322590 research outputs found
Sort by
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
Get PDFThe 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
Get PDFBackground/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
Get PDFWe prove the Singer conjecture for varieties with semismall Albanese map and residually finite fundamental group
Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration
No full textVanishing White Matter Disease (VWMD) is a devastating, currently incurable neurodevelopmental disorder primarily affecting white matter. The prevailing view attributes VWMD to the activation of the canonical integrated stress response (c-ISR). However, recent studies have identified a novel, distinct pathway called the split ISR (s-ISR), though its activation has so far only been documented in mouse stem cells harboring a single eIF2B mutation, leaving uncertainty about whether it occurs in human cells, whether other mutations can trigger it, and what role it plays in the disease. Here, we used prime editing (PE) to engineer multiple eIF2B pathogenic mutations into HEK293T and induced pluripotent stem cells (iPSCs), generating human models. We demonstrated PE's effectiveness and safety, marking the first successful application of PE for modeling VWMD. We found that all modeled mutations activate the s-ISR, indicating that this response is a common feature across VWMD mutations, and that it can be further amplified by stress-induced c-ISR and effectively suppressed by ISRIB. Mechanistically, we show that s-ISR hinders mutant iPSCs from achieving the high protein synthesis levels necessary for proper differentiation, expecially into astrocytes. This impairment disrupts their maturation process, directly linking s-ISR activation to the white matter abnormalities of VWMD
A Haldane–Anderson Hamiltonian model for hyperthermal hydrogen scattering from a semiconductor surface
No full textCollisions of atoms and molecules with metal surfaces create electronic excitations in the metal, leading to nonadiabatic energy dissipation, inelastic scattering, and sticking. Mixed quantum-classical molecular dynamics simulation methods, such as molecular dynamics with electronic friction, are able to capture nonadiabatic energy loss during dynamics at metal surfaces. Hydrogen atom scattering from semiconductors, on the other hand, exhibits strong adsorbate-surface energy transfer only when the projectile kinetic energy exceeds the bandgap of the substrate. Electronic friction fails to describe this effect. Here, we report a first-principles parameterization of a simple Haldane–Anderson Hamiltonian model of hydrogen atom gas-surface scattering on Ge(111)c(2 × 8), for which hyperthermal scattering experiments have been reported. We subsequently perform independent-electron surface hopping and Ehrenfest dynamics simulations on this model and validate these results through numerically exact quantum-dynamical simulations using the hierarchical equation of motion approach. While mean-field dynamics yield weak nonadiabatic energy loss that is independent of the initial kinetic energy, independent electron surface hopping simulations qualitatively agree with the experimental observation that nonadiabatic energy dissipation only occurs if the initial kinetic energy exceeds the bandgap of the surface
Drell-Yan lepton pair production at low invariant masses: transverse-momentum resummation and non-perturbative effects in QCD
No full textWe consider the transverse-momentum (q(T)) distribution of Drell-Yan lepton pairs produced with invariant masses (M) from low values up to the Z-boson peak (4 <= M <= 116 GeV). We present perturbative predictions obtained by consistently combining the resummation of logarithmically enhanced QCD corrections at small q(T) (q(T) << M) up to next-to-next-to-next-to-next-to-leading logarithmic accuracy with the available fixed-order calculations at next-to-next-to-leading order (i.e. O (alpha(3)(S)) valid at large q(T). For very low q(T) (q(T) similar to Lambda(QCD)), non-perturbative (NP) QCD effects become dominant and have been included through a NP form factor with a small number of free-parameters. We compare our results with multiple experimental datasets from hadron colliders, finding excellent agreement between theory and data. By fitting the NP parameters, we achieve a precise extraction of the NP form factor and the so-called Collins-Soper kernel