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Abstract To minimize the toxicity and impact of combined antiretroviral therapy (cART) on the lifestyle of people living with Human Immunodeficiency Virus (PLWH), scientific community evaluated the efficacy, safety and sustained virologic response of two drugs antiretroviral regimens, in particular dolutegravir (DTG). The effects of deintensification therapy on inflammatory settings are currently unknown in PLWH. Thus, our study explored the inflammatory state in virologically suppressed HIV individuals between patients in treatment with a DTG-containing dual therapy (2DR) versus triple regimen therapies (3DR). We enrolled a total of 116 subjects in 2DRs or 3DRs regimens, and the plasma levels of pro- and anti-inflammatory cytokines (in particular IL-1β, IL-10, IL-18, IL-33, IL-36 and IFN-γ) have been evaluated. CD4 + cell’s median value was 729.0 cell/µL in the 3DR group and 771.5 cell/µL in 2DR group; the viral load was negative in all patients. Significant differences were found in levels of IL-18 (648.8 cell/µL in 3DR group vs. 475.0 cell/µL in 2DR group, p = 0.034) and IL-36 (281.7 cell/µL in 3DR group vs. 247.0 cell/µL in 2DR group, p = 0.050), and a correlation between IL-18 and IL-36 was found in 3DR group (rho = 0.266, p = 0.015). This single-center retrospective pharmacological study confirms the absence of significant differences in IL-1β, IL-10, IL-33, and IFN-γ levels between patients on two-drug antiretroviral regimens compared to patients on 3DR antiretroviral regimens. Patients in 2DR show greater control over IL-18 and IL-36 serum levels, cytokines related to an increased cardiovascular risk and development of age-related chronic diseases. Based on our results, we suggest that DTG-based 2DR antiretroviral regimens could be associated with better control of the chronic inflammation that characterizes the population living with HIV in effective ART.

Abstract Background Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods In this study, 382 infants born at 24+0–27+6 weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. The secondary outcomes are BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0–27+6 weeks’ gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks’ postmenstrual age of life. Trial registration ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Abstract Background SMYD3 has been found implicated in cancer progression. Its overexpression correlates with cancer growth and invasion, especially in gastrointestinal tumors. SMYD3 transactivates multiple oncogenic mechanisms, favoring cancer development. Moreover, it was recently shown that SMYD3 is required for DNA restoration by promoting homologous recombination (HR) repair. Methods In cellulo and in vivo models were employed to investigate the role of SMYD3 in cancer chemoresistance. Analyses of SMYD3-KO cells, drug-resistant cancer cell lines, patients’ residual gastric or rectal tumors that were resected after neoadjuvant therapy and mice models were performed. In addition, the novel SMYD3 covalent inhibitor EM127 was used to evaluate the impact of manipulating SMYD3 activity on the sensitization of cancer cell lines, tumorspheres and cancer murine models to chemotherapeutics (CHTs). Results Here we report that SMYD3 mediates cancer cell sensitivity to CHTs. Indeed, cancer cells lacking SMYD3 functions showed increased responsiveness to CHTs, while restoring its expression promoted chemoresistance. Specifically, SMYD3 is essential for the repair of CHT-induced double-strand breaks as it methylates the upstream sensor ATM and allows HR cascade propagation through CHK2 and p53 phosphorylation, thereby promoting cancer cell survival. SMYD3 inhibition with the novel compound EM127 showed a synergistic effect with CHTs in colorectal, gastric, and breast cancer cells, tumorspheres, and preclinical colorectal cancer models. Conclusions Overall, our results show that targeting SMYD3 may be an effective therapeutic strategy to overcome chemoresistance.

Introduction: Multicentric Castleman’s disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman’s disease (CD) is usually a challenge, especially in case of cutaneous involvement. Case Presentation: We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. Conclusion: We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings.

Abstract Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

Background Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).Patients and methods Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab.Results In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.Conclusions Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.Trial registration number NCT03668119.

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

For decades, the evolutionary role of melanism in reptiles has been highly debated. According to the thermal melanism hypothesis, melanistic phenotypes should provide thermal advantages, thus positively impacting various biological aspects of these individuals. Nevertheless, these benefits seem to be countered by environmental constraints and predatory pressure. Here, we mapped for the first time the distribution of the melanistic phenotypes in the highly polymorphic asp viper (Vipera aspis). We focused our research effort on the Italian peninsula, where this species reaches its highest level of taxonomic diversity with three currently described subspecies. Furthermore, we investigated via bioclimatic niche modelling, the influence of a wide array of bioclimatic variables on the distribution of melanism in Italian asp vipers. In general, our results seem to support the implications of the thermal melanism hypothesis, highlighting the central influence of mean annual temperature and elevation on the geographic distribution of melanistic V. aspis. At the finest scale, our analyses have highlighted a distinction in bioclimatic niches among the three assessed subspecies. However, further fine-scale investigations are needed in order to exclude the potential influence of latitude and elevation on the observed the intersubspecific bioclimatic niche segregation pattern.

BackgroundImage and Performance-Enhancing Drugs (IPEDs) can enhance mental and physical capabilities and impact one’s overall health. Initially confined in sport environments, IPEDs use has become increasingly widespread in a high-performing society. The present study was aimed at profiling IPEDs use during the COVID-19 lockdown among an international sample of young adults.MethodsA cross-sectional observational study was carried out in eight countries (United Kingdom, Italy, Lithuania, Hungary, Portugal, Spain, Brazil, and Japan) between April and May 2020. The survey questionnaire included validated measurements such as Exercise Addiction Inventory (EAI), Appearance Anxiety Inventory (AAI), and Self-Compassion Scale (SCS) as well as questions about the type of IPEDs, purchasing methods and socio-demographic information.ResultsA total of 736 IPEDs users were included in the survey. Their mean age was 33.05 years (±SD = 10.06), and 64.2% were female participants. Overall, 6.8% were found at risk of exercise addiction (EAI >24), 27.6% presented high levels of appearance anxiety, and 24.9% revealed low levels of emotional regulation’s self-compassion. Most participants (55.6%) purchased IPEDs through pharmacies/specialized shops, while 41.3% purchased IPEDs on the Internet. Online IPEDs buyers were mainly men who had higher scores on the Exercise Addiction Inventory. One or more IPEDs classifiable as “potentially risky” were used by 66.3% of the sample. Users of “potentially risky IPEDs” were younger and primarily men. They showed higher scores both on the Exercise Addiction Inventory and Appearance Anxiety Inventory.ConclusionThis study profiled users of IPEDs when the most restrictive COVID-19 lockdown policies were implemented in all the participating countries. More targeted post-COVID 19 prevention strategies should be implemented according to the emerged socio-demographic and psychopathological traits and cross-cultural differences emerged. Longitudinal studies will also be needed to determine the long-term effect of the COVID-19 lockdown on IPEDs consumption.

When Calvino died, he was at work on the Harvard lectures, which remained incomplete. This incompleteness leads one to realize that  Lezioni americane is in fact a work in Italian that Calvino never really imagined, nor actually wrote. An apocryphal book of sorts, of which only an original nucleus is left that tells us about his idea of literature as reflected in his library of similarly apocryphal books; hidden books that preside over and inspire the process of writing. What remains of the planned lectures are various layers of sunken work, an underground archive of notebooks, handwritten notes, typescripts sent out to be translated only to be written over and reworked. There are also traces of previous stages of Calvino’s study of the books he utilized, annotated and commented, and reused to write the lectures.This is, however, the first time that Calvino takes the measure of his entire mental library in order to recount his idea of literature and offer mirror images of himself as writer and reader through the paths of his memory and poetic imaginary. For the first time, Calvino looks for himself systematically among the books of his library, both mental and real, and searches for his place in the frame that holds together six ideal shelves. These ideal shelves are reflections of images of himself and of an idea of literature whereby all forms of knowledge arise from anomalies hidden in the great library of the world. Through new insights based on research conducted in Calvino’s personal archives and his library (preserved in the writer’s house in Rome’s Campo Marzio until the death of Esther Calvino), this article presents a reading of Calvino’s Norton Lectures as a tale about the idea of an apocryphal library, or, in other words, a hidden library, which may be the originary secret of his work.

Abstract In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade. Trial registration: NCT02460224. Registered 02/06/2015.

Objective: Prostate cancer (PCa) patients might experience lower urinary tract symptoms as those diagnosed with benign prostatic hyperplasia (BPH). Some of them might be treated for their lower urinary tract symptoms instead of PCa. We aimed to test the effect of PCa versus BPH on surgical outcomes after transurethral prostate surgery, namely complication and mortality rates. Methods: Within the American College of Surgeons National Surgical Quality Improvement Program database (2011–2016), we identified patients who underwent transurethral resection of the prostate, photoselective vaporization, or laser enucleation. Patients were stratified according to postoperative diagnosis (PCa vs. BPH). Univariable and multivariable logistic regression models evaluated the predictors of perioperative morbidity and mortality. A formal test of interaction between diagnosis and surgical technique used was performed. Results: Overall, 34 542 patients were included. Of all, 2008 (5.8%) had a diagnosis of PCa. The multivariable logistic regression model failed to show statistically significant higher rates of postoperative complications in PCa patients (odds ratio: 0.9, 95% confidence interval: 0.7–1.1; p=0.252). Moreover, similar rates of perioperative mortality (p=0.255), major acute cardiovascular events (p=0.581), transfusions (p=0.933), and length of stay of more than or equal to 30 days (p=0.174) were found. Additionally, all tests failed to show an interaction between post-operative diagnosis and surgical technique used. Conclusion: Patients diagnosed with PCa do not experience higher perioperative morbidity or mortality after transurethral prostate surgery when compared to their BPH counterparts. Moreover, the diagnosis seems to not influence surgical technique outcomes.

Abstract Animal models have demonstrated that structural changes affect the macula during peripheral rhegmatogenous retinal detachment. This study aimed to assess photoreceptors, retinal and choriocapillaris perfusion in non-macula involving rhegmatogenous retinal detachment by analyzing en-face images from structural OCTA segmented at the ellipsoid zone (EZ) level, calculating (1) “normalized” reflectivity as a surrogate biomarker of photoreceptor damage (2) perfusion density (PD), vessel length density (VLD) and vessel diameter index (VDI) of superficial capillary plexus (SCP) and deep capillary plexus (DCP) (3) perfusion density of choriocapillaris (PDCC). Twenty-one eyes affected by macula-on rhegmatogenous retinal detachment (RRD) were enrolled at the University “G. d’Annunzio”, Chieti-Pescara. The fellow unaffected eye was used as control. The mean age at the onset of RRD was 60.09 ± 10.22 (range 34–83). Compared with fellow eyes, we found lower EZ “normalized” reflectivity in macula-on (0.42 ± 0.15 in fellow eyes and 0.31 ± 0.09 in macula on p = 0.004). The affected eye was also characterized by impaired perfusion in SCP (17.26 ± 3.34% in macula on and 20.56 ± 3.62% in the fellow eye p = 0.004) and CC (50.21 ± 6.20% in macula on the eye and 57.43 ± 6.20% in the fellow eye p = 0.004). Macula-on rhegmatogenous retinal detachment has subclinical changes in photoreceptors, SCP, and CC. Future longitudinal studies should evaluate if early changes could impact post-operative macular function.

Abstract Introduction We conducted a cross-sectional study to compare macular pigment optical density (MPOD) in eyes with idiopathic macular holes with bumpy (bbMH) and smooth borders (sbMH) and to assess the relation between MPOD and optical coherence tomography findings. Thirty eyes from thirty patients affected by idiopathic macular hole were studied. Methods All patients underwent SD-OCT and macular pigment optical density (MPOD) analysis. Comparison between the two border phenotypes were estimated at baseline, as well as the differences in MPOD, minimum and basal hole diameter, tractional hole index (THI), macular hole index (MHI), diameter hole index (DHI), and ELM integrity metrics between the two groups. Results The mean MPOD was 0.09 ± 0.08 in bbMHs and 0.16 ± 0.11 in sbMHs (p = 0.010). Correlation analysis between MPOD and minimum hole diameter revealed a negative association (rho = − 0.707, p = 0.008) in bbMH and a positive association (rho = 0.702, p = 0.019) in sbMH. MPOD and basal diameter were negatively correlated in bbMH (rho = − 0.77, p = 0.001) and positively correlated in sbMH (rho = 0.675, p = 0.019). Indeed, MPOD is negatively correlated with THI and MHI in sbMH (rho = − 0.684 p = 0.019; rho = − 0.665 p = 0.019, respectively) and positively correlated in bbMH (rho = 0.593 p = 0.037; rho = 0.658 p = 0.018, respectively). Conclusions MPOD is significantly reduced in bbMHs compared to sbMHs. The two border phenotypes also differ for tractional and tangential indexes, possibly reflecting a different pathogenesis. Further studies are needed to understand the prognostic role of MPOD.

Abstract Background Activation of the Wnt pathway has been linked to colorectal cancer (CRC). Previous reports suggest that Wnt3a can activate p38. Besides, p38α feeds into the canonical Wnt/β-catenin pathway by inhibiting GSK3β through phosphorylation. Recently, we identified p38α as a new druggable member of β-catenin chromatin-associated kinase complexes in CRC. Methods The functional relationship between p38α and β-catenin was characterized in CRC cells, patient-derived CRC stem cells, patient-derived tumor intestinal organoids, and in vivo models (C57BL/6-APCMin/+ mice). The role of p38α in β-catenin transcriptional activity was assessed by pharmacological inhibition with ralimetinib. Results We used the GSK3β inhibitor TWS-119, which promotes the activation of Wnt signaling, to uncouple p38α nuclear/cytoplasmatic functions in the Wnt pathway. Upon GSK3β inhibition, nuclear p38α phosphorylates β-catenin at residues S111 and T112, allowing its binding to promoter regions of Wnt target genes and the activation of a transcriptional program implicated in cancer progression. If p38α is pharmacologically inhibited in addition to GSK3β, β-catenin is prevented from promoting target gene transcription, which is expected to impair carcinogenesis. Conclusions p38α seems to play a dual role as a member of the β-catenin destruction complex and as a β-catenin chromatin-associated kinase in CRC. This finding may help elucidate mechanisms contributing to human colon tumor pathogenesis and devise new strategies for personalized CRC treatment.

IntroductionCoronavirus disease 2019 (COVID-19) is a highly contagious viral illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has had a dramatic effect on the world, resulting in millions of deaths worldwide and causing drastic changes in daily life. A study reported that septic complications were associated with high mortality in COVID-19 patients. This study aimed to evaluate how the COVID-19 pandemic changed the pre-pandemic and post-pandemic prevalence of sepsis in ICUs and to evaluate the different risk factors associated with mortality and the different diffusion of microorganisms and their resistance.Materials and methodsWe conducted a single-center retrospective observational clinical study, observing all patients in the ICU of the SS Annunziata Hospital in Chieti (Italy) who were diagnosed with sepsis and had a bacterial isolate from their blood culture. Sepsis was diagnosed by SEPSIIS III criteria. We enrolled all in-patients in the ICU from January 2018 to December 2021. We divided the patients into three groups: (1) non-pandemic period (Np) hospitalized in 2018–2019, (2) pandemic period (Pp)-COVID hospitalized in 2020–2021 with a diagnosis of COVID-19, and (3) Pp-non-COVID patients hospitalized in 2020–2021 without a diagnosis of COVID-19.ResultsFrom January 2018 to December 2021, 1,559 patients were admitted to the ICU, of which 211 patients [36 (17.1%) in 2018, 52 (24.6%) in 2019, 73 (34.6%) in 2020, and 50 (23.7%) in 2021, respectively] met the selection criteria: 88 patients in period Np, 67 patients in Pp without COVID-19, and 56 patients Pp with COVID-19. The overall mortality of these patients was high (65.9% at 30 days in Np), but decreased during the Pp (60.9%): Pp-non-COVID was 56.7% vs. Pp-COVID 66.1%, with a statistically significant association with APACHE III score (OR 1.08, 95%CI 1.04–1.12, p

Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3 BRAFV600E mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes.

Introduction The sense of agency (SoA) indicates a person’s ability to feel her/his own motor acts as actually being her/his, and through them to exert control over the course of external events. Disruptions in SoA may profoundly affect the individual’s functioning, as observed in several neuropsychiatric disorders. Objectives This is the first article to systematically review studies that investigated intentional binding (IB), a quantitative proxy for SoA measurement, in neurological and psychiatric patients. Methods Eligible were studies of IB involving patients with neurological and/or psychiatric disorders. The research adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results We included 15 studies involving 692 individuals. Risk of bias was low throughout studies. Eligible studies dealt with data from 357 patients with neuropsychiatric disorders matched with 335 HCs. Of included patients, 95 were with schizophrenia (SCZ), 30 with a putative prodromal psychosis (PP), 21 with borderline personality disorder (BPD), 66 with Parkinson’s disease (PD), 38 with an autism spectrum disorder (ASD), 29 with functional movement disorders (FMDs), 25 with Gilles de la Tourette syndrome (GTS), 52 with anorexia nervosa (AN; 22 with active disorder and 30 after they had recovered), and 10 with Cortico-Basal syndrome (CBS). Temporal binding was calculated in eleven studies using variations of the experimental procedure introduced by Haggard et al. (Haggard et al. Nat Neurosci 2002;5 382-385)(Figure 1, A), while four studies utilized a different paradigm named interval estimation (IE)(Figure 1, B). Image: Conclusions Abnormally increased action-outcome binding was found in schizophrenia and in patients with Parkinson’s disease taking dopaminergic medications or reporting impulsive-compulsive behaviours. A decreased IB effect was observed in Tourette’s disorder and functional movement disorders whereas increased action-outcome binding was found in patients with cortico-basal syndrome. The extent of IB deviation from healthy control values correlated with the severity of symptoms in several disorders. Inconsistent effects were found for autism spectrum disorders, anorexia nervosa, and borderline personality disorder. Findings pave the way for treatments specifically targeting SoA in neuropsychiatric disorders where IB is altered. Disclosure of Interest None Declared

Background: In Europe, flu vaccination coverage has decreased, and there are complex barriers to overcome to vaccinate against flu. Many studies have been conducted to estimate vaccination coverage. The COVID-19 pandemic threatens to disrupt immunization programs in many countries, including Italy, where vaccination against the flu is recommended but not mandatory. This paper aims to understand changes in flu vaccine uptake in Italian regions. Methods: Using functional data analysis and fuzzy functional k-means clustering, we investigated changes in flu vaccine coverage in Italian regions before (2010–2019) and after (2020–2022) the COVID-19 vaccination period. Results: The period of COVID-19 pandemic brought an increase in vaccine coverage globally. Elbow's method determined that the optimal number of clusters in vaccination uptake is 2. Apulia, Basilicata, Emilia Romagna, Liguria, Molise, Tuscany, and Umbria in 2019 belong less to the group with low flu vaccination uptake (G1) but increase their tendency to belong to this group over time: they decrease their propensity to be vaccinated for flu. For others, it seems that COVID-19 served as a push to increase flu vaccination coverage rates. Sicily appears to be the region that has responded best to the pandemic, changing its membership value from 2019 to 2022. Conclusion: The present study highlights that the COVID-19 era has resulted in a higher flu vaccination coverage rate. Moreover, the regional level's improvement or worsening in flu vaccination coverage rate is not affected by the historical gap and socio-cultural and economic differences prevailing among Italian regions.

Abstract This study aimed at predicting the filtration surgery (FS) outcome using a machine learning (ML) approach. 102 glaucomatous patients undergoing FS were enrolled and underwent ocular surface clinical tests (OSCTs), determination of surgical site-related biometric parameters (SSPs) and conjunctival vascularization. Break-up-time, Schirmer test I, corneal fluorescein staining, Meibomian gland expressibility; conjunctival hyperemia, upper bulbar conjunctiva area of exposure, limbus to superior eyelid distance; and conjunctival epithelial and stromal (CET, CST) thickness and reflectivity (ECR, SCR) at AS-OCT were considered. Successful FS required a 30% baseline intraocular pressure reduction, with values ≤ 18 mmHg with or without medications. The classification tree (CT) was the ML algorithm used to analyze data. At the twelfth month, FS was successful in 60.8% of cases, whereas failed in 39.2%. At the variable importance ranking, CST and SCR were the predictors with the greater relative importance to the CART tree construction, followed by age. CET and ECR showed less relative importance, whereas OSCTs and SSPs were not important features. Within the CT, CST turned out the most important variable for discriminating success from failure, followed by SCR and age, with cut-off values of 75 µm, 169 on gray scale, and 62 years, respectively. The ROC curve for the classifier showed an AUC of 0.784 (0.692–0.860). In this ML approach, CT analysis found that conjunctival stroma thickness and reflectivity, along with age, can predict the FS outcome with good accuracy. A pre-operative thick and hyper-reflective stroma, and a younger age increase the risk of FS failure.

Porokeratosis is a group of well-known clinically distinct entities, characterised by different clinical aspects, but sharing a single common histological aspect, namely the cornoid lamella. Usually, porokeratosis occurs in the limbs and trunk, while it rarely involves the face, especially as an exclusive, single, and solitary lesion. We report the case of a 52-year-old Caucasian woman, with an 11-month history of a 2-cm slowly growing solitary, keratotic lesion on her left cheekbone. The patient did not present other cutaneous lesions on the face, as well as in other body sites. A cutaneous biopsy showed epidermal hyperplasia with multiple, sharply defined cornoid lamella, associated with an underlying attenuation of the granular layer and scattered dyskeratotic cells in the spinous layer. The superficial dermis underneath showed a mild lymphocytic infiltrate and fibrosis with remodelled collagen bundles. A final diagnosis of solitary facial porokeratosis was made.

Ophidiomyces ophidiicola, the causative agent of ophidiomycosis, poses a potential threat to wild snakes worldwide. This study aimed to retrospectively investigate the prevalence of O. ophidiicola in archived snake moults collected from the San River Valley in the Bieszczady Mountains, Poland, from 2010 to 2012. Using qPCR for O. ophidiicola detection and conventional PCR for clade characterisation, we analysed 58 moults and one road-killed specimen of Zamenis longissimus and Natrix natrix. A novel combination of primers (ITS2L) was used to simultaneously confirm SYBR Green-based qPCR results and perform genotyping. O. ophidiicola has been detected from two Z. longissimus and one N. natrix specimens. The identified clade (I-B) is consistent with those found in wild snakes of eastern Europe and San River Valley, indicating that O. ophidiicola has been present in this region for at least a decade. This study underscores the value of historical samples in understanding the long-term presence of pathogens and highlights the potential role of environmental reservoirs in the persistence of O. ophidiicola. Our findings are crucial for informing conservation strategies for the endangered Aesculapian snake populations in Poland, emphasising the need for ongoing monitoring and habitat management to mitigate the potential impact of ophidiomycosis.

Reptiles are usually asymptomatic carriers of Salmonella, with the manifestation of typical clinical signs of acute forms in adult and non-immunocompromised animals being considered exceptions. In the present case, an adult male corn snake (Pantherophis guttatus) was found dead due to septic shock 48 h after consuming a feeder mouse purchased online. The snake’s tissue samples and faeces were cultured for bacteria isolation. Microbiological examinations of the snake and mouse livers revealed the presence of Salmonella enterica subsp. enterica serovar Midway. A whole-genome analysis of these two isolates showed a high correlation between them: they belonged to the strain type ST-357 for the classic MLST scheme and to the strain type ST 171322 for the cgMLST scheme. Also, a virulence gene analysis revealed the presence of stdB and STM3026 genes. This report conveys a case of food-borne salmonellosis in a pet snake, transmitted from a feeder mouse, likely responsible for the snake’s death due to septic shock. It highlights the relevance of feeder mice as a source of Salmonella infections in snakes and the associated risks to human health.

L'oeuvre de Ricoeurprésente une contribution á la méditation sur les relations interpersonnelles, dans les perspectives éthique et anthropologique. L'article examine Ies questions de I'identité, de estirne de soi, du souci envers I'autre, et des institutions justes, en tant que celles-ci sont I'expréssion, au niveau de la vie sociale, du respect à la personne humaine.

Abstract SAR439459, a ‘second‐generation’ human anti‐transforming growth factor‐beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti‐programmed cell death protein‐1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first‐in‐human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose‐escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose‐expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ‐pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune‐excluded’ to ‘immune‐infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response.

Jellyfish are aquatic animals of the phylum Cnidaria found in seas all over the world. They are characterized by the presence of cnidocytes, cells that contain a secretory organelle, the cnidocyst, mainly used for predation and defense purposes. An adult female patient presented to our Unit of Dermatology, for a 10 days-old history of macular-erythematous lesions in her right upper limb, due to a sting by a mauve stinger Pelagia noctiluca. Dermoscopy showed a general pinkish background surmounted by numerous brown dots and lines, distributed along the surface of the skin. Reflectance confocal microscopy (RCM) showed the presence of multiple partially hyperreflective, highly coiled, hollow, and harpoonlike structures through the epidermis but without the barbed tubes found in a previous RCM report, likely due to a greater time elapsed between the sting and the dermatological visit. This case highlights how dermoscopy and RCM may help clinicians for the diagnosis of jellyfish stings.

The genus Vipera encompasses most species of medically significant venomous snakes of Europe, with Italy harbouring four of them. Envenomation by European vipers can result in severe consequences, but underreporting and the absence of standardised clinical protocols hinder effective snakebite management. This study provides an updated, detailed set of guidelines for the management and treatment of Vipera snakebite tailored for Italian clinicians. It includes taxonomic keys for snake identification, insights into viper venom composition, and recommendations for clinical management. Emphasis is placed on quick and reliable identification of medically relevant snake species, along with appropriate first aid measures. Criteria for antivenom administration are outlined, as well as indications on managing potential side effects. While the protocol is specific to Italy, its methodology can potentially be adapted for other European countries, depending on local resources. The promotion of comprehensive data collection and collaboration among Poison Control Centres is advocated to optimise envenomation management protocols and improve the reporting of epidemiological data concerning snakebite at the country level.

To analyze in vivo scleral changes induced by MicroPulse transscleral laser therapy (MP-TLT) in refractory glaucoma using anterior segment–optical coherence tomography (AS-OCT). Forty-two candidate patients for MP-TLT were consecutively enrolled and underwent AS-OCT at baseline and after six months. MP-TLT success was defined as an intraocular pressure (IOP) reduction by one-third. The main outcome measures were the mean superior (S-), inferior (I-), and total (T-) intra-scleral hypo-reflective space area (MISHA: mm2) and scleral reflectivity (S-SR, I-SR, T-SR; arbitrary scale) as in vivo biomarkers of uveoscleral aqueous humor (AH) outflow. The IOP was the secondary outcome. The relations between the baseline-to-six months differences (D) of DS-MISHA, DI-MISHA, and DT-MISHA and DS-SR, DI-SR, DT-SR, and DIOP, were investigated. At 6 months, the median IOP reduction was 21% in the failures and 38% in the successes. The baseline S-MISHA, I-MISHA, and T-MISHA did not differ between the groups, while S-SR and T-SR were higher in the successes (p < 0.05). At six months, successful and failed MP-TLTs showed a 50% increase in S-MISHA (p < 0.001; p = 0.037), whereas I-SR and T-SR reduced only in the successes (p = 0.002; p = 0.001). When comparing DS-MISHA, DI-MISHA, and DT-MISHA and DS-SR, DI-SR, and DT-SR, there were no significant differences between the groups. In the successful procedures, DIOP was positively correlated with DT-MISHA and DI-MISHA (ρ = 0.438 and ρ = 0.490; p < 0.05). MP-TLT produced potentially advantageous modifications of the sclera in refractory glaucoma. Given the partial correlation between these modifications and post-treatment IOP reduction, our study confirmed that the activation of the uveoscleral AH outflow route could significantly contribute to the IOP lowering after MP-TLT.

Background. As artificial intelligence is expanding its applications in medicine, metabolic imaging is gaining the ability to retrieve data otherwise missed by even an experienced naked eye. Also, new radiopharmaceuticals and peptides aim to increase the specificity of positron emission tomography (PET) scans. Herein, a preliminary experience is reported regarding searching for a texture signature in routinely performed [F18]Fluciclovine imaging in prostate cancer. Materials and methods. Twenty-nine patients who underwent a PET/computed tomography (CT) scan with [18F]Fluciclovine because of biochemical prostate cancer relapse were retrospectively enrolled. First- and second-order radiomic features were manually extracted in lesions visually considered pathologic from the Local Image Features Extraction (LIFEx) platform. Statistical analysis was performed on a database of 29 lesions, one1 per patient. The dataset was split to have 20 lesions for the model training set and 9 lesions for the validation set. The Wilcoxon–Mann–Whitney test was used on the training set to select the most significant features (p-value < 0.05) predicting the dichotomous outcome in a univariate analysis. Results. The best model for predicting the outcome was found to be a multiple logistic linear regression model with two features as variables: an intensity histogram type and a gray-level size zone-based type. Conclusions. Texture analysis of [F18]Fluciclovine PET scans helps in defining prostate cancer relapse in a daily clinical setting.

Background: Dual disorders (DD) entail the coexistence of a substance use disorder (SUD) and another mental health condition, often within psychotic and affective disorders. This study aims to evaluate lurasidone, an innovative atypical antipsychotic, in individuals diagnosed with schizophrenia spectrum disorder and concurrent comorbidities of alcohol use disorder/substance use disorder (AUD/SUD). Methods: A cohort of 23 subjects diagnosed with schizophrenia spectrum disorder and comorbid AUD/SUD underwent psychometric assessments at baseline (T0) and one-month (T1) post-lurasidone initiation. Results: Lurasidone exhibited significant reductions in psychopathological burden, evidenced by decreased total PANSS scores (Z = 2.574, p = 0.011). Positive symptoms, substance craving (VAS Craving; Z = 3.202, p = 0.001), and aggressivity (MOAS scale; Z = 2.000, p = 0.050) were notably reduced. Clinical Global Impression (CGI) scores significantly improved (Z = 2.934, p = 0.003). Quality of life enhancements were observed in SF-36 subscales (energy, emotional well-being, and social functioning) (p < 0.05) and Q-LES-Q-SF scale (Z = −2.341, p = 0.021). A safety analysis indicated lurasidone’s good tolerability, with only 8.7% reporting discontinuation due to side effects. Conclusions: This study offers initial evidence supporting lurasidone’s efficacy and safety in dual diagnoses, highlighting positive effects on psychopathology, substance craving, and quality of life. These findings emphasize the need for tailored, comprehensive treatment strategies in managing the complexities of this patient population.

Background: Dual disorders (DDs) involve the coexistence of a substance use disorder (SUD) with another mental illness, often from the psychotic and affective categories. They are quite common in clinical practice and present significant challenges for both diagnosis and treatment. This study explores the effectiveness of brexpiprazole, a third-generation antipsychotic, in an Italian sample of individuals diagnosed with schizophrenia spectrum disorder and a comorbid SUD. Methods: Twenty-four patients, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and enrolled in several Italian hospitals, underwent a psychometric assessment at baseline (T0) and one month (T1) after starting brexpiprazole treatment administered at a mean dosage of 2 mg/day. Results: Brexpiprazole demonstrated significant reductions in psychopathological burden (Positive and Negative Syndrome Scale/PANSS total score: p < 0.001). Positive (p = 0.003) and negative (p = 0.028) symptoms, substance cravings (VAS craving: p = 0.039), and aggression (MOAS scale: p = 0.003) were notably reduced. Quality of life improved according to the 36-item Short Form Health Survey (SF-36) subscales (p < 0.005). Conclusions: This study provides initial evidence supporting brexpiprazole’s efficacy and safety in this complex patient population, with positive effects not only on psychopathology and quality of life, but also on cravings. Further studies involving larger cohorts of subjects and extended follow-up periods are needed.

New Psychoactive Substances (NPS) are modifying the drug scenario worldwide and have become a public health concern because of their toxicological profiles and their harmful physical/psychological effects. 3-Methoxy-Phencyclidine (3-MeO-PCP), a non-competitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors, belongs to the phencyclidine-like subfamily of arylcyclohexylamines and has gained attention for its toxic, sometimes fatal, effects. Despite several cases of intoxication and death reported in the literature, little is known about substance-induced psychotic disorders (SIP) and potential cognitive impairment following 3-MeO-PCP intake. This literature review aimed to summarize available evidence about 3-MeO-PCP mechanisms of action and physical and psychotropic effects and to spread preliminary findings about persistent psychotic symptoms and impaired cognitive functioning. Additionally, the case of an SIP is reported in a 29-year-old man with small oral intakes of 3-MeO-PCP over two weeks until a high dose ingestion. Psychometric and neuropsychological assessment and brain [18F]-fluorodeoxyglucose positron emission tomography integrated with computed tomography were used to support clinical description. Identifying and addressing the characteristic clinical features and neural substrates of NPS-induced psychoses might help clinicians with a more precise differentiation from other psychotic disorders. Although further studies are required, phenotyping the cognitive profile of NPS users might provide targets for tailored therapeutic approaches.

Obesity and overweight are common and complex conditions influenced by multiple genetic and environmental factors. Several genetic variants located in the genes involved in clock systems and fat taste perception can affect metabolic health. In particular, the polymorphisms in CLOCK and BMAL1 genes were reported to be significantly related to cardiovascular disease, metabolic syndrome, sleep reduction, and evening preference. Moreover, genetic variants in the CD36 gene have been shown to be involved in lipid metabolism, regulation of fat intake, and body weight regulation. The aim of this study is to evaluate, for the first time, the association between variants in some candidate genes (namely, BMAL1 rs7950226 (G>A), CLOCK rs1801260 (A>G), CLOCK rs4864548 (G>A), CLOCK rs3736544 (G>A), CD36 rs1984112 (A>G), CD36 rs1761667 (G>A)) and overweight/obesity (OB) in pregnant women. A total of 163 normal-weight (NW) and 128 OB participants were included. A significant correlation was observed between A-allele in CLOCK rs4864548 and an increased risk of obesity (OR: 1.97; 95% CI 1.22–3.10, p = 0.005). In addition, we found that subjects carrying the haplotype of rs1801260-A, rs4864548-A, and rs3736544-G are likely to be overweight or obese (OR 1.47, 95% CI 1.03–2.09, p = 0.030), compared with those with other haplotypes. Moreover, a significant relation was observed between third-trimester lipid parameters and genetic variants—namely, CD36 rs1984112, CD36 rs1761667, BMAL1 rs7950226, and CLOCK rs1801260. A multivariate logistic regression model revealed that CLOCK rs4864548 A-allele carriage was a strong risk factor for obesity (OR 2.05, 95% CI 1.07–3.93, p = 0.029); on the other hand, greater adherence to Mediterranean diet (OR 0.80, 95% CI 0.65–0.98, p = 0.038) and higher HDL levels (OR 0.96, 95% CI 0.94–0.99, p = 0.021) were related to a reduced risk of obesity. Interestingly, an association between maternal CLOCK rs4864548 and neonatal birthweight was detected (p = 0.025). These data suggest a potential role of the polymorphisms in clock systems and in fat taste perception in both susceptibility to overweight/obesity and influencing the related metabolic traits in pregnant women.

Abstract Background In older patients with acute myeloid leukemia (AML), the definition of fitness, prognosis, and risk of death represents an open question. Methods In the present study, we tested the impact on survival of disease‐ and patient‐related parameters in a large cohort of elderly AML patients homogeneously assigned to treatment with hypomethylating agents (HMAs). Results In 131 patients with a median age of 76 years, we confirmed that early response (