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Efficacy of liver transplantation after response to atezolizumab-bevacizumab downstaging of intermediate and advanced hepatocellular carcinoma (ImmunoXXL)
No full textBackground & aims: Liver transplantation (LT) is a curative treatment in early and intermediate hepatocellular carcinoma (HCC) after downstaging with locoregional therapies (LRT). Tumor response to immune check-point inhibitors may extend LT eligibility to intermediate and advanced stages. Methods: In this prospective phase II study, intermediate and advanced HCCs beyond extended transplant criteria, not amenable to further locoregional treatments and downstaged with atezolizumab-bevacizumab (Atezo-Bev) underwent LT. Primary endpoint was recurrence-free survival (RFS) with safety and efficacy as additional registered outcomes. Spectral quantitative pathology and immune signatures on tumor tissue and in peripheral blood were longitudinally studied. Results: 16 HCC patients presenting beyond expanded transplant criteria [median size: 6.5 cm (IQR: 3-8), median AFP 283 (IQR: 6-1080), portal vein thrombosis: 50%] were downstaged to LT after a median of 4.7 months (IQR: 2.4-7.6). Previous LRTs were employed in 15 (94%) patients. Washout period from last Atezo-Bev to transplant was 57.5 (IQR: 29-87) days. Median follow-up was 16 (95%CI: 4-22) months. Pre-transplant immune-related adverse events occurred in 3 (19%) patients while post-transplant acute rejection in 4 (25%). Post-LT 90-day morbidity and mortality were 62.5% (95%CI: 35-85%) and 6.3% (95%CI: 0.2-30%) respectively. Explant pathology revealed 10 complete and 6 partial responses. Responding patients harboured a tumour microenvironment with features suggestive of immune activation/extinguishment, correlated with duration of Atezo-Bev treatment and length of pre-LT washout. One (6.2%) HCC post-LT recurrence occurred during follow-up. Recurrence-free and post-transplant overall survival were 90% and 94% after 2 years, respectively. Conclusions: LT after Atezo-Bev is characterized by competitive RFS estimates in intermediate and advanced HCC presenting beyond transplant indications. Acute rejection seems increased but remains clinically manageable. LT should be considered after HCC response to immunotherapy
Person-centred care in congenital heart disease: Intercountry variation in patient-reported experiences across 32 countries
No full textIntroduction: Person-centred care (PCC) is widely recommended by the World Health Organisation and other leading healthcare organisations. Although individuals with congenital heart disease (CHD) require lifelong follow-up, it remains unclear whether healthcare systems worldwide provide PCC to this population. This study investigated one key component of PCC, autonomy support, using patient-reported experiences in a global sample of adults with CHD. Methods: The study was part of the international cross-sectional APPROACH-IS-II. Data were obtained from 8367 adults with congenital heart disease across 53 centres in 32 countries. Perceived autonomy support was measured using a modified version of the Health Care Climate Questionnaire. A general linear mixed model was used to analyse the data. Results: Autonomy support scores ranged from 27.9 (SD ± 9.4) to 37.7 (SD ± 6.3) on a six - 42 point scale. A significant clinical difference in perceived autonomy was observed, with calculated effect sizes using Cohen's D exceeding eight in several countries. Higher autonomy scores were associated with having a high school diploma and older age. Patient characteristics accounted for 1.4 % of the variance, while geographical location explained 7.5 %. A large proportion of the variance remained unexplained. Conclusion: This study highlights significant global differences in perceived autonomy support from healthcare providers among adults with CHD. Education and age were associated with higher levels of perceived autonomy support. The experience of PCC is challenged by diverse expectations of individuals and families, healthcare providers' beliefs and values, institutional policies, and broader sociocultural contexts
Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants
No full textBackground and aims Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. Methods We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. Results The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. Conclusions Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances
Reduced neuroinflammation and pain with a functional sourdough bread enriched with legumes and ancient cereals in a mouse model of LPS-induced inflammation
No full textNutritional strategies based on sourdough fermented breads with wholemeal ancient grains and legumes are emerging as promising modulators of (neuro)immune processes. This study investigated whether prolonged consumption of a sourdough bread enriched with a mixture of ancient cereals and legumes, commercially available in Italy (Primus® bread, P®B), modulates neuroimmune systemic responses to repeated lipopolysaccharide (LPS) challenge in mice. For this study, male C57BL/6J mice were fed for 14 days with either a standard diet (SD) or P®B. Animals then received intraperitoneal LPS (3 mg/kg/day for 3 days) or vehicle. Body weight and food intake were monitored throughout. Pain-like behaviours were assessed by von Frey, plantar and tail flick tests, and plasma cytokine (32-plex panel), splenocyte and peritoneal macrophage cytokine expression, and expression of pro-inflammatory cytokines in sciatic nerves, dorsal root ganglia (DRG) and the spinal cord were analyzed by Reverse Transcription–quantitative Polymerase Chain Reaction (RT-qPCR). P®B prevented LPS-induced body weight loss and reduced splenomegaly. Unlike SD mice, which exhibited widespread plasmatic cytokine upregulation, P®B-fed mice displayed only limited increases Interleukin (IL)-1β, IL-12p40 and Tumor Necrosis Factor (TNF)α. Ex vivo cultures of splenocytes and macrophages confirmed attenuated cytokine overexpression. LPS-induced hypersensitivity to mechanical, thermal and nociceptive stimuli was significantly reduced in P®B mice. Molecular analyses revealed that the P®B diet blunted the pro-inflammatory cytokine expression present after LPS challenge in the sciatic nerves and DRG, with partial attenuation in the spinal cord. Our findings highlight the great potential of functional foods as affordable dietary strategies to mitigate systemic immune and neuroimmune dysregulatio
Unsupervised noisy image segmentation using deep image prior
Full text linkThe so called Deep Image Prior paradigm stands as an exceptional advancement at the intersection of inverse problems and deep learning. By leveraging the inherent regularization properties of deep networks, Deep Image Prior has recently emerged as a landmark approach in addressing various imaging problems, including denoising, JPEG artifacts removal, inpainting, and super-resolution. The aim of this paper is to extend the Deep Image Prior idea to the segmentation of noisy images in order to benefit of both traditional variational models and new deep learning techniques. Indeed the resulting method consists of an unsupervised deep learning approach based on the minimization of very well known variational energies (such as the Mumford–Shah functional and its approximation proposed by Ambrosio and Tortorelli) properly parametrized in terms of the weights of convolutional neural networks. The implicit regularization provided by the network allows to make the traditional variational models more robust with respect to both the noise corrupting the data and the selection of the parameters which balance the role of the regularization terms. Several numerical experiments on noisy segmentation problems show promising results of the suggested approach
Regional Inequities in the Distribution of the Nursing Workforce in Italy
Full text linkBackground/Objectives: Inequalities in access to nursing professionals represent a significant challenge to achieving equity in healthcare systems. In decentralized countries like Italy, disparities in the distribution of nurses persist despite a universal national health system. This study investigates the extent and determinants of regional inequality in the distribution of the nursing workforce in Italy. Methods: A retrospective ecological analysis was conducted using administrative data from official national sources (ISTAT, Ministry of Health) concerning the number of nurses and population per region, along with Human Development Index (HDI) data from 2021. Descriptive statistics, the Gini coefficient, Lorenz curve, and Pearson correlation were used to assess inequality and identify influencing factors. Results: The national Gini coefficient was 0.136, indicating a moderate degree of inequality in the distribution of nurses across Italian regions. A strong positive correlation was observed between HDI and nurse-to-population ratio (r = 0.76, p < 0.001), suggesting that more developed regions have higher nursing density. Conclusions: Despite a universal healthcare system, Italy shows persistent regional disparities in nurse distribution. These findings emphasize the need for targeted policies and coordinated planning to reduce inequalities and ensure equitable access to nursing care across all regions
Singer conjecture for varieties with semismall Albanese map and residually finite fundamental group
Full text linkWe prove the Singer conjecture for varieties with semismall Albanese map and residually finite fundamental group
Dernière Vague et Hard Transmedia : une lecture des enjeux scénaristiques dans Pauvre Folle (2023) et Phallers (2024) de Chloé Delaume
No full textThis article examines the significance of transmedia choices in two of Chlo�e
Delaume’s most recent works, Pauvre folle Delaume (2023) and Phallers
(2024c), within the context of feminist discourse and the evolving cultural
landscape of the post-#MeToo era. Engaging with themes of gender-based
violence, Delaume challenges the dominant narratives shaping mainstream
imagination, instead advocating for a radical subversion of conventional gen-
dered representation. This shift also necessitates a reconsideration of media
strategies for conveying a message that overturns the perception of women
as victims. Employing humor and gore as subversive narrative tools, Delaume
seeks to extend her storytelling beyond the literary sphere (“hard trans-
media”) to navigate the strenuous constraints imposed by patriarchal barriers
in the show business, which continue to hinder the dissemination of counter-
discourses within popular visual culture. By examining the narrative and
esthetic transitions between Pauvre Folle and Phallers, this study elucidates
how Delaume’s work actively engages with civil society, fostering a reconfig-
uration of collective consciousness to reshape socio-cultural scenarios
OPPORTUNITIES AND CHALLENGES OF BIOCATALYSIS IN PHARMACEUTICAL SCIENCES: DEVELOPING TAILORED BIOCATALYSTS FOR SYNTHETIC APPLICATIONS
No full textBiocatalysis has emerged as a powerful and sustainable alternative to traditional chemical synthesis, particularly in the preparation of stereochemically complex pharmaceutical intermediates. This doctoral research focuses on the development of tailored biocatalysts, specifically amine transaminases (ATAs), for the synthesis of pharmaceutically relevant compounds. To overcome typical limitations of wild-type enzymes, such as insufficient operational stability and narrow substrate scope, two complementary strategies were applied: enzyme immobilization and protein engineering.
First, a biocatalytic cascade combining the ThDP-dependent enzyme Ao:DCPIP OR with stereoselective ATAs was established for the synthesis of (1S)-nor(pseudo)ephedrine analogues. The cascade was further optimized by covalent enzyme immobilization, enabling enhanced stability, efficient reuse, and integration into continuous-flow processes. This resulted in improved productivity, excellent stereoselectivity, and a more sustainable synthetic route.
A second enzymatic workflow was developed for the synthesis of piperidine scaffolds, key intermediates in bioactive molecules. After identifying suitable ATAs and optimizing reaction conditions, the enzyme was immobilized and the process was transferred to a packed-bed flow reactor, achieving high conversion and diastereomeric excess.
Finally, the (S)-selective Sbv333-ATA was biochemically and structurally characterized, revealing notable thermostability and solvent tolerance. Site-directed mutagenesis led to variants with an expanded substrate scope toward sterically demanding amines. Directed evolution efforts aimed at improving asymmetric amination are currently ongoing.
Overall, this work highlights how biocatalysis is consolidating its role as an essential resource in modern synthetic chemistry. Technological advances are progressively shifting the paradigm from the passive use of naturally available enzymes to the proactive creation of optimized catalysts tailored for specific needs. In this perspective, the results achieved in this thesis provide a valuable contribution to the development of next-generation biocatalytic processes for the synthesis of chiral amines and exemplify the transformative potential of enzyme tailoring for the future of chemical manufacturing
