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Matteo Bellia, Mariangela Greco, Monia Lunghi, Riccardo Moia, Gianluca Gaidano, Andrea Patriarca Department of Translational Medicine, Division of Hematology, Universita’ del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, 28100, ItalyCorrespondence: Matteo Bellia, Department of Translational Medicine, Division of Hematology, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Via Solaroli 17, Novara, 28100, Italy, Tel +39-346-5988355, Email matteo.bellia@uniupo.itBackground: Jaundice and hyperbilirubinemia are common clinical problems characterized by the presence of bile pigments in the blood and their deposition in body tissues. This clinical condition can be associated with a broad spectrum of potential benign and malignant causes, including hepatic inflammation, biliary obstruction, impaired bilirubin conjugation and bilirubin overproduction Therefore, the hyperbilirubinemia diagnostic work-up sometimes can be highly challenging and its therapeutic management can require a multidisciplinary approach.Case Report: We report on a unique case of life-threatening jaundice and hepatic failure in a 20-year-old female who presented to the emergency room with complaints of fever, constant left abdominal pain and generalized profuse fatigue. A complete and detailed medical history, multiple tests for various infection, radiologic investigations and histological tests were performed in order to clarify the etiology of that rapidly progressive clinical condition. Based on the results, the patient jaundice was caused by an Epstein-Barr virus (EBV) infection and secondary cold agglutinin syndrome. Given the rare and complex diagnosis, multiple clinical specialists were asked to carry out the best patient management.Conclusion: This rare case highlights how challenging the differential diagnosis and treatment of hyperbilirubinemia can be, presenting a unique case of life-threatening multifactorial hepatic failure treated successfully with rituximab.Keywords: jaundice, Epstein-Barr virus infection, secondary cold agglutinin syndrome, rituximab

Liver transplantation (LT) is a potentially curative experimental treatment for unresectable intrahepatic cholangiocarcinoma (iCC). Pre-transplant downstaging may help defining tumor aggressiveness and drive patient selection. We report the preliminary results of LT for liver-limited unresectable iCC after sequential downstaging with systemic chemotherapy and radioembolization (SYS-TARE). In case of sustained disease stability after SYS-TARE, patients underwent surgical nodal sampling and, if negative, were listed for LT. In this study, 13 patients with unresectable iCC underwent downstaging with SYS-TARE. The median age was 70 years and 77% were female. All had single bulky lesions at diagnosis. After SYS-TARE, 9 (69%) dropped out: 3 due to progressive disease after TARE with no response to second-line, 4 due to extrahepatic disease development and 2 due to positive nodal disease at pre-listing abdominal exploration. The median OS after dropout was 11.5 months. Four (31%) were successfully listed and transplanted. At pathology, viable tumor ranged from 30% to less than 5%. All four patients are alive and disease-free at 73, 40, 12, and 8 months from LT. LT for unresectable iCC after downstaging with SYS-TARE appears to select suitable patients for LT, achieving optimal oncological outcomes in case of response to therapy and no lymphnodal spread.

TABLE OF CONTENTS INTRODUCTION 488 I. ALIENATING SOVEREIGN RIGHTS AT THE FOUNDING 494 A. The Background Rules 495 1. General Rules of Interpretation 498 2. Rules for the Adjustment of [...], Since the Constitution was first proposed, courts and commentators have debated the extent to which it alienated the States' preexisting sovereign immunity from suit by individuals. During the ratification period, these debates focused on the language of the citizen-state diversity provisions of Article III. After the Supreme Court read these provisions to abrogate state sovereign immunity in Chisholm v. Georgia, Congress and the States adopted the Eleventh Amendment to prohibit this construction. The Court subsequently ruled that States enjoy sovereign immunity independent of the Eleventh Amendment, which neither conferred nor diminished it. In the late twentieth-century, Congress began enacting statutes seeking to override state sovereign immunity. In reviewing these acts, the Court established that Congress may abrogate immunity when exercising its powers to enforce the Fourteenth Amendment, but not when exercising its Article I powers. This distinction is consistent with the original public meaning of the constitutional text understood in historical context. Recently, in a surprising turnabout, the Court abandoned this established paradigm by finding that the States agreed to an implied "structural waiver" of their sovereign immunity in the "plan of the Convention" whenever such immunity would "thwart" or "frustrate" the purpose underlying a congressional power that is "complete in itself." The Court's new purposive approach to state sovereign immunity is incompatible with the Constitution because it gives courts open-ended discretion to alter the federal-state balance established by the instrument. As Alexander Hamilton explained, because the Constitution "aims only at a partial union or consolidation," "the whole tenor of the instrument" requires adherence to "the rule that all authorities, of which the States are not explicitly divested in favor of the Union, remain with them in full vigor." Under this rule, the "plan of the Convention"--properly understood--divested the States of their sovereign rights only when it did so clearly and expressly or by unavoidable implication. By relying on a strongly purposive methodology to find implied structural waivers of state sovereign immunity, the Court's new approach disregards this fundamental rule and thus the Constitution itself.

Regorafenib is a multikinase inhibitor approved for treatment of patients with metastatic Colo-Rectal Cancer (mCRC) and Gastro-Intestinal Stromal Tumor (GIST) progression after the administration of other tyrosine-kinase inhibitors such as imatinib and sunitinib.Only a handful of severe side effects such as intestinal perforations and fistulas have been described in the literature in patients undergoing multikinase inhibitor treatment. We report a case of a patient with peritoneal mCRC who experienced an intestinal perforation during the administration of Regorafenib and review the literature. A 48-year-old man with previously resected sigmoid colon cancer and peritoneal metastatic disease under Regorafenib treatment presented to our Emergency Department with severe abdominal pain and asthenia. Abdominal X-ray and contrast-enhanced computed tomography examination revealed an intestinal perforation. The patient underwent emergency surgery which demonstrated acute diffuse peritonitis, necrosis, and perforation of a distal ileal loop affected by peritoneal metastatic disease. The necrosis of peritoneal implants on bowel walls could be regarded as a potential factor leading to intestinal perforation in metastatic colorectal cancer patients undergoing Regorafenib treatment complaining of severe abdominal pain and asthenia.Surgeons, radiologists and oncologists should always keep in mind this rare adverse event during Regorafenib administration. Appropriate diagnostic tests and treatments should be carried out.

IntroductionThis study investigates the interplay between body composition, dietary patterns, and physical activity across genders, focusing on gender-specific differences in food preferences and eating behaviors. Understanding these interactions is crucial for developing targeted nutritional and lifestyle interventions.MethodsA cross-sectional study was conducted with 1,333 participants (58.7% female, 41.3% male), aged 18–65 years. Participants were categorized into tertiles based on their fat mass to fat-free mass (FM-to-FFM) ratio. Data on dietary choices, eating behaviors, and physical activity were collected and analyzed to identify gender-specific trends.ResultsSignificant gender-specific differences were observed in food preferences and eating behaviors. Males experienced greater hunger in the late afternoon, while females felt more hunger in the morning. Males showed a preference for processed and red meats, whereas females preferred cooked vegetables. Eating behaviors such as meal skipping, uncontrolled eating, nocturnal eating, and taste preferences (sweet or salty) varied distinctly between FM-to-FFM tertiles and genders. Higher FM-to-FFM ratios correlated with lower physical activity levels, particularly in strength training and general sports engagement.DiscussionThese findings highlight the complex interactions between body composition, dietary habits, and lifestyle factors, emphasizing gender-specific differences. The results suggest that body composition and BMI significantly impact health-related behaviors, necessitating tailored interventions to address these differences and promote healthier lifestyles.

Purpose This research aims to look at the description of the characteristics and factors that influence the categories of income levels under class (vulnerable and poor) and aspiring middle class in informal sector labor in Indonesia 2022. Design/methodology/approach The dataset from raw data of the National Labor Survey (SAKERNAS) in February 2022 collected by Badan Pusat Statistik (BPS). This research used the ordinal logistic regression, model of partial proportional odds (PPOM). The dependent variable used is the income level category based on the classification determined by World Bank. Findings This research finds that 58 percent of the population are informal labor. The results of the analysis show that the level of education, job training, work experience, type of work, age, gender, marital status, working hours, and residential area classification have a significant effect on income level categories. Research limitations/implications This research only includes sample of informal sector labor who have income and based on the main job status classification from BPS. Originality/value In this research, income of informal sector labor are categorized based on classification determined by World Bank. Then there has not been much research on the characteristics of informal sector labor and what influences the level of their income category.

Abstract Obsessive Compulsive Disorder (OCD) is listed as one of the top 10 most disabling neuropsychiatric conditions in the world. The neurobiology of OCD has not been completely understood and efforts are needed in order to develop new treatments. Beside the classical neurotransmitter systems and signalling pathways implicated in OCD, the possible involvement of the endocannabinoid system (ECS) has emerged in pathophysiology of OCD. We report here selective downregulation of the genes coding for enzymes allowing the synthesis of the endocannabinoids. We found reduced DAGLα and NAPE-PLD in blood samples of individuals with OCD (when compared to healthy controls) as well as in the amygdala complex and prefrontal cortex of dopamine transporter (DAT) heterozygous rats, manifesting compulsive behaviours. Also mRNA levels of the genes coding for cannabinoid receptors type 1 and type 2 resulted downregulated, respectively in the rat amygdala and in human blood. Moreover, NAPE-PLD changes in gene expression resulted to be associated with an increase in DNA methylation at gene promoter, and the modulation of this gene in OCD appears to be correlated to the progression of the disease. Finally, the alterations observed in ECS genes expression appears to be correlated with the modulation in oxytocin receptor gene expression, consistently with what recently reported. Overall, we confirm here a role for ECS in OCD at both preclinical and clinical level. Many potential biomarkers are suggested among its components, in particular NAPE-PLD, that might be of help for a prompt and clear diagnosis.

Abstract BackgroundThe increasing demand for skin quality interventions in aesthetic medicine underscores the necessity for objective, evidence-based assessment tools that may be used to evaluate novel interventions or devices. ObjectivesTo develop and validate a 5-point photonumeric rating scale for assessing overall skin quality, including radiance, color evenness, and smoothness. MethodsThe IBSA (Institut Biochimique SA) Composite Skin Quality Scale was developed and underwent live validation with 88 real-world patients, chosen to encompass a broad spectrum of skin qualities and Fitzpatrick skin types. Scale validation was performed by board-certified plastic surgeons and dermatologists over 2 rounds, 2 weeks apart. Reliability was assessed through intrarater and interrater agreements, utilizing weighted kappa statistics and intraclass correlation coefficient (ICC). The scale’s ability to discern a clinically relevant 1-grade difference was evaluated with 72 photo pairs. ResultsCombined intrarater reliability results showed weighted kappa values of 0.812 (right side) and 0.815 (left side) and an ICC of 0.903 for both sides, indicating an almost perfect agreement. Interrater reliability ranged from substantial to almost perfect, with kappa coefficients between 0.654 and 0.853 and ICCs between 0.657 and 0.855 across all rater pairs in both rounds. The ability to detect a clinically relevant 1-point difference using the scale was established. ConclusionsIntegrating various key aspects of skin quality, the IBSA Composite Skin Quality Scale is a clinically relevant and highly reliable tool, suitable for skin assessment in clinical studies of new aesthetic technologies and products. Level of Evidence: 3

In this article I wish to demonstrate the value of a quality relationship and good communication in the therapeutic process of counselling and psychotherapy. From the very first session, it is important to establish a trusting interaction between the client and the therapist in order to achieve a correct assessment and to establish a meaningful therapeutic alliance. The article focuses on the skills of the therapist which are needed in psychotherapy and counselling, and critiques the restricted dogmatic positions in the literature that classify cases and methods according to pre-conceived criteria. I advocate for skilled therapists, who are able to use wisdom, discernment and intuition, and who are free from any binding external sources, so that they may assess every case according to its own complexities and uniqueness.

Abstract The potentially problematic use of the Internet is a growing concern worldwide, which causes and consequences are not completely understood yet. The neurobiology of Internet addiction (IA) has attracted much attention in scientific research, which is now focusing on identifying measurable biological markers. Aim of this study was to investigate epigenetic and genetic regulation of oxytocin receptor (OXTR), dopamine transporter (DAT1) and serotonin transporter (SERT) genes using DNA obtained from saliva samples of young university students: the Internet Addiction Test (IAT) was administered to evaluate the potential existence and intensity of IA. Significant changes in DNA methylation levels at OXTR, DAT1 and SERT genes were observed in the 30 50 subjects (considered as moderately addicted). Moreover, epigenetic markers were significantly correlated, either directly (for OXTR and DAT1) or inversely (OXTR and DAT1 versus SERT), to the psychometric properties. Our data confirmed the association of OXTR, DAT1 and SERT genes in processes related to behavioural addictions and might be of relevance to suggest possible biological predictors of altered behaviours and the eventual vulnerability to develop an IA. Different other genetic pathways have been suggested to play a role in IA and research is ongoing to better define them, in order to help in the early diagnosis as well as in the development of new potential treatments.

Background: Coping with stress is essential for mental well-being and can be critical for highly sensitive individuals, characterized by a deeper perception and processing of stimuli. So far, the molecular bases characterizing high-sensitivity traits have not been completely investigated and gene × environment interactions might play a key role in making some people more susceptible than others. Methods: In this study, 104 young adult university students, subjects that might face overwhelming experiences more than others, were evaluated for the genetics and epigenetics of dopamine (DAT1) and serotonin (SERT) transporter genes, in addition to the expression of miR-132, miR-491, miR-16, and miR-135. Results: We found an increase in DNA methylation at one specific CpG site at DAT1 5’UTR in highly sensitive students reporting high levels of perceived stress when compared to those less sensitive and/or less stressed. Moreover, considering DAT1 VNTR at 3’UTR, we observed that this effect was even more pronounced in university students having the 9/9 genotype when compared to those with the 9/10 genotype. These data are corroborated by the higher levels of miR-491, targeting DAT1, in highly sensitive subjects with high levels of perceived stress. SERT gene DNA methylation at one specific CpG site was reported to instead be higher in subjects reporting lower perceived stress when compared to more stressed subjects. Consistently, miR-135 expression, regulating SERT, was lower in subjects with higher perceived stress. Conclusions: We here suggest that the correlation of DAT1 and SERT genetic and epigenetic data with the analysis of stress and sensitivity might be useful to suggest possible biomarkers to monitor mental health wellness in vulnerable subjects.

Hyaluronic acid (HA)-based dermal fillers are among the most popular non-invasive facial aesthetic treatments. To ensure an effective and safe treatment experience, knowledge of their biophysical and rheological characteristics, such as: HA concentration, molecular weight (MW), G′, and the degree of cross-linking is essential. Products with a higher MW, G′, and degree of cross-linking are more suitable for promoting volume and lift. Dermal fillers with a lower MW, G′, and degree of cross-linking can produce a soft filling effect that regulates hydration and elasticity. This review discusses how these rheological characteristics can inform treatment choice and their effects on clinical outcomes. The Aliaxin® line of HA dermal fillers, which are tailored to different clinical applications due to their rheological characteristics, highlights that extensive knowledge of the product can provide very safe and effective procedures for patients, whilst respecting their natural facial aesthetics. This review discusses studies using Aliaxin® dermal fillers for volumizing and hydrating treatments and fillers that can be used for lip augmentation. Treatment with Aliaxin® was overall very effective, with no reported adverse events. A full facial treatment using tailored dermal fillers may be a future approach to achieve an effective and safe harmonized and natural aesthetic.

Abstract Background and Aims Hyaluronic acid (HA)‐based injections are used worldwide to improve skin defects associated with aging and ultraviolet light/environmental exposure. HA formulations developed according to molecular weight or with additional components, for example, cross‐linking reagents, are limited by their low biological activity and concentration limit. NAHYCO™ technology has enabled the production of hybrid cooperative complexes (HCCs) of low and high molecular weight HA. Developed for injection into the fat compartments of the face and previously demonstrating potential benefits for adipose tissue restoration, Profhilo Structura® is a new 2 mL HCC formulation comprising low molecular weight HA (45 mg/mL) and high molecular weight HA (45 mg/mL). To evaluate the efficacy and tolerability of Profhilo Structura® to restore adipose tissue compartments in the lateral cheek fat compartment. Methods Fifty healthy enrolled subjects received two injections, 1 month apart, and were evaluated 3 months posttreatment. Investigators performed clinical evaluations (Facial Volume Loss Scale [FVLS] and Wrinkle Severity Rating Scale [WSRS]) at different time points. Subjects also completed self‐evaluation assessments following treatment. Results A significant improvement in FVLS and WSRS clinical scores after the first treatment was observed; treatment benefit was maintained 3 months after treatment completion and confirmed by subject self‐assessment. Most participants reported an improvement, particularly a marked reduction of wrinkles and increased skin firmness. No serious adverse events were reported, confirming the excellent safety profile of HCC injectable devices. Conclusions Overall, the study highlighted the efficacy and tolerability of the studied medical device proving its effect on adipose tissue.

AimsAfter the acute phase of SARS-CoV-2 infection, the onset of glycemic impairment and diabetes have been reported. Nevertheless, the exact burden of glycemic impairment and diabetes after COVID-19 has not been clearly described.Materials and methodsElectronic search was run in Pubmed (MEDLINE), Web of Science, Scopus, and ClinicalTrial.org for reports published from database inception to September 2022. We included observational studies reporting quantitative data on diabetes prevalence or its onset in subjects with a history of SARS-CoV-2 infection from at least 60 days. Risk of bias was assessed by the JBI’s critical appraisal checklist. Random effect model was used to calculate pooled data. The review protocol was registered on PROSPERO (CRD42022310722).ResultsAmong 1,630 records screened, 20 studies were included in the analysis. The mean or median age of participants ranged from ~ 35 to 64 years, with a percentage of males ranging from 28% to 80%. Only two studies were considered at low risk of bias. The estimate of diabetes prevalence, calculated on a total of 320,948 participants pooled with 38,731 cases, was 16% (95%CI: 11-22%). The estimate of proportion of incident cases of diabetes was 1.6% (95%CI: 0.8-2.7%). Subgroup analysis showed that previous hospitalization increased the prevalence of diabetes and the proportion of incident cases.ConclusionDiabetes is common in individuals who have experienced SARS-CoV-2 infection, especially if they required hospitalization. This data may be helpful to screen for diabetes and manage its complications in individuals who experienced COVID-19.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022310722, identifier CRD42022310722.

Abstract BackgroundThe Hybrid Cooperative Complexes of high and low molecular weight hyaluronic acids (HHCC) improve skin structure and bioactivity. Massive weight loss damages cellular composition and morphological structure of skin. An injective treatment of postobese skin consisting of HHCC may have a role in counteracting these histopathological alterations. ObjectivesTo analyze the histological effects of HHCC injection in the cutaneous tissues of massive weight loss patients suffering from arm laxity. MethodsNine ex-obese patients with postweight-loss-related arm laxity and ptosis requiring brachioplasty were prospectively recruited at the first author's department. HHCC injection was performed on only 1 arm, which included 2 injective sessions separated by 30 days. One month posttreatment, patients underwent a bilateral brachioplasty, and the surgical specimens were histologically examined, searching for any variation in the cutaneous connective tissue following injections. Histology on treated specimens showed a statistically significant increased density of elastic fibers along with a lower fragmentation of the same fibers compared to the untreated tissue. Fibroblasts demonstrated a swollen appearance as if involved in a bioactivation process. ResultsTreatment with HHCC increases the number of elastin fibers and determines a more regular elastin deposition and architecture, as well as the bioactivation of fibroblasts. The contralateral untreated area showed an irregular structure with elastosis and elastolysis. ConclusionsMore studies are necessary, but histologically proven benefits are demonstrated in the HHCC-treated skins when compared with basal controlateral skin. These data support the use of HHCC formulations for the treatment of postobese skin laxity. Level of Evidence: 5

This paper aims to analyse recent studies which have raised new hypotheses concerning archaeomusicology, archaeoacoustics, and aural architecture as an emerging trend in humanities research, with a particular focus on the intersection of musical performances, theatrical spaces, and sound experience in the past. These studies have highlighted how theatrical buildings not only defined a place for performances, but also established the setting for multisensorial events in which music, dance, and other sonic events played an important role. This overview also takes into consideration how digital technologies can help shape our understanding of the architecture-sound nexus.

The aim of this work is to analyse recent studies which have raised new hypotheses concerning aural architecture as an emerging trend in humanities research, with a particular focus on the intersection of sacred space, rituals, and sound in the past. These studies have highlighted how sacred buildings not only defined a sacred place as a physical and symbolic expression of a specific form of worship but also established the setting for performative and multisensorial ceremonies in which music, dance, and other sonic events played an important role. In this contribution, we investigate studies on aural architecture to explore if the location of sacred spaces indicates whether ancient people reacted to ritual and musical developments by modifying sanctuaries or by designing and constructing new buildings and spaces for performances. In addition, this article explores studies on aural architecture to obtain an overview of how specific sonic features could have influenced the soundscape of sacred spaces, which consisted not only of songs, music, prayers, recitations and religious sonic and vocal utterances but also of natural elements, such as animals, water, and wind. This overview also takes into consideration how digital technologies and virtual acoustics can help shape our understanding of the architecture-sound nexus.

Background: Isolated tracheo-esophageal fistulas (TEF) are rare and challenging, possibly leading to severe complications. We evaluated the outcomes in a large series of patients treated in 9 referral Centers for airway surgery, and suggested an ideal management algorithm. Methods: A multicentric retrospective study on TEF was performed. Results: 186 cases were collected. Among 101 patients with recurrent TEF after EA repair, 1 was treated successfully with thoracoscopy, 23 with open surgery with TEF division and tissue interposition, with 15 complete resolution (65 %), 2 TEF recurrence (9 %) and 6 other complications (26 %), and 77 received TCA endoscopic cauterization, with complete resolution in 61 (79 %). Among 54 patients with congenital H-type fistula, 1 received conservative treatment with resolution; 4 underwent thoracoscopy (50 % resolution); 6 had endoscopic cauterization (33 % resolution); 44 received open surgery, with 43 (98 %) successes. In the last group, the majority of TEF was ligated and divided with tissue interposition. Among 26 post-traumatic fistulas (mechanical trauma, battery or caustic ingestion), 6 patients received endoscopic procedure and 5 of them (83 %) reached complete resolution. The other 19 received open surgery (trans-tracheal direct FTE closure with tracheal resection), and 12 had complete resolution (63 %). Two patients eventually died and complication rate was 23 %. Other 5 cases (3 Bronchial-Esophageal Fistulas and 2 TEF after cleft repair) were treated endoscopically or with open approach. Conclusion: Endoscopic cauterization can be the preferred treatment for recurrent TEF after EA, while for the congenital H-type and post-traumatic TEF the open approach remains our first choice.