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Abstract Immunotherapy with anti-PD-1 antibodies significantly improved the prognosis in advanced melanoma patients, but most of them develop primary or secondary resistance to the treatment. In this study, we evaluated efficacy and safety of a chemotherapy regimen with weekly carboplatin plus paclitaxel (wCP) in patients previously treated with anti-PD-1 antibodies. We retrospectively identified 30 patients with advanced melanoma treated at our Institute over the last eight years with wCP. The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). In addition, we evaluated treatment tolerability. For this patient cohort, median PFS and OS were 3.25 and 7.69 months, respectively. All included patients had previously received anti-PD-1 immunotherapy, most of them had ECOG PS 0–1, and only 5 patients had a BRAF V600 mutation. In univariable analysis, we observed shorter OS in patients with > 2 involved metastatic sites, superficial spreading histology, and serum lactate dehydrogenase (LDH) values above the median. Liver metastases were associated with worse outcomes, while radiotherapy treatment of brain metastases was associated with improved OS. However, in a multivariable Cox regression model, only LDH above the median, superficial spreading histology, and female sex were significantly associated with worse OS. We reported grade 3 and 4 treatment-related toxicities in 4 and 0 patients, respectively. In conclusion, chemotherapy with wCP is a valid palliative treatment in advanced melanoma who progressed with anti-PD-1 antibodies.

Wernicke encephalopathy (WE) is a rare but severe neurological syndrome characterized, in its classic form, by the acute onset of ocular disturbances, ataxia, and cognitive impairment. It is caused by a deficiency of thiamine (vitamin B1) and mainly affects chronic alcoholics, although it can also affect patients with pathologies that lead to malnutrition. We present a case of a 58-year-old woman, who presented with significant weight loss over the past 6 months and who came to the emergency department for episodes of repetitive vomiting and a sleepy state. The patient underwent blood chemistry tests and a brain CT scan, which revealed symmetrical and bilateral hypodensity of the medial portion of the thalamus, tectal plate, and periaqueductal gray matte, suggestive of WE. She was subsequently referred to the Department of Neurology and underwent a brain MRI, which confirmed the clinical suspicion. She also had an abdominal CT scan and ileo-colonoscopy and was diagnosed with Crohn's disease. Immediately after the clinical diagnosis of WE, a replacement therapy based on intravenous thiamine at high doses was promptly set up, and the patient improved from a clinical point of view.Wernicke encephalopathy can be difficult to diagnose when it occurs in non-alcoholic patients; WE associated with IBD is a rare condition, and it can present with atypical and more subtle symptoms. Radiologists and physicians must be aware of this condition and imaging findings for rapid diagnosis and treatment.

Mitochondria-derived reactive oxygen species production at a moderate physiological level plays a fundamental role in the anti-aging signaling, due to their action as redox-active sensors for the maintenance of optimal mitochondrial balance between intracellular energy status and hormetic nutrients. Iron regulatory protein dysregulation, systematically increased iron levels, mitochondrial dysfunction, and the consequent oxidative stress are recognized to underlie the pathogenesis of multiple neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Central to their pathogenesis, Nrf2 signaling dysfunction occurs with disruption of metabolic homeostasis. We highlight the potential therapeutic importance of nutritional polyphenols as substantive regulators of the Nrf2 pathway. Here, we discuss the common mechanisms targeting the Nrf2/vitagene pathway, as novel therapeutic strategies to minimize consequences of oxidative stress and neuroinflammation, generally associated to cognitive dysfunction, and demonstrate its key neuroprotective and anti-neuroinflammatory properties, summarizing pharmacotherapeutic aspects relevant to brain pathophysiology.

Introduction Most kidney diseases are associated with the dysfunction of the glomerular filtration barrier (GFB), which comprises 3 layers, including the glomerular endothelial cells (GEC), the glomerular basement membrane (GBM) [...], Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these supra-modal traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a general response pattern factor for each supra-modal construct and determine the added value of modality-specific response pattern scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ωH = .800) but not a supra-modal HYPO construct (ωH = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ωH = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many real-world sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

IntroductionAutism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by a range of intellectual and language abilities. Its heterogeneity is acknowledged in modern diagnostics, complicating research and necessitating precision medicine and a multidimensional approach for individualized treatment and accurate assessment. Intellectual and language functioning influence adaptive skills and symptomatology. Thus, assessing adaptive functioning in a multidimensional and multi-informant manner is crucial, highlighting the importance of comprehensive evaluations. This study explores the interplay between autistic traits, demographic variables, IQ, adaptive functioning, and the applicability of ICD-11 classifications.MethodsWe analyzed data from the initial global evaluation of 60 diverse autistic children (aged 35 to 120 months; IQ range 16 to 118). Parent-reports using the Vineland Adaptive Behavior Scale (VABS-II) were compared with standardized assessments from the PsychoEducational Profile (PEP-3). Children’s intellectual levels were assessed using Griffiths Scales of Child Development (Griffiths III) and the Autism Diagnostic Observation Schedule (ADOS-2) was used for autistic traits. They were further classified according to the ICD-11 diagnostic system, functional language, and intellectual functioning levels. Correlations among variables, group comparisons, and multivariate analyses were performed.ResultsThe analysis indicates a linear effect of IQ on all adaptive scales and the impact of autistic traits on directly measured adaptive functioning. A factorial effect was observed due to changes concerning specific age, intellectual, and linguistic levels, which do not completely align with ICD-11 categorization. Additionally, a negative correlation between intelligence and measured autistic traits was found. Parental age, education level, and age at childbirth were also found to affect various adaptive scales.DiscussionThe study questions the ICD-11’s proposed distinctions in IQ and language functioning for ASD, advocating for more refined categorization and developmental considerations. It underscores the intricate relationship between autistic traits, IQ, and communication skills, casting doubt on the precision of diagnostic tools across the spectrum. Parental reports and direct assessments are essential for comprehensive evaluation, with parental education and age influencing children’s behaviors and skills. The study calls for a nuanced approach to ASD assessment, integrating various metrics and sources of information for a detailed phenotyping necessary for personalized interventions and biological research.

Background and aimsGiulia, an 11-year-old girl diagnosed with ligyrophobia, has been experiencing intense anxiety related to loud noises since the age of two. This case report aims to explore the efficacy of Third-Wave Cognitive Behavioral Therapy, specifically Acceptance and Commitment Therapy (ACT), in addressing Giulia’s anxiety and avoidance behaviors. The primary goal is to examine the impact of ACT on reducing ligyrophobic symptoms and enhancing psychological flexibility.MethodsThe therapeutic intervention spanned 24 sessions and was divided into two phases. The initial phase focused on emotional competence using characters from the movie “Inside Out,” aiding Giulia in recognizing and understanding her emotions. The subsequent phase targeted the six processes of psychological inflexibility identified in ACT, fostering increased flexibility.ResultsThroughout the intervention, Giulia demonstrated significant improvements in anxiety symptoms, as evidenced by a decrease in Subjective Units of Distress (SUD) scores. Avoidance behaviors also diminished, and Giulia exhibited enhanced mindfulness skills. She became more cognizant of her emotional experiences and more certain of her personal ideals as a result of the therapy. Giulia’s active participation and commitment to exposure exercises led to a substantial reduction in ligyrophobic reactions.DiscussionThe successful application of ACT in Giulia’s case suggests that targeting psychological inflexibility through mindfulness and values clarification can be effective in treating ligyrophobia in children. The integration of metaphors and creative exercises proved valuable in engaging Giulia and fostering therapeutic progress. The findings underscore the importance of a tailored, third-wave therapeutic approach in addressing specific phobias in pediatric populations.

Abstract Human hemoglobin (Hb) is the preferred iron source of Staphylococcus aureus. This pathogenic bacterium exploits a sophisticated protein machinery called Iron-regulated surface determinant (Isd) system to bind Hb, extract and internalize heme, and finally degrade it to complete iron acquisition. IsdB, the surface exposed Hb receptor, is a proven virulence factor of S. aureus and the inhibition of its interaction with Hb can be pursued as a strategy to develop new classes of antimicrobials. To identify small molecules able to disrupt IsdB:Hb protein–protein interactions (PPIs), we carried out a structure-based virtual screening campaign and developed an ad hoc immunoassay to screen the retrieved set of commercially available compounds. Saturation-transfer difference (STD) NMR was applied to verify specific interactions of a sub-set of molecules, chosen based on their efficacy in reducing the amount of Hb bound to IsdB. Among molecules for which direct binding was verified, the best hit was submitted to ITC analysis to measure the binding affinity to Hb, which was found to be in the low micromolar range. The results demonstrate the viability of the proposed in silico/in vitro experimental pipeline to discover and test IsdB:Hb PPI inhibitors. The identified lead compound will be the starting point for future SAR and molecule optimization campaigns.

The thermal properties of ultra-high temperature ceramics (UHTCs) in the MB2-WC (M = Ti, Zr, Hf) system and tungsten were studied for potential application as plasma-facing materials in fusion power plants. The sintered UHTC and tungsten samples were subjected to deuterium plasma or protons irradiation. Thermal diffusivity was measured using the laser flash method, and superficial thermal conductivity was analyzed through atomic force microscopy. Results showed that the thermal properties did not degrade when exposed to relevant environments and remained stable over a range of temperatures, unlike the reference tungsten material. Thermal conductivity ranged from 61 to 68 W m−1 K−1 for TiB2-2(WC-6Co), from 53 to 63 W m−1 K−1 for ZrB2-6WC, from 67 to 75 W m−1 K−1 for HfB2-6WC, and from 180 to 119 W m−1 K−1 for tungsten across the temperature range from room temperature to 1200 °C. The increasing trend of thermal effusivity, over 19000 J s−0.5 m−2 K−1 at 1200 °C, justifies further testing and of UHTC materials for fusion applications.

Interoception, the body's perception of its own internal states, is thought to be altered in autism, though results of empirical studies have been inconsistent. The current study systematically reviewed and meta-analyzed the extant literature comparing interoceptive outcomes between autistic (AUT) and neurotypical (NT) individuals, determining which domains of interoception demonstrate robust between-group differences. A three-level Bayesian meta-analysis compared heartbeat counting performance, heartbeat discrimination performance, heartbeat counting confidence ratings, and self-reported interoceptive attention between AUT and NT groups (15 studies; n[subscript AUT] = 467, n[subscript NT] = 478). Autistic participants showed significantly reduced heartbeat counting performance [g = - 0.333, CrI[subscript 95%] (- 0.535, - 0.138)] and higher confidence in their heartbeat counting abilities [g = 0.430, CrI[subscript 95%] (0.123, 0.750)], but groups were equivalent on other meta-analyzed outcomes. Implications for future interoception research in autism are discussed.

Abstract Counting animal populations is fundamental to understand ecological processes. Counts make it possible to estimate the size of an animal population at specific points in time, which is essential information for understanding demographic change. However, in the case of large populations, counts are time‐consuming, particularly if carried out manually. Here, we took advantage of convolutional neural networks (CNN) to count the total number of nest‐entrances in 222 photographs covering the largest known Psittaciformes (Aves) colony in the world. We conducted our study at the largest Burrowing Parrot Cyanoliseus patagonus colony, located on a cliff facing the Atlantic Ocean in the vicinity of El Cóndor village, in north‐eastern Patagonia, Argentina. We also aimed to investigate the distribution of nest‐entrances along the cliff with the colony. For this, we used three CNN architectures, U‐Net, ResUnet, and DeepLabv3. The U‐Net architecture showed the best performance, counting a mean of 59,842 Burrowing Parrot nest‐entrances across the colony, with a mean absolute error of 2.7 nest‐entrances over the testing patches, measured as the difference between actual and predicted counts per patch. Compared to a previous study conducted at El Cóndor colony more than 20 years ago, the CNN architectures also detected noteworthy differences in the distribution of the nest‐entrances along the cliff. We show that the strong changes observed in the distribution of nest‐entrances are a measurable effect of a long record of human‐induced disturbance to the Burrowing Parrot colony at El Cóndor. Given the paramount importance of the Burrowing Parrot colony at El Cóndor, which concentrates 71% of the world's population of this species, we advocate that it is imperative to reduce such a degree of disturbance before the parrots reach the limit of their capacity of adaptation.

BackgroundStage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event.Case presentationWe describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma.ConclusionThere is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering them an adjuvant treatment, reducing the risk of hyperprogression. From these cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile.

ABSTRACT The focus of this case report is to technically describe a noninvasive diagnostic evaluation of bow Hunter's syndrome using a dynamic computed tomography angiography protocol and discuss its advantages. In addition, we aimed to exemplify the quality of the study by presenting images of a 3D-printed model generated to help plan the surgical treatment for the patient. The dynamic computed tomography angiography protocol consisted of a first image acquisition with the patient in the anatomic position of the head and neck. This was followed by a second acquisition with the head and neck rotated to the side that triggered the symptoms, with technical parameters similar to the first acquisition. The acquired images were used to print a 3D model to better depict the findings for the surgical team. The dynamic computed tomography angiography protocol developed in this study helped visualize the vertebrobasilar arterial anatomy, detect vertebral artery stenosis produced by head and neck rotation, depict the structure responsible for artery stenosis (e.g., bony structure or membranes), and study possible complications of the disease (e.g., posterior cerebral circulation infarction). Additionally, the 3D-printed model better illustrated the findings of stenosis, aiding in surgical planning. In conclusion, dynamic computed tomography angiography for the evaluation of bow Hunter's syndrome is a feasible noninvasive technique that can be used as an alternative to traditional diagnostic methods.

Carbon fibre-reinforced ultra-high temperature ceramics (UHTCs) are considered a class of promising materials for several applications, the most appealing ones being in the aerospace sector. Reinforcement is necessary to overcome the brittleness and low thermal shock resistance of ceramics and is often provided through the addition of carbon fibres or other carbon-based phases, such as nanotubes, graphene, and graphite. The present work is focused on the toughening of UHTCs through incorporation of 30−50 vol% thin, ordered graphite layers from conventional filter paper followed by hot pressing sintering. Cellulose filter paper was selected because it undergoes thermolysis with no melting stage forming a strong carbonaceous residue that can be used as toughener. Microstructure and mechanical properties of toughened composites were compared to those of other materials reinforced with short carbon fibres and the effect of different distribution of graphite was studied. Addition of graphite allowed toughness to be increased from 3−4 MPa·m1/2 (for un-reinforced materials) to 5.1−5.5 MPa·m1/2, similar to results obtained with short fibre reinforcement. The high-temperature properties, such as strength and toughness as well as oxidation resistance at 1500 ℃, were also examined.

(1) Background: Mucosal melanoma (MM) is a rare tumor, accounting for about 1% of all diagnosed melanomas. The etiology and pathogenesis of this tumor are unknown. It is characterized by an aggressive phenotype with poor prognosis and a low response rate to approved treatments. (2) Methods: We retrospectively analyzed the clinical features, treatments and outcomes of patients diagnosed with MM from different sub-sites (head and neck, gynecological and gastro-intestinal region) between 2013 and 2023 at our Institute. Survival times were estimated with the Kaplan–Meier method. Multivariate Cox regression was used to test the independence of significant factors in univariate analysis. (3) Results: Twenty-five patients were included in this study; the disease was equally distributed among females and males. The median age at diagnosis was 74 years old. The majority had MM originating from the head and neck (56%), particularly from the nasal cavity. BRAF V600 mutations were detected in 16% of the study population, limited to gastro-intestinal and gynecological MM. At diagnosis, at least half the patients (52%) had the disease located also at distant sites. The median overall survival (OS) in the whole study population was 22 months, with a longer OS for patients diagnosed at an early stage (38 months, p < 0.001). Longer OSs were reported for head and neck MM compared to other anatomic regions (0.06). Surgery of the primary tumor and radiotherapy were performed in 64% and 36% of the study population, respectively. Radiotherapy was performed only in head and neck MM. At multivariate analysis, the single factor that showed a reduced hazard ratio for death was radiotherapy. (4) Conclusions: The overall survival of MM from different sub-sites treated at our Italian Institution was 22 months, with better outcomes for early-stage disease and head and neck MM. Performing radiotherapy may have a protective effect on OS for head and neck MM. New treatment strategies are urgently needed to improve the outcome in this disease.

This study examined the effects of extruded linseed and algae Padina pavonica extract on the reproductive performance, milk production, and gastrointestinal health of female rabbits. Thirty-six nulliparous New Zealand White female rabbits were randomly assigned to three groups (n = 12) with different diets. The control group (CNT) received a standard diet, while the other two groups received modified isoenergetic diets in which part of the CNT diet ingredients were replaced with 5% extruded linseed (L5%) and 5% extruded linseed plus 0.2% Padina pavonica algae extract (L5%PP). The rabbits were monitored from artificial insemination until the weaning of the rabbit kits, evaluating different reproductive parameters. Our results indicate that extruded linseed and alga Padina pavonica extract did not affect the feed intake or body weight of female rabbits. Additionally, no clinically significant histological changes were observed at the gastrointestinal level. The reproductive parameters, including litter size, litter weight, and milk yield, showed no significant differences among groups. Notably, perinatal and pre-weaning mortalities were reduced in litters born to females receiving omega-3 integrated diets (p < 0.05). While these findings are promising, further studies are needed to confirm these results and explore the specific mechanisms by which omega-3 affects reproductive function and litter health.