IRIS UniSR (’Università Vita-Salute San Raffaele)
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La percezione dell’ingiustizia nei primati non-umani. Per un’indagine comparativa interspecifica della giustizia
No full textRecenti ricerche sulla esistenza di forme di normatività nel mondo sociale degli animali suggeriscono tuttavia nuove domande per l’indagine della giustizia: l’idea di giustizia ha senso solo nel mondo umano o può avere senso anche in natura, nel mondo degli animali non-umani? In altre parole, c’è spazio per la giustizia nel mondo animale o questo è solo un mondo dove domina la legge del più forte, cioè un mondo dominato da rapporti di mera forza bruta (un “might is right” world)
Assessment of long-term outcomes following Milligan-Morgan hemorrhoidectomy with Doppler transperineal ultrasound and endoscopy: a pilot study
Get PDFPurpose: Hemorrhoidectomy remains the gold-standard treatment for advanced hemorrhoidal disease, but long-term outcomes vary depending on the surgical technique and assessment method. This study aims to show the long-term results achieved using a combination of transperineal ultrasound (TPUS) and endoscopy in patients who underwent Milligan-Morgan hemorrhoidectomy (MM). Methods: A consecutive series of MM patients treated between February 2020 and December 2023 were contacted and underwent a clinical proctological evaluation, a Doppler TPUS, and an endoscopic check of the anal canal. All investigations were performed using the ESAOTE MyLab XPRO80. TPUS anatomy, including Doppler views, was assessed on the axial, sagittal, and coronal planes. Outcome measures consisted of the description of Doppler TPUS modifications following MM, and their relationship with clinical and endoscopic findings. Results: Twenty-three patients were available for the analysis at 26 months of follow-up (range 14–48). Fifteen patients had a Doppler vascular pattern (65.2%), eight patients a scattered pattern (34.8%). No correlation was present between residual symptoms and the Doppler vascular pattern (p = 0.089). The vascular pattern was associated with endoscopic signs of recurrences (p = 0.003), and its absence was able to predict the lack of internal recurrences in all patients (100%). Conclusion: Doppler TPUS could help in the long-term assessment of patients presenting residual symptoms after MM. If confirmed in larger future cohort studies, the 100% negative predictive value of the vascular pattern could be used to exclude internal recurrences during postoperative follow-up
Comparable glycemic outcomes with insulin glargine and insulin degludec during exercise in adolescents with type 1 diabetes using a standardized management protocol
No full textExploring and Mapping the Lived Experiences of Stigma Among People Living with a Mental Illness: A Scoping Review of Qualitative Studies
Get PDFAbstract Introduction. Stigma affects a large proportion of people with mental health conditions and it can be a potent social stressor, presenting persistent challenges to individuals’ coping abilities. The present study aimed at mapping and exploring the direct experiences of stigma encountered by individuals with mental health conditions. Methods. A scoping review was conducted according to Joanna Briggs Institute guidelines. Searches of PubMed, PsycINFO, EmBASE, and CINAHL led to 18 eligible qualitative studies. Results. Four primary themes emerged: self-stigma, involving the internalization of societal stereotypes; descriptions of social and public stigma; lack of knowledge in mental illnesses’ course; and the consequences of stigma for individuals’ lives. Discussion. Results highlight the deeply negative and exclusionary impact of stigma surrounding mental disorders, outlining its manifestation and repercussions for social life. Future research is needed to identify a direct approach to the issue and to detect the most appropriate approaches in facing it. To help limiting the experience of stigma, healthcare providers should ensure an individualized care relationship, in a secure and empathetic environment filled with elements of understanding, consent and informativeness
Association of candidate surrogate endpoints with overall survival in advanced biliary tract cancer
No full textBackground & aims: The use of surrogate endpoints in trials including biliary tract cancers (BTC) is growing. While this may expedite drug approval and decrease costs, it may not always correlate with an overall survival (OS) advantage. We aimed to explore the association of progression-free survival (PFS), objective response rate (ORR) and disease-control rate (DCR) with OS at the trial- and patient-level. Methods: For the trial-level analysis, we performed a systematic review of Pubmed/MEDLINE, Embase, Cochrane, clinicaltrials.gov and conference proceedings for phase II-III trials in advanced BTC. We used a weighted linear regression to measure the correlation of OS with PFS, ORR and DCR. For the patient-level analysis, we analyzed patients included in five randomized trials and three real-world datasets. The protocol is registered with PROSPERO, CRD42023398279. Results: For the trial-level analysis, we included 41 studies, involving 88 treatment arms and 7817 patients. The coefficient of determination (R2) of the model was 0.71 (95% CI 0.56-0.86) for PFS, 0.01 (0-0.08) for ORR and 0.39 (0.14-0.64) for DCR. Predefined subgroup analysis showed consistent results. For the patient-level analysis, we included a total of 2506 patients, 783 in randomized trials (first-line 512, second-line 271) and 1723 in routine clinical care (first-line chemotherapy 773, first-line chemotherapy-durvalumab 628, second-line chemotherapy 322). Across the distinct datasets, the correlation coefficient ranged from 0.73 to 0.86 for PFS. A responder analysis found no association between response and survival. Conclusion: PFS shows a moderate correlation with OS both at the trial- and patient-level, while ORR and DCR show a low correlation. Whilst PFS is currently the best candidate surrogate marker for OS, our results highlight the need for novel endpoints in this field. Impact and implications: The use of validated surrogate endpoints in biliary tract cancer trials may decrease costs and improve study feasibility, particularly with agents that only target small subsets of patients or in trials that incorporate a cross-over design. A formal statistical validation of surrogacy requires patient-level and trial-level data. This is the first comprehensive analysis to incorporate novel agents (including immunotherapies and targeted agents), include patient-level data and rigorously and homogeneously extract appropriate measures of treatment effect for endpoint correlation. These results show a moderate correlation for progression-free survival both at the trial- and patient-level and a low correlation for disease-control rate and response rate. This information will aid clinicians in appropriately interpreting contemporary clinical trials and guide clinical researchers and trial sponsors involved in clinical trial design. Furthermore, it has important implications for the regulatory approval process and may aid agencies in appropriately evaluating novel drugs
Notizie che violano le regole del giornalismo: un approccio istituzionale alle fake news sul cambiamento climatico
No full textQuesta tesi ridefinisce il concetto filosofico di fake news per affrontare un problema di
necessità concettuale e analizzare in modo più efficace i casi di fake news legati al
cambiamento climatico. Gli obiettivi vengono sviluppati in quattro capitoli: i primi tre
sono dedicati alla ridefinizione del concetto, mentre l’ultimo lo applica al contesto del
cambiamento climatico.
Il Capitolo I esamina le basi storiche e definitorie del concetto di fake news,
ripercorrendo la sua evoluzione e le relative sfide concettuali. Attraverso l’analisi delle
definizioni conservative e privative di fake news in epistemologia, il capitolo ne critica
la ridondanza e sottolinea la necessità di un approccio diverso.
Il Capitolo II sviluppa una nuova concezione della notizia come entità istituzionale,
ispirandosi alla teoria dei fatti istituzionali di John Searle. Da questa prospettiva, le
notizie sono definite come una funzione di status che discende dalle pratiche
giornalistiche, le quali attribuiscono specifici diritti e obblighi sia ai produttori che ai
consumatori di notizie. Inquadrando le notizie come costrutti istituzionali, il capitolo
affronta i limiti degli approcci conservativi e privativi, risolvendo alcune ambiguità e
sottolineando le aspettative normative che distinguono le notizie da altre forme di
comunicazione.
Il Capitolo III propone una nuova definizione di fake news come notizie che non
meritano il loro status, articolata in due dimensioni complementari. La prima (FNA)
riguarda le violazioni delle norme giornalistiche, come la mancanza di verifica o
trasparenza. La seconda (FNB) si riferisce al mancato soddisfacimento delle aspettative
realistiche dei consumatori, basate sugli standard giornalistici. Integrando queste
prospettive, focalizzate rispettivamente sui produttori e sui consumatori, il capitolo offre
un quadro completo per comprendere le fake news sia come violazione normativa sia
come tradimento delle aspettative del pubblico.
Il Capitolo IV applica questa ridefinizione al cambiamento climatico, distinguendo le
fake news climatiche dalla disinformazione. Analizza casi in cui le notizie sul clima
violano le norme giornalistiche, ad esempio titoli ingannevoli o articoli che sfruttano i
pregiudizi del pubblico. Questi esempi mostrano come le fake news possano rafforzare
credenze preesistenti senza diffondere direttamente falsità, utilizzando strategie più
sottili per influenzare il pubblico. Il capitolo si conclude con un invito a sviluppare
strumenti analitici più sofisticati per affrontare le diverse sfaccettature
dell’intenzionalità nei fenomeni di disinformazione, in particolare quelli che
coinvolgono le predisposizioni del pubblico.
Ancorando il concetto di fake news alle norme e alle aspettative giornalistiche,
questa tesi intende offrire un quadro utile per una maggiore chiarezza concettuale e
un’analisi pratica, soprattutto in contesti come il cambiamento climatico, in cui il
termine “fake news” viene spesso confuso con la disinformazione.This dissertation redefines the philosophical concept of fake news to address an issue of
conceptual necessity and to analyze cases of fake news related to climate change more
effectively. These objectives are addressed in four chapters, with the first three focusing
on redefining the concept and the final chapter applying it to climate change.
Chapter I explores the historical and definitional foundations of fake news, tracing its
evolution and conceptual challenges. By examining conservative and privative accounts
in epistemology, the chapter critiques their redundancy and highlights the necessity for a
different approach.
Chapter II develops a novel understanding of news as an institutional entity, drawing
on John Searle’s theory of institutional facts. This perspective conceptualizes news as a
status function stemming from journalistic practices, which confer specific rights and
obligations on both producers and consumers. By framing news as an institutional
construct, the chapter addresses the limitations of privative and conservative
approaches, resolving ambiguities while emphasizing the normative expectations that
distinguish news from other forms of communication.
Chapter III introduces a redefined notion of fake news as news that does not deserve
its status, bifurcated into two complementary dimensions. The first (FNA) pertains to
violations of journalistic norms, such as failures in verification or transparency. The
second (FNB) reflects the failure of news to meet realistic consumer expectations
informed by journalistic standards. By integrating these producer-and-consumer-
focused perspectives, the chapter provides a comprehensive framework for
understanding fake news as both a normative breach and a failure to fulfill public trust.
Chapter IV applies this redefinition to climate change, differentiating climate fake
news from disinformation. It examines cases where climate news violates journalistic
norms, such as deceptive headlines or articles exploiting audience biases. These cases
reveal how fake news can reinforce pre-existing beliefs without directly disseminating
falsehoods, employing a subtler strategy to influence perception. The chapter concludes
by advocating for refined analytical tools to address the diverse notions of intentionality
in disinformation phenomena, particularly those involving audience predispositions.
By anchoring fake news in journalistic norms and expectations, this thesis offers a
framework for conceptual clarity and practical analysis, especially in contexts like
climate change, where the term is frequently conflated with disinformation
A practical approach to uveitis screening in children with juvenile idiopathic arthritis
No full textBackground Juvenile idiopathic arthritis (JIA)associated uveitis typically presents as a silent chronic anterior uveitis and can lead to blindness. Adherence to current screening guidelines is hampered by complex protocols which rely on the knowledge of specific JIA characteristics. The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to simplify screening to enable local eye care professionals (ECPs), who carry the main burden, to screen children with JIA appropriately and with confidence. Methods A consensus meeting took place in January 2023 in Barcelona, Spain, with an expert panel of 10 paediatric rheumatologists and 5 ophthalmologists with expertise in paediatric uveitis. A summary of the current evidence for JIA screening was presented. A nominal group technique was used to reach consensus. Results The need for a practical but safe approach that allows early uveitis detection was identified by the panel. Three screening recommendations were proposed and approved by the voting members. They represent a standardised approach to JIA screening taking into account the patient’s age at the onset of JIA to determine the screening interval until adulthood. Conclusion By removing the need for the knowledge of JIA categories, antinuclear antibody positivity or treatment status, the recommendations can be more easily implemented by local ECP, where limited information is available. It would improve the standard of care on the local level significantly. The proposed protocol is less tailored to the individual than the’gold standard’ ones it references and does not aim to substitute those where they are being used with confidence.Background Juvenile idiopathic arthritis (JIA)associated uveitis typically presents as a silent chronic anterior uveitis and can lead to blindness. Adherence to current screening guidelines is hampered by complex protocols which rely on the knowledge of specific JIA characteristics. The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to simplify screening to enable local eye care professionals (ECPs), who carry the main burden, to screen children with JIA appropriately and with confidence. Methods A consensus meeting took place in January 2023 in Barcelona, Spain, with an expert panel of 10 paediatric rheumatologists and 5 ophthalmologists with expertise in paediatric uveitis. A summary of the current evidence for JIA screening was presented. A nominal group technique was used to reach consensus. Results The need for a practical but safe approach that allows early uveitis detection was identified by the panel. Three screening recommendations were proposed and approved by the voting members. They represent a standardised approach to JIA screening taking into account the patient’s age at the onset of JIA to determine the screening interval until adulthood. Conclusion By removing the need for the knowledge of JIA categories, antinuclear antibody positivity or treatment status, the recommendations can be more easily implemented by local ECP, where limited information is available. It would improve the standard of care on the local level significantly. The proposed protocol is less tailored to the individual than the’gold standard’ ones it references and does not aim to substitute those where they are being used with confidence
DEFINITION OF MOLECULAR NETWORKS OF ERYTHROPOIESIS AND HEMATOPOIESIS IN BETA-THALASSEMIA
No full textThe hematopoietic stem cell (HSC) compartment is an heterogenous pool which
promptly and dynamically responds to inflammation, anaemia and other stress, thus
adapting the hematopoietic process to peculiar physiological demands. The anaemia and
the ineffective erythropoiesis together with the impairment of the bone marrow (BM)
microenvironment give to Beta-thalassemia (Bthal) features of ‘stress related disease’.
Nevertheless, how inflammation and chronic anaemia have an impact on primitive HSCs,
thus shaping their lineage commitment and the hematopoietic process, is still missing.
Our recent findings revealed for the first time that Bthal HSCs have an enhanced
erythroid potential and transcriptome profile unveiled downregulation in pathways
related to inflammation involved in the control of HSC quiescence and differentiation,
such as TNFα via-NFkB signalling. We hypothesized that stress conditions in Bthal BM
niche (i.e. iron overload, ROS accumulation, marrow expansion) alter the activation of
NFkB pathway in HSCs, enhancing their preferential differentiation towards the erythroid
lineage.
We found low basal NFkB p65 activation in Bthal HSCs, whereas Megakaryocyte
(Mk)/Erythroid (E) biased-MPPs (MPPsMk/E) showed an active one, suggesting their
major role in sustaining the haematopoiesis. We uncovered that Bthal BM plasma is
characterized by high dose of TNFα, and preliminary results supported the involvement
of CD4+ T cells, increased in frequency compared to control, as main TNFα producers.
In vitro and in vivo studies with TNFα and NFkB inhibitors revealed that MPPsMk/E, but
not Bthal HSCs, are the cells able to respond to additional inflammatory stimulus and a
deregulated NFkB signalling enhances the erythroid commitment. Importantly, in vivo
treatments reducing TNFα levels restores the balance in the differentiation potential of
Bthal HSCs, thus corroborating, for the first time, the role of this inflammatory molecule
on lineage commitment in a disease different from haematological malignancy.
Our study will provide new insights in the hematopoietic process in Bthal helping
to develop new strategies to preserve HSC functionality and restore the balance of the
hematopoietic commitment, to be combined with gene therapy (GT) approach.Il compartimento delle cellule staminali ematopoietiche (CSE) è un gruppo eterogeneo che risponde prontamente e dinamicamente all'infiammazione, all'anemia e ad altri stress, adattando così il processo ematopoietico a peculiari esigenze fisiologiche. L’anemia e l’eritropoiesi inefficace insieme al deterioramento del microambiente del midollo osseo (MO) conferiscono alla Beta-talassemia (Btal) caratteristiche di “malattia correlata allo stress”. Tuttavia, non è ancora chiaro il modo in cui l'infiammazione e l'anemia cronica abbiano un impatto sulle CSE primitive, modellando così il loro impegno di lignaggio e il processo emopoietico.
Le nostre recenti scoperte hanno rivelato per la prima volta che le CSE Btal hanno un potenziale eritroide potenziato e un profilo trascrittomico ha rivelato un livello di espressione più bassi nei percorsi correlati all'infiammazione coinvolti nel controllo della quiescenza e della differenziazione delle CSE, come la segnalazione del TNFα tramite NFkB. Abbiamo ipotizzato che le condizioni di stress nella nicchia Btal MO (cioè sovraccarico di ferro, accumulo di specie reattive all’ossigeno, espansione del midollo) alterano l'attivazione della via NFkB nelle CSE, migliorando la loro differenziazione preferenziale verso la linea eritroide.
Abbiamo trovato una bassa attivazione basale di NFkB p65 nelle CSE di Btal, mentre i progenitori multipotenti (MPP) polarizzati da megacariociti (Mk)/eritroidi (E) (MPPsMk/E) hanno mostrato un'alta attivazione basale, suggerendo il loro ruolo principale nel sostenere l'ematopoiesi. Abbiamo scoperto che il plasma MO di Btal è caratterizzato da un'elevata dose di TNFα e i risultati preliminari hanno supportato il coinvolgimento delle cellule T CD4+, con frequenza maggiore rispetto al controllo, come principali produttori di TNFα. Studi in vitro e in vivo con inibitori del TNFα e NFkB hanno rivelato che le MPPs Mk/E, ma non le CSE Btal, sono le cellule in grado di rispondere a stimoli infiammatori aggiuntivi e una segnalazione deregolamentata di NFkB migliora l'impegno eritroide. È importante sottolineare che i trattamenti in vivo che riducono i livelli di TNFα ripristinano l’equilibrio nel potenziale di differenziazione delle CSE Btal, corroborando così, per la prima volta, il ruolo di questa molecola infiammatoria sul processo differenziativo in una malattia diversa dalla neoplasia ematologica.
Il nostro studio fornirà nuove informazioni sul processo ematopoietico in Btal aiutando a sviluppare nuove strategie per preservare la funzionalità delle CSE e ripristinare l'equilibrio dell'impegno ematopoietico, da combinare con l'approccio della terapia genica
Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models
Get PDFValproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery
Modelling pathological spread through the structural connectome in the frontotemporal dementia clinical spectrum
No full text: The ability to predict the pathology spreading in patients with frontotemporal dementia (FTD) is crucial for early diagnosis and targeted interventions. This study examined the relationship between network vulnerability and longitudinal atrophy progression in FTD patients, using Network Diffusion Model (NDM) of pathology spread. Thirty behavioural-variant FTD (bvFTD), 13 semantic-variant primary progressive aphasia (svPPA), 14 nonfluent-variant PPA (nfvPPA) and 12 semantic behavioral variant FTD (sbvFTD) patients underwent longitudinal T1-weighted MRI. Fifty young controls (YC) (20-31 years) underwent multi-shell diffusion MRI scan. NDM was developed to model FTD pathology progression as a spreading process from a seed through the healthy structural connectome, using connectivity measures from fractional anisotropy (FA) and intra-cellular volume fraction (ICVF) in YC. Four disease epicenters were initially identified from the peaks of atrophy of each FTD variant: left insula (bvFTD), left temporal pole (svPPA), right temporal pole (sbvFTD) and left supplementary motor area (nfvPPA). Pearson's correlations were calculated between NDM-predicted atrophy in YC and the observed longitudinal atrophy in FTD patients over a follow-up of 24 months. The NDM was then run for all the 220 brain seeds to verify whether the four epicenters were among those that yielded the highest correlation. Using NDM, predictive maps in YC showed pathology progression from the peaks of atrophy in svPPA, nfvPPA, and sbvFTD over 24-months. svPPA exhibited early involvement of left temporal and occipital lobes, progressing to extensive left hemisphere impairment. nfvPPA and sbvFTD similarly spread bilaterally to frontal, sensorimotor, and temporal regions, with sbvFTD additionally affecting the right hemisphere. Moreover, the NDM-predicted atrophy of each region was positively correlated to longitudinal real atrophy, with a greater effect in svPPA and sbvFTD. In bvFTD, the model starting from the left insula (the peak of atrophy) demonstrated a highly left-lateralized pattern, with pathology spreading to frontal, sensorimotor, temporal, and basal ganglia regions, with minimal extension to the contralateral hemisphere by 24 months. However, unlike the atrophy peaks observed in the other three phenotypes, the left insula did not show the strongest correlation between the estimated and actual atrophy. Instead, the bilateral superior frontal gyrus emerged as optimal seeds for modelling atrophy spread, showing the highest correlation ranking in both hemispheres. Overall, NDM applied on ICVF connectome yielded higher correlations relative to NDM applied on FA maps. The NDM implementation using cross-sectional structural connectome is a valuable tool to predict atrophy patterns and pathology spreading in FTD clinical variants