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Abstract Efficient generation of cardiomyocytes from human-induced pluripotent stem cells (hiPSCs) is important for their application in basic and translational studies. Space microgravity can significantly change cell activities and function. Previously, we reported upregulation of genes associated with cardiac proliferation in cardiac progenitors derived from hiPSCs that were exposed to space microgravity for 3 days. Here we investigated the effect of long-term exposure of hiPSC-cardiac progenitors to space microgravity on global gene expression. Cryopreserved 3D hiPSC-cardiac progenitors were sent to the International Space Station (ISS) and cultured for 3 weeks under ISS microgravity and ISS 1 G conditions. RNA-sequencing analyses revealed upregulation of genes associated with cardiac differentiation, proliferation, and cardiac structure/function and downregulation of genes associated with extracellular matrix regulation in the ISS microgravity cultures compared with the ISS 1 G cultures. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes mapping identified the upregulation of biological processes, molecular function, cellular components, and pathways associated with cell cycle, cardiac differentiation, and cardiac function. Taking together, these results suggest that space microgravity has a beneficial effect on the differentiation and growth of cardiac progenitors.

INTRODUCCIÓN: Las oftalmoparesias (disfunción en los movimientos oculares) pueden deberse a un daño de las vías supranucleares, internucleares (del tronco encefálico), propiamente de los nervios motores oculares o de la unión neuromuscular y puede expresarse clínicamente como diplopía (visión doble) binocular, la cual constituye un motivo de consulta común, tanto en pacientes ambulatorios, como en el departamento de emergencias. En el inicio de los cuadros agudos de oftalmoparesia es necesaria una evaluación neurorradiológica eficiente para ayudar a diferenciar entre los distintos diagnósticos, curso clínico y opciones de tratamiento. OBJETIVO: Describir los hallazgos imagenológicos en la RMN de cerebro en pacientes con oftalmoparesias. Especificar los diagnósticos derivados de cada hallazgo. Identificar el par craneal afectado con mayor frecuencia. Determinar si existe relación entre la presencia de sintomatología extraocular y resultado patológico de la RMN de cerebro. MATERIAL Y METODOS: Estudio observacional, retrospectivo, analítico en el que se incluyeron pacientes entre 16 y 90 años que consultaron entre el año 2020 y 2023 por diplopía y/o limitación en la movilidad ocular, o hubiesen sido las mismas evidenciadas mediante el examen físico neurológico. Se evaluaron las siguientes variables: edad, sexo, oftalmoparesia unilateral, combinada, desviación de la mirada conjugada, resultado de RMN de cerebro, diagnóstico etiológico, par craneal afectado, ubicación anatómica de la lesión, presencia de sintomatología extraocular. Para las variables cualitativas se calcularon medidas porcentuales y absolutas. Para las variables cuantitativas, medidas de posición y dispersión. Para comparar variables cualitativas (presencia de sintomatología extraocular y RMN de cerebro patológica) se utilizó el test de Chi cuadrado. El nivel de significancia se consideró menor al 5%. RESULTADOS: Se incluyeron 62 pacientes, 34 (54.80%) de sexo femenino. La edad media (desviación estándar) fue de 50.00 (18.37) años. La neuroimagen fue patológica en 40 (64.51%) casos. Las lesiones isquémicas fueron el hallazgo más frecuente en 13 (20.97%) casos, y dentro de ellas, la ubicación en el tronco encefálico su localización más usual en 6 (46.15%) casos. Las hemorragias intracraneales representaron el segundo hallazgo patológico en RMN de cerebro (N= 6; 9.67%). Otros hallazgos fueron: signos radiológicos de hipertensión endocraneana (N=4, 6.45%), lesiones desmielinizantes (N= 3; 4.83%), realce meníngeo (N= 3; 4.83%) y atrofia mesencefálica (N= 2; 3.22%). Las lesiones metastásicas en músculos extraoculares, quistes pineales y tumores glómicos mostraron una frecuencia individual de 1 (1.61%) caso. 21 El par craneal afectado con mayor frecuencia fue el VI en 25 (40%) casos. En lo que respecta a las características clínicas, en 40 (64.51%) casos hubo sintomatología extraocular. Entre los pacientes que tuvieron manifestaciones extraoculares, la RMN fue patológica en 36 (90%) casos en comparación con los que no tuvieron manifestaciones extraoculares, en cuyo caso la RMN fue patológica en 4 (10%); p< 0.001. CONCLUSIONES: En este estudio, más de la mitad de los pacientes con oftalmoparesia presentaron hallazgos en la RMN de cerebro. A pesar de que el mismo se realizó en una muestra de pacientes jóvenes, la principal etiología responsable de los hallazgos neuro-imagenológicos fue la patología cerebrovascular. Dado que la presencia de síntomas extra-oculares se asoció con hallazgos anormales en la RMN de cerebro, sugerimos la realización de una neuroimagen en todo aquel paciente que consulta por oftalmoparesia aguda acompañada de sintomatología extraocular

The aim of this study was to explore the role of gender, age, and academic year in shaping dispositional mindfulness (DM) and the association between DM facets and empathy dimensions in a sample of undergraduate nursing students. In a multicenter cross-sectional study design, the Five Facet Mindfulness Questionnaire (FFMQ), the Interpersonal Reactivity Index (IRI), and socio-demographic questions were administrated to a convenience sample of Italian nursing students. 622 nursing students (82.2% female) participated in the study (response rate = 86.15%). Females had higher levels of Acting with Awareness (p < .001, d = .54) and lower levels of Non-reacting (p < .001, d = .52) facets of DM than males. Older students displayed higher scores on the Observing (r = .112, p = .005) and on the Non-reacting (r = .187, p < .001) FFMQ subscales than younger ones. No statistically significant differences in DM levels between the three academic years were found (ps > .202). After controlling for socio-demographic factors, DM facets were generally positively related to Perspective Taking ([beta]s from .131 to .208, ps < .007) and Empathic Concern ([beta]s from -.156 to .189, ps < .001), whereas negatively related to Personal Distress ([beta]s from -.141 to -.261, ps < .001). Nursing students with higher levels of DM were more able to consider others' cognitive perspective and to feel compassion, and were less emotionally distressed when facing tense interpersonal situations. Tailored mindfulness interventions might be useful to foster functional empathy within nursing undergraduate programs., Author(s): Stefano Ardenghi [sup.1] , Selena Russo [sup.1] , Michela Luciani [sup.1] , Valerio Salvarani [sup.1] [sup.2] , Giulia Rampoldi [sup.1] , Marco Bani [sup.1] , Davide Ausili [sup.1] , [...]

Abstract Background Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation. Methods hiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli. Results Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features—including enhanced Ca2+ transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells. Conclusion AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.

Abstract Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain‐of‐function mutations, end‐organ damage and disease progression in ADTKD. Based on two prevalent missense UMOD mutations with divergent disease progression, we generated UmodC171Y and UmodR186S knock‐in mice that showed strong allelic and gene dosage effects on uromodulin aggregates and activation of ER stress and unfolded protein and immune responses, leading to variable kidney damage. Deletion of the wild‐type Umod allele in heterozygous UmodR186S mice increased the formation of uromodulin aggregates and ER stress. Studies in kidney tubular cells confirmed differences in uromodulin aggregates, with activation of mutation‐specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased uromodulin aggregates. These studies substantiate the role of toxic aggregates as driving progression of ADTKD‐UMOD, relevant for therapeutic strategies to improve clearance of mutant uromodulin.

The present study contributes to the literature by examining the association between personal values (PVs), assessed with the Schwartz's Portrait Values Questionnaire, and empathy, assessed with the Davis' Interpersonal Reactivity Index, in a sample of first-year medical students. We also examined medical students' PVs profile and gender differences in terms of PVs. All participants (N = 398) were Italian, young (average age = 19.62 years, SD = 1.22), and unmarried; none had children. Zero-order correlations and hierarchical multiple regression models were performed to verify the association between PVs and empathy; in contrast, t-tests were run to explore gender differences in scoring on PVs. Benevolence and Universalism correlated positively with both the emotional and cognitive dimensions of empathy, whereas Power, Achievement, Hedonism, and Security were negatively associated with empathy. The three most important PVs in the whole sample were Benevolence, Self-Direction, and Universalism. Male medical students outscored their female counterparts on Power, Achievement, and Hedonism, whereas female students outscored the males on Benevolence, Universalism, Conformity, and Tradition. Our findings highlight the importance of fostering self-transcending PVs and discouraging self-enhancing PVs in medical students during the early years of medical school, as a means of supporting other-oriented responses such as empathy in future doctors., Author(s): Stefano Ardenghi [sup.1] , Giulia Rampoldi [sup.2] , Marco Bani [sup.1] , Maria Grazia Strepparava [sup.1] [sup.3] Author Affiliations: (1) grid.7563.7, 0000 0001 2174 1754, Department of Medicine and [...]

Thoracentesis is one of the most important invasive procedures in the clinical setting. Particularly, thoracentesis can be relevant in the evaluation of a new diagnosed pleural effusion, thus allowing for the collection of pleural fluid so that laboratory tests essential to establish a diagnosis can be performed. Furthermore, thoracentesis is a maneuver that can have therapeutic and palliative purposes. Historically, the procedure was performed based on a physical examination. In recent years, the role of ultrasound has been established as a valuable tool for assistance and guidance in the thoracentesis procedure. The use of ultrasound increases success rates and significantly reduces complications. The aim of this educational review is to provide a detailed and sequential examination of the procedure, focusing on the two main modalities, the ultrasound-assisted and ultrasound-guided form.

OBJECTIVES/GOALS: Using a natural canine model of kidney stone disease, we previously identified a pathogenic variant in the uromodulin gene (UMOD) that imparts a dramatic risk for calcium oxalate (CaOx) stones. This study was designed to characterize the effects of the pathogenic variant on uromodulin processing, specifically polymerization and peptide excretion. METHODS/STUDY POPULATION: Uromodulin polymerization status and peptides were measured in random urine samples from CaOx stone-forming dogs with the pathogenic UMOD variant and breed-, sex-, and age-matched healthy control dogs. Polymerization status was determined using an ultracentrifugation protocol and Western blotting in 6 CaOx cases and 3 controls; relative abundance of the polymerizing and nonpolymerizing forms was evaluated. Uromodulin peptide abundances were measured by LC-MS/MS with 4 dogs per group; results were summed to determine total uromodulin peptide excretion for each dog, and individual peptide abundances were calculated as a percentage of the total. Polymerization status and peptides were compared between groups. RESULTS/ANTICIPATED RESULTS: Dogs with the pathogenic UMOD variant had abnormalities in both uromodulin polymerization and peptide processing. The polymerization data showed that the polymerizing form of uromodulin was abundant in all healthy controls but absent or severely reduced in most dogs with the variant. In contrast, nonpolymerizing uromodulin was detected in all dogs with no observed difference between those with and without the variant. The peptidomics data showed that stone-forming dogs with the pathogenic UMOD variant lacked a peptide cleavage site, resulting in the loss of two common peptides that terminate at that site and the presence of longer peptides that span the site. DISCUSSION/SIGNIFICANCE: These findings implicate uromodulin polymerization and peptide processing defects in kidney stone risk. Future studies will define the mechanisms through which these defects affect stone formation, ultimately informing development of novel preventative therapies.

Background & Aims: Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006–2020) in Italy. Methods: Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006–2010; 2011–2015; 2016–2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Results: Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia,

Abstract Digital trauma amputations and digital agenesis strongly affect the functionality and aesthetic appearance of the hand. Autologous reconstruction is the gold standard of treatment. Unfortunately, microsurgical options and transplantation procedures are not possible for patients who present contraindications or refuse to undergo transplantation from the toe (e.g. toe‐to‐thumb transplantation). To address these issues, osseointegrated finger prostheses are a promising alternative. The functional assessments registered during follow‐up confirmed the promising outcomes of osseointegrated prostheses in the treatment of hand finger amputees. This review outlines (a) a detailed analysis of osseointegrated finger metallic components of the implants, (b) the surgical procedures suggested in the literature, and (c) the functional assessments and promising outcomes that demonstrate the potential of these medical osseointegrated devices in the treatment of finger amputees.

Abstract Background To evaluate the potential benefits of the Magnetic Resonance-guided high intensity Focused Ultrasound (MRgFUS) introduction in the clinical practice, for the treatment of uterine fibroids, in comparison with the standard “conservative” procedures, devoted to women who wish to preserve their uterus or enhance fertility: myomectomy and uterine artery embolization (UAE). Methods A Health Technology Assessment was conducted, assuming the payer’s perspective (Italian National Healthcare Service). The nine EUnetHTA Core Model dimensions were deeply investigated, by means of i) a literature review; ii) the implementation of health economics tools (useful for uterine fibroids patients’ clinical pathway economic evaluation, and budget impact analysis), to define MRgFUS economic and organizational sustainability, and iii) administration of specific questionnaires filled by uterine fibroids’ experts, to gather their perceptions on the three possible conservative approaches (MRgFUS, UAE and myomectomy). Results Literature revealed that MRgFUS would generate several benefits, from a safety and an efficacy profile, with significant improvement in symptoms relief. Advantages emerged concerning the patients’ perspective, thus leading to a decrease both in the length of hospital stay (p-value

Introduction: University psychological counselling services represent a frontline defence to detect, treat or refer students with a wide range of (clinical and non‐clinical) difficulties. Nevertheless, only few studies describe their impact on academic self‐efficacy and report follow‐up data. Evidence on students' actual access to further psychological support in times of hardship is also scant and most needed. This study aimed to fill these gaps, exploring the stability of improvement in clinical conditions in a wide sample of university students and reporting post‐intervention referrals to mental health services. Methods: In a longitudinal study, 218 students who accessed a psychological counselling service at the University of Milano‐Bicocca between 2015 and 2019 completed an assessment at the beginning (T0), conclusion (T1) and 6 months after (T2) a brief cognitive behavioural intervention. The assessment included psychological symptoms, general distress, emotion dysregulation and academic self‐efficacy. Information about students' choices to continue a psychological intervention in other services was also collected and contrasted with the counsellor's indication. Results: At follow‐up, the improvement in academic self‐efficacy remained stable, with more than 60% of the students maintaining a reliable clinical change, and nearly half of them reporting having accessed (or being willing to contact) a mental health service outside the university services. Conclusion: These findings highlight the key role of counselling services in addressing students' distress and academic performances in the long term and in building bridges with mental health services outside the university system for students who need longer and specialised treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: Transjugular intrahepatic portosystemic shunt (TIPS) is an established procedure for the treatment of several complications of portal hypertension (PH), including non‐neoplastic portal vein thrombosis (PVT). Selection criteria for TIPS in PVT are not yet well established. Despite anecdotal, cases of thromboembolic events from paradoxical embolism due to the presence of patent foramen ovale (PFO) after TIPS placement have been reported in the literature. Therefore, we aimed at describing our experience in patients with non‐neoplastic splanchnic vein thrombosis (SVT) who underwent TIPS following PFO screening. Methods: We conducted a single‐centre retrospective study, including consecutive patients who underwent TIPS for the complications of cirrhotic and non‐cirrhotic portal hypertension (NCPH) and having SVT. Results: Of 100 TIPS placed in patients with SVT, 85 patients were screened for PFO by bubble‐contrast transthoracic echocardiography (TTE) with PFO being detected in 22 (26%) cases. PFO was more frequently detected in patients with non‐cirrhotic portal hypertension (NCPH) (23% in the PFO group vs. 6% in those without PFO, p =.04) and cavernomatosis (46% in the PFO group vs. 19% in those without PFO, p =.008). Percutaneous closure was effectively performed in 11 (50%) after multidisciplinary evaluation of anatomical and clinical features. No major complications were observed following closure. Conclusions: PFO screening and treatment may be considered feasible for patients with SVT who undergo TIPS placement. [ABSTRACT FROM AUTHOR]

Anderson-Fabry Disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA, the gene encoding the lysosomal hydrolase α-galactosidase A (α-Gal A), leading to accumulation of glycosphingolipids in the lysosomes. FD is a multisystemic disorder leading to progressive cardiovascular, cerebrovascular and kidney dysfunction. Phenotypes are divided in two main classes, classic or non-classic, depending on substrate accumulation, age at onset, disease manifestation, severity and progression. The more severe classical phenotype is generally associated with mutations leading to absent or strongly reduced α-Gal A activity, while mutations with higher residual activity generally lead to the non-classical one. Approximately 70% of the over 1,000 Fabry disease-associated mutations are missense mutations, some leading to endoplasmic reticulum (ER) retention of mutant protein. We hypothesized that such mutations could be associated, besides the well-known absence of α-Gal A function/activity, to a possible gain of function effect due to production of a misfolded protein. We hence expressed α-Gal A missense mutations in HEK293 GLA−/− cells and investigated the localization of mutant protein and induction of ER stress and of the unfolded protein response (UPR). We selected a panel of 7 missense mutations, including mutants shown to have residual or no activity in vitro. Immunofluorescence analysis showed that mutants with residual activity have decreased lysosomal localization compared with wild type, and partial retention in the ER, while missense mutants with no residual activity are fully retained in the ER. UPR (ATF6 branch) was significantly induced by all but two mutants, with clear correlation with the extent of ER retention and the predicted mutation structural effect. These data identify a new molecular pathway, associated with gain of function effect, possibly involved in pathogenesis of FD.