322590 research outputs found
Sort by
RARE BLEEDING DISORDERS: INSIGHTS INTO CLINICAL PRESENTATION, LABORATORY PHENOTYPE, AND GENETIC CHARACTERIZATION
No full textI disturbi emorragici rari (RBD) rappresentano circa il 3–5% di tutte le condizioni emorragiche ereditarie e comprendono carenze di fibrinogeno, protrombina e fattori FV, FVII, X, XI e XIII, per lo più ad ereditarietà autosomica recessiva. Questi disturbi derivano da varianti patogeniche nei geni dei singoli fattori. Tra i RBD, i disturbi congeniti del fibrinogeno (CFD) rappresentano circa l’8% e si distinguono in quantitativi (afibrinogenemia, ipofibrinogenemia) e qualitativi (disfibrinogenemia, ipodisfibrinogenemia). Questa tesi integra analisi genetiche, valutazioni cliniche standardizzate e fenotipizzazione di laboratorio, contribuendo a un significativo avanzamento nel campo.
(I) Nel primo capitolo abbiamo analizzato genotipo e fenotipo di laboratorio di 526 casi di RBD, una delle coorti più grandi fino a oggi studiata. La carenza di FVII è risultata essere la più comune (23%), mentre FII e FV+FVIII le più rare (6%). Tra 257 varianti geniche uniche, l’86% era patogenica e l’11% mai riportata in precedenza; le varianti missenso predominano (57%), soprattutto negli esoni dei domini catalitici (48%). (II) Nel secondo capitolo abbiamo confrontato due sistemi di punteggio emorragico (ISTH-BAT e EN-RBD-BSS) per identificare pazienti con CFD e valutato la correlazione con livelli di fibrinogeno e gradi di severità. Entrambi gli strumenti hanno mostrato buona sensibilità, classificando correttamente la gravità clinica in quasi due terzi dei casi. (III) Nel terzo capitolo 166 casi di CFD sono stati caratterizzati tramite il Prospective Rare Bleeding Disorders Database, fornendo informazioni sui profili clinici, di laboratorio e genetici. I gradi di gravità emorragica corrispondevano alle soglie di attività dei fattori in quasi metà dei casi con difetti quantitativi di fibrinogeno. (IV) Nel quarto capitolo abbiamo esaminato le complicanze ginecologiche e ostetriche nelle donne con CFD. La coorte includeva 59 donne, con 70 gravidanze in 32 individui. L’ipermenorrea era il sintomo più frequente nell’afibrinogenemia (75% dei casi), ma anche emorragia post-partum (36%) e aborto spontaneo (23%) erano presenti in un elevato numero di casi. Non sono state osservate differenze significative nel rischio ostetrico tra donne disfibrinogeniche con o senza varianti geniche hotspot. Questi risultati sottolineano l’importanza di una diagnosi precoce e di eventuale profilassi, anche nei casi asintomatici.Rare bleeding disorders (RBDs) account for approximately 3–5% of all inherited bleeding conditions. RBDs include deficiencies of fibrinogen, factor (F) II, V, VII, X, XI, and XIII, most of which follow an autosomal recessive inheritance pattern. These disorders typically arise from pathogenic variants in the genes encoding specific coagulation factors. Among RBDs, congenital fibrinogen disorders (CFDs) account for ~8% of RBDs and are classified based on fibrinogen activity and antigen levels into quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia, hypodysfibrinogenemia) deficiencies. This thesis represents an innovative and comprehensive effort to advance the understanding of RBDs, integrating genetic analyses, standardized clinical assessments, and laboratory phenotyping, and contributing to a major step forward in the field.
(I) In the first chapter, we analyzed the genotype and laboratory phenotype of 526 RBD cases, one of the largest cohorts to date. In our study, FVII deficiency was the most common (23%), while FII (prothrombin) and FV+FVIII deficiencies were the rarest (6%). Among 257 unique variants identified, 86% were predicted pathogenic and 11% were novel. Missense variants predominated (57%), mainly affecting exons encoding catalytic domains (48%). (II) In the second chapter, we compared the adequacy of two bleeding score systems (ISTH-BAT and EN-RBD-BSS) in identifying patients with CFDs, and analyzed their correlation with fibrinogen levels and clinical severity grades. Our findings suggest that, alongside ISTH-BAT, the EN-RBD-BSS can also be useful for identifying CFD patients. Both tools demonstrated good sensitivity for detecting fibrinogen deficiency, and bleeding severity scores correctly classified clinical severity in nearly two-thirds of cases. (III) In the third chapter, a total of 166 CFD cases were comprehensively characterized using the Prospective Rare Bleeding Disorders Database. This large multicenter study offered valuable insights into the clinical, laboratory, and genetic profiles of CFDs patients. Bleeding severity grades aligned with the established factor activity thresholds in nearly half of the cases with quantitative fibrinogen defects. (IV) In chapter four, we addressed gynecologic and obstetric complications in women with congenital fibrinogen disorders. Our cohort included 59 women with CFDs, encompassing 70 pregnancies in 32 individuals. Heavy menstrual bleeding was most common in afibrinogenemia, affecting 75% of cases. Postpartum hemorrhage (36%) and miscarriage (23%) rates were notably high. No significant difference in obstetric risk was found between dysfibrinogenemic women with and without hotspot variants. These results highlight the need for early diagnosis and possible prophylaxis, even in asymptomatic cases
A 2 au Resolution View by ALMA of the Planet-hosting WISPIT 2 Disk
No full textWe present deep, high-spatial-resolution interferometric observations of 0.88 mm continuum emission from the
TYC 5709-354-1 system, hereafter WISPIT 2, obtained with the goal of detecting circumplanetary emission in the
vicinity of the newly discovered WISPIT 2b planet. Observations with the most extended baseline configuration
offered by the Atacama Large Millimeter/submillimeter Array, achieving an angular resolution of 25 × 17 mas
(3.3 × 2.2 au), revealed a single, narrow ring with a deprojected radius of 144.4 au and width of 7.2 au, and no
evidence of circumplanetary emission within the cavity. Injection and recovery tests demonstrate that these
observations can rule out pointlike emission at the location of WISPIT 2b brighter than ≈ 45 μJy at the 3σ level.
While these data can rule out PDS 70 c-like circumplanetary emission, the upper limit is consistent with empirical
mass–flux relationships extrapolated from the stellar regime. Visibility modeling of the continuum ring confirms
that WISPIT 2b lies significantly interior to the millimeter dust ring, raising doubts about the ability of WISPIT 2b
to be the only driver of the dust structure. Possible solutions include either another lower-mass companion,
residing between WISPIT 2b and the cavity edge, likely in the gap seen by SPHERE at ∼130 au, or that
WISPIT 2b is either substantially more massive than estimates based on IR photometry (∼15 MJup) or on a
moderately eccentric orbit. The combination of observations sensitive to the gas and dust distributions on larger
spatial scales and dedicated hydrodynamical modeling will help differentiate between scenarios
Defining the optimal duration of maintenance mitomycin C in intermediate-risk Ta NMIBC: a multicenter retrospective landmark analysis
No full textPurpose: While mitomycin C (MMC) is widely used for intravesical therapy, the optimal maintenance regimen for non-muscle invasive bladder cancer (NMIBC) remains unclear. This study assessed the impact of MMC maintenance on recurrence-free survival (RFS) in patients with intermediate-risk Ta NMIBC and aimed to identify the optimal number of instillations for improved outcomes. Methods: We conducted a retrospective multicenter analysis of patients with Ta NMIBC treated with transurethral resection and adjuvant MMC across 13 Italian centers (2010–2023). Patients were grouped based on MMC maintenance duration: no maintenance, short-term (≤ 6 instillations), and long-term (> 6 instillations). Kaplan–Meier curves, Cox regression, and CART analysis were used to evaluate RFS and high-grade RFS (HG-RFS). Results: Among 292 patients included, maintenance therapy significantly improved 2-year and 3-year RFS compared to no maintenance (78% vs. 55% and 67% vs. 30%, respectively; p < 0.001). CART analysis identified > 6 instillations as the threshold for optimal benefit. Long-term maintenance was associated with a lower risk of recurrence (HR 0.23 vs. no maintenance; HR 0.39 vs. short-term; both p < 0.001). No significant difference in HG-RFS was observed between no maintenance, long-term, and short-term groups. Conclusion: Long-term MMC maintenance (> 6 instillations) significantly prolongs RFS in patients with Ta NMIBC. These findings suggest that extended MMC regimens may improve patients’ outcomes and should be considered in clinical practice. Prospective studies are needed to confirm these results and guide evidence-based treatment strategies
Real-Life Perception of Treatment Effectiveness After 24 Weeks of Topical Ruxolitinib in Non-Segmental Vitiligo: Insights From Patient-Reported Outcomes
No full textLeft Atrial Volumetric Enlargement in Heart Failure With Reduced Ejection Fraction
No full textBackground: Left atrial (LA) remodeling, characterized by progressive enlargement, is commonly observed in heart failure with reduced ejection fraction and reflects left ventricular (LV) dysfunction and functional mitral regurgitation (FMR). However, its independent prognostic significance remains uncertain. Objectives: This study aims to investigate the independent association between LA volume index (LAVI) and long-term mortality in patients with heart failure, considering its interaction with FMR severity. Methods: A cohort of 13,954 patients who received a diagnosis of heart failure stage B or C and a first diagnosis of reduced LV ejection fraction (<50%) at Mayo Clinic was analyzed. Comprehensive echocardiographic quantification of LAVI, LV function, FMR, and hemodynamics was performed. Survival analysis included Kaplan-Meier curves, Cox proportional hazards models, and spline modeling, adjusted for demographic, clinical, and echocardiographic variables. Results: Mean LAVI increased with worsening FMR (35 ± 14 mL/m2 in no FMR to 61 ± 23 mL/m2 in severe FMR). Higher LAVI was associated with increased mortality (HR: 1.13 per 10 mL/m2; P < 0.0001), independent of LV function, FMR, and comorbidities. A mortality risk threshold emerged at LAVI >40 mL/m2, with excess mortality increasing steeply beyond this point. Stratification showed significant interactions between LAVI, LV ejection fraction, atrial fibrillation, and pulmonary hypertension. Although LAVI threshold of excess mortality shifted from about 40 mL/m2 in no-mild FMR to about 60 mL/m2 in severe FMR, the slope of the relationship persisted unaltered, confirming the graded relationship between LAVI and outcome at each FMR grade (P for interaction = 0.35). Conclusions: LAVI is an independent predictor of mortality in heart failure stage B or C, with excess risk starting at 40 mL/m2. The prognostic impact of LAVI persisted with a graded relationship in all FMR severity grades, emphasizing its role in risk stratification. These findings support the integration of LA remodeling assessment into heart failure management to refine prognostic evaluation and therapeutic strategies
A critical guideline for controlling monocyte-derived macrophages phenotypes
No full textMacrophages (Mφ) are an extremely heterogeneous and rapidly adapting set of innate immune cells that are scattered throughout all tissues in humans from mid-gestation onwards. Their original definition as key players in phagocytosis and defense against pathogens is too restrictive nowadays, as Mφ are central to tissue homeostasis, repair, and complex immune regulations involving adaptive immunity. The Mφ exhibit different ontogenies, originating from either embryonic progenitors or bone marrow, and their fate is shaped by tissue-specific microenvironments, which determine their adaptive phenotypes. This results in functional flexibility, exemplified by their ability to polarize into pro- (M1) or anti- (M2) inflammatory states in response to environmental cues. Such a dynamic process is critical for resolving infections, repairing tissue, and maintaining immune balance. Dysregulated Mφ polarization is indeed implicated in various pathologies, including chronic inflammation, cancer, and fibrosis. Despite their importance, the study of tissue-resident Mφ is still limited by technical challenges related to their isolation, maintenance, and donor variability. As an alternative, monocyte-derived macrophages (MDMs) represent an easier in vitro system to model human Mφ biology under controlled conditions. However, MDMs differ from tissue-resident Mφ in their developmental origin and functional specialization. This review outlines the key principles and limitations of MDM-based models, discusses commonly used differentiation protocols, and proposes methodological strategies to enhance reproducibility and physiological relevance in macrophage research
Multicenter Real-World Outcomes of Risankizumab in Crohn's Disease: The RESOLVE IG-IBD Study
No full textAim: to assess the effectiveness and safety of Risankizumab (RZB) in a large, nationwide real-world cohort of Crohn's disease (CD) patients. Methods: We conducted a multicentre, retrospective observational cohort of adults initiating RZB with assessments at weeks 12, 26, and 52. Co-primary endpoints were (i) week-12 steroid-free clinical remission (SFCR) (HBI <5 in the absence of systemic corticosteroids or budesonide) and (ii) week-52 endoscopic remission (SES-CD 0-2 or Rutgeerts i0-i1 post-operatively). The main effectiveness analysis was as-observed; a preplanned sensitivity analysis included patients expected to reach week-52 before database lock and applied non-responder imputation. Results: We included 520 patients, 45.0% failed ≥3 and 54.8% were ustekinumab-exposed. At week 12, clinical response was 76.5% and 60.8% achieved SFCR. By week 52, SFCR was 65.6%; endoscopic remission occurred in 37.5%, while radiologic remission and transmural healing were 24.6% and 9.8%, respectively. Ustekinumab-naïve patients showed significantly superior early clinical outcomes (week-12 SFCR: 69.8% vs 53.3%) and a higher rate of endoscopic remission at week 52 (56.5% vs 28.6%) compared with ustekinumab-exposed patients. Notably, week-52 effectiveness was comparable between patients with 2 and those with ≥3 prior failures. Extra-intestinal manifestations decreased over time, while perianal disease improved modestly. In the sensitivity cohort (N = 213), SFCR was 47% at week-52. Risankizumab was well-tolerated with no new safety signals identified. Conclusions: In a large, refractory, real-world CD population, RZB induced rapid and sustained favorable clinical, endoscopic, and radiologic outcomes. Importantly, one-year effectiveness was similar in patients with 2, and ≥3 prior failures, supporting RZB as a valuable option for a refractory population
Assessing the Role of Chirality in Magnetic Proximity Effect at Fe-CNTs Interfaces: A First Principle study
No full textThis work investigates the role of chirality in the magnetic proximity effect at ferromagnetic-carbon nanotubes (Fe-CNTs) interfaces using first-principles calculations. Motivated by the unresolved microscopic origin of Chirality-Induced Spin Selectivity (CISS), which predicts spin-dependent electron transport in chiral systems, we analyze whether nanotubes chirality significantly affects spin polarization induced by a ferromagnetic iron substrate.
Electronic structure calculations were performed within Density Functional Theory (DFT) using periodic SIESTA simulations with the PBE–GGA functional, non-collinear spin–orbit coupling (SOC), and fully relativistic pseudopotentials. Hydrogen-terminated CNTs with different chiralities were placed on an Fe surface, and the interface geometry was optimized to maximize magnetization transfer. Spin polarization was evaluated by computing the difference in the S_z component of carbon atoms between isolated CNTs and Fe–CNT hybrid systems.
The results show that, although individual nanotubes exhibit specific variations in their magnetic response, the overall magnetization trend is similar for chiral and achiral structures. If CISS originates purely from structural chirality and SOC, a clear chirality-dependent response should appear already at the equilibrium ground-state DFT level. Since such dependence is not observed, our results constrain theoretical descriptions of CISS, and suggest that additional mechanisms, such as nonequilibrium effects or environmental interactions, may play an essential role in the underlying physics of CISS
Cardiopulmonary exercise test criteria for heart transplantation referral of patients with ambulatory heart failure in the current era
No full textBackground: Current guidelines recommend evaluating patients with ambulatory heart failure (HF) for heart transplantation if their peak oxygen consumption (peak VO2) is <12 mL/kg/min. However, these recommendations are based on decades-old data. Methods: We retrospectively analysed 8060 patients with ambulatory HF with cardiopulmonary exercise testing (CPET) data. The primary analysis focused on 1218 patients with left ventricular ejection fraction <40% and peak VO2 <12 mL/kg/min, enrolled between 2010 and 2022. Survival outcomes (composite of death/left ventricular assist device/heart transplantation) were compared with those of heart transplantation recipients from the International Society for Heart and Lung Transplantation registry. Patients were stratified by ventilatory efficiency (ventilation versus CO2 production slope (VE/VCO2) >34 vs ≤34) and presence of exercise oscillatory ventilation. Survival analyses were performed using Kaplan-Meier curves compared with log-rank tests and Cox proportional hazards models, with heart transplantation survival curves reconstructed from aggregate data. Results: Patients with peak VO2 <12 mL/kg/min demonstrated better survival than heart transplantation recipients, with survival curves intersecting at approximately 2.7 years. Among those with VE/VCO2 ≤34, 10-year mortality risk was halved (p<0.01), with survival curves crossing those of heart transplantation recipients around year 4. Absence of exercise oscillatory ventilation was similarly associated with a 50% lower long-term mortality. Combining VE/VCO2 and exercise oscillatory ventilation identified four distinct risk groups with significantly different 10-year outcomes (p<0.01). Patients with peak VO2 <12 mL/kg/min, VE/VCO2 ≤34 and no exercise oscillatory ventilation exhibited survival comparable to heart transplantation recipients at year 5. Conclusions: In contemporary practice, a peak VO2 <12 mL/kg/min alone may not reliably identify patients with HF with sufficiently high short-term mortality to warrant heart transplantation referral. VE/VCO2 and exercise oscillatory ventilation provide important additional risk stratification, supporting re-evaluation of transplant referral criteria to reflect improved HF management and outcomes
Dental students' knowledge, attitudes and perceptions of artificial intelligence tools to aid in the diagnosis of oral cancer and oral potentially malignant disorders
No full textBackground: Artificial intelligence (AI) has emerged as a promising tool in dentistry, particularly in the early detection of oral cancer (OC) and oral potentially malignant disorders (OPMDs). Data focused on European dental students and their knowledge/attitudes towards the use of AI for diagnosing OC/OPMDs are limited. Methods: A cross-sectional online survey was conducted among final-year dental students from six European countries. The questionnaire assessed knowledge, attitudes, and perceived barriers regarding AI in the diagnosis of OC and OPMDs. Data were analysed using descriptive and comparative statistics to evaluate differences between countries. Results: A total of 328 students participated (75% female, 25% male). Most students stated that they had not received formal training in AI (61%) and emphasised the need to incorporate such training into the dental curriculum (47%). Students from Portugal had highest overall knowledge scores, but at the same time, lowest overall attitude scores. The most commonly perceived barrier was insufficient training (87.8%). Conclusion: Final-year dental students demonstrate positive attitudes towards AI aiding in diagnosis of OC and OPMDs, although significant knowledge and skill gaps remain. Integrating structured AI education into dental curricula is essential to prepare future academics and clinicians for responsible and effective AI use