMDS could be associate to the symptomatologic severity of ASD. Our results showed lower scores of General Quotient and all sub-quotients of GMDS from first (T0) to second assessment (T1), except for the Performance sub-quotient. Three sub-quotients (Personal-Social, Hearing and Language and Practical Reasoning) also associate symptom severity at the time when the diagnosis of ASD is made. [ABSTRACT FROM AUTHOR]

Although the pharmacological therapy of ADHD has been widely studied, little has been done to compare the different therapeutic approaches (e.g., drug therapy vs. psychological treatments) and even less has been done to compare the outcome of the therapy between centers. This multicenter observational study aims to assess between-center variation in functional outcome of ADHD patients one year after the diagnosis, according to the treatment received. We used the Regional ADHD Registry data on 1429 patients enrolled in 16 ADHD centers in the 2011–2022 period. To evaluate the effectiveness of the therapy we used a generalized linear mixed model with the center as the random effect, including patient condition at diagnosis and center characteristics, weighting by the inverse of the propensity score of the treatment received by the patient. Between-center variation was expressed as the relative difference in odds-ratios between the observed and the expected number of patients whose condition improved, using the Clinical Global Impressions—Improvement Scale (CGI-I), and the relative 95% CI. Patients who received combined treatment were significantly more likely to improve compared to other treatment groups (65.5% vs 54.4% for methylphenidate alone, 53.4% for psychological treatment alone, or 40.5% for no therapy). Adjusted for patients and center characteristics, the log-odds ratio ranged from 0.85 (0.29–1.55 95% CI) to − 0.64 (− 1.17–− 0.18 95% CI). The mean expected probability of improvement after one year of therapy for an average patient with ADHD for each center was 47.7% in a center at the 25th percentile and 61.2% in a center at the 75th percentile of the outcome distribution after adjustments. The wide between-center variation in patient functional improvement one year after the diagnosis of ADHD could be largely explained by center-specific therapeutic approaches or attitudes. More careful and stringent work is needed to reduce differences in responses between centers, as could formal and periodic audit programs within and between centers. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the relationship between SARS-CoV-2 infection and autoimmunity in type 1 diabetes (T1D) and SARS-CoV-2 antibodies frequency at diagnosis of T1D during pandemic. Methods: The presence of T1D-specific autoimmunity was evaluated in a cohort of 99 children and adolescents without diabetes that contracted SARS-CoV-2 infection. Moreover, the frequency of IgM- and IgG-SARS-CoV-2 antibodies was evaluated in 41 newly diagnosed T1D patients not yet vaccinated against SARS-CoV-2 disease, collected during the pandemic, compared to healthy subjects (CTRL). Results: None of the 99 patients that contracted SARS-CoV-2 infection during the pandemic period was found positive for T1D autoantibodies. The frequency of SARS-CoV-2 antibodies was not significantly different in patients newly diagnosed with T1D (12.2%), compared with CTRL (8.4%). Among SARS-CoV-2 antibody positive T1D patients, 80% were target of diabetes autoantibodies and 60% had another concomitant autoimmune disease. Among the CTRL subjects positive for SARS-CoV-2Abs (n = 10), none was found positive for T1D autoantibodies. Conclusions: The results of the present study do not confirm, at least in the short term, a role of COVID-19 as a potential trigger of T1D autoimmunity and do not provide evidence of an increased frequency of SARS-CoV-2 antibodies in newly diagnosed T1D patients in comparison with healthy population. [ABSTRACT FROM AUTHOR]

Background: Mechanisms of myocardial ischemia in obstructive and non-obstructive coronary artery disease (CAD), and the interplay between clinical, functional, biological and psycho-social features, are still far to be fully elucidated. Objectives: To develop a machine-learning (ML) model for the supervised prediction of obstructive versus non-obstructive CAD. Methods: From the EVA study, we analysed adults hospitalized for IHD undergoing conventional coronary angiography (CCA). Non-obstructive CAD was defined by a stenosis < 50% in one or more vessels. Baseline clinical and psycho-socio-cultural characteristics were used for computing a Rockwood and Mitnitski frailty index, and a gender score according to GENESIS-PRAXY methodology. Serum concentration of inflammatory cytokines was measured with a multiplex flow cytometry assay. Through an XGBoost classifier combined with an explainable artificial intelligence tool (SHAP), we identified the most influential features in discriminating obstructive versus non-obstructive CAD. Results: Among the overall EVA cohort (n = 509), 311 individuals (mean age 67 ± 11 years, 38% females; 67% obstructive CAD) with complete data were analysed. The ML-based model (83% accuracy and 87% precision) showed that while obstructive CAD was associated with higher frailty index, older age and a cytokine signature characterized by IL-1β, IL-12p70 and IL-33, non-obstructive CAD was associated with a higher gender score (i.e., social characteristics traditionally ascribed to women) and with a cytokine signature characterized by IL-18, IL-8, IL-23. Conclusions: Integrating clinical, biological, and psycho-social features, we have optimized a sex- and gender-unbiased model that discriminates obstructive and non-obstructive CAD. Further mechanistic studies will shed light on the biological plausibility of these associations. Clinical trial registration: NCT02737982. [ABSTRACT FROM AUTHOR]

Adding steel fibers to concrete improves the post-cracking tensile strength of the composite material due to fibers bridging the cracks. The residual performance of the material is influenced by fiber type, content and orientation with respect to the crack plane. The latter is a main issue in fiber-reinforced concrete elements, since it significantly influences the structural behavior. The aim of this research is to develop a tailor-made composite material and casting method to orient fibers in order to optimize the performance of the material for structural applications. To this aim, a mechanized concreting device that induces such preferred fiber orientation is designed and fabricated. It uses vibration and a series of narrow channels to guide and orient fibers. A composite with oriented fibers is produced using a hybrid system of macro and micro fibers and high-performance concrete. From the same concrete batch, specimens are cast both with and without the fiber orientation device, obtaining different levels of fiber orientation. Three-point bending tests are performed to measure and compare the residual tensile strength capacities with standard specimens cast according to EN 14651. Elements with favorable fiber orientation show a significant increase in residual tensile strength with respect to the standard beams. Finally, computed tomography and an electromagnetic induction method are employed to better assess the orientation and distribution of fibers in the beams. Their results are in good agreement and enable to link the residual tensile strength parameters with fiber orientation. [ABSTRACT FROM AUTHOR]

The effects of the COVID-19 lockdown on deposition and surface water chemistry were investigated in an area south of the Alps. Long-term data provided by the monitoring networks revealed that the deposition of sulfur and nitrogen compounds in this area has stabilized since around 2010; in 2020, however, both concentrations and deposition were significantly below the average values of the previous decade for SO4 and NO3. Less evident changes were observed for NH4 and base cation. The estimated decrease of deposition in 2020 with respect to the previous decade was on average − 54% and − 46% for SO4 and NO3, respectively. The lower deposition of SO4 and NO3 recorded in 2020 was caused by the sharp decrease of SO2 and particularly of NOx air concentrations mainly due to the mobility restrictions consequent to the COVID-19 lockdown. The limited effects on NH4 deposition can be explained by the fact that NH3 emission was not affected by the lockdown, being mainly related to agricultural activities. A widespread response to the decreased deposition of S and N compounds was observed in a group of pristine freshwater sites, with NO3 concentrations in 2020 clearly below the long-term average. The rapid chemical recovery observed at freshwater sites in response to the sharp decrease of deposition put in evidence the high resilience potential of freshwater ecosystems in pristine regions and demonstrated the great potential of emission reduction policy in producing further substantial ameliorations of the water quality at sensitive sites. [ABSTRACT FROM AUTHOR]

Tsunami warning centres face the challenging task of rapidly forecasting tsunami threat immediately after an earthquake, when there is high uncertainty due to data deficiency. Here we introduce Probabilistic Tsunami Forecasting (PTF) for tsunami early warning. PTF explicitly treats data- and forecast-uncertainties, enabling alert level definitions according to any predefined level of conservatism, which is connected to the average balance of missed-vs-false-alarms. Impact forecasts and resulting recommendations become progressively less uncertain as new data become available. Here we report an implementation for near-source early warning and test it systematically by hindcasting the great 2010 M8.8 Maule (Chile) and the well-studied 2003 M6.8 Zemmouri-Boumerdes (Algeria) tsunamis, as well as all the Mediterranean earthquakes that triggered alert messages at the Italian Tsunami Warning Centre since its inception in 2015, demonstrating forecasting accuracy over a wide range of magnitudes and earthquake types. Probabilistic tsunami forecasting (PTF) defines an approach to tsunami early warning based on uncertainty quantification, enhancing forecast accuracy and enabling rational decision making. PTF is here developed for near-source tsunami warning, and tested in hindcasting mode over a wide range of past earthquakes. [ABSTRACT FROM AUTHOR]

High mountain lakes provide essential ecosystem services and have a high conservation value. Therefore, understanding how glacier retreat will affect their ecological functioning and water quality is crucial. Here, we tested how shallow high mountain lakes having different glacial influences differ in their abiotic main features and food web structure using a multiple ecological indicator approach. We identified 13 functional groups within the planktonic and littoral communities, each one representing a biotic indicator and a node in a simplified food web network. The abiotic environment and most functional groups differed significantly as a consequence of the glacial influence. In general, runoff from glacial meltwaters resulted in highly simplified food webs. Considering that many turbid glacially fed lakes are losing their hydrological connection with disappearing/retreating glaciers and shifting to a clear state, our results suggest that this shift could enhance food web complexity, but at the cost of losing specific habitats. Further, retreat of large glaciers will form new glacially fed lakes, but it remains unclear whether this will buffer the expected habitat and biodiversity loss. [ABSTRACT FROM AUTHOR]

The complexity of coseismic slip distributions influences the tsunami hazard posed by local and, to a certain extent, distant tsunami sources. Large slip concentrated in shallow patches was observed in recent tsunamigenic earthquakes, possibly due to dynamic amplification near the free surface, variable frictional conditions or other factors. We propose a method for incorporating enhanced shallow slip for subduction earthquakes while preventing systematic slip excess at shallow depths over one or more seismic cycles. The method uses the classic k−2 stochastic slip distributions, augmented by shallow slip amplification. It is necessary for deep events with lower slip to occur more often than shallow ones with amplified slip to balance the long-term cumulative slip. We evaluate the impact of this approach on tsunami hazard in the central and eastern Mediterranean Sea adopting a realistic 3D geometry for three subduction zones, by using it to model ~ 150,000 earthquakes with M w from 6.0 to 9.0. We combine earthquake rates, depth-dependent slip distributions, tsunami modeling, and epistemic uncertainty through an ensemble modeling technique. We found that the mean hazard curves obtained with our method show enhanced probabilities for larger inundation heights as compared to the curves derived from depth-independent slip distributions. Our approach is completely general and can be applied to any subduction zone in the world. [ABSTRACT FROM AUTHOR]

Improvements in ischemic heart disease (IHD) management have been unbalanced between sexes, with coronary microvascular dysfunction considered the likely underlying reason. The Endocrine Vascular disease Approach (EVA) is an observational study (Clinicaltrial.gov NCT02737982) aiming to assess sex and gender interactions between coronary circulation, sexual hormones, and platelet function. Consecutive patients with IHD undergoing coronary angiography will be recruited: (1) to assess sex and gender differences in angiographic reperfusion indexes; (2) to evaluate the effects of estrogen/androgen on sex-related differences in myocardial ischemia; (3) to investigate the platelet biology differences between men and women with IHD; (4) to verify sex- and gender-driven interplay between response to percutaneous coronary intervention, platelets, sex hormones, and myocardial damage at baseline and its impact on 12-month outcomes. The integration of sex and gender in this translational project on IHD will contribute to the identification of new targets for further innovative clinical interventions. [ABSTRACT FROM AUTHOR]

Trichophyton rubrum and Trichophyton mentagrophytes spp. are two of the most frequently isolated dermatophytes causing dermatophytosis worldwide. Since the incidence of resistance to antifungal agents is increasing, antifungal susceptibility tests are needed to successfully treat dermatophytoses. Most of the methods currently available are complicated, time-consuming and lack of reference procedures. The aim of this work was to establish a simple protocol to test the susceptibility of dermatophytes isolated from clinical samples against five antifungal drugs using E-test and disk diffusion methods. We used the E-test on non-supplemented Mueller–Hinton agar plates to determine the minimum inhibitory concentrations (MICs) of fluconazole, itraconazole, voriconazole and amphotericin B, and disk diffusion method to determine the interpretive MIC of terbinafine. Fifty dermatophytes—10 T. rubrum and 40 T. mentagrophytes spp.—were assessed after only 96 h of colony growth. Terbinafine was the most active antifungal agent with an inhibition diameter greater than 70 mm (sensitivity > 20 mm), followed by voriconazole, itraconazole and amphotericin B with MICs ranging from 0.032 to 0.38 µg/mL, from 0.006 to 0.125 µg/mL and from 0.5 to 1.5 µg/mL, respectively. All isolates were resistant to fluconazole. Collectively, the less laborious E-test and disk diffusion method were shown to be suitable and reliable to determine antifungal sensitivity of dermatophytes. This simple standard protocol could be employed in the routine of clinical laboratories. [ABSTRACT FROM AUTHOR]

Background: A new prepared oral viscous budesonide (PVB) has been effective in inducing clinical and histological remission in pediatric eosinophilic esophagitis (EoE).Aims: To evaluate the efficacy of a 12-week maintenance therapy on clinical, endoscopic, and histological remission using half of the dose used in the induction therapy.Methods: We prospectively enrolled pediatric patients with active EoE. After 12 weeks of induction therapy with PVB (< 150 cm: 2 mg/day; ≥ 150 cm: 4 mg/day) patients received a maintenance dose of half of the dose used in the induction therapy (1 mg or 2 mg) for another 12 weeks. A 12-week follow-up was then performed in all patients after the end of therapy. Endoscopy was performed at weeks 0, 12, 24, and 36. Symptoms, endoscopy, and histology scores were also calculated. Serum cortisol was evaluated during the treatment period.Results: We enrolled 20 children (15 males; median age 10 years; range 4-17). After the 12-week induction therapy 18 patients (90%) were in remission, with a significant decrease in the median peak of eosinophil count/HPF as well as a marked reduction in clinical, endoscopic, and histological scores (p < 0.01). At the end of the maintenance therapy (week 24), 17 patients (85%) were still in remission, while there were only 9 at week 36 (45%). No significant changes in cortisol levels were observed during the study period.Conclusions: The 12-week maintenance treatment with the half the dose of PVB was effective in sustaining remission at week 24; however, no reduction in the rate of relapse after suspension of treatment occurred. [ABSTRACT FROM AUTHOR]

Fish stocking is a serious threat to originally fishless mountain lakes. We used non-chemical eradication methods (i.e. gillnetting and electrofishing) in four high mountain lakes in the Gran Paradiso National Park (Western Italian Alps) to eradicate alien brook trout Salvelinus fontinalis. Data of amphibians, macroinvertebrates, zooplankton, chlorophyll-a, nutrient concentrations, and water transparency were used as indicators of the recovery process. All treated lakes were returned to their original fishless condition in spite of their different sizes and habitat complexity, without permanent negative side-effects for native species. Several ecological indicators showed that many impacts of introduced fish can be reversed over a short time period following eradication. The present study adds to a still growing body of specialized literature on the recovery of habitats after the eradication of alien species and provides further evidence that physical eradication methods are effective and can be part of a more general strategy for the conservation of high mountain lake biota. [ABSTRACT FROM AUTHOR]

The household travel survey (HTS) finds itself in the midst of rapid technological change. Traditional methods are increasingly being sidelined by digital devices and computational power—for tracking movements, automatically detecting modes and activities, facilitating data collection, etc.. Smartphones have recently emerged as the latest technological enhancement. FMS is a smartphone-based prompted-recall HTS platform, consisting of an app for sensor data collection, a backend for data processing and inference, and a user interface for verification of inferences (e.g., modes, activities, times, etc.). FMS, has been deployed in several cities of the global north, including Singapore. This paper assesses the first use of FMS in a city of the global south, Dar es Salaam. FMS in Dar was implemented over a 1-month period, among 581 adults chosen from 300 randomly selected households. Individuals were provided phones with data plans and the FMS app preloaded. Verification of the collected data occurred every 3 days, via a phone interview. The experiment reveals various social and technical challenges. Models of individual likelihood to participate suggest little bias. Several socioeconomic and demographic characteristics apparently do influence, however, the number of days fully verified per individual. Similar apparent biases emerge when predicting the likelihood of a given day being verified. Some risk of non-random, non-response is, thus, evident. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1007/s00592-023-02103-1. B Correction to: Acta Diabetologica b https://doi.org/10.1007/s00592-023-02103-1 Given name and family name of authors published incorrect in the original publication. Correction to: No effects of COVID-19 on the development of type 1 diabetes autoimmunity and no evidence of an increased frequency of SARS-CoV-2 antibodies in newly diagnosed type 1 diabetes patients relative to healthy subjects. [Extracted from the article]

The present study examined the extent to which individual differences in personality that have been previously associated with aggression in non-clinical subjects (Caprara et al., European Journal of Personality, 27(3), 290-303, 2013, Caprara et al., Developmental Psychology, 50(1), 71-85, 2014) account for aggression among adolescents referred to psychiatric services with diagnosis within the externalizing spectrum (i.e., conduct disorder, oppositional defiant disorder, and attention deficit hyperactivity disorder). In particular a conceptual model was examined in which individual differences in basic traits (i.e., emotional instability and agreeableness), lower order traits (i.e., irritability and hostile rumination), and social cognitive mechanisms (i.e., moral disengagement) account for aggressive behavior. One hundred and nine adolescents (81 males, 74.3%), ranging in age from 11 to 18 ( M = 13.83, SD = 1.70) and referred to psychiatric services for the above diagnoses, participated at the study. Adolescents filled in questionnaires measuring the Big Five traits, as well as irritability, hostile rumination, and moral disengagement; their parents filled in the Child Behavior Checklist to assess children's aggressive behavior. Findings corroborated the posited pattern of relations previously found in non-clinical samples. In accordance with those findings, moral disengagement largely mediated the association between traits and aggressive behavior. The model explained a significant portion of variance in aggressive behavior. As a novelty, findings showed a direct association between emotional instability and aggressive behavior, pointing to the major relevance of emotional disregulation in adolescents referred for externalizing problem behaviors in comparison to non-clinical adolescents. [ABSTRACT FROM AUTHOR]

In this study, we attempt to improve the standards in Probabilistic Seismic Hazard Assessment (PSHA) towards a time-dependent hazard assessment by using the most advanced methods and new databases for the Calabria region, Italy. In this perspective we improve the knowledge of the seismotectonic framework of the Calabrian region using geologic, tectonic, paleoseismological, and macroseismic information available in the literature. We built up a PSHA model based on the long-term recurrence behavior of seismogenic faults, together with the spatial distribution of historical earthquakes. We derive the characteristic earthquake model for those sources capable of rupturing the entire fault segment (full-rupture) independently with a single event of maximum magnitude. We apply the floating rupture model to those earthquakes whose location is not known sufficiently constrained. We thus associate these events with longer fault systems, assuming that any such earthquake can rupture anywhere within the particular fault system (floating partial-rupture) with uniform probability. We use a Brownian Passage Time (BPT) model characterized by mean recurrence, aperiodicity, or uncertainty in the recurrence distribution and elapsed time since the last characteristic earthquake. The purpose of this BPT model is to express the time-dependence of the seismic processes to predict the future ground motions in the region. Besides, we consider the influence on the probability of earthquake occurrence controlled by the change in static Coulomb stress (ΔCFF) due to fault interaction; to pursue this, we adopt a model built on the fusion of BPT model (BPT + ΔCFF). We present our results for both time-dependent (renewal) and time-independent (Poisson) models in terms of Peak Ground Acceleration (PGA) maps for 10% probability of exceedance in 50 years. The hazard may increase by more than 20% or decrease by as much as 50% depending on the different occurrence model. Seismic hazard in terms of PGA decreases about 20% in the Messina Strait, where a recent major earthquake took place, with respect to traditional time-independent estimates. PGA near the city of Cosenza reaches ~ 0.36 g for the time-independent model and 0.40 g for the case of the time-dependent one (i.e. a 15% increase). Both the time-dependent and time-independent models for the period of 2015-2065 demonstrate that the city of Cosenza and surrounding areas bear the highest seismic hazard in Calabria. [ABSTRACT FROM AUTHOR]

Background: A celiac disease (CD) diagnosis is based on duodenal histology, with the exception of children showing anti-tissue transglutaminase (anti-tTG) serum levels exceeding ten times the cut-off. Our aim was to reproduce this simplified approach in adults, identifying an anti-tTG threshold value useful to diagnose CD without endoscopic procedures.Methods: A total of 671 adult CD patients were subjected to blood sampling to determine anti-tTG serum levels, as well as to endoscopy with biopsy to perform duodenal histology. The anti-tTG serum levels/cut-off ratio was compared with the degree of duodenal lesions.Results: Anti-tTG serum levels/cut-off ratio determined in patients with type IIIc was significantly higher than that measured in patients with type IIIb (p < 0.001), IIIa (p < 0.001), II (p < 0.05) and 0 (p < 0.001) of Marsh-Oberhuber histological classification. A significant correlation (r = 0.297, p < 0.0001) was found between the anti-tTG serum levels/cut-off ratio and the degree of duodenal lesions. The anti-tTG serum levels/cut-off ratio was classified as an accurate parameter (AUC = 0.715, p < 0.0001), with the best diagnostic performance obtained considering the threshold value >3.6 (sensitivity = 76.8 %, PPV = 97.2 %).Conclusions: The anti-tTG serum levels/cut-off ratio correlates with the degree of duodenal lesions and, if used with the threshold value >3.6, could avoid endoscopy with biopsy in about 75 % of seropositive adults waiting for CD diagnosis. However, since this procedure could also imply CD diagnosis in almost 3 % of seropositive patients with normal villous architecture, a consensus opinion is needed to suggest its use in the diagnosis of adult CD. [ABSTRACT FROM AUTHOR]

Emerging insects are important nutrient vectors for lake-to-land linkages, but they are affected by fish predation. We manipulated the fish density in four high altitude lakes in connection with a brook trout eradication project. We used a paired benthic and surface funnel trap design to test whether fish density affects abundance, size, and proportion of aquatic insects reaching the surface in the pelagic zone. The study was complemented with benthic macroinvertebrates and fish diet data. Due to sample size, we focused on midge pupae, which rely on water surface tension (water-air interface) to emerge. Conspicuous insects emerging along the shoreline (water-land interface) were rarely collected in the traps, even if they rapidly recovered through the eradication. There was a positive relationship between fish density and midge abundance, and negative relationship for size and proportion reaching the surface. The increase in the emergence of midges in the presence of fish supports several other studies, but we have provided evidence that this pattern exists in conjunction with a size reduction even when fish consume a substantial amount of midges. The inclusion of small Diptera emergence at the water-air interface is a likely keystone in understanding fish impact on insect subsidy. [ABSTRACT FROM AUTHOR]

The present paper deals with an experimental study on the fatigue behavior under bending of plain and steel fiber reinforced concrete (SFRC). Notched beams were tested under three point bending test: both monotonic and fatigue tests on pre-cracked specimens (in which a fracture process zone was present) were performed. In order to quantify the influence of fiber reinforcement on the fatigue performance of SFRC, two volume fractions of fibers (0.5 and 1.0 %) and three fatigue load levels were adopted. Test results are compared in terms of cyclic creep curves and Wöhler diagrams, crack opening rate, toughness and energy dissipation. Experimental results show that the fatigue deformations at failure match the monotonic stress-strain curves with a good agreement. Fibers seem to improve the fatigue life of concrete, whereas their effectiveness tends to decrease under high-cycle fatigue. In both cases, however, the addition of fibers ensures an increase of the energy dissipation at failure. [ABSTRACT FROM AUTHOR]

These authors contributed equally: Luigi Nezi, Teresa Manzo. Correction to: I Nature Communications i https://doi.org/10.1038/s41467-022-34467-3, published online 08 November 2022 In this article the funding from the Italian Ministry of Health with Ricerca Corrente and 5x1000 was omitted. [Extracted from the article]

A numerical non-linear procedure able to represent the behavior of cracked steel fiber reinforced concrete (SFRC) is herein presented and verified. The involved post-cracking mechanisms, particularly tension softening and tension stiffening, have been investigated and properly taken into account. Different tension softening relationships have been implemented and discussed, one based on a micro-mechanical approach, another obtained from inverse analysis and finally the Model Code 2010 (MC2010) law. These models have been adopted in conjunction with a smeared crack approach to perform FE simulations of R/FRC ties characterized by different cross-sections and fiber volume fractions. Numerical results have been validated against a comprehensive experimental program on R/FRC (characterized by a tension softening behavior) and RC ties recently carried out at the University of Brescia. Comparisons between experimental and numerical results indicate that smeared models can be adopted also for the analysis of this structural typology, subjected to a uniaxial state of stress, as a valuable alternative to discrete approaches. [ABSTRACT FROM AUTHOR]

Aim/hypothesis: Insulin is the most specific beta cell antigen and a potential primary autoantigen in type 1 diabetes. Insulin autoantibodies (IAAs) are the earliest marker of beta cell autoimmunity; however, only slightly more than 50% of children and even fewer adults newly diagnosed with type 1 diabetes are IAA positive. The aim of this investigation was to determine if oxidative post-translational modification (oxPTM) of insulin by reactive oxidants associated with islet inflammation generates neoepitopes that stimulate an immune response in individuals with type 1 diabetes. Methods: oxPTM of insulin was generated using ribose and various reactive oxygen species. Modifications were analysed by SDS-PAGE, three-dimensional fluorescence and MS. Autoreactivity to oxPTM insulin (oxPTM-INS) was observed by ELISA and western blotting, using sera from participants with type 1 or type 2 diabetes and healthy controls as probes. IAA was measured using the gold-standard radiobinding assay (RBA). Results: MS of oxPTM-INS identified chlorination of Tyr16 and Tyr26; oxidation of His5, Cys7 and Phe24; and glycation of Lys29 and Phe1 in chain B. Significantly higher binding to oxPTM-INS vs native insulin was observed in participants with type 1 diabetes, with 84% sensitivity compared with 61% sensitivity for RBA. oxPTM-INS autoantibodies and IAA co-existed in 50% of those with type 1 diabetes. Importantly 34% of those with diabetes who were IAA negative were oxPTM-INS positive. Altogether, 95% of participants with type 1 diabetes presented with autoimmunity to insulin by RBA, oxPTM-INS or both. Binding to oxPTM-INS was directed towards oxPTM-INS fragments with slower mobility than native insulin. Conclusion/interpretation: These data suggest that oxPTM-INS is a potential autoantigen in individuals with new-onset type 1 diabetes. [ABSTRACT FROM AUTHOR]

A highly sensitive electrochemical immunoassay for the initial diagnosis of celiac disease (CD) in saliva samples that overcomes the problems related to its high viscosity and to the low concentration of anti-transglutaminase antigen (tTG) IgA in this medium has been developed for the first time. The system uses magnetic beads (MBs) covered with tTG, which reacts with the anti-tTG IgA antibodies present in positive saliva samples. An anti-human IgA, conjugated with alkaline phosphate (AP) enzyme, was used as the label and a strip of eight magnetized screen-printed electrodes as the electrochemical transducer. In particular, two different immunoassay approaches were optimized and blindly compared to analyze a large number of saliva samples, whose anti-tTG IgA levels were independently determined by the radioimmunoassay (RIA) method. The obtained results, expressed as Ab index, were used to perform a diagnostic test evaluation through the construction of receiver operating characteristic (ROC) curves. The approach, involving a pre-incubation between the anti-human IgA-AP and saliva samples prior to the addition of MBs-tTG, showed a cutoff of 0.022 with 95 % clinical sensitivity and 96 % clinical specificity. The area under the ROC curve is equal to 1, a result that classifies our test as 'perfect.' This study demonstrates that it is possible to perform the screening of CD with a rapid, simple, inexpensive, and sensitive method able to detect anti-tTG antibodies in saliva samples, which are easily obtained by non-invasive techniques. This aspect is of fundamental importance to screen a large number of subjects, especially in the pediatric age. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

To assess the frequency of celiac-associated humoral autoimmunity in patients with long-standing childhood- and adult-onset type 1 diabetes (LDM1) and whether it occurs more frequently as the disease progresses. IgA-/IgG-anti-tissue transglutaminase (IgA-tTG and IgG-tTG) and IgA-/IgG-deamidated gliadin (DGP) antibodies were analyzed in 277 LDM1 sera (120 females; disease duration 19.3 ± 12.3 years, range 5.0-54.0 years). Of the 277 patients, 147 were childhood-onset LDM1 (LDM1) and 130 adult-onset LDM1 (LDM1); 6.1 % LDM1 sera were tTG- and/or DGP-antibody-positive, with a lower frequency among LDM1 as compared with LDM1 patients (3.4 vs 9.2 %, p = 0.048). Celiac-associated immunoreactivity was significantly more frequent in LDM1 with >15 years of disease duration (9.4 vs 2.9 % in those with ≤15 years, p = 0.042) and among them in LDM1 (14.7 vs 4.2 % LDM1, p = 0.043). Celiac disease humoral immunoreactivity should be screened not only at diabetes onset, but also in long-standing patients, especially adults with disease duration >15 years. [ABSTRACT FROM AUTHOR]

It has been proposed that the neurotrophin brain-derived neurotrophic factor (BDNF) may be involved in attention deficit-hyperactivity disorder (ADHD) etiopathogenesis. Alterations in BDNF serum levels have been observed in childhood/adulthood neurodevelopmental pathologies, but no evidence is available for BDNF serum concentrations in ADHD. The study includes 45 drug-naïve ADHD children and 45 age-sex matched healthy subjects. Concentration of serum BDNF was determined by the ELISA method. BDNF serum levels in patients with ADHD were not different from those of controls (mean ± SD; ADHD: 39.33 ± 10.41 ng/ml; controls: 38.82 ± 8.29 ng/ml, t = −0.26, p = 0.80). Our findings indicate no alteration of serum BDNF levels in untreated patients with ADHD. A further stratification for cognitive, neuropsychological and psychopathological assessment in a larger sample could be useful to clarify the role of BDNF in the endophenotype characterization of ADHD. [ABSTRACT FROM AUTHOR]

Fish introduction is a major threat to alpine lake biota leading to the loss of native species and to the degeneration of natural food-webs. This study provides an extensive investigation on the impact of the introduced fish Salvelinus fontinalis on the native communities of alpine lakes in the Gran Paradiso National Park. We compared the macroinvertebrate and zooplankton communities of six stocked and nine fishless lakes with a repeated sampling approach during the summers 2006-2009. The impact of fish presence on alpine lake fauna is often mediated by the strong seasonality governing these ecosystems, and it dramatically affects the faunal assemblage of littoral macroinvertebrates and the size, structure, and composition of the pelagic zooplankton community with a strong selective predation of the more visible taxa. Direct ecological impacts include a decrease or extinction of non-burrower macroinvertebrates and of large zooplankton species, while small zooplankton species and burrower macroinvertebrates were indirectly advantaged by fish presence. Due to the existence of a compensation between rotifers and crustaceans, fish presence does not affect total zooplankton biomass and diversity even if fish are a factor of ecological exclusion for large crustaceans. These compensatory mechanisms are a key process surrounding the impact of introduced fish in alpine lakes. [ABSTRACT FROM AUTHOR]

Purpose: Celiac disease (CD), a systemic autoimmune disorder that typically involves duodenal mucosa, can also affect other intestinal areas. Duodenal and oral mucosa organ culture has already been demonstrated as a reliable procedure to identify CD. The present study investigated gluten-dependent immunological activation of colonic mucosa in CD patients. We took advantage of the numerous colonoscopies performed for various clinical conditions or only for defensive medicine. Methods: Forty-four patients with gastrointestinal symptoms or in need of colorectal cancer screening were divided into patients with serum anti-endomysium (EMA) and anti-tissue transglutaminase (anti-tTG) antibody positive results (Group A), patients with serum antibody negative results (Group B), and patients with inflammatory bowel disease (IBD) (Group C). The autoantibodies EMA and anti-tTG were evaluated in supernatants of cultured sigmoid and duodenal biopsies from patients on a gluten-containing diet. Results: In Group A, EMA and anti-tTG resulted positive in all duodenal culture supernatants. In sigmoid culture supernatants, EMA and anti-tTG were detected in 12/16 (75 %) and 13/16 (81.3 %) patients, respectively. In Group B, none of the 17 patients showed EMA and anti-tTG positive results in both duodenal and sigmoid cultures. In Group C, all 11 patients presented EMA negative results in sigmoid cultures. Only in one patient, anti-tTG were detectable in the sigmoid culture supernatant, as expected in cases of IBD. Conclusions: Data confirm that the gluten-dependent immunological activation affects more intestinal tracts with different degrees of involvement, suggesting that the organ culture of colonic biopsies could represent a new tool to opportunistically detect CD. [ABSTRACT FROM AUTHOR]

The avoidance of visually feeding fish has long been considered as the primary driver of diel vertical migration of zooplankton. The diurnal vertical distribution of Cyclops gr. abyssorum, Arctodiaptomus alpinus, and Daphnia gr. longispina from 13 alpine lakes with fish ( Salvelinus fontinalis) and without, was compared in order to understand whether fish in transparent lakes reduce the presence of large zooplankton from the irradiated zone. We used the light level at each sampling depth and the size of each specimen as proxies of predation risk, and we tested two predictions: (P1) the relative abundance of zooplankton in the well-lit surface waters vs. the darker waters will be greater in fishless lakes; (P2) the size of zooplankton in the well-lit surface waters vs. the deeper, darker waters will be greater in fishless lakes. We did not find any evidence of the validity of P1, but we confirmed P2 for Arctodiaptomus alpinus. These results support with new field data the Transparency Regulator Hypothesis, which argues that in transparent lakes, fish predation is less important for the vertical distribution of zooplankton than ultraviolet radiation, and further suggest that zooplankton size rather than vertical distribution may be more effective against visual predators in transparent lakes. [ABSTRACT FROM AUTHOR]

This review focuses specifically on the diagnostic value of T2-weighted imaging in the assessment of Crohn's disease (CD) inflammation. In general, T2-weighted imaging has been less extensively investigated than T1-weighted gadolinium-enhanced imaging, even if it may offer similar information on disease activity. Furthermore, T2-weighted imaging allows CD characterization, which is crucial in the management of the disease when differentiating intestinal edema from fibrosis. Technical aspects, morphological findings and signs of active intestinal inflammation and fibrosis detectable on T2-weighted images will be reviewed and shown. Correlation between T2-weighted imaging findings, clinical activity indexes and histopathology features will be discussed. Since T2-weighted imaging is essential in the evaluation of CD activity, it should always complement with T1-weighted imaging, although it could also be used alone in the assessment of CD. [ABSTRACT FROM AUTHOR]

We present a DFT study of the structural and spectroscopic properties of the complex formed by Cu with the peptide fragment Ac-PHREN-NH, which encompasses the putative cell binding domain of angiogenin, as well as with its Ac-PHRQN-NH variant. Analysis of structures, energies and spectroscopic parameters has allowed to conclude that the metal coordination environment at pH 8 is formed by a nitrogen atom of His, two deprotonated amide groups, and an oxygen atom from the COO side chain of Glu, in nice agreement with recent experimental results (La Mendola et al. in Dalton Trans, 39:10678, ). Moreover, DFT results allowed to reveal that the Glu side chain of the Ac-PHREN-NH peptide is coordinated in equatorial position, in a tetrahedrically distorted square planar arrangement, fully disclosing the effects of Cu binding on the structural properties of this key angiogenin portion. In the Ac-PHRQN-NH variant, the carboxylate group is replaced by a HO molecule in a coordination arrangement similar to that of the wild-type system. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Measurement of transglutaminase autoantibodies (TGAA) is considered to be the most efficient single serologic test for celiac disease (CD) by the American Gastroenterological Association Institute. We hypothesized that a large international collaborative effort toward improving and standardizing TGAA measurement is both feasible and necessary. The primary aim of this workshop is to compare TGAA assays among various research and clinical laboratories and examine assay concordance and improve (and eventually standardize) the TGAA assay. METHODS: A total of 20 laboratories (5 commercial laboratories, 15 research and clinical laboratories) participated that included enzyme-linked immunosorbent assay (ELISA) and radiobinding assays. A total of 150 serum samples were distributed to each laboratory, with each laboratory receiving an equal aliquot that was coded and blinded, composed of 100 healthy control sera and 50 CD sera. RESULTS: Laboratory sensitivity ranged from 69% to 93% and specificity ranged from 96% to 100% . By receiver operator characteristic analysis, the area under the curve (C index) ranged from 0.9488 to 0.9904. When analyzing for linear correlation, r-squared was as high as 0.8882 but as low as 0.4244 for the celiac samples between different laboratories performing ELISA. CONCLUSIONS: This transglutaminase autoantibody workshop allows for larger-scale international participation for the purposes of improving and eventually standardizing the TGAA assay with subsequent workshops. [ABSTRACT FROM AUTHOR]

We calculated the expected impact on the Italian coast of the Adriatic Sea of a large set of tsunamis resulting from potential earthquakes generated by major fault zones. Our approach merges updated knowledge on the regional tectonics and scenario-like calculations of expected tsunami impact. We selected six elongated potential source zones. For each of them we determined a Maximum Credible Earthquake and the associated Typical Fault, described by its size, geometry and kinematics. We then let the Typical Fault float along strike of its parent source zone and simulated all tsunamis it could generate. Simulations are based on the solution of the nonlinear shallow water equations through a finite-difference technique. For each run we calculated the wavefields at specified simulation times and the maximum water height field (above mean sea level), then generated travel-time maps and maximum water height profiles along the target coastline. Maxima were also classified in a three-level code of expected tsunami threat. We found that the southern portion of Apulia facing Albania and the Gargano promontory are especially prone to the tsunami threat. We also found that some bathymetric features are crucial in determining the focalization-defocalization of tsunami energy. We suggest that our results be taken into account in the design of early-warning strategies. [ABSTRACT FROM AUTHOR]

Adiponectin, an adipocyte-derived protein, is an essential modulator of insulin sensitivity and several studies suggest an important role of adiponectin in the processes leading to atherosclerosis, thus indicating the adiponectin gene as a potential candidate for coronary artery disease (CAD). In the present study we have studied the association between two single nucleotide polymorphisms (SNPs) (+ 45T>G and + 276 G>T) of the adiponectin gene and CAD, looking also into the possible influence of these SNPs on adiponectin plasma levels. The SNPs were analysed in a first cohort of 595 subjects, 325 with CAD and 270 matched controls. We observed a significant association ( p<0.001) between the SNP + 276G>T in the adiponectin gene and CAD. In multivariate analysis, carriers of the + 276G>T SNP had an odds ratio (OR) for CAD of 4.99 ( p<0.0007). A strong interaction between the + 276G>T SNP and age was also present (OR, 1.03; p<0.0001). The increase in CAD risk was most evident among individuals with early-onset CAD (age ≤50 years), whereas in older CAD subjects other factors, and not the adiponectin SNP, were the major determinants. Furthermore, in CAD subjects with early-onset disease this SNP was also a significant determinant of lower levels of serum adiponectin levels. This association resulted independent from the other variables known to be associated with CAD in our population, including sex, body mass index, high-density lipoprotein and Homeostasis Model Assessment for insulin resistance. To confirm the results the + 276G>T SNP was analysed in a second cohort of CAD and controls. The difference between CAD and controls in the + 276G>T SNP frequencies showed a similar trend as before, although not significant. The combination of the two cohorts (1,046 subjects: 580 CAD and 466 controls) showed a statistically significant association, particularly in CAD subjects with early-onset of disease. In addition, we confirmed that in younger CAD subjects the SNP was a significant determinant of lower levels of adiponectin. In view of these results, it could be speculated that the adiponectin gene variant, or a mutation in linkage with it, determines lower adiponectin gene expression, causing in turn an increased risk to develop insulin resistance, atherosclerosis and cardiovascular disease. The significant association of the adiponectin gene in subjects with early-onset CAD also suggests that that genetic factors for late-onset diseases may exert a greater influence in younger persons, when other risk factors are not as prevalent as in older age groups. [ABSTRACT FROM AUTHOR]

The objective was to evaluate HLA DR/DQ alleles and their risk factor for type 1 diabetes in the Abruzzo region (central Italy). Sixty incident cases from the Abruzzo region were studied together with 120 unrelated control subjects living in the same administrative areas. The relative risk of diabetes associated with the alleles under study was calculated by deriving the odds ratio (OR) maximum likelihood estimates and their 95% confidence intervals (CI) by the exponentiation of the logistic regression beta–parameter. The combination DRB1*03/DQA1*0501/DQB1*0201 was found in 20.0% of patients and 7.1% of the control subjects, conferring an OR of 4.04 and a CI of 1.97–8.49. The combination DRB1*04/DQA1*0301/DQB1*0302 was found in 23.3% of diabetic patients and 6.7% of controls, giving an OR of 5.69 and a CI of 2.77–12.05. DRB1*11/DQA1*0505/DQB1*0301 and DQA1*0505/DQB1*0301 were negatively associated with type 1 diabetes (OR=0.27, CI 0.11–0.57; OR=0.07, CI 0.02–0.19). The DQA1 genotype at risk was found to be DQA1*0301/DQA1*0501: OR=23.80, CI 2.97–190.89, as it occurred with the highest frequency in the patient group. The DQB1 genotype at risk was found to be DQB1*0201/DQB1*0302, which occurred in 13.3% of patients but in only 1.1% of the control group (OR=29.75, CI 5.36–549.25). Our results shed further light on the risk of development of this disease during a specific time period in an area where the overall incidence of type 1 diabetes is known. [ABSTRACT FROM AUTHOR]

Several genetic variants of peroxisome proliferator-activated receptor-?2 (PPAR-?2) have been identified, among which Pro12Ala, a missense mutation in exon 2, is highly prevalent in Caucasian populations. Up to now, conflicting results with regard to the association between this mutation and complex traits, such as obesity, insulin sensitivity and Type 2 diabetes, have been reported. We investigated the influence of the Pro12Ala polymorphism of PPAR-?2 on insulin sensitivity in a large Italian population sample, n=1215, in whom extensive clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated; in the obese/overweight subjects an oral glucose tolerance test (OGTT) was also performed and the Matsuda insulin sensitivity index (ISI) calculated. The insulin secretion index (homeostasis model assessment of percentß-cell function, HOMA-ß%) was utilized to evaluateß-cell function. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared to Pro/Pro (P=0.01 after correction for multiple comparisons) in all subjects. Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (P=0.013 after correction for multiple comparisons) in all cohort. Moreover, no significant interaction effect was observed between body mass index and X12Ala polymorphism and between gender and X12Ala polymorphism in modulating insulin sensitivity. Our observations substantially extend previous findings and demonstrated that X12Ala variant is significantly associated with greater insulin sensitivity.European Journal of Human Genetics (2004) 12, 1050-1054. doi:10.1038/sj.ejhg.5201283 Published online 15 September 2004 [ABSTRACT FROM AUTHOR]

Background The authors describe a myopic choroidal neovascular membrane excised 4 months after photodynamic therapy (PDT). Methods A 68-year-old woman with classic choroidal neovascularization (CNV) due to pathologic myopia underwent PDT with verteporfin in the left eye. Four months after treatment a full-thickness macular hole was diagnosed in the same eye and the patient underwent vitrectomy with submacular membranectomy. The subfoveal membrane was studied by light microscopy and immunohistochemical techniques. Results Light microscopy showed a thin fibrovascular membrane covered by residual retinal pigment epithelium. The membrane contained homogeneous matrix with small collagen bundles, fibroblasts and small blood vessels. The distribution of blood vessels was nonuniform: extravasated red blood cells, macrophages and other inflammatory elements were not present in the fibrous matrix. Endothelial cells were highlighted by CD34 immunostaining and did not show any significant alteration. There was no evidence of inflammatory cells or thrombosis inside vascular lumina. Conclusions Histologic examination of the neovascular membrane showed features similar to those of surgically excised myopic CNV without PDT treatment. Our findings suggest that PDT-induced occlusion is temporary. Fluorescein leakage from CNV after a single PDT treatment can be considered as an sign of blood vessel regrowth or recanalization indicating that multiple treatments are necessary. [ABSTRACT FROM AUTHOR]