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Mesenchymal stem cells (MSCs) are novel therapeutics for the treatment of Crohn's disease. However, their mechanism of action is unclear, especially in disease-relevant chronic models of inflammation. Thus, we used SAMP-1/YitFc (SAMP), a chronic and spontaneous murine model of small intestinal inflammation, to study the therapeutic effects and mechanism of action of human bone marrow-derived MSCs (hMSC). hMSC dose-dependently inhibited naïve T lymphocyte proliferation via prostaglandin E2 (PGE2) secretion and reprogrammed macrophages to an anti-inflammatory phenotype. We found that the hMSCs promoted mucosal healing and immunologic response early after administration in SAMP when live hMSCs are present (until day 9) and resulted in a complete response characterized by mucosal, histological, immunologic, and radiological healing by day 28 when no live hMSCs are present. hMSCs mediate their effect via modulation of T cells and macrophages in the mesentery and mesenteric lymph nodes (mLN). Sc-RNAseq confirmed the anti-inflammatory phenotype of macrophages and identified macrophage efferocytosis of apoptotic hMSCs as a mechanism that explains their long-term efficacy. Taken together, our findings show that hMSCs result in healing and tissue regeneration in a chronic model of small intestinal inflammation and despite being short-lived, exert long-term effects via sustained anti-inflammatory programming of macrophages via efferocytosis.

Abstract Introduction This study assessed the efficacy, durability, and safety of faricimab in patients with neovascular age-related macular degeneration (nAMD), previously treated with aflibercept or ranibizumab with unsatisfactory results. Methods This was a single-center, prospective cohort study of all consecutive patients with nAMD switched to intravitreally administered faricimab from traditional anti-vascular endothelial growth factor (anti-VEGF) treatments between September 2022 and April 2023 because of unsatisfactory response (maximal fluid-free interval ≤ 8 weeks). Faricimab was administered with a loading dose of four 4-weekly injections, followed by a treat-and-extend regimen. The primary outcome measures were maximum fluid-free interval after the switch and last assigned treatment interval. Secondary outcome measures included best-corrected visual acuity (BCVA) and structural optical coherence tomography parameters. Results Thirty-three eyes of 33 patients were included. Patients were followed for a median of 72 weeks [interquartile range 61, 76]. Median maximum fluid-free treatment interval after switch to faricimab and the last assigned interval were significantly longer than before the switch (7 vs. 4 weeks, p

Abstract Background Metabolic acidosis is a frequent finding in patients admitted to the intensive care unit (ICU). It can be caused by prolonged fasting due to surgical procedures or by medical conditions that lead to starvation ketoacidosis (SKA). Early recognition and treatment of SKA could prevent several life-threatening complications, improving survival and reducing the ICU length of stay. Methods We retrospectively screened all medical records of patients admitted to the ICU (Maggiore Hospital, Bologna, North Italy) from May 2022 to April 2023. We included patients aged 18 years or older who presented ketonuria detected in the urine sample. Results We analyzed 190 patients with ketonuria at ICU admission. Postsurgical patients showed lower levels of albumin and a higher rate of shock compared to medical patients. Ketonuric patients with shock had a lower body mass index (BMI) compared to patients without shock (24 versus 26 kg/m2, respectively). There were no differences within groups regarding mortality and ICU readmission rate. Medical patients had a significantly higher ICU length of stay. Conclusions This retrospective observational descriptive study showed that patients with ketonuria, hypoalbuminemia, and low BMI at ICU admission have high risk of hemodynamic instability and shock. Surgical patients compared to medical patients are exposed to a catabolic trigger that could worsen a state of malnutrition and induce anabolic resistance; elective and urgent surgical patients did not differ in terms of risk of shock and mortality, probably due to the activation of this catabolic pathway. Early recognition and treatment of starvation ketoacidosis and perioperative nutritional optimization could reduce incidence of hemodynamic and metabolic complications.

Abstract Background Intravitreal faricimab, a bispecific antibody targeting both angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), was recently introduced for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema and cystoid macular oedema secondary to retinal vein occlusion. The aim of our study was to assess the efficacy, safety and durability of intravitreal faricimab in a real-world cohort of treatment-naïve patients with nAMD. Methods Single-centre, prospective cohort study of 21 eyes from 19 treatment-naïve nAMD patients who were treated with intravitreal faricimab from October 2022 to April 2024. Patients underwent a loading dose (LD) of 4 monthly faricimab injections followed by a treat-and-extend regimen. Primary outcomes included best-corrected visual acuity (BCVA) and structural parameters from spectral-domain optical coherence tomography (SD-OCT). Secondary outcomes included the proportion of eyes achieving a dry macula, maximal fluid-free interval and intended interval at last follow-up. Results The study included 21 eyes of 19 patients (mean age 83.1 years). After LD, 93.3% of eyes achieved a dry macular SD-OCT scan within a median time of 8 weeks. At the first extension, 53% of eyes remained dry, while 47% showed fluid recurrence. Long-term analysis (n = 14) revealed significant reductions in macular volume (MV), central subfield thickness (CST), and pigment epithelial detachment (PED) height over a median follow-up of 64.9 weeks, with sustained visual and anatomical improvements. Median BCVA, CST, and MV at the final follow-up were significantly improved from baseline (p

Insomnia is one of the most common co-occurring disorders in children with autism spectrum disorder (ASD). The purpose of this cross-sectional cohort study of 270 children with ASD was to assess the prevalence of insomnia using the Pediatric Sleep Clinical Global Impression Scale and to correlate sleep problems with cognitive level, adaptive behavior, parental stress, behavioral and emotional problems, and severity of core symptoms. Our findings revealed that one-third of children had insomnia and were related to reduced adaptive behaviors and higher levels of parental stress and behavioral and emotional problems. Insomnia must be evaluated in children with ASD to define an appropriate intervention to potentially alleviate the severity of clinical correlates and parental burden.

Abstract Background Sharing and fairness are important prosocial behaviors that help us navigate the social world. However, little is known about how and whether individuals with Williams Syndrome (WS) engage in these behaviors. The unique phenotype of individuals with WS, consisting of high social motivation and limited social cognition, can also offer insight into the role of social motivation in sharing and fairness when compared to typically developing (TD) individuals. The current study used established experimental paradigms to examine sharing and fairness in individuals with WS and TD individuals. Methods We compared a sample of patients with WS to TD children (6-year-olds) matched by mental age (MA) on two experimental tasks: the Dictator Game (DG, Experiment 1, N = 17 WS, 20 TD) with adults modeling giving behaviors used to test sharing and the Inequity Game (IG, Experiment 2, N = 14 WS, 17 TD) used to test fairness. Results Results showed that the WS group behaved similarly to the TD group for baseline giving in the DG and in the IG, rejecting disadvantageous offers but accepting advantageous ones. However, after viewing an adult model giving behavior, the WS group gave more than their baseline, with many individuals giving more than half, while the TD group gave less. Combined these results suggest that social motivation is sufficient for sharing and, in particular, generous sharing, as well as the self-focused form of fairness. Further, individuals with WS appear capable of both learning to be more generous and preventing disadvantageous outcomes, a more complex profile than previously known. Conclusions In conclusion, the present study provides a snapshot into sharing and fairness-related behaviors in WS, contributing to our understanding of the intriguing social-behavioral phenotype associated with this developmental disorder.

Prospective memory (PM) is the ability to remember and realize one’s intentions in the future; therefore, it is crucial for the daily functioning of children and adolescents and their ability to become independent from caregivers. PM errors can have repercussions during childhood, such as influencing school performance and social relationships. The aim of this systematic review was to synthesize studies analysing PM in children and adolescents (age range: 0–16 years) following PRISMA guidelines. The goal was to outline the most commonly used tasks, offering information on the development of PM, and—through a detailed analysis of the assessment of specific cognitive processes carried out in the primary studies included—providing information on the main cognitive processes involved in PM within this age group. Forty-nine studies were selected that examined PM in children and adolescents with typical development. The studies used many different tasks that can be traced back to eleven different main paradigms to evaluate PM, each structured into a PM and an ongoing task. Older children performed better on PM targets than younger children, suggesting a developmental trajectory of PM that follows a J-shaped function. Children as young as 2 years old exhibited the first signs of PM, while adolescents performed similarly to adults on PM tasks. Several factors are involved in PM development: retrospective memory, executive functions (planning, working memory, inhibitory control, monitoring), attention, metamemory, and motivation. This review May be considered a starting point to summarize the most used tools to evaluate PM in children and adolescents, and to shed light on the primary cognitive functions involved in PM, potentially offering indications to researchers in selecting optimal tasks for measuring PM across different age groups. Additionally, it underscores the importance of developing standardized measures for potential clinical applications.

IntroductionSevere depression is a prevalent psychiatric illness in children and adolescents associated with high levels of morbidity, disability, and a high risk of suicidal behavior. Cognitive factors associated with depression severity in juveniles have been poorly reported. MethodsWe investigated the relationship between depression severity and intelligence quotient (IQ)with its subscales in 65 juveniles (aged 10–17 years) with a current major depressive episode evaluated at the Mood Disorder Program of Bambino Gesù Children’s Hospital in Rome. Pearson’s correlation analyses were followed by a Benjamini–Hochberg correction and linear multivariable regression model. ResultsDepression severity measured with the total score of the Children’s Depression Rating Scale-Revised (CDRS-R) was positively associated with the Verbal Comprehension Index (VCI; Pearson’s r = 0.309 [0.042−0.534]; p = 0.024). The CDRS-R subscales positively associated with VCI by Pearson’s correlation were depressed feelings, suicidal ideation, excessive weeping, and reduced facial expressions. Suicidal ideation was the only factor independently and significantly associated with higher VCI in the multivariable linear regression model.DiscussionSuicidal ideation was significantly and independently associated with higher verbal comprehension, indicating that depressed juveniles with better verbal ability may be at a greater risk of showing suicidal ideation.

Abstract Purpose The aim of the present review is to analyze dynamic interactions between nutrigenomics, environmental cues, and parental influence, which can all lead to children’s neophobic reactions and its persistence in time. Methods We reviewed studies available on electronic databases, conducted on children aged from birth to 18 years. We also considered official websites of Italian Institutions, providing advice on healthy eating during infancy. Results Modern day societies are faced with an eating paradox, which has severe and ever-growing implications for health. In face of a wider availability of healthy foods, individuals instead often choose processed foods high in fat, salt and sugar content. Economic reasons surely influence consumers’ access to foods. However, there is mounting evidence that food choices depend on the interplay between social learning and genetic predispositions (e.g., individual eating traits and food schemata). Neophobia, the behavioral avoidance of new foods, represents an interesting trait, which can significantly influence children’s food refusal. Early sensory experiences and negative cognitive schemata, in the context of primary caregiver–child interactions, importantly contribute to the priming of children’s food rejection. Conclusions As neophobia strongly affects consumption of healthy foods, it will be relevant to rule definitively out its role in the genesis of maladaptive food choices and weight status in longitudinal studies tracking to adulthood and, in meanwhile, implement early in life effective social learning strategies, to reduce long-term effects of neophobia on dietary patterns and weight status. Level of evidence Level II, controlled trials without randomization.

Abstract Rotating magnetic fields enable biomedical microrobots to overcome physiological barriers and promote extravasation and accumulation in tumors. Nevertheless, targeting deeply situated tumors requires suppression of off-target actuation in healthy tissue. Here, we investigate a control strategy for applying spatially selective torque density to microrobots by combining rotating fields with magnetostatic selection fields. Taking magnetotactic bacteria as diffuse torque-based actuators, we numerically model off-target torque suppression, indicating the feasibility of centimeter to millimeter resolution for human applications. We study focal torque application in vitro, observing off-target suppression of actuation-dependent effects such as colonization of bacteria in tumor spheroids. We then design and construct a mouse-scale torque-focusing apparatus capable of maneuvering the focal point. Applying this system to a mouse tumor model increased accumulation of intravenously injected bacteria within tumors receiving focused actuation compared to non-actuated or globally actuated groups. This control scheme combines the advantages of torque-based actuation with spatial targeting.

ABSTRACT The paper proposes a brief analysis of the main elements that, on a theoretical, normative and situational basis, affect the value of properties placed as collateral for loans, with particular reference to the value they assume in the event that they are affected by an enforced procedure instead of being subject to normal sale, in free market conditions. Starting from the classic analytical estimate of the fair market value of a real estate asset in free market conditions, the paper will quantify the value that the asset should have when the appraiser has to indicate the value from which to start the judicial auction. Considering the regulatory mechanisms in place in Italy, the paper will put in evidence how a value calculated for an execution sale of a property occurring in a foreclosure process is considerably far from its fair market value and even more from its final judicial value, considered as the amount that will be recovered at the end of the sale of the property by judicial auction. For both debtors and creditors, the significant differences between fair market, execution and judicial values become an increasingly topical issue in the face of the growing number of default and distress of loans.

The practice of transporting a patient affected by a Highly Transmissible Disease (HTD) with a high risk of fatal evolution using biocontainment isolators requires careful planning and preparation. To date, there is only limited literature regarding aeromedical transport, most of which is military-derived, and it does not address patient transfer by road vehicles. To standardize these practices, or at least some of their most critical aspects, we tried to schematize a few of the improvements each author implemented during their practices as a scaffold, which could eventually be based on operative protocols. In particular, we focused on the series of actions that needed to be performed and planned to guarantee the safety of both the patient and operators during the entire duration of the operations.

In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects in the context of metabolic and cardiovascular diseases. We performed a study to delineate clinical and multiomics characteristics of human subjects characterized by low and high IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight, low-grade inflammation, and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis in colon tissue revealed the enrichment of several signaling, regulatory, and metabolic processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in highIPA group while in lowIPA group Escherichia-Shigella, megasphera, and Desulfovibrio genus were more abundant.Next, we tested the hypothesis that treatment with IPA in a mouse model may recapitulate the observations of human subjects, at least in part. We found that a short treatment with IPA (4 days at 20/mg/kg) improved glucose tolerance and Akt phosphorylation in the skeletal muscle level, while regulating blood BCAA levels and gene expression in colon tissue, all consistent with results observed in human subjects stratified for IPA levels. Our results suggest that treatment with IPA may be considered a potential strategy to improve insulin resistance in subjects with dysbiosis.

Sewage sludge (biosolids) management represents a worldwide issue. Due to its valuable properties, approximately one half of the EU production is recovered in agriculture. Nevertheless, growing attention is given to potential negative effects deriving from the presence of harmful pollutants. It is recognized that a (even very detailed) chemical characterization is not able to predict ecotoxicity of a mixture. However, this can be directly measured by bioassays. Actually, the choice of the most suitable tests is still under debate. This paper presents a multilevel characterization protocol of sewage sludge and other organic residues, based on bioassays and chemical-physical-microbiological analyses. The detailed description of the experimental procedure includes all the involved steps: the criteria for selecting the organic matrices to be tested and compared; the sample pre-treatment required before the analyses execution; the chemical, physical and microbiological characterisation; the bioassays, grouped in three classes (baseline toxicity; specific mode of action; reactive mode of action); data processing. The novelty of this paper lies in the integrated use of advanced tools, and is based on three pillars: • the direct ecosafety assessment of the matrices to be reused. • the adoption of innovative bioassays and analytical procedures. • the original criteria for data normalization and processing.

Abstract Mesenchymal stem cells (MSCs) are novel therapeutics for the treatment of Crohn’s disease. However, their mechanism of action is unclear, especially in disease-relevant chronic models of inflammation. Thus, we used SAMP-1/YitFc (SAMP), a chronic and spontaneous murine model of small intestinal inflammation, to study the therapeutic effects and mechanism of action of human bone marrow-derived MSCs (hMSC). hMSC dose-dependently inhibited naïve T lymphocyte proliferation via prostaglandin E2 (PGE2) secretion and reprogrammed macrophages to an anti-inflammatory phenotype. We found that the hMSCs promoted mucosal healing and immunologic response early after administration in SAMP when live hMSCs are present (until day 9) and resulted in a complete response characterized by mucosal, histological, immunologic, and radiological healing by day 28 when no live hMSCs are present. hMSCs mediate their effect via modulation of T cells and macrophages in the mesentery and mesenteric lymph nodes (mLN). Sc-RNAseq confirmed the anti-inflammatory phenotype of macrophages and identified macrophage efferocytosis of apoptotic hMSCs as a mechanism that explains their long-term efficacy. Taken together, our findings show that hMSCs result in healing and tissue regeneration in a chronic model of small intestinal inflammation and despite being short-lived, exert long-term effects via sustained anti-inflammatory programming of macrophages via efferocytosis.

ABSTRACTThe digital transformation is an important driver of long-run productivity growth and, as such, it has the potential to promote a more inclusive and sustainable growth. However, digital capabilities, crucial to develop and govern new digital technologies, are unevenly distributed across European regions, increasing the risk of divergence and polarisation. By taking advantage of a set of original indicators capturing the level of digital skills in the regional workforce, this work analyses the factors shaping the process of digital skill accumulation in the EU over the period 2011–2018. Relying on transition probability matrices and dynamic random effects probit models, we provide evidence of a strong and persistent regional polarisation in the adoption and deployment of digital skills. Further, we investigate whether structural factors and European funds (European Regional Development Fund, Cohesion Funds and European Social Funds) are capable of shaping the digitalisation process and favouring regional convergence.

Background/Objectives: Urinary tract infections (UTIs) are infections that involve the urethra, bladder, and, in much more severe cases, even kidneys. These infections represent one of the most common diseases worldwide. Various pathogens are responsible for this condition, the most common being Escherichia coli (E. coli). Bromelain is a proteolytic complex obtained from the stem and stalk of Ananas comosus (L.) Merr. showing several beneficial activities. In addition to bromelain, N-acetylcysteine (NAC) has also been used. Methods: The purpose of this experiment was to evaluate the antibacterial, anti-motility, and anti-biofilm effects of a new polyenzymatic complex (DIF17BRO®) in combination with NAC (the Formulation) on various strains of E. coli isolated from patients with UTIs. Subsequently, the anti-inflammatory and antioxidant effects of the Formulation were studied in an ex vivo model of cystitis, using bladder samples from mice exposed to E. coli lipopolysaccharide (LPS). Results: Our results showed that the Formulation significantly affects the capability of bacteria to form biofilm and reduces the bacteria amount in the mature biofilm. Moreover, it combines the interesting properties of NAC and a polyenzyme plant complex based on bromelain in a right dose to affect the E. coli adhesion capability. Finally, the Formulation exhibited protective effects, as confirmed by the inhibitory activities on multiple inflammatory and oxidative stress-related pathways on bladder specimens exposed to LPS. Conclusions: This blend of active compounds could represent a promising and versatile approach to use to overcome the limitations associated with conventional therapies.

Chronic inflammation is a recognized risk factor for various cancers, including prostate cancer (PCa). We aim to explore the potential protective effects of aged black garlic extract (ABGE) against inflammation-induced prostate damage and its impact on prostate cancer cell lines. We used an ex vivo model of inflammation induced by Escherichia coli lipopolysaccharide (LPS) on C57BL/6 male mouse prostate specimens to investigate the anti-inflammatory properties of ABGE. The gene expression levels of pro-inflammatory biomarkers (COX-2, NF-κB, and TNF-α, IL-6) were measured. Additionally, we evaluated ABGE’s therapeutic effects on the prostate cancer cell lines through in vitro functional assays, including colony formation, tumorsphere formation, migration assays, and phosphorylation arrays to assess the signaling pathways (MAPK, AKT, JAK/STAT, and TGF-β). ABGE demonstrated significant anti-inflammatory and antioxidant effects in preclinical models, partly attributed to its polyphenolic content, notably catechin and gallic acid. In the ex vivo model, ABGE reduced the gene expression levels of COX-2, NF-κB, TNF-α, and IL-6. The in vitro studies showed that ABGE inhibited cell proliferation, colony and tumorsphere formation, and cell migration in the prostate cancer cells, suggesting its potential as a therapeutic agent. ABGE exhibits promising anti-inflammatory and anti-cancer properties, supporting further investigation into ABGE as a potential agent for managing inflammation and prostate cancer.

BACKGROUND: Knowing whether shift work negatively affects the immune system’s response to COVID-19 vaccinations could be valuable for planning future vaccination campaigns for healthcare workers. We aimed to determine the impact of working late or night shifts on serum anti-SARS-CoV-2 spike protein immunoglobulin G (anti-S) antibody levels after primary SARS-CoV-2-mRNA vaccination. METHODS: To obtain detailed information on shift work, we sent a separate online questionnaire to 1475 eligible healthcare workers who participated in a prospective longitudinal study conducted in 15 healthcare institutions in Switzerland. We asked all vaccinated healthcare workers with available anti-S antibody levels after vaccination to complete a brief online survey on their working schedules within one week before and after primary mRNA vaccination. We used multivariate regression to evaluate the association between work shifts around primary vaccination and anti-S antibody levels. We adjusted for confounders already known to influence vaccine efficacy (e.g. age, sex, immunosuppression, and obesity) and for variables significant at the 0.05 alpha level in the univariate analyses. RESULTS: The survey response rate was 43% (n = 638). Ninety-eight responders were excluded due to unknown vaccination dates, different vaccines, or administration of the second dose shortly (within 14 days) after or before serologic follow-up. Of the 540 healthcare workers included in our analysis, 175 (32.4%) had worked at least one late or night shift within seven days before and/or after primary vaccination. In the univariate analyses, working late or night shifts was associated with a nonsignificant −15.1% decrease in serum anti-S antibody levels (p = 0.090). In the multivariate analysis, prior infection (197.2% increase; p