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Background: Sotorasib showed a significant improvement of progression free survival (PFS), safety and quality of life over docetaxel in patients with KRASp.G12C-mutated advanced non-small-cell lung cancer (NSCLC) within the CodeBreak-200 study. Here we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP). Methods: Sotorasib (960 mg, orally, once daily) was available on physician request for KRASp.G12C mutant advanced NSCLC patients. Clinical-pathological and molecular data were collected from the Italian ATLAS real-world registry. Patients underwent CT-scan and responses were evaluated by RECIST criteria. Efficacy and tolerability outcomes have been assessed. Results: A total of 196 advanced NSCLC patients were treated across 30 Italian centers. Median age was 69 years old (range 33-86). Most patients were male (61 %), former (49 %) or current smokers (43 %), with ECOG-PS 0/1 (84 %) and adenocarcinoma subtype (90 %). 45 % and 32 % of patients received sotorasib in 2nd and 3rd line, respectively. Overall, response rate was 26 % and the median duration of response was 5.7 months (95 % CI: 4.4-7.0). Median PFS and OS were 5.8 months (95 % CI: 5 - 6.5) and 8.2 months (95 % CI: 6.3 - 9.9). Grade 3-4 TRAEs occurred in 16.5 % of patients, with Grade >= 3 liver enzyme increase and TRAEs-related discontinuation reported in 12 % and 4.6 % of cases. Conclusion: Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients.

Background: Work functioning impairment is a key diagnostic and prognostic criterion in patients with psychiatric disorders and work inclusion is a major goal of their therapeutic pathway. Since 2009, the Regional Innovative Program (PIR) TR106, promoted by ASST Fatebenefratelli-Sacco of Milan in collaboration with other Departments of Mental Health and Addictions (DSMDs) in the town of Milan (Italy), has been developing the employment inclusion of psychiatric patients. Aims: The objective of this study is to evaluate its outcomes over 8 years of observation. Method: We reported the results of a retrospective epidemiologic analysis on 2,142 interventions on 1,066 patients recruited, investigating PIR TR106 outcomes per year focusing on different subgroups. We focused on 'positive', 'negative', and 'other' outcomes. Results: We preliminary calculated job maintenance interventions (5%, 107) and excluded these interventions from the overall. We observed 29 job firing (1.4%) and 15 job resignations (0.7%) as negative results (equal to 2.2% of the total) and 388 job hiring (16.6%), 647 traineeships (31.8%), and 413 work formation (20.3%) as positive outcomes (equal to 68.75%). In other outcomes (29.1%) we found 305 dismissals from PIR TR 106 (15%) and transitory outcomes (14.1%). Job hiring increased from 8.9% in 2012 to 23.8 % in 2019 (p < .001), while the dismissals diminished from 26.7% to 13.3% (p < .001). The effectiveness of traineeships in terms of job hiring increased in the ratio of annual job hiring versus job traineeship (+48.8%). The majority of hired patients (15.1%) were affected by a psychotic disorder. A significant hiring increase was observed in patients with psychotic disorders and personality disorders (p < .005). Results: We preliminary calculated job maintenance interventions (5%, 107) and excluded these interventions from the overall. We observed 29 job firing (1.4%) and 15 job resignations (0.7%) as negative results (equal to 2.2% of the

L’Università degli Studi di Milano-Bicocca pubblica la relazione annuale sulle attività di Open Science. Riferita all’anno 2023, essa rappresenta la prima edizione di tale documento con lo scopo di esporre e monitorare i dati frutto delle azioni che, su diversi fronti, contribuiscono alla realizzazione della scienza aperta nel nostro contesto accademico.

The assessment of antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to verify the protective efficacy of available vaccines. Hospital healthcare workers play an essential role in the care and treatment of patients and were particularly at risk of contracting the SARS-CoV-2 infection during the pandemic. The vaccination protocol introduced in our hospital protected the workers and contributed to the containment of the infection’ s spread and transmission, although a reduction in vaccine efficacy against symptomatic and breakthrough infections in vaccinated individuals was observed over time. Here, we present the results of a longitudinal and prospective analysis of the anti-SARS-CoV-2 antibodies at multiple time points over a 17-month period to determine how circulating antibody levels change over time following natural infection and vaccination for SARS-CoV-2 before (T0–T4) and after the spread of the omicron variant (T5–T6), analyzing the antibody response of 232 healthy workers at the Pio XI hospital in Desio. A General Estimating Equation model indicated a significant association of the antibody response with time intervals and hospital area, independent of age and sex. Specifically, a similar pattern of antibody response was observed between the surgery and administrative departments, and a different pattern with higher peaks of average antibody response was observed in the emergency and medical departments. Furthermore, using a logistic model, we found no differences in contracting SARS-CoV-2 after the third dose based on the hospital department. Finally, analysis of antibody distribution following the spread of the omicron variant, subdividing the cohort of positive individuals into centiles, highlighted a cut-off of 550 BAU/mL and showed that subjects with antibodies below this are more susceptible to infection than those with a concentration above the established cut-off value.

Background: Conventional low-density lipoprotein cholesterol (LDL-C) quantification includes cholesterol attributable to lipoprotein(a) (Lp(a)-C) due to their overlapping densities. Objectives: The purposes of this study were to compare the association between LDL-C and LDL-C corrected for Lp(a)-C (LDLLp(a)corr) with incident coronary heart disease (CHD) in the general population and to investigate whether concomitant Lp(a) values influence the association of LDL-C or apolipoprotein B (apoB) with coronary events. Methods: Among 68,748 CHD-free subjects at baseline LDLLp(a)corr was calculated as “LDL-C—Lp(a)-C,” where Lp(a)-C was 30% or 17.3% of total Lp(a) mass. Fine and Gray competing risk-adjusted models were applied for the association between the outcome incident CHD and: 1) LDL-C and LDLLp(a)corr in the total sample; and 2) LDL-C and apoB after stratification by Lp(a) mass (≥/<90th percentile). Results: Similar risk estimates for incident CHD were found for LDL-C and LDL-CLp(a)corr30 or LDL-CLp(a)corr17.3 (subdistribution HR with 95% CI) were 2.73 (95% CI: 2.34-3.20) vs 2.51 (95% CI: 2.15-2.93) vs 2.64 (95% CI: 2.26-3.10), respectively (top vs bottom fifth; fully adjusted models). Categorization by Lp(a) mass resulted in higher subdistribution HRs for uncorrected LDL-C and incident CHD at Lp(a) ≥90th percentile (4.38 [95% CI: 2.08-9.22]) vs 2.60 [95% CI: 2.21-3.07]) at Lp(a) <90th percentile (top vs bottom fifth; Pinteraction0.39). In contrast, apoB risk estimates were lower in subjects with higher Lp(a) mass (2.43 [95% CI: 1.34-4.40]) than in Lp(a) <90th percentile (3.34 [95% CI: 2.78-4.01]) (Pinteraction0.49). Conclusions: Correction of LDL-C for its Lp(a)-C content provided no meaningful information on CHD-risk estimation at the population level. Simple categorization of Lp(a) mass (≥/<90th percentile) influenced the association between LDL-C or apoB with future CHD mostly at higher Lp(a) levels.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in kidney transplant recipients (KTRs). Current vaccine strategies for KTRs seem to be unable to provide effective protection against coronavirus disease 2019 (COVID-19), and the occurrence of severe disease in some vaccinated KTRs suggested a lack of immunity. We initially analyzed the antibody response in a group of 32 kidney transplant recipients (KTRs) followed at the nephrology and dialysis unit of the Hospital Pio XI of Desio, ASST-Brianza, Italy. Thus, we studied the differences in antibody levels between subjects who contracted SARS-CoV-2 after the booster (8 individuals) and those who did not contract it (24 individuals). Furthermore, we verified if the antibody response was in any way associated with creatinine and eGFR levels. We observed a significant increase in the antibody response pre-booster compared to post-booster using both a Roche assay and DIAPRO assay. In the latter, through immunotyping, we highlight that the major contribution to this increase is specifically due to IgG S1 IgM S2. We observed a significant increase in IgA S1 and IgA NCP (p = 0.045, 0.02) in the subjects who contracted SARS-CoV-2. We did not find significant associations for the p-value corrected for false discovery rate (FDR) between the antibody response to all assays and creatinine levels. This observation allows us to confirm that patients require additional vaccine boosters due to their immunocompromised status and therapy in order to protect them from infections related to viral variants. This is in line with the data reported in the literature, and it could be worthwhile to deeply explore these phenomena to better understand the role of IgA S1 and IgA NCP antibodies in SARS-CoV-2 infection.

Nel contesto educativo odierno, la ricerca di nuove modalità didattiche è essenziale per soddisfare le mutevoli esigenze degli studenti. Questo studio esamina il potenziale della gamification tramite Classcraft per rivoluzionare l'apprendimento degli studenti. La ricerca è guidata dalla domanda principale: "In che modo i diversi elementi di gioco introdotti nella didattica possono influenzare l'esperienza degli studenti nella scuola secondaria di primo grado italiana?". Basandoci sull'esperienza di Don Milani e il Manifesto "Una scuola," troviamo interessanti connessioni pedagogiche per affrontare le sfide educative contemporanee.

Xylene monooxygenase (XMO) from Pseudomonas putida stands out for its ability to oxidize inert substrates with a structure like toluene and xylene. Nevertheless, its catalytic efficacy is curtailed by a mysterious inhibition mechanism, the details of which remain elusive. Presently, our research endeavors focus on employing wet and computational methodologies to unravel the structural intricacies and catalytic dynamics of XMO atoms. This enzyme exhibits high sequence homology with alkane monooxygenase (alkB), with its distinctive catalytic site where two iron atoms are situated at an unusual distance of 6 Å within a histidine-rich environment. This peculiar catalytic site underlines a catalytic mechanism unknown to this day. While our investigation is ongoing, our preliminary molecular modeling and simulation efforts aim to shed light on the fundamental aspects of its function and inhibition. Through this ongoing work, we anticipate laying the groundwork for potential strategies to enhance the stability and efficiency of XMO. Our endeavors hold significant promise for advancing both the fundamental understanding and practical applications of XMO in biotechnological contexts such as industrial processes.

SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants.

Cognitively impaired and spared patient subgroups were identified in psychosis and depression, and in clinical high-risk for psychosis (CHR). Studies suggest differences in underlying brain structural and functional characteristics. It is unclear whether cognitive subgroups are transdiagnostic phenomena in early stages of psychotic and affective disorder which can be validated on the neural level. Patients with recent-onset psychosis (ROP; N = 140; female = 54), recent-onset depression (ROD; N = 130; female = 73), CHR (N = 128; female = 61) and healthy controls (HC; N = 270; female = 165) were recruited through the multi-site study PRONIA. The transdiagnostic sample and individual study groups were clustered into subgroups based on their performance in eight cognitive domains and characterized by gray matter volume (sMRI) and resting-state functional connectivity (rsFC) using support vector machine (SVM) classification. We identified an impaired subgroup (NROP = 79, NROD = 30, NCHR = 37) showing cognitive impairment in executive functioning, working memory, processing speed and verbal learning (all p < 0.001). A spared subgroup (NROP = 61, NROD = 100, NCHR = 91) performed comparable to HC. Single-disease subgroups indicated that cognitive impairment is stronger pronounced in impaired ROP compared to impaired ROD and CHR. Subgroups in ROP and ROD showed specific symptom- and functioning-patterns. rsFC showed superior accuracy compared to sMRI in differentiating transdiagnostic subgroups from HC (BACimpaired = 58.5%; BACspared = 61.7%, both: p < 0.01). Cognitive findings were validated in the PRONIA replication sample (N = 409). Individual cognitive subgroups in ROP, ROD and CHR are more informative than transdiagnostic subgroups as they map onto individual cognitive impairment and specific functioning- and symptom-patterns which show limited overlap in sMRI and rsFC.

For non-relativistic thermal dark matter, close-to-threshold effects largely dominate the evolution of the number density for most of the times after thermal freeze-out, and hence affect the cosmological relic density. A precise evaluation of the relevant interaction rates in a thermal medium representing the early universe includes accounting for the relative motion of the dark matter particles and the thermal medium. We consider a model of dark fermions interacting with a plasma of dark gauge bosons, which is equivalent to thermal QED. The temperature is taken to be smaller than the dark fermion mass and the inverse of the typical size of the dark fermion-antifermion bound states, which allows for the use of non-relativistic effective field theories. For the annihilation cross section, bound-state formation cross section, bound-state dissociation width and bound-state transition width of dark matter fermion-antifermion pairs, we compute the leading recoil effects in the reference frame of both the plasma and the center-of-mass of the fermion-antifermion pair. We explicitly verify the Lorentz transformations among these quantities. We evaluate the impact of the recoil corrections on the dark matter energy density. Our results can be directly applied to account for the relative motion of quarkonia in the quark-gluon plasma formed in heavy-ion collisions. They may be also used to precisely assess thermal effects in atomic clocks based on atomic transitions; the present work provides a first field theory derivation of time dilation for these processes in vacuum and in a medium., Comment: 52 pages, 9 figures, published version, improved discussion of the effective Lagrangian

Diese kumulative Dissertation umfasst zwei Veröffentlichungen zu drei Bereichen der Emotionskommunikation. Ziel war es, zu untersuchen, ob OP-Masken die Emotionswahrnehmung, die Affiliation und die emotionale Mimikry (d.h. die automatische, aber zielabhängige Imitation des emotionalen Ausdrucks von Interaktionspartner:innen) reduzieren. In zwei Online-Experimenten (Studie 1: N=200, britische Stichprobe; Studie 2: N=235, deutsche Stichprobe) wurden subjektive Bewertungen und die emotionale Mimikry als Reaktion auf maskierte und unmaskierte Gesichter untersucht. Die wahrgenommene Emotionsintensität und die Genauigkeit der Emotionserkennung dienten als Indikatoren für die Emotionswahrnehmung. Die wahrgenommene zwischenmenschliche Nähe diente als Indikator für die Affiliation. Die emotionale Mimikry wurde mit Hilfe einer Gesichtsaktivitätserkennungstechnologie gemessen. In der ersten Studie sahen erwachsene Proband:innen erwachsene Zielpersonen, die Freude und Trauer ausdrückten, eingebettet in Innen- und Außenszenen. In der zweiten Studie sahen erwachsene Proband:innen Erwachsene und Kinder, die Freude, Trauer oder Ärger ausdrückten. Die Freudemimikry wurde durch Masken reduziert, insbesondere wenn die Zielpersonen Kinder waren. Im Gegensatz dazu war die Trauermimikry bei Kindergesichtern stärker und wurde, wie auch die Ärgermimikry, durch Masken nicht beeinträchtigt. Wir konnten auch zeigen, dass durch Gesichtsmasken verringerte Freudewahrnehmung und Nähe mit einer verringerten Freudemimikry verbunden waren. Die Studien zeigen somit, wie erwartet wurde, eine maskenbedingte Verringerung der Emotionswahrnehmung, der Affiliation, und der emotionalen Mimikry. Insgesamt trägt die vorliegende Arbeit zu unserem Verständnis der sozio-affektiven Auswirkungen der partiellen Gesichtsverdeckung bei und stützt die Theorie der emotionalen Mimikry im sozialen Kontext von Hess und Fischer, nach der Emotionswahrnehmung und Affiliation die emotionale Mimikry beeinflussen., This cumulative doctoral dissertation encompasses two publications on three domains of emotion communication. The goal of the dissertation was to assess if surgical face masks reduce emotion perception, affiliation, and emotional mimicry (i.e., automatic but goal-dependent imitation of an interaction partner's emotional display). We conducted two online experiments (Study 1: N=200, U.K. sample; Study 2: N=235, German sample) that assessed subjective ratings and emotional mimicry in response to masked and unmasked faces. Perceived emotion intensity and emotion recognition accuracy served as indicators of emotion perception. Perceived interpersonal closeness (via the Inclusion of Other in the Self Scale) served as an indicator of affiliation. Emotional mimicry was measured using facial activity recognition technology. We also took into account socio-spatial context effects. In the first study, adult perceivers saw adult targets who expressed happiness and sadness embedded into indoor and outdoor scenes. In the second study, adult perceivers saw adult and child targets who expressed happiness, sadness, and anger. We found that happiness mimicry was reduced by masks, particularly when expressers were children. In contrast, sadness mimicry was stronger for children and, like anger mimicry, unaffected by masks. We also found that reduced emotion perception and closeness due to masks were associated with reduced happiness mimicry. The studies support evidence from before and during the COVID-19 pandemic for mask-related reductions of emotion perception and affiliation. Moreover, the studies provide unprecedented evidence on reductions of emotional mimicry in response to masked faces and child targets. Overall, the present work contributes to our understanding of the socio-affective effects of partial face occlusion and supports emotional mimicry in social context theory by Hess and Fischer, according to which emotion perception and affiliation influence emotional mimicry.

As on land, oceans exhibit high temporal and spatial temperature variation. This ocean weather contributes to the physiological and ecological processes that ultimately determine the patterns of species distribution and abundance, yet is often unrecognized, especially in tropical oceans. Here, we tested the paradigm of temperature stability in shallow waters (<12.5 m) across different zones of latitude. We collated hundreds of in situ, high temporal-frequency ocean temperature time series globally to produce an intuitive measure of temperature variability, ranging in scale from quarter-diurnal to annual time spans. To estimate organismal sensitivity of ectotherms (i.e. microbes, algae, and animals whose body temperatures depend upon ocean temperature), we computed the corresponding range of biological rates (such as metabolic rate or photosynthesis) for each time span, assuming an exponential relationship. We found that subtropical regions had the broadest temperature ranges at time spans equal to or shorter than a month, while temperate and tropical systems both exhibited narrow (i.e. stable) short-term temperature range estimates. However, temperature-dependent biological rates in tropical regions displayed greater ranges than in temperate systems. Hence, our results suggest that tropical ectotherms may be relatively more sensitive to short-term thermal variability. We also highlight previously unexplained macroecological patterns that may be underpinned by short-term temperature variability.

Introduction: Risk stratification scores such as the European Systematic COronary Risk Evaluation (SCORE) are used to guide individuals on cardiovascular disease (CVD) prevention. Adding high-sensitivity troponin I (hsTnI) to such risk scores has the potential to improve accuracy of CVD prediction. We investigated how applying hsTnI in addition to SCORE may impact management, outcome, and cost-effectiveness. Methods: Characteristics of 72,190 apparently healthy individuals from the Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project were included into a discrete-event simulation comparing two strategies for assessing CVD risk. The standard strategy reflecting current practice employed SCORE (SCORE); the alternative strategy involved adding hsTnI information for further stratifying SCORE risk categories (S-SCORE). Individuals were followed over ten years from baseline examination to CVD event, death or end of follow-up. The model tracked the occurrence of events and calculated direct costs of screening, prevention, and treatment from a European health system perspective. Cost-effectiveness was expressed as incremental cost-effectiveness ratio (ICER) in € per quality-adjusted life year (QALYs) gained during 10 years of follow-up. Outputs were validated against observed rates, and results were tested in deterministic and probabilistic sensitivity analyses. Results: S-SCORE yielded a change in management for 10.0% of individuals, and a reduction in CVD events (4.85% vs. 5.38%, p<0.001) and mortality (6.80% vs. 7.04%, p<0.001). S-SCORE led to 23 (95%CI: 20–26) additional event-free years and 7 (95%CI: 5–9) additional QALYs per 1,000 subjects screened, and resulted in a relative risk reduction for CVD of 9.9% (95%CI: 7.3–13.5%) with a number needed to screen to prevent one event of 183 (95%CI: 172 to 203). S-SCORE increased costs per subject by 187€ (95%CI: 177 € to 196 €), leading to an ICER of 27,440€/QALY gained. Sensitivity analysis was p

Cancer cells are continuously challenged by a limited oxygen, nutrients supply, and elevated protein synthesis. All these circumstances induce ER stress and Unfolded Protein Response (UPR). A huge amount of evidence demonstrates that the UPR is a crucial process for cancer cells to keep malignancy but also that, prolonged pharmacological induction of UPR, can be effective for promoting cancer cell death. Here we show that inhibition of the Hexosamine Biosynthetic Pathway (HBP) by means of a specific HBP inhibitor, FR054, causes a prolonged activation of the UPR that induces, in breast cancer (BC) cells, ROS accumulation and cell death. Conversely, such a ROS-dependent mechanism is somewhat inhibited in pancreatic cancer (PC) cells. However parallel inhibition of xCT/SLC7A11, involved in glutathione biosynthesis, by erastin (ERA), a recognized ferroptosis inducer, significantly enhanced the FR054 effect causing a noteworthy increase in cancer cell proliferation arrest and death.

Cancer cells are continuously challenged by a limited oxygen, nutrients supply, and elevated protein synthesis. All these circumstances induce ER stress and Unfolded Protein Response (UPR). A huge amount of evidence demonstrates that the UPR is a crucial process for cancer cells to keep malignancy but also that, prolonged pharmacological induction of UPR, can be effective for promoting cancer cell death. Here we show that inhibition of the Hexosamine Biosynthetic Pathway (HBP) by means of a specific HBP inhibitor, FR054, causes a prolonged activation of the UPR that induces, in breast cancer (BC) cells, ROS accumulation and cell death. Conversely, such a ROS-dependent mechanism is somewhat inhibited in pancreatic cancer (PC) cells. However parallel inhibition of xCT/SLC7A11, involved in glutathione biosynthesis, by erastin (ERA), a recognized ferroptosis inducer, significantly enhanced the FR054 effect causing a noteworthy increase in cancer cell proliferation arrest and death.

Breast and pancreatic cancer remain difficult adversaries in the landscape of oncology, characterised by their aggressive behaviour, high metastatic potential, and limited treatment efficacy. These cancer cells are continuously challenged by limited oxygen, nutrient supply, and elevated protein synthesis that may cause induction of the Unfolding Protein Response (UPR), a complex signalling network activated by Endoplasmic Reticulum (ER) stress to restore cellular homeostasis. Accumulating evidence highlights the vital role of the UPR as a critical process that enables tumour cells to sustain malignancy. On the other hand, prolonged pharmacological activation of the UPR has been demonstrated to induce cell death in cancer. Considering this, we decided to use for our experiments, FR054, a competitive inhibitor of PGM3 enzyme. By inhibiting the Hexosamine Biosynthetic Pathway (HBP), FR054 causes a decrease in the N-glycosylation (N-GlcNAc) protein level and, consequently, an accumulation of misfolded proteins into the ER. This stress condition triggers a prolonged activation of UPR that induces ROS accumulation and subsequent cell death in breast cancer (BC) cells. Otherwise, as demonstrated by the non-complete restoration after N-Acetyl Cysteine (NAC) co-treatment, in pancreatic cancer (PC) cells this ROS-dependent cell death mechanism is somewhat inhibited. Our transcriptional data suggests a potential key player in this inhibition: the xCT/SLC7A11 antiporter. This antiporter indeeed is responsible for mediating the uptake of extracellular cystine in exchange for glutamate thereby participating in glutathione biosynthesis. To confirm this hypothesis, we observed how the inhibition of xCT/SLC7A11 by erastin, a recognized ferroptosis inducer, significantly enhanced the FR054 effect causing a noteworthy increase in cancer cell proliferation arrest and death. In conclusion, HBP inhibition triggers UPR in both breast and pancreatic cancer cells. Notably, pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable clinical challenge due to its aggressiveness and resistance to treatment. Notably, PDAC exhibits a pronounced resistance to various therapeutic modalities, often attributed to a wide metabolic reprogramming involving also the Hexosamine Biosynthetic Pathway (HBP). Transcriptional and bioinformatics analyses, performed under inhibition of HBP in PDAC cell models, indicated that activation of ER stress and Unfolded Protein Response (UPR), due to HBP inhibition, activates an NRF2-dependent antioxidative response, characterized by activation of several genes involved in glutathione (GSH) metabolism. Indeed, inhibition of both HBP and the xCT protein, the cystine/glutamate antiporter involved in GSH synthesis, in PDAC cells significantly reduced cell proliferation, enhanced cell death, altered cellular redox status, heightened sensitivity to oxidative stress, increased dependence on glutamine metabolism, and induced ferroptosis. These findings underscore the potential of HBP inhibition to synergize with ERA, offering a promising therapeutic strategy for managing PDAC.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. It is characterized by the formation of cysts in kidneys. This condition has a significant impact on people’s lives. It causes not only physical suffering but also psychological suffering. People with ADPKD may experience psychological distress, depending on their personal and health conditions. The inability to accept or adapt to the disease and its resulting changes causes individuals difficulties that appear in different levels of their lives: intrapersonal, interpersonal, social, and occupational. In the context of ADPKD, the psychologist is involved both at clinical and research levels. The psychologist has a crucial role in supporting patients by assessing how they react to the disease, to its related limitations, and to the resulting disabilities. The proposal of psychological support, considered as an intervention instrument, is helpful both at the diagnostic stage and in follow-up, as the disease worsens. The support aims to encourage acceptance and adaptation to the disease, process changes, and physical and mental consequences., Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disease. It is characterized by the formation of cysts in kidneys. This condition has a significant impact on people's lives, it causes not only physical suffering but also psychological suffering. People with ADPKD may experience psychological distress, depending on their personal and health conditions. The inability to accept or adapt to the disease and its resulting changes causes individuals difficulties that manifest on different levels of their lives: intrapersonal, interpersonal, social, and occupational. In the context of ADPKD, the psychologist is involved both at clinical and research levels. The psychologist has a crucial role in supporting patients by assessing how they react to the disease, to its related limitations, and the resulting disabilities. The present of psychological support, considered as an intervention instrument, is helpful both at the diagnostic stage and in follow-up, as the disease worsens. The support aims to encourage acceptance and adaptation to the disease, process changes, physical and mental consequences.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetically inherited kidney disease and the fourth leading cause of renal replacement therapy worldwide. It is characterized by the development of multiple cysts in the kidneys and in other organs, the increase in renal volume and the progressive loss of renal function. ADPKD outcome seems to be sensitive to hormonal fluctuations, particularly those of sex hormones. Despite the limited literature available, this review presents the first comprehensive overview of contraception and hormonal replacement therapy in women with ADPKD, delving into the risks and benefits associated with different contraceptive methods, including hormonal, intrauterine devices, and non-hormonal approaches. It also explores personalized strategies for contraception based on the severity of renal disease and the presence of comorbidities. Although the protective role of female sex hormones in slowing the progression of renal failure is acknowledged, hormonal therapy in women with ADPKD remains intricate and challenging due to its potential impact on liver disease progression. Women with ADPKD typically experience a slower progression of renal disease compared to men, largely influenced by hormonal dynamics. This literature review underscores the importance of a multidisciplinary assessment and a thorough patient discussion to identify the most suitable contraceptive method for each woman affected by polycystic kidney disease., Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetically inherited kidney disease and the fourth leading cause of renal replacement therapy worldwide. It is characterized by the development of multiple cysts in the kidneys and in other organs, increase in renal volume and the progressive loss of renal function. ADPKD outcome seems to be sensitive to hormonal fluctuations, particularly those of sex hormones. Despite the limited literature available, this review presents the first comprehensive overview of contraception and hormonal replacement therapy in women with ADPKD, delving into the risks and benefits associated with different contraceptive methods, including hormonal, intrauterine devices, and non-hormonal approaches. It also explores personalized strategies for contraception based on the severity of renal disease and the presence of comorbidities. Although the protective role of female sex hormones in slowing the progression of renal failure is acknowledged, hormonal therapy in women with ADPKD remains intricate and challenging due to its potential impact on liver disease progression. Women with ADPKD typically experience a slower progression of renal disease compared to men, largely influenced by hormonal dynamics. This literature review underscores the importance of a multidisciplinary assessment and thorough patient discussion to identify the most suitable contraceptive method for each woman affected by polycystic kidney disease.

Introduction: Risk stratification scores such as the European Systematic COronary Risk Evaluation (SCORE) are used to guide individuals on cardiovascular disease (CVD) prevention. Adding high-sensitivity troponin I (hsTnI) to such risk scores has the potential to improve accuracy of CVD prediction. We investigated how applying hsTnI in addition to SCORE may impact management, outcome, and cost-effectiveness. Methods: Characteristics of 72,190 apparently healthy individuals from the Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project were included into a discrete-event simulation comparing two strategies for assessing CVD risk. The standard strategy reflecting current practice employed SCORE (SCORE); the alternative strategy involved adding hsTnI information for further stratifying SCORE risk categories (S-SCORE). Individuals were followed over ten years from baseline examination to CVD event, death or end of follow-up. The model tracked the occurrence of events and calculated direct costs of screening, prevention, and treatment from a European health system perspective. Cost-effectiveness was expressed as incremental cost-effectiveness ratio (ICER) in € per quality-adjusted life year (QALYs) gained during 10 years of follow-up. Outputs were validated against observed rates, and results were tested in deterministic and probabilistic sensitivity analyses. Results: S-SCORE yielded a change in management for 10.0% of individuals, and a reduction in CVD events (4.85% vs. 5.38%, p<0.001) and mortality (6.80% vs. 7.04%, p<0.001). S-SCORE led to 23 (95%CI: 20–26) additional event-free years and 7 (95%CI: 5–9) additional QALYs per 1,000 subjects screened, and resulted in a relative risk reduction for CVD of 9.9% (95%CI: 7.3–13.5%) with a number needed to screen to prevent one event of 183 (95%CI: 172 to 203). S-SCORE increased costs per subject by 187€ (95%CI: 177 € to 196 €), leading to an ICER of 27,440€/QALY gained. Sensitivity analysis was p

Introduction: Risk stratification scores such as the European Systematic COronary Risk Evaluation (SCORE) are used to guide individuals on cardiovascular disease (CVD) prevention. Adding high-sensitivity troponin I (hsTnI) to such risk scores has the potential to improve accuracy of CVD prediction. We investigated how applying hsTnI in addition to SCORE may impact management, outcome, and cost-effectiveness. Methods: Characteristics of 72,190 apparently healthy individuals from the Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project were included into a discrete-event simulation comparing two strategies for assessing CVD risk. The standard strategy reflecting current practice employed SCORE (SCORE); the alternative strategy involved adding hsTnI information for further stratifying SCORE risk categories (S-SCORE). Individuals were followed over ten years from baseline examination to CVD event, death or end of follow-up. The model tracked the occurrence of events and calculated direct costs of screening, prevention, and treatment from a European health system perspective. Cost-effectiveness was expressed as incremental cost-effectiveness ratio (ICER) in € per quality-adjusted life year (QALYs) gained during 10 years of follow-up. Outputs were validated against observed rates, and results were tested in deterministic and probabilistic sensitivity analyses. Results: S-SCORE yielded a change in management for 10.0% of individuals, and a reduction in CVD events (4.85% vs. 5.38%, p<0.001) and mortality (6.80% vs. 7.04%, p<0.001). S-SCORE led to 23 (95%CI: 20–26) additional event-free years and 7 (95%CI: 5–9) additional QALYs per 1,000 subjects screened, and resulted in a relative risk reduction for CVD of 9.9% (95%CI: 7.3–13.5%) with a number needed to screen to prevent one event of 183 (95%CI: 172 to 203). S-SCORE increased costs per subject by 187€ (95%CI: 177 € to 196 €), leading to an ICER of 27,440€/QALY gained. Sensitivity analysis was p

Clinical and neuroimaging data has been increasingly used in recent years to disentangle heterogeneity of treatment response to cognitive training (CT) and predict which individuals may achieve the highest benefits. CT has small to medium effects on improving cognitive and social functioning in recent onset psychosis (ROP) patients, who show the most profound cognitive and social functioning deficits among psychiatric patients. We employed multivariate pattern analysis (MVPA) to investigate the potential of cognitive data to predict social functioning improvement in response to 10 h of CT in patients with ROP. A support vector machine (SVM) classifier was trained on the naturalistic data of the Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study sample to predict functioning in an independent sample of 70 ROP patients using baseline cognitive data. PRONIA is a part of a FP7 EU grant program that involved 7 sites across 5 European countries, designed and conducted with the main aim of identifying (bio)markers associated with an enhanced risk of developing psychosis in order to improve early detection and prognosis. Social functioning was predicted with a balanced accuracy (BAC) of 66.4% (Sensitivity 78.8%; Specificity 54.1%; PPV 60.5%; NPV 74.1%; AUC 0.64; P = 0.01). The most frequently selected cognitive features (mean feature weights > ± 0.2) included the (1) correct number of symbol matchings within the Digit Symbol Substitution Test, (2) the number of distracting stimuli leading to an error within 300 and 200 trials in the Continuous Performance Test and (3) the dynamics of verbal fluency between 15 and 30 s within the Verbal Fluency Test, phonetic part. Next, the SVM classifier generated on the PRONIA sample was applied to the intervention sample, that obtained 54 ROP patients who were randomly assigned to a social cognitive training (SCT) or treatment as usual (TAU) group and dichotomized into good (GF-S ≥ 7) and poor (GF-S < 7) function

BACKGROUND: Chronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes, reflecting a potential transdiagnostic dimension. Previous investigations have focused on distinct illness categories in people with enduring illness, but few have explored inflammatory changes. We sought to identify an inflammatory signal and the associated brain function underlying anhedonia among young people with recent-onset psychosis and recent-onset depression. METHODS: Resting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from 108 (mean [SD] age = 26.2 [6.2] years; female = 50) participants with recent-onset psychosis (n = 53) and recent-onset depression (n = 55) from the European Union/Seventh Framework Programme-funded PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Time series were extracted using the Schaefer atlas, defining 100 cortical regions of interest. Using advanced multimodal machine learning, an inflammatory marker model and a functional connectivity model were developed to classify participants into an anhedonic group or a normal hedonic group. RESULTS: A repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic recent-onset psychosis/recent-onset depression groups with a balanced accuracy of 63.9% and an area under the curve of 0.61. The functional connectivity model produced a balanced accuracy of 55.2% and an area under the curve of 0.57. Anhedonic group assignment was driven by higher levels of interleukin 6, S100B, and interleukin 1 receptor antagonist and lower levels of interferon gamma, in addition to connectivity within the precuneus and posterior cingulate. CONCLUSIONS: We identified a potential transdiagnostic anhedonic subtype that was accounted for by an inflammatory profile and functional connectivity. Results have implications

BACKGROUND: Patients with psychosis and patients with depression exhibit widespread neurobiological abnormalities. The analysis of dynamic functional connectivity (dFC) allows for the detection of changes in complex brain activity patterns, providing insights into common and unique processes underlying these disorders. METHODS: We report the analysis of dFC in a large sample including 127 patients at clinical high risk for psychosis, 142 patients with recent-onset psychosis, 134 patients with recent-onset depression, and 256 healthy control participants. A sliding window-based technique was used to calculate the time-dependent FC in resting-state magnetic resonance imaging data, followed by clustering to reveal recurrent FC states in each diagnostic group. RESULTS: We identified 5 unique FC states, which could be identified in all groups with high consistency (mean r = 0.889 [SD = 0.116]). Analysis of dynamic parameters of these states showed a characteristic increase in the lifetime and frequency of a weakly connected FC state in patients with recent-onset depression (p < .0005) compared with the other groups and a common increase in the lifetime of an FC state characterized by high sensorimotor and cingulo-opercular connectivities in all patient groups compared with the healthy control group (p < .0002). Canonical correlation analysis revealed a mode that exhibited significant correlations between dFC parameters and clinical variables (r = 0.617, p < .0029), which was associated with positive psychosis symptom severity and several dFC parameters. CONCLUSIONS: Our findings indicate diagnosis-specific alterations of dFC and underline the potential of dynamic analysis to characterize disorders such as depression and psychosis and clinical risk states.

Despite their apparent benevolence, positive stereotypes have negative effects on person and group perception. However, little is known about how exposure can intensify these negative consequences. In two pre-registered experiments (total N = 240) we investigated the effect of exposure on believability and moral condemnation of positive stereotypes. In Experiment 1, participants rated the truth value of positive stereotypes, which were either previously encountered or not during an exposure phase. Repeated positive stereotypes were perceived as more true than unrepeated ones, indicating a truth effect. In Experiment 2, we replicated the truth effect and further found that exposure to stereotypes reduced their moral condemnation, indicating a moral-repetition effect. Extending the truth effect and moral-repetition effect research to positive stereotypes, our findings emphasize the need to raise awareness of the impact of exposure on reinforcing the believability and moral condemnation of stereotypical beliefs.

Una delle grandi questioni che maggiormente preoccupano i nostri giovani – soprattutto al termine di un percorso di laurea o di master quando, dopo anni di sacrifici, desiderano con tutto se stessi dare avvio a un proprio curriculum professionale – è come valorizzare le relazioni intessute durante gli studi, in vista di un ingresso qualificato nel mondo del lavoro. Ci siamo affacciati con questa domanda al vastissimo tema del networking. In primis: per una passione educativa, un’attenzione verso i nostri studenti, interessati - come siamo - ad accompagnare i giovani che scelgono il nostro Ateneo nella grande avventura di conoscenza, dal momento dell’immatricolazione all’entrata nel più complesso ambito lavorativo e oltre. In secondo luogo, perché parlare di networking non è diverso dal riferirsi a una dimensione comunitaria dell’esistenza, soprattutto nell’affrontare le tappe più significative della vita, come per esempio la ricerca di un lavoro, o lo sviluppo di una professione. E l’università si ritrova nel proprio DNA questa funzione comunitaria, essendo oltretutto inserita in un più ampio contesto sociale, economico, culturale, che la considera come uno dei principali attori protagonisti del cambiamento.

Judgements of trustworthiness based on facial features have mainly been investigated by presenting faces in isolation. However, real-life situations often involve contextual cues. Here, we review our work showing that judgements of trustworthiness from faces are influenced by contextual threat. Individuals are judged as less trustworthy when their faces are surrounded by threatening, as opposed to neutral or merely negative, contexts. Delving into the mechanisms underlying face-context integration, our work reveals that the bond between trustworthiness and threat goes beyond mere stimuli congruency, suggesting that threatening contexts alter person evaluation by conveying information of adaptive significance. We propose an inferential approach to face-context integration, where faces and contexts are encoded relationally: modifying this relational encoding, via verbal or emotional cues, results in changes in face-context integration. We conclude by outlining the significance of embracing the impact of contextual cues in shaping impressions from faces.

The rise of far-right parties with antifeminist sentiments constitutes a new challenge in the path to gender equality. Here, we aim to identify strategies to promote men’s acceptance of social change towards equality. Thus, we first examined key concerns about gender equality held by far-right supporters through a discourse analysis of 120 men. The findings revealed a focus on male victimhood, the negation and only partial recognition of inequality, and the delegitimization of feminism. Given the centrality of victimhood in the discourse of far-right male supporters and its social relevance, we developed several non-confrontational strategies based on men’s suffering and supposed (im)morality, and then compared the effectiveness of these strategies for getting men to commit more to gender equality. Two experimental studies (n = 417 and 428 men) revealed that recognizing that men are generally moral or that they also suffer because of gender stereotypes led participants to increase their willingness to participate in collective action for women’s rights. In contrast, questioning their morality by denouncing men’s violence against women had no impact on their intentions. We conclude that non-confrontational strategies that address men's concerns about feminist advancement can prevent potential defensive reactions and make them more receptive to social change towards gender equality.

Nostalgia is a social, self-relevant, and bittersweet (although mostly positive) emotion that arises when reflecting on fond past memories and serves key psychological functions. The majority of evidence concerning the prevalence, triggers, and functions of nostalgia has been amassed in samples from a handful of largely Western cultures. If nostalgia is a fundamental psychological resource, it should perform similar functions across cultures, although its operational dynamics may be shaped by culture. This study (N=2,606) examined dispositional nostalgia, self-reported triggers of nostalgia, and functions of experimentally induced nostalgia in young adults across 28 countries and a special administrative region of China (i.e., Hong Kong). Results indicated that nostalgia is frequently experienced across cultures, albeit better valued in more-developed countries (i.e., higher national wealth and life-expectancy). Nostalgia is triggered by psychological threats (especially in warmer countries), sensory stimuli (especially in more-developed countries), and social gatherings (especially in less-developed countries). The positive or negative affect prompted by experimentally induced nostalgia varied by country, but was mild overall. More importantly, recalling a nostalgic (vs. ordinary) memory increased social connectedness, self-continuity, and meaning in life across cultures. In less-developed countries, recalling an ordinary memory also conferred some of these functions, reducing the effect size of nostalgia. Finally, recalling a nostalgic (vs. ordinary) memory augmented state satisfaction with life in countries with lower quality of living (i.e., lower life-expectancy and life-satisfaction). Overall, findings confirm the relevance of nostalgia across a wide range of cultures and indicate cultural nuances in its functioning.

The article presents the Manifesto “Una scuola” (2014, 2018), proposing a comparison with the school of Barbiana, 100 years after the birth of Don Lorenzo Milani, and the coeval Manifesto of Avanguardie Educative (Indire). In particular, through the five key dimensions of the Manifesto “Una scuola” (Encounters, Contexts, Styles, Possibilities, Languages), an analysis is conducted of the challenges shared by the school of the 1960s and the contemporary school in order to rethink the school of today and tomorrow in an innovative way.

Purpose: Although dalbavancin is currently approved for the treatment of ABSSIs, several studies suggest its efficacy and tolerance as long-term therapy for other off-label indications requiring prolonged intravenous antibiotic administration. Methods: We conducted a prospective nationwide study of dalbavancin use in real-life settings for both approved and off-label indications analysing for each case the clinical and microbiological characteristics of infection the efficacy and safety of treatments. Results: During the study period (from December 2018 to July 2021), the ID specialists from 14 different centres enrolled 223 patients treated with dalbavancin [141 males (63%) and 82 females (37%); male/female ratio 1.72; mean age 59 (SD 17.2) years, (range 15–96). Most patients in the study population (136/223; 61.0%) came from community rather than health care facilities and most of them were visited in Infectious Diseases wards (93/223; 41.7%) and clinics (55/223; 24.7%) even though some patients were cured in other settings, such as surgery wards (18/223; 8.1%), orthopaedic wards (11/223; 4.9%), Emergency Rooms (7/223; 3.1%) and non-surgical other than ID wards (6/223; 2.7%). The most common ID diagnoses were osteomyelitis (44 cases/223; 19.7%; of which 29 acute and 15 chronic osteomyelitis), cellulitis (28/223; 12.5%), cutaneous abscess (23/223; 10.3%), orthopaedic prosthesis-associated infection (22/223; 9.9%), surgical site infection (20/223; 9.0%) and septic arthritis (15/223; 6.7%). Conclusion: In conclusion, by virtue of its PK/PD properties, dalbavancin represents a valuable option to daily in-hospital intravenous or outpatient antimicrobial regimens also for off-label indications requiring a long-term treatment of Gram-positive infections.

Optical sensors and sensing technologies are playing a more and more important role in our modern world. From micro-probes to large devices used in such diverse areas like medical diagnosis, defence, monitoring of industrial and environmental conditions, optics can be used in a variety of ways to achieve compact, low cost, stand-off sensing with extreme sensitivity and selectivity. Actually, the challenges to the design and functioning of an optical sensor for a particular application requires intimate knowledge of the optical, material, and environmental properties that can affect its performance. This roadmap on optical sensors addresses different technologies and application areas. It is constituted by twelve contributions authored by world-leading experts, providing insight into the current state-of-the-art and the challenges their respective fields face. Two articles address the area of optical fibre sensors, encompassing both conventional and specialty optical fibres. Several other articles are dedicated to laser-based sensors, micro- and nano-engineered sensors, whispering-gallery mode and plasmonic sensors. The use of optical sensors in chemical, biological and biomedical areas is discussed in some other papers. Different approaches required to satisfy applications at visible, infrared and THz spectral regions are also discussed.

Optical sensors and sensing technologies are playing a more and more important role in our modern world. From micro-probes to large devices used in such diverse areas like medical diagnosis, defence, monitoring of industrial and environmental conditions, optics can be used in a variety of ways to achieve compact, low cost, stand-off sensing with extreme sensitivity and selectivity. Actually, the challenges to the design and functioning of an optical sensor for a particular application requires intimate knowledge of the optical, material, and environmental properties that can affect its performance. This roadmap on optical sensors addresses different technologies and application areas. It is constituted by twelve contributions authored by world-leading experts, providing insight into the current state-of-the-art and the challenges their respective fields face. Two articles address the area of optical fibre sensors, encompassing both conventional and specialty optical fibres. Several other articles are dedicated to laser-based sensors, micro- and nano-engineered sensors, whispering-gallery mode and plasmonic sensors. The use of optical sensors in chemical, biological and biomedical areas is discussed in some other papers. Different approaches required to satisfy applications at visible, infrared and THz spectral regions are also discussed.

Laura Brambilla,1 Valeria Frangione,2 Marisa Meloni1 1VitroScreen, in vitro Research Laboratory, Milan, Italy; 2IBSA Institut Biochimique SA, Pambio-Noranco, SwitzerlandCorrespondence: Marisa Meloni, VitroScreen, Via Mosè Bianchi, 103, Milan, 20149, Italy, Tel +39 02 89077608, Email marisa.meloni@vitroscreen.comPurpose: Medical Device Regulation (EU) 2017/745 requires the principal mode of action (MoA) to be demonstrated by experimental data. The MoA of Ialuril® Prefill (combined as HA+CS+CaCl2: sodium hyaluronate 1.6%, sodium chondroitin sulphate 2% w/v and calcium chloride 0.87%) Class III medical device, indicated for intravesical instillation to reduce urinary tract infections, has been evaluated on a 3D reconstructed human bladder epithelium (HBE).Methods: Three experimental designs; i) E. coli strain selection (DSM 103538, DSM 1103) to investigate the HA+CS+CaCl2 properties in modifying bacterial growth in liquid broth (CFU 4h and 24h) at 80%, 50% and 25% concentrations; ii) evaluation of film forming properties on HBE after 15 min exposure by quantifying caffeine permeation across the epithelium; iii) capacity to counteract E. coli adhesion and biofilm formation on colonized HBE by viable counts and ultrastructural analysis by scanning electron microscopy (SEM) using ciprofloxacin as the reference antimicrobial molecule.Results: No significant differences were observed in bacterial viability for both the E. coli strains. HA+CS+CaCl2 reduced caffeine permeation of 51.7% and 38.1% at 1h and 2h, respectively and determined a significant decrease in caffeine permeation rate at both timepoints supporting HA+CS+CaCl2 capacity to firmly adhere to the bladder epithelium creating a physical barrier on the surface. The viable counts in HBE treated tissues then infected with E. coli resulted not different from the negative control suggesting that the device did not inhibit E. coli growth. SEM images showed homogenous product distribution over the HBE surface and confi

It is commonly thought that the biodiversity crisis includes widespread declines in the spatial variation of species composition, called biotic homogenization. Using a typology relating homogenization and differentiation to local and regional diversity changes, we synthesize patterns across 461 metacommunities surveyed for 10 to 91 years, and 64 species checklists (13 to 500+ years). Across all datasets, we found that no change was the most common outcome, but with many instances of homogenization and differentiation. A weak homogenizing trend of a 0.3% increase in species shared among communities/year on average was driven by increased numbers of widespread (high occupancy) species and strongly associated with checklist data that have longer durations and large spatial scales. At smaller spatial and temporal scales, we show that homogenization and differentiation can be driven by changes in the number and spatial distributions of both rare and common species. The multiscale perspective introduced here can help identify scale-dependent drivers underpinning biotic differentiation and homogenization.

It is commonly thought that the biodiversity crisis includes widespread declines in the spatial variation of species composition, called biotic homogenization. Using a typology relating homogenization and differentiation to local and regional diversity changes, we synthesize patterns across 461 metacommunities surveyed for 10 to 91 years, and 64 species checklists (13 to 500+ years). Across all datasets, we found that no change was the most common outcome, but with many instances of homogenization and differentiation. A weak homogenizing trend of a 0.3% increase in species shared among communities/year on average was driven by increased numbers of widespread (high occupancy) species and strongly associated with checklist data that have longer durations and large spatial scales. At smaller spatial and temporal scales, we show that homogenization and differentiation can be driven by changes in the number and spatial distributions of both rare and common species. The multiscale perspective introduced here can help identify scale-dependent drivers underpinning biotic differentiation and homogenization.

BACKGROUND: BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities. METHODS: The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology. DISCUSSION: BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accura, Study Protocol.Funded by the Joint Transnational Call for Proposals (JTC) 2022 on "Prevention in Personalised Medicine " within the framework of ERA PerMed, ERAPERMED2022-087—BIPCOM. This project was supported by: 1. Fondazione Regionale per la Ricerca Biomedica (Italy); 2. Bundesministerium für Bildung und Forschung (Germany); 3. VINNOVA (Sweden); 4. Norges Forskningsråd (Norway); 5. Agence Nationale de la Recherche (France); 6. Departament de Salut, Generalitat de Catalunya (Spain); 7. Sächsisches Staatsministerium für Wissenschaft und Kunst (Germany); under the frame of ERA PerMed.

For non-relativistic thermal dark matter, close-to-threshold effects largely dominate the evolution of the number density for most of the times after thermal freeze-out, and hence affect the cosmological relic density. A precise evaluation of the relevant interaction rates in a thermal medium representing the early universe includes accounting for the relative motion of the dark matter particles and the thermal medium. We consider a model of dark fermions interacting with a plasma of dark gauge bosons, which is equivalent to thermal QED. The temperature is taken to be smaller than the dark fermion mass and the inverse of the typical size of the dark fermion-antifermion bound states, which allows for the use of non-relativistic effective field theories. For the annihilation cross section, bound-state formation cross section, bound-state dissociation width and bound-state transition width of dark matter fermion-antifermion pairs, we compute the leading recoil effects in the reference frame of both the plasma and the center-of-mass of the fermion-antifermion pair. We explicitly verify the Lorentz transformations among these quantities. We evaluate the impact of the recoil corrections on the dark matter energy density. Our results can be directly applied to account for the relative motion of quarkonia in the quark-gluon plasma formed in heavy-ion collisions. They may be also used to precisely assess thermal effects in atomic clocks based on atomic transitions; the present work provides a first field theory derivation of time dilation for these processes in vacuum and in a medium., Comment: 52 pages, 9 figures

Monitoring population dynamics is of fundamental importance in conservation but assessing trends in abundance can be costly, especially in large and rough areas. Obtaining trend estimations from counts performed in only a portion of the total area (sample counts) can be a cost‐effective method to improve the monitoring and conservation of species difficult to count.We tested the effectiveness of sample counts in monitoring population trends of wild animals, using as a model population the Alpine ibex Capra ibex in the Gran Paradiso National Park (Italy), both with computer simulations and using historical count data collected over the last 65 years. Despite sample counts failed to correctly estimate the true population abundance, sampling half of the target area could reliably monitor the trend of the target population. In case of strong changes in abundance, an even lower proportion of the total area could be sufficient to identify the direction of the population trend. However, when there is a high yearly trend variability, the required number of samples increases and even counting in the entire area can be ineffective to detect population trends. The effect of other parameters, such as which portion of the area is sampled and detectability, was lower, but these should be tested case by case.Sample counts could therefore constitute a viable alternative to assess population trends, allowing for important, cost‐effective improvements in the monitoring of wild animals of conservation interest.

Cellulose nanocrystals (CNCs) are cellulose-derived nanomaterials that can be easily obtained, e.g., from vegetable waste produced by circular economies. They show promising antimicrobial activity and an absence of side effects and toxicity. This study investigated the ability of CNCs to reduce microbial adherence and biofilm formation using in vitro microbiological models reproducing the oral environment. Microbial adherence by microbial strains of oral interest, Streptococcus mutans and Candida albicans, was evaluated on the surfaces of salivary pellicle-coated enamel disks in the presence of different aqueous solutions of CNCs. The anti-biofilm activity of the same CNC solutions was tested against S. mutans and an oral microcosm model based on mixed plaque inoculum using a continuous-flow bioreactor. Results showed the excellent anti-adherent activity of the CNCs against the tested strains from the lowest concentration tested (0.032 wt. %, p < 0.001). Such activity was significantly higher against S. mutans than against C. albicans (p < 0.01), suggesting a selective anti-adherent activity against pathogenic strains. At the same time, there was a minimal, albeit significant, anti-biofilm activity (0.5 and 4 wt. % CNC solution for S. mutans and oral microcosm, respectively, p = 0.01). This makes CNCs particularly interesting as anticaries agents, encouraging their use in the oral field.

This article presents a literature review, encompassing a scoping review, and a narrative review within the broader context of game studies. Inside a project focused on Classcraft in Italian secondary school, the aim is to answer the research question: Are the students actually playing while they are using a gamified system? Our review reveals a multitude of definitions especially related to gamification in educational contexts, reflecting the complexity and evolving nature of the field. The two different levels of review serve to filter and organize the myriad definitions in the literature. The implications extend to the design and implementation of educational technologies, emphasizing the need for clarity to enhance project themes. This article contributes to the discourse surrounding gamified learning, guiding future research and the application of game elements in educational settings.

Background and Aims Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. Methods Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). Results Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23–1.72) and 1.48 (1.23–1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03–1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98–1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). Conclusions While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds., Background and Aims Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. Methods Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). Results Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). Conclusions While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.

Background: Mitral transcatheter edge-to-edge repair (M-TEER) is a guideline-recommended treatment option for patients with severe symptomatic mitral regurgitation (MR). Outcomes with the PASCAL system in a post-market setting have not been established. Objectives: The authors report 30-day and 1-year outcomes from the MiCLASP (Transcatheter Repair of Mitral Regurgitation with Edwards PASCAL Transcatheter Valve Repair System) European post-market clinical follow-up study. Methods: Patients with symptomatic, clinically significant MR were prospectively enrolled. The primary safety endpoint was clinical events committee–adjudicated 30-day composite major adverse event rate and the primary effectiveness endpoint was echocardiographic core laboratory–assessed MR severity at discharge compared with baseline. Clinical, echocardiographic, functional, and quality-of-life outcomes were assessed at 1 year. Results: A total of 544 patients were enrolled (59% functional MR, 30% degenerative MR). The 30-day composite major adverse event rate was 6.8%. MR reduction was significant from baseline to discharge and sustained at 1 year with 98% of patients achieving MR ≤2+ and 82.6% MR ≤1+ (all P < 0.001 vs baseline). One-year Kaplan-Meier estimate for survival was 87.3%, and freedom from heart failure hospitalization was 84.3%. Significant functional and quality-of-life improvements were observed at 1 year, including 71.6% in NYHA functional class I/II, 14.4-point increase in Kansas City Cardiomyopathy Questionnaire score, and 24.2-m improvement in 6-minute walk distance (all P < 0.001 vs baseline). Conclusions: One-year outcomes of this large cohort from the MiCLASP study demonstrate continued safety and effectiveness of M-TEER with the PASCAL system in a post-market setting. Results demonstrate high survival and freedom from heart failure hospitalization, significant and sustained MR reduction, and improvements in symptoms, functional capacity, and quality of life.

The rising number of objects in low Earth orbit heightens the likelihood of orbital debris impact on spacecrafts at an increasingly fast pace. Thus, the need for lightweight shielding from hypervelocity impacts has grown considerably. Direct observation of hypervelocity impacts are almost impossible and experimental campaigns are expensive, and so numerical simulation has become a fundamental tool for hypervelocity impact modelling. These simulations involve multiple coupled physics mechanism, including fragmentation and stress waves propagation. While various simulation techniques exist for this problem, none effectively capture the interaction between fragmentation and stress wave propagation within the velocity range relevant to orbital impacts while being suitable for modelling of full-scale satellite fragmentation events. The objective of this thesis is to address this limitation by proposing an approach for a fragmentation framework based the Discontinuous Galerkin/Cohesive Zone Method finite element formulation and the Decomposition Contact Response contact algorithm., Aerospace Engineering

We compute the suppression of bottomonium in the quark-gluon plasma using the three-loop QCD static potential. The potential describes the spin-averaged bottomonium spectrum below threshold with a less than 1% error. Within potential nonrelativistic quantum chromodynamics and an open quantum systems framework, we compute the evolution of the bottomonium density matrix. The values of the quarkonium transport coefficients are obtained from lattice QCD measurements of the bottomonium in-medium width and thermal mass shift; we additionally include for the first time a vacuum contribution to the dispersive coefficient ${\gamma}$. Using the three-loop potential and the values of the heavy quarkonium transport coefficients, we find that the resulting bottomonium nuclear modification factor is consistent with experimental observations, while at the same time reproducing the lattice measurements of the in-medium width., Comment: 15 pages, 3 figures, 1 table

Transparency and explainability in image classification are essential for establishing trust in machine learning models and detecting biases and errors. State-of-the-art explainability methods generate saliency maps to show where a specific class is identified, without providing a detailed explanation of the model's decision process. Striving to address such a need, we introduce a post-hoc method that explains the entire feature extraction process of a Convolutional Neural Network. These explanations include a layer-wise representation of the features the model extracts from the input. Such features are represented as saliency maps generated by clustering and merging similar feature maps, to which we associate a weight derived by generalizing Grad-CAM for the proposed methodology. To further enhance these explanations, we include a set of textual labels collected through a gamified crowdsourcing activity and processed using NLP techniques and Sentence-BERT. Finally, we show an approach to generate global explanations by aggregating labels across multiple images., Comment: International Joint Conference on Artificial Intelligence 2024 (to be published)