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The aging population in Western countries has led to a rise in predementia conditions like Mild Cognitive Impairment (MCI). Social Assistive Robotics (SAR) interventions, among novel technological tools, offer a promising interdisciplinary approach to mitigate cognitive and social symptoms' progression in this clinical group. This systematic review aims to identify existing clinical protocols employing social robots for treating cognitive and social cognition skills in individuals with MCI. The review protocol adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. From six databases, we retrieved and analyzed 193 articles, of which 19 met the inclusion criteria, featuring samples diagnosed with MCI and subjected to cognitive and/or social interventions through SAR. The review encompasses both qualitative and quantitative studies, with a focus on assessing bias risk. Articles were categorized into four primary areas: study participants' samples, types of robots and programming used, assessment of cognitive abilities, and the nature of interventions (i.e., cognitive and and social cognition skills). While the findings highlight the potential benefits of using SAR for MCI interventions in both cognitive and social cognition domains, the studies primarily emphasized robot acceptability rather than intervention outcomes. Methodological limitations such as clinical heterogeneity, absence of control groups, and non-standardized assessments restrict the generalizability of these findings. This review underscores the promising role of Social Assistive Robotics in MCI interventions, emphasizing the importance of social cognition skills interventions and advocating for increased collaboration between clinicians and robotic researchers to overcome current limitations and enhance future outcomes.

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Introduzione. Durante il percorso universitario, gli studenti della Facoltà di infermieristica sono esposti a diversi fattori di rischio per l’attività svolta nel tirocinio pratico ospedaliero, in particolare se riferito al rischio biologico. Risulta, pertanto, importante, nel corso della sorveglianza sanitaria ex D.lgs. 81/08, la valutazione della risposta anticorpale individuale per le malattie infettive per le quali è prevista la vaccinazione obbligatoria durante l’infanzia e che possono avere rilevanza in termini di rischio di contagio e trasmissione per lo studente stesso oltre che per il personale sanitario ed i pazienti (Epatite B, Morbillo, Parotite, Rosolia e Varicella). Obiettivi. L’obiettivo del presente studio è quello di indagare le caratteristiche di sieroprevalenza degli anticorpi IgG anti-HBsAg, anti-Morbillo, anti-Parotite, anti- Rosolia ed anti-Varicella, negli studenti della Facoltà di infermieristica di un “Teaching Hospital” in Roma. L’analisi comprende, inoltre, lo studio descrittivo dei fattori demografici del campione osservato. Materiali e Metodi. È stato effettuato uno studio osservazionale trasversale su 357 studenti della Facoltà di infermieristica, sottoposti a visita preventiva di sorveglianza sanitaria per rischio biologico potenziale. È stata valutata la risposta immunitaria ai virus in relazione al range di riferimento: Epatite B (positivo ≥10 mUI/ml, negativo <10 mUI/ml), Morbillo (positivo ≥150 mUI/ml, negativo <150 mUI/ml), Parotite (positivo ≥230 UA/ml, negativo <230 UA/ml), Rosolia (positivo ≥10 UI/ml, negativo <10 UI/ml), Varicella (positivo ≥50 mUI/ml, negativo <50 mUI/ml). È stata poi eseguita, con software STATA 17, un’analisi statistica descrittiva delle variabili qualitative e quantitative prese in esame ed un’analisi bivariata per studiare l’associazione tra copertura vaccinale e variabili rilevanti. Risultati. Il campione osservato è composto da 357 studenti, età media 21,2 (SD 4,1), dei quali 67 (18,8%) m

Introduzione. Durante la pandemia da COVID-19 è aumentato a livello globale l’utilizzo di dispositivi digitali connessi da remoto nello svolgimento delle più svariate attività lavorative, rappresentando da una parte una sfida innovativa per i lavoratori di tutte le età e dall’altra un rischio aggiuntivo per le potenziali ripercussioni sul loro benessere psicofisico. Il lavoro a distanza è stato preferito da alcuni lavoratori per la maggiore flessibilità nell’organizzazione della giornata lavorativa; tuttavia, esso ha anche comportato difficoltà logistiche legate all’ambiente di lavoro e maggiori rischi inerenti l’ergonomia delle postazioni di lavoro al videoterminale. Obiettivi. L’obiettivo dello studio è stato indagare la prevalenza dei disturbi muscolo-scheletrici e visivi legati all’uso del computer e alle postazioni di lavoro da remoto, con particolare riferimento all’attività in smart working durante la pandemia da COVID-19, al fine di valutare ed eventualmente suggerire strategie di miglioramento del comfort lavorativo e del benessere psicofisico del lavoratore. Materiali e Metodi. Su iniziativa del Medico Competente, è stata somministrata una checklist (Computer Workstation Ergonomics: Self-Assessment Checklist National Institutes of Health), tramite piattaforma Google Forms, al personale d’ufficio di un’azienda internazionale italiana. Il questionario comprendeva 35 domande ed era diviso in due sezioni: la prima sezione indagava le caratteristiche sociodemografiche; la seconda sezione, invece, intendeva valutare l’ergonomia della postazione di lavoro (es. utilizzo sedia da ufficio, tastiera, monitor) in relazione allo stato di salute del lavoratore (es. comparsa di sintomatologia dolorosa). Le ultime domande, inoltre, indagavano la frequenza e la modalità di effettuazione delle pause lavorative. Risultati e Conclusioni. I risultati dello studio hanno evidenziato che le pause posturali avevano un effetto protettivo sulla sintomatologia dolorosa a livello dell

Introduzione. La violenza sui luoghi di lavoro è un problema di salute pubblica ed occupazionale, che può causare, oltre ad ansia, stress e depressione, anche insoddisfazione lavorativa, ed intenzione a cambiare lavoro (1-3). Nel contesto sanitario, la violenza verbale è il tipo di violenza più comune, ed è definita come l’uso di parole, toni o modi che minacciano, incolpano o mancano di rispetto agli operatori sanitari (3). In letteratura esistono diverse meta-analisi che indagano questo fenomeno, ma la diversità dei contesti e delle popolazioni considerate rende difficile utilizzare i dati disponibili per mettere in atto contromisure volte ad affrontare questa problematica. Obiettivi. In considerazione dell’impatto di questa problematica per la salute pubblica ed occupazionale, l’obiettivo di questa umbrella review è quello di raccogliere le meta-analisi volte ad indagare la violenza verbale sul luogo di lavoro contro gli operatori sanitari, per esaminare la prevalenza globale del fenomeno ed indagare le sue principali caratteristiche. Metodi. È stata elaborata una query utilizzando la metodologia PICO, includendo termini MeSH per le parole chiave: “operatori sanitari”, “violenza sul luogo di lavoro”, “meta-analisi”. Seguendo le linee guida Preferred Reporting Items for Systematic Reviews and Meta- Analyses, sono state cercate su PubMed, Scopus e ISI Web of Science le revisioni sistematiche e le meta-analisi rilevanti, pubblicate in lingua inglese fino a novembre 2022. Sono stati estratti i dati relativi ad autori, anno, paese, prevalenza, tipo di setting, popolazione. È stata effettuata una valutazione della qualità tramite la scala Risk Of Bias due to Missing Evidence (ROBIS). Risultati. Sono stati identificati 997 articoli nei tre database. Al termine del processo di screening per titolo ed abstract e valutazione dei full-text, state incluse 9 metaanalisi sulla violenza verbale. La maggior parte delle meta-analisi includeva studi condotti in più di un Paese (n=

Introduzione. Le “Linee guida per la valutazione e la gestione del rischio per la sicurezza dell’acqua nei sistemi di distribuzione interni degli edifici prioritari e non prioritari e in talune navi ai sensi della Direttiva (UE) 2020/2184”, trasposta con D. L.vo 18/2023, pubblicate all’interno del RAPPORTO ISTISAN 22/32, permettono di valutare, individuare e monitorare le potenziali fonti di pericoli chimici e microbiologici legati al sistema idrico, nonché sviluppare programmi di ispezione o verifiche per specifici parametri, come piombo e Legionella, riconosciuti anche all’interno del D.lgs. 81/2008 tra i composti e gli agenti biologici per cui è prevista la sorveglianza sanitaria. Obiettivi. Le Linee Guida intendono essere uno strumento per realizzare adeguate misure di gestione e controllo dei rischi legati al sistema di distribuzione idrico interno agli edifici, a partire dai “locali prioritari” sottoposti agli obblighi normativi, ovvero immobili di grandi dimensioni con numerosi utenti: ospedali, strutture assistenziali, navi, stazioni, aeroporti, ecc. Metodi. In una fase iniziale le linee guida sono state redatte da un gruppo multidisciplinare di esperti nei settori dell’acqua, della prevenzione sanitaria, igiene e salute pubblica, e impianti idraulici. Successivamente, al fine di garantire l’adeguatezza e la sostenibilità delle azioni e delle misure di controllo raccomandate, è stato condotto un confronto con esperti del Terzo settore. Sulla base di un’analisi complessiva dei rischi sono state definite cinque classi di edifici con diverse priorità di adozione di adeguati sistemi di gestione e controllo dei rischi: prioritari (classi A-D) e non prioritari (classe E). Risultati. Le Linee Guida permettono di individuare i “locali prioritari” in cui la valutazione del rischio e la gestione della sicurezza idrica nei sistemi di distribuzione interna è resa obbligatoria ai sensi del DL.vo 18/2023 e descrive i relativi sistemi di gestione e controllo dei rischi da

Introduzione. Durante la pandemia da COVID-19, è stato evidenziato, sia a livello mondiale che nazionale, un aumento delle dimissioni volontarie (1). In Italia l’impatto di questo fenomeno non è ancora ben documentato, è noto tuttavia che riguarda principalmente giovani tra i 25 ed i 45 anni di età, e dipendenti con anzianità in azienda da 1 a 5 anni (2). Tra le motivazioni principalmente addotte per le dimissioni vi sono: i cambiamenti del mercato del lavoro, la ricerca di migliori condizioni economiche, la ricerca di un maggior equilibrio tra vita privata e lavorativa, l’ambiente di lavoro ostile (2). Obiettivi. L’obiettivo del presente studio è quello di indagare le caratteristiche sociali, demografiche e culturali dei giovani che hanno dato le dimissioni volontarie durante la pandemia COVID-19. Gli obiettivi secondari sono, inoltre, stabilire le motivazioni, le concause, ed il periodo temporale in cui questo fenomeno ha raggiunto le sue dimensioni maggiori. Metodi. Lo studio condotto è di tipo osservazionale trasversale. È stato somministrato un questionario ad un campione di convenienza rispecchiante la popolazione target (giovani tra i 25 ed i 45 anni che abbiano dato dimissioni volontarie durante la pandemia). Il questionario era composto da 9 domande a carattere sociodemografico (genere, età, area geografica, etc) e da 7 domande volte ad indagare le motivazioni ed il periodo delle dimissioni. È stata effettuata un’analisi statistica descrittiva delle variabili e delle analisi di correlazione utilizzando il software STATA16. Risultati. Il campione è stato di 72 giovani, di cui 41 (56.9%) donne. Il 50% (n=36) dei partecipanti non avevano mai contratto il COVID-19 e quasi tutti (n=69, 95.8%) avevano ricevuto la terza dose di vaccinazione anti-COVID-19. Quarantadue soggetti avevano trovato un nuovo impiego dopo le dimissioni (58.3%). La causa principale di dimissione è stata l’insoddisfazione lavorativa (n=28, 38.9%); mentre la prospettiva futura che ha maggiorm

Fully Homomorphic Encryption (FHE), which enables arbitrary computation to be performed directly on encrypted data, is becoming promising for privacy-oriented applications, paving the way for widespread adoption of cloud computing with ideal security. The challenge for FHE lies in the speed-optimized and area-optimized implementation of Number Theoretic Transform (NTT), which is the most computation-intensive primitive in FHE. Moreover, most existing works concentrate on NTT implementations with small moduli and limited levels of parallelism. The NTT designs for a wider range of parameters with high scalability, however, are not fully developed. This paper proposes an FPGA-based hardware accelerator for NTT with high speed and area efficiency. A novel algorithmic implementation of NTT modeled on tensor products is first proposed, which provides high flexibility in parameter sets and high scalability in processing elements (PEs). Different levels of parallelism are then explored to adapt to the trade-off between performance and area efficiency. With the help of stride permutation, a non-conflict data flow control is built to significantly simplify the memory access pattern, contributing to higher performance of NTT. Implemented on a Xilinx VIRTEX-7 platform, our RTL-based design outperforms state-of-the-art FPGA works customized for FHE by 1.21× ∼ 2.73× in performance and 1.11× ∼ 9.81× in area efficiency. It can achieve an enhancement of 2.49×/ 1.25×/ 2.53×/ 2.15× on average on the resource usage of LUTs/ FFs/ BRAMs/ DSPs, respectively.

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Advances in the surgical and systemic therapeutic landscape of hepatocellular carcinoma have increased the complexity of patient management. A dynamic adaptation of the available staging-based algorithms is required to allow flexible therapeutic allocation. In particular, real-world hepatocellular carcinoma management increasingly relies on factors independent of oncological staging, including patients' frailty, comorbid burden, critical tumour location, multiple liver functional parameters, and specific technical contraindications impacting the delivery of treatment and resource availability. In this Policy Review we critically appraise how treatment allocation strictly based on pretreatment staging features has shifted towards a more personalised treatment approach, in which expert tumour boards assume a central role. We propose an evidence-based framework for hepatocellular carcinoma treatment based on the novel concept of multiparametric therapeutic hierarchy, in which different therapeutic options are ordered according to their survival benefit (ie, from surgery to systemic therapy). Moreover, we introduce the concept of converse therapeutic hierarchy, in which therapies are ordered according to their conversion abilities or adjuvant abilities (ie, from systemic therapy to surgery).

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Unlabelled: The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Methods: A modified Delphi process was led by three large pan-national liver associations. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Results: A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms 'non-alcoholic' and 'fatty' were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350 g/week and 210 to 420 g/week for females and males respectively). Conclusions: The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification.

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Background: Sinusoidal obstruction syndrome, also known as veno-occlusive disease, is a potentially life-threatening complication of haematopoietic stem-cell transplantation (HSCT). We aimed to compare defibrotide prophylaxis plus best supportive care versus best supportive care alone for sinusoidal obstruction syndrome prevention after HSCT. Methods: This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines; defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by sinusoidal obstruction syndrome risk, age, and country. The primary endpoint, sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407. Findings: Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0–41·0] were randomly assigned to the defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurel

Juvenile myelomonocytic leukemia (JMML) is a rare clonal stem cell disorder that occurs in early childhood and is characterized by the hyperactivation of the RAS pathway in 95% of the patients. JMML is characterized by a hyperproliferation of granulocytes and monocytes, and little is known about the heterogeneous nature of leukemia-initiating cells, as well as of the cellular hierarchy of the JMML bone marrow. In this study, we report the generation and characterization of a novel patient-derived three-dimensional (3D) in vitro JMML model, called patient-derived JMML Atypical Organoid (pd-JAO), sustaining the long-term proliferation of JMML cells with stem cell features and patient-specific hallmarks. JMML cells brewed in a 3D model under different microenvironmental conditions acquired proliferative and survival advantages when placed under low oxygen tension. Transcriptomic and microscopic analyses revealed the activation of specific metabolic energy pathways and the inactivation of processes leading to cell death. Furthermore, we demonstrated the pd-JAO-derived cells' migratory, propagation, and self-renewal capacities. Our study contributes to the development of a robust JMML 3D in vitro model for studying and defining the impact of microenvironmental stimuli on JMML disease and the molecular mechanisms that regulate JMML initiating and propagating cells. Pd-JAO may become a promising model for compound tests focusing on new therapeutic interventions aimed at eradicating JMML progenitors and controlling JMML disease.

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Hypodiploidy, defined as modal numbers (MNs) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study, we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed from 2000 to 2015 in 14 childhood AML groups from the International Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs, 45 (n = 66); 44 (n = 10) and 43 (n = 5). The most frequently lost chromosomes were chromosome 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52%, respectively, for the hypodiploid cohort. Children with MN≤44 (n = 15) had inferior EFS (21%) and OS (33%) compared with children with MN = 45 (n = 66; EFS, 37%; OS, 56%). Adjusted hazard ratios (HRs) were 4.9 (P = .001) and 6.1 (P = .003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n = 18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5; P = .42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in the patients treated with SCT in CR1.

Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Methods: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <-1·455 vs -1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. Findings: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a me

Main recommendations Obesity is a chronic, relapsing, degenerative, multifactorial disease that is associated with many co-morbidities. The global increasing burden of obesity has led to calls for an urgent need for additional treatment options. Given the rapid expansion of bariatric endoscopy and bariatric surgery across Europe, the European Society of Gastrointestinal Endoscopy (ESGE) has recognized the need to formalize and enhance training in bariatric endoscopy and the endoscopic treatment of bariatric surgical adverse events. This manuscript represents the outcome of a formal Delphi process resulting in an official Position Statement of the ESGE and provides a framework to develop and maintain skills in bariatric endoscopy and the endoscopic treatment of bariatric surgical adverse events. This curriculum is set out in terms of the prerequisites prior to training, minimum number of procedures, the steps for training and quality of training, and how competence should be defined and evidenced before independent practice. 1 ESGE recommends that every endoscopist should have achieved competence in upper gastrointestinal endoscopy before commencing training in bariatric endoscopy and the endoscopic treatment of bariatric surgical adverse events. 2 Trainees in bariatric endoscopy and the endoscopic treatment of the complications of bariatric surgery should have basic knowledge of the definition, classification, and social impact of obesity, its pathophysiology, and its related co-morbidities. The recognition and management of gastrointestinal diseases that are more common in patients with obesity, along with participation in multidisciplinary teams where obese patients are evaluated, are mandatory. 3 ESGE recommends that competency in bariatric endoscopy and the endoscopic treatment of the complications of bariatric surgery can be learned by attending validated training courses on simulators initially, structured training courses, and then hands-on training in tertia

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Theory of Mind (ToM), the ability to understand and attribute mental states to ourselves and others, could be impaired in Multiple Sclerosis (MS), a neurodegenerative disease affecting young adults. Considering that ToM is strictly connected to Quality of Life (QoL) in MS and that could enhance the social support network -which is particularly important for this population-, we aimed to design and implement a novel ToM rehabilitation training. To make the training as much ecological as possible, we have devised a protocol enhancing ToM through stimuli depicting real-world conditions (video-clips taken from cinema movies, literary fictions, and audio voices). We test training’s effect on both cognitive and affective components of ToM in a sample of 13 subjects, randomly assigned to the ToM training Group and to the Control Group. The following ToM tasks were administered: the Reading the Mind in the Eyes (RMET), the Strange Stories task, the Faux Pas Task and the False Belief First- and Second - Order Task (FB II and III order). We also administered a psycho-behavioral assessment through the Toronto Alexithymia Scale (TAS-20). Results show that our novel ToM training is useful in enhancing ToM abilities measured by the following tasks: the RMET (affective task, p = 0.015) and the FB II-order task (FB, cognitive task, p = 0.032). Our ToM training had also a significant effect on the total score of the TAS-20 Scale (p = 0.018) and on its “Difficulty Describing Feelings subscale” (p = 0.018), indicating a reduction of the alexithymia traits. Future works with larger samples could investigate the ToM training effectiveness in a more representative MS populations.

Background and aims: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. Approach and results: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). Conclusions: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.

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The technical progression of artificial intelligence (AI) research has been built on breakthroughs in fields such as computer science, statistics, and mathematics. However, in the past decade AI researchers have increasingly looked to the social sciences, turning to human interactions to solve the challenges of model development. Paying crowdsourcing workers to generate or curate data, or data enrichment, has become indispensable for many areas of AI research, from natural language processing to reinforcement learning from human feedback (RLHF). Other fields that routinely interact with crowdsourcing workers, such as Psychology, have developed common governance requirements and norms to ensure research is undertaken ethically. This study explores how, and to what extent, comparable research ethics requirements and norms have developed for AI research and data enrichment. We focus on the approach taken by two leading conferences: ICLR and NeurIPS, and journal publisher Springer. In a longitudinal study of accepted papers, and via a comparison with Psychology and CHI papers, this work finds that leading AI venues have begun to establish protocols for human data collection, but these are are inconsistently followed by authors. Whilst Psychology papers engaging with crowdsourcing workers frequently disclose ethics reviews, payment data, demographic data and other information, similar disclosures are far less common in leading AI venues despite similar guidance. The work concludes with hypotheses to explain these gaps in research ethics practices and considerations for its implications., Comment: 10 pages

Background: In the KEYNOTE-826 study, the addition of the anti-PD-1 monoclonal antibody pembrolizumab to chemotherapy with or without bevacizumab improved overall survival and progression-free survival (primary endpoints) versus placebo plus chemotherapy with or without bevacizumab, with manageable toxicity, in patients with persistent, recurrent, or metastatic cervical cancer. In this Article, we report patient-reported outcomes (PROs) from KEYNOTE-826. Methods: KEYNOTE-826 is a multicentre, randomised, phase 3 trial in 151 cancer treatment centres in 19 countries. Eligible patients were aged 18 years or older with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy (previous radiosensitising chemotherapy was allowed) and not amenable to curative treatment and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) centrally by means of an interactive voice response system in a double-blind manner to receive either pembrolizumab 200 mg or placebo every 3 weeks intravenously for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 plus cisplatin 50 mg/m2 or carboplatin area under the curve 5 mg/mL per min, intravenously) with or without bevacizumab 15 mg/kg every 3 weeks intravenously. Randomisation (block size of 4) was stratified by metastatic disease at diagnosis, planned bevacizumab use, and PD-L1 combined positive score. Patients, investigators, and other study personnel involved in study treatment administration or clinical evaluation of patients were unaware of treatment group assignments. PRO instruments were the EORTC Quality-of-Life-Core 30 (QLQ-C30), the EORTC cervical cancer module (QLQ-CX24), and the EuroQol-5 dimension-5 level (EQ-5D-5L) visual analogue scale, each collected before treatment at cycles 1-14 and every other cycle thereafter. Primary endpoints were overall survival and progression-free survival per RECIST version 1.1 by investigator

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with few therapeutic options available. Despite immunotherapy has revolutionised cancer treatment, the results obtained in PDAC are still disappointing. Emerging evidence suggests that chemokines/CXCRs-axis plays a pivotal role in immune tumour microenvironment modulation, which may influence immunotherapy responsiveness. Here, we evaluated the effectiveness of CXCR1/2 inhibitor ladarixin, alone or in combination with anti-PD-1, against immunosuppression in PDAC. Methods A set of preclinical models was obtained by engrafting mouse PDAC-derived cells into syngeneic immune-competent mice, as well as by orthotopically transplanting patient-derived PDAC tumour into human immune-system-reconstituted (HIR) mice (HuCD34-NSG-mice). Tumour-bearing mice were randomly assigned to receive vehicles, ladarixin, anti-PD-1 or drugs combination. Results CXCR1/2 inhibition by ladarixin reverted in vitro tumour-mediated M2 macrophages polarisation and migration. Ladarixin as single agent reduced tumour burden in cancer-derived graft (CDG) models with high-immunogenic potential and increased the efficacy of ICI in non-immunogenic CDG-resistant models. In a HIR mouse model bearing the immunogenic subtype of human PDAC, ladarixin showed high efficacy increasing the antitumor effect of anti-PD-1. Conclusion Ladarixin in combination with anti-PD-1 might represent an extremely effective approach for the treatment of immunotherapy refractory PDAC, allowing pro-tumoral to immune-permissive microenvironment conversion.

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRAS(G12)) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRAS(G12) mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRAS(G12) mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRAS(G12) mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRAS(G13) mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRAS(G12) mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRAS(G12) mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.A combination of real-world evidence and a reanalysis of phase 3 clinical trial data unveils KRAS codon G12 mutations as a biomarker of resistance to trifluridine/tipiracil in metastatic

This article proposes a methodology that enables one who has actual cost figures to perform the calculations for benefit-to-cost, strictly from the tactical and logistical standpoints, on the performance equivalence not of nuclear vs. air-independent-propulsion (AIP) submarines, but of nuclear v. AIP submarine fleets. With that in hand, it becomes possible for whomever might have sounder figures than what we could find about the complete life-cycle cost of either alternative to figure out, given our results about the benefit assessment, what would be the result of a benefit-to- cost analysis. We didn't perform the latter, due to uncertainty about the methodology by which the public available cost estimates were calculated. By providing a method for benefit calculation of the military worth of alternatives to support an assessment of the SSN/SSP fleet alternatives, we hope to have provided a sounder point of departure for debate, both in general terms, a method, and for the Brazilian case in particular, an application., Este artigo propõe uma metodologia que permite a quem tem valores de custo reais realizar os cálculos de custo-benefício, estritamente do ponto de vista tático e logístico, sobre a equivalência de desempenho, não de submarinos de propulsão nuclear versus de propulsão independente do ar (AIP) , mas de frotas de submarinos nucleares vs. AIP. Com isso em mãos, torna-se possível para quem quer que tenha números mais sólidos do que poderíamos encontrar sobre o custo do ciclo de vida completo de qualquer alternativa descobrir, dados os nossos resultados sobre a avaliação de benefícios, qual seria o resultado de um benefício. análise de custo. Não realizamos o último, devido à incerteza sobre a metodologia pela qual as estimativas de custo disponíveis ao público foram calculadas. Ao fornecer um método de cálculo do benefício do valor militar das alternativas para apoiar uma avaliação das alternativas da frota SSN / SSP, esperamos ter fornecido um ponto de partida mais sólido para o debate, tanto em termos gerais, um método, como para o brasileiro caso em particular, um aplicativo., Este artículo propone una metodología que permite a quien tiene cifras de costos reales realizar los cálculos de beneficio a costo, estrictamente desde el punto de vista táctico y logístico, en la equivalencia de desempeño no de los submarinos nucleares frente a los de propulsión independiente del aire (AIP). , pero de flotas de submarinos nucleares v. AIP. Con eso en la mano, es posible que cualquiera que tenga cifras más sólidas que las que podríamos encontrar sobre el costo del ciclo de vida completo de cualquiera de las alternativas, averigüe, dados nuestros resultados sobre la evaluación de beneficios, cuál sería el resultado de un beneficio. análisis de costes. No realizamos lo último, debido a la incertidumbre sobre la metodología mediante la cual se calcularon las estimaciones de costos disponibles para el público. Al proporcionar un método para el cálculo de beneficios del valor militar de las alternativas para respaldar una evaluación de las alternativas de la flota SSN / SSP, esperamos haber proporcionado un punto de partida más sólido para el debate, tanto en términos generales, como para el método brasileño. caso en particular, una aplicación.

This article proposes a methodology that enables one who has actual cost figures to perform the calculations for benefit-to-cost, strictly from the tactical and logistical standpoints, on the performance equivalence not of nuclear vs. air-independent-propulsion (AIP) submarines, but of nuclear v. AIP submarine fleets. With that in hand, it becomes possible for whomever might have sounder figures than what we could find about the complete life-cycle cost of either alternative to figure out, given our results about the benefit assessment, what would be the result of a benefit-to- cost analysis. We didn't perform the latter, due to uncertainty about the methodology by which the public available cost estimates were calculated. By providing a method for benefit calculation of the military worth of alternatives to support an assessment of the SSN/SSP fleet alternatives, we hope to have provided a sounder point of departure for debate, both in general terms, a method, and for the Brazilian case in particular, an application., Este artigo propõe uma metodologia que permite a quem tem valores de custo reais realizar os cálculos de custo-benefício, estritamente do ponto de vista tático e logístico, sobre a equivalência de desempenho, não de submarinos de propulsão nuclear versus de propulsão independente do ar (AIP) , mas de frotas de submarinos nucleares vs. AIP. Com isso em mãos, torna-se possível para quem quer que tenha números mais sólidos do que poderíamos encontrar sobre o custo do ciclo de vida completo de qualquer alternativa descobrir, dados os nossos resultados sobre a avaliação de benefícios, qual seria o resultado de um benefício. análise de custo. Não realizamos o último, devido à incerteza sobre a metodologia pela qual as estimativas de custo disponíveis ao público foram calculadas. Ao fornecer um método de cálculo do benefício do valor militar das alternativas para apoiar uma avaliação das alternativas da frota SSN / SSP, esperamos ter fornecido um ponto de partida mais sólido para o debate, tanto em termos gerais, um método, como para o brasileiro caso em particular, um aplicativo., Este artículo propone una metodología que permite a quien tiene cifras de costos reales realizar los cálculos de beneficio a costo, estrictamente desde el punto de vista táctico y logístico, en la equivalencia de desempeño no de los submarinos nucleares frente a los de propulsión independiente del aire (AIP). , pero de flotas de submarinos nucleares v. AIP. Con eso en la mano, es posible que cualquiera que tenga cifras más sólidas que las que podríamos encontrar sobre el costo del ciclo de vida completo de cualquiera de las alternativas, averigüe, dados nuestros resultados sobre la evaluación de beneficios, cuál sería el resultado de un beneficio. análisis de costes. No realizamos lo último, debido a la incertidumbre sobre la metodología mediante la cual se calcularon las estimaciones de costos disponibles para el público. Al proporcionar un método para el cálculo de beneficios del valor militar de las alternativas para respaldar una evaluación de las alternativas de la flota SSN / SSP, esperamos haber proporcionado un punto de partida más sólido para el debate, tanto en términos generales, como para el método brasileño. caso en particular, una aplicación.

Recombinant Factor VIII Fc Fusion Protein for First-time Immune Tolerance Induction: Final Results of the verITI-8 Study

Background: Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. Methods: WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. Findings: Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0-4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 d

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Theory of Mind (ToM), a high-order human social cognition skill, is relevant for mental health and wellbeing and frequently impaired in many clinical conditions. To detect ToM difficulties, validated and standardized measures need to be adopted in clinical practice. The Yoni task provides a comprehensive evaluation of first-order, second-order, affective and cognitive mentalistic inferences. However, the Yoni task remains a time-demanding tool without normative data. To fill this gap, we explored the convergent and discriminant validity, the inter-item reliability and provided normative data of the Italian version of the Yoni task (98 items), and developed two short versions (48 and 36 items). For the validation, internal consistency and convergent/discriminant validity have been considered. Then, the effects of demographical variables on 98 item Yoni were explored, and normative data were provided. Our data demonstrated high reliability and a good convergent validity in all the Yoni versions. Then, two composite scores were proposed to obtain: 1) a global ToM level and 2) the balance between affective and cognitive ToM components, whose alteration represents a signature of several clinical conditions. The future standardization of the short versions of Yoni will allow a comprehensive and quick examination of ToM abilities, suitable for both research and clinical settings.

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The Summary: "UNCAN.eu" refers to a collective European effort seeking to enable a leap forward in our understand-ing of cancer. This initiative, which includes the creation of a European cancer research data hub, will pave the way to new advances in cancer care. Starting on September 1, 2022, a 15-month coordination and support action will generate a blueprint for UNCAN.eu. Here, we summarize the cancer research issues that the blueprint will propose to tackle at the European level.

Asplenia (the congenital or acquired absence of the spleen) and hyposplenism (defective spleen function) are common causes of morbidity and mortality. The spleen is a secondary lymphoid organ that is responsible for the regulation of immune responses and blood filtration. Hence, asplenia or hyposplenism increases susceptibility to severe and invasive infections, especially those sustained by encapsulated bacteria (namely, Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type b). Asplenia is predominantly due to splenectomy for either traumatic events or oncohaematological conditions. Hyposplenism can be caused by several conditions, including haematological, infectious, autoimmune and gastrointestinal disorders. Anatomical disruption of the spleen and depletion of immune cells, especially IgM memory B cells, seem to be predominantly responsible for the clinical manifestations. Early recognition of hyposplenism and proper management of asplenia are warranted to prevent overwhelming post-splenectomy infections through vaccination and antibiotic prophylaxis. Although recommendations are available, the implementation of vaccination strategies, including more effective and immunogenic vaccines, is needed. Additionally, screening programmes for early detection of hyposplenism in high-risk patients and improvement of patient education are warranted.Asplenia and hyposplenism can have multiple and complex causes and lead to morbidity and mortality, especially owing to overwhelming post-splenectomy infections. In this Primer, Lenti and colleagues review epidemiology, pathophysiology, diagnosis and management of these conditions, and discuss patient quality of life and future strategies.

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OBJECTIVE: Advanced forms of wrist osteoarthritis in the elderly are quite common and often under-treated, preferring a conservative management of the condition due to the age of the patient. However, in elderly people who are still active, sporty and physically demanding, surgical management of wrist osteoarthritis should be considered. Proximal Row Carpectomy associated with a Resurfacing Capitate Pyrocarbon Implant (RCPI), allows the management of a wide range of wrist arthrosis, involving both the radio-carpal and the mid-carpal joints. This treatment has been already reported as a solution in younger people affected by degenerative pathologies of the wrist, giving overall good results. Authors aimed at verifying how this technique could be useful in elderly patients, resolving the severe pain often related to this pathology and letting them recover strength and motion. PATIENTS AND METHODS: This is a retrospective analysis involving 7 cases of elderly men (mean age = 68 y.o.), suffering from severe wrist arthritis and treated with RCPI between 2016 and 2021. RESULTS: All patients reported a return to manual activities between 6 and 12 months after surgery, significantly improving pain. Two patients complained moderate pain under strain at follow-up, with residual difficulty in performing manual tasks. In all cases, an increase of strength and improvement in terms of stiffness was registered. No cases of infections or implant mobilization were reported. CONCLUSIONS: RCPI combined with proximal row carpectomy shows satisfying results in all published studies and it has been confirmed in our series as well. Indications for this procedure should be widened to elderly people, as useful alternatives to more aggressive salvage procedures, such as total prosthesis or arthrodesis.

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Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4 is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4 expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1 has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4 in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4 limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients.

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Background: 2-year follow-up data from our randomised controlled trial showed that peroral endoscopic myotomy is associated with a significantly higher efficacy than pneumatic dilation as initial treatment of therapy-naive patients with achalasia. Here we report therapeutic success rates in patients treated with peroral endoscopic myotomy compared with pneumatic dilation at the 5-year follow-up. Methods: We did a multicentre, randomised controlled trial in six hospitals in the Netherlands, Germany, Italy, Hong Kong, and the USA. Adults aged 18–80 years with newly diagnosed symptomatic achalasia (based on an Eckardt score >3) were eligible for inclusion. Patients were randomly assigned (1:1) to peroral endoscopic myotomy or pneumatic dilation using web-based randomisation with a random block size of 8 and stratification according to site. Randomisation concealment for treatment type was double blind until official study enrolment. Treatment was unmasked because of the different technical approach of each procedure. Patients in the pneumatic dilation group were dilated with a single series of 30–35 mm balloons. The need for subsequent dilations in the pneumatic dilation group, and the need for dilation after initial treatment in the peroral endoscopic myotomy group, was considered treatment failure. The primary outcome was therapeutic success (Eckardt score ≤3 in the absence of severe treatment-related complications and no need for retreatment). Analysis of the primary outcome was by modified intention to treat, including all patients randomly assigned to a group, excluding those patients who did not receive treatment or were lost to follow-up. Safety was assessed in all included patients. This study is registered at the Dutch Trial Registry, NTR3593, and is completed. Findings: Between Sept 21, 2012, and July 20, 2015, 182 patients were assessed for eligibility, 133 of whom were included in the study and randomly assigned to peroral endoscopic myotomy (n=67) or pn

Several treatment options are available for chronic lymphocytic leukemia (CLL) and, for this reason, treatment choice can result challenging after introducing oral targeted agents. This study aims at comparing patients' and hematologists' preferences for attributes of CLL treatments. An online cross-sectional survey has been delivered to clinicians and patients affected by CLL in Italy. A discrete choice experiment has been conducted so to estimate each attribute's relative importance (RI) and assess the preference weight for each level of each attribute. An expert panel agreed on investigating the following attributes: progression-free survival (PFS) and measurable residual disease, route of administration/therapy duration and follow-up frequency, incidence of diarrhea (episodes/day), serious infections (grade 3 or 4), and atrial fibrillation. Overall, 746 patients and 109 clinicians accessed the survey, and 215 and 69, respectively, filled it in. The most important attributes were PFS (RI 30%) for hematologists and the risk of severe infections (RI 24%) for patients. Clinicians rated preference for maximum efficacy and lowest risk of severe infection very high (30%). Both patients and clinicians preferred oral administration while considering duration of therapy less relevant. The frequency of hospital appointments was negligible for patients, while clinicians preferred a quarterly frequency. Considering all attributes, diarrhea was weighted more by clinicians than by patients. Atrial fibrillation was not relevant for clinicians, while it was not negligible for patients. In conclusion, clinicians and patients favor an oral therapy, including continuous treatment, if associated with prolonged PFS, albeit with particular attention to the risk of serious infections.

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