IRIS UniSR (’Università Vita-Salute San Raffaele)
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Sex hormone-related factors and the risk of PIRA in women with multiple sclerosis
No full textBackground: Sex-related differences affect multiple sclerosis (MS), but the impact of sex hormones on disease progression remains unclear. We investigated whether sex hormone-related factors influence progression independent of relapse activity (PIRA) in women with MS over a long-term follow-up. Methods: The study analysed 1210 female MS patients from the San Raffaele MS Center using data from an environmental survey (2019-2023). PIRA was defined as 12-week confirmed disability progression independent of recent relapses (<30 days). Cox proportional-hazard models (adjusted for confounding factors) were used to assess the effect of hormone-related factors on PIRA risk. Results: Patients who used oral contraceptives before MS diagnosis had a 26% lower risk of PIRA and a delayed median time to the first PIRA event (9.94 vs 7.5 years; HR=0.74; 95% CI 0.61 to 0.89; p=0.0018). Conversely, menopause at diagnosis (HR=1.82; 95% CI 1.24 to 2.67; p=0.0022) and pregnancy before diagnosis (HR=1.22; 95% CI 1.006 to 1.47; p=0.043) were associated with a shorter time to PIRA. No significant differences were found with abortion, menstrual irregularity or fertility therapy. Conclusions: This study suggests that early oral contraceptives may delay future disability progression, supporting the importance of sex hormones in MS and prompting further prospective investigations on oral contraceptives to slow disease progression
Impact of Antibiotic Therapy in Patients with Cholangiocarcinoma Treated with Chemoimmunotherapy
No full textIntroduction: Patients with biliary tract cancers (BTCs) often require antibiotic therapy before starting systemic treatment that includes an immune checkpoint inhibitor. This study aimed to evaluate the prognostic impact of antibiotic therapy administered in the 15 days prior to the start of chemoimmunotherapy in patients with BTC. Methods: The study population included patients with metastatic or locally advanced BTC from Western and Eastern populations treated with first-line chemoimmunotherapy. The aim of the study was to evaluate the impact of antibiotic therapy in the 15 days prior to starting oncological treatment (AT population) compared to patients who did not receive antibiotic therapy (NAT). Univariate and multivariate analyses were used to evaluate predictive factors for overall survival (OS) and progression-free survival (PFS), while prognostic factors were analyzed by univariate and multivariate analysis using Cox regression model. Results: A total of 666 patients were enrolled in the study: 93 (14%) in AT cohort and 573 (86%) in NAT cohort. In the AT population, the incidence of cholangitis (p = 0.0017), alanine aminotransferase elevation (p = 0.0009), fever (p = 0.0021), decreased appetite (p = 0.0007), itching (p = 0.0081), and rash (p = 0.012) was significantly higher compared to the NAT. The median OS was 15.9 months (95% confidence interval [CI]: 13.8-18.3) in NAT cohort versus 10.1 months (95% CI: 7.9-12.4) in AT cohort (NAT vs. AT, hazard ratio [HR]: 0.43, 95% CI: 0.27-0.70, p = 0.0006), while median PFS was 8.5 months in NAT cohort versus 5.4 months in AT cohort (NAT vs. AT, HR: 0.49, 95% CI: 0.34-0.71, p = 0.0001). Multivariate analysis confirmed the prognostic role of antibiotic for OS and PFS. Finally, NAT cohort showed better overall response rate compared with AT cohort (31.4% vs. 20.4%, p = 0.03). Conclusions: The use of antibiotic therapy in the 15 days prior to starting chemoimmunotherapy is an independent unfavorable prognostic factor for survival in our cohort of patients with advanced BTC treated with cisplatin, gemcitabine and durvalumab
Corpo filosofico, corpo filmico e corpo comico
No full textThe filmic body represents a challenge to our understanding of ourselves as thinking and free bodies. In cinema, the body has multiple dimensions and is limited differently from physicality. The filmic body has several dimensions (the actor, the image/character, the viewer, the film itself) and in any case its material remains an unsurpassable datum. In particular, the comic body, as happens in Buster Keaton, represents the persistence of the real body in the cinematographic dimension
Circulating inflammatory markers predict depressive symptomatology in COVID-19 survivors
No full textGrowing evidence suggests the neurobiological mechanism upholding post-COVID-19 depression mainly relates to immune response and subsequent unresolved low-grade inflammation. Herein we exploit a broad panel of cytokines serum levels measured in COVID-19 survivors at one- and three-month since infection to predict postCOVID-19 depression. 87 COVID survivors were screened for depressive symptomatology at one- and three-month after discharge through the Beck Depression Inventory (BDI-13) and the Zung Self-Rating Depression Scale (ZSDS) at San Raffaele Hospital. Blood samples were collected at both timepoints and analyzed through Luminex. We entered onemonth 42 inflammatory compounds into two separate penalized logistic regression models to evaluate their reliability in identifying COVID-19 survivors suffering from clinical depression at the two timepoints, applied within a machine learning routine. Delta values of analytes lowering between timepoints were entered in a third model predicting presence long-term depression. 5000 bootstraps were computed to determine significance of predictors. The cross-sectional model reached a balance accuracy (BA) of 76 % and a sensitivity of 70 %. Post-COVID-19 depression was predicted by high levels of CCL17, CCL22. On the other hand, CXCL10, CCL2, CCL3, CCL8, CXCL5, CCL15, CCL23, CXCL13, and GM-CSF showed protective effects. The longitudinal model obtained good performance as well (BA = 74 % and sensitivity = 68 %), revealing CXCL16 and CCL25 as additional drivers of clinical depression. Moreover, dynamic changes of analytes over time accurately predicted long-term depression (BA = 76 % and sensitivity = 75 %). Our findings unveil a putative immune profile upholding post-COVID-19 depression, thus reinforcing the need to deepen molecular mechanisms to appropriately target depression
Health literacy: a new challenge for laboratory medicine
No full textPoor health literacy and inappropriate test prescribing hamper the value of laboratory medicine. The disintermediation between test producers and interpreters may happen both in Point of Care Tests, where doctor mediation is provided, but laboratory expert supervision is not, and in Direct to Consumer Testing, where no medical mediation is provided at all. In these cases, the respect for patient's autonomy must not preclude the principles of non-maleficence (as an individual concern) and justice (as a societal concern), as wrong test interpretation can generate confusion, anxiety, inappropriate social behavior, useless medical examinations and considerable cost increase. Considering how different is patient ability to understand test results (if any) and handle any physical and psychological consequence, promoting health literacy and professional laboratory mediation become crucial professional priorities. The aims of this review are 1) to describe the importance of health literacy on laboratory test interpretation, medical advice and therapeutic compliance; 2) to discuss doctor-level, patient-level and caregiver-level educational interventions in light of the four principles of the value-based framework (personal value, technical value, allocative value and societal value). Based on these premises, the authors support the need to enhance health literacy in patients, help doctors improve the communication of results and validate commercial tests under the scrutiny of scientific community.Poor health literacy and inappropriate test prescribing hamper the value of laboratory medicine. The disintermediation between test producers and interpreters may happen both in Point of Care Tests, where doctor mediation is provided, but laboratory expert supervision is not, and in Direct to Consumer Testing, where no medical mediation is provided at all. In these cases, the respect for patient's autonomy must not preclude the principles of non-maleficence (as an individual concern) and justice (as a societal concern), as wrong test interpretation can generate confusion, anxiety, inappropriate social behavior, useless medical examinations and considerable cost increase. Considering how different is patient ability to understand test results (if any) and handle any physical and psychological consequence, promoting health literacy and professional laboratory mediation become crucial professional priorities. The aims of this review are 1) to describe the importance of health literacy on laboratory test interpretation, medical advice and therapeutic compliance; 2) to discuss doctor-level, patient-level and caregiver-level educational interventions in light of the four principles of the value-based framework (personal value, technical value, allocative value and societal value). Based on these premises, the authors support the need to enhance health literacy in patients, help doctors improve the communication of results and validate commercial tests under the scrutiny of scientific community
Defective formation of germinal centres underlies B cell dysfunction in pancreatic cancer
No full textPancreatic ductal adenocarcinoma (PDAC) is an aggressive disease, whereby chronic inflammation is key to the establishment of an immunosuppressive tumour microenvironment (TME). Although referred to as immunologically cold, PDAC is populated by heterogenous immune cells, including B lymphocytes that organise into tertiary lymphoid structures (TLSs). While TLSs generally correlate with better prognosis and response to immunotherapies in patients, a mechanistic understanding of TLS contribution to anti-tumour immunity in PDAC remains elusive. Here, we set out to elucidate the functional properties of B cells within TLSs and dissect molecular signals that regulate B cell activity in pancreatic cancer. We established the formation of TLSs as a recurrent event in human PDAC and multiple mouse models, harbouring B cell subsets corresponding to discrete differentiation states. By integrating histological and transcriptomic analyses of mouse PDAC, we reported defective formation of germinal centres (GCs) in TLSs, indicating alternative activation of B cells within these structures. Paired single-cell RNA and B cell receptor (BCR)-sequencing revealed that deficiency of GCs in PDAC TLSs leads to the predominance of extrafollicular (EF) responses, which promotes the differentiation of atypical memory (AtM) B cells and the acquisition of inflammatory and immunoregulatory gene expression programs. By developing an in vitro model of B cell function, we identified prostaglandin E2 (PGE2) as a candidate PDAC TME inflammatory factor that impairs B cell activation and differentiation towards GCs. Notably, genetic ablation of tumour-derived PGE2 production rescued GC responses within PDAC TLSs in vivo. Collectively, our findings highlight PGE2 as a negative regulator of GC formation within PDAC TLSs, providing a promising therapeutic target to modulate B cell responses for effective PDAC immunotherapy.L’adenocarcinoma duttale del pancreas (PDAC) è una malattia aggressiva, nella quale l’infiammazione cronica svolge un ruolo chiave per la creazione di un microambiente tumorale immunosoppressivo. Sebbene indicato come immunologicamente freddo, il PDAC è caratterizzato da un infiltrato immunitario eterogeneo, che include linfociti B organizzati in strutture linfoidi terziarie (TLS, da “tertiary lymphoid structures”). Nonostante la presenza di TLS sia generalmente correlata con una prognosi favorevole e una migliore risposta all’immunoterapia, il contributo dei TLS nell’immunità anti-tumorale rimane poco chiaro nel PDAC. In questo studio, ci siamo proposti di definire le proprietà funzionali dei linfociti B nei TLS associati al PDAC e di identificare i segnali molecolari che ne regolano l’attività. I dati ottenuti hanno evidenziato la formazione di TLS in campioni umani di PDAC e in diversi modelli murini, mostrando la presenza di sottopopolazioni di linfociti B che corrispondono a diversi stadi di differenziamento. Integrando analisi istologiche e trascrittomiche, abbiamo osservato che i TLS associati al PDAC sono privi di centri germinativi (GC, da “germinal centre”), suggerendo un’attivazione alternativa dei linfociti B in queste strutture. L’analisi del trascrittoma e della sequenza del recettore delle cellule B (BCR) ha collegato l’assenza di GC nei TLS con una predominanza della risposta extra-follicolare (EF), che promuove il differenziamento in cellule B della memoria atipiche e l’acquisizione di programmi di espressione genica infiammatori e immunoregolatori. Infine, abbiamo identificato la prostaglandina E2 (PGE2) come fattore associato al microambiente del PDAC in grado di compromettere l’attivazione dei linfociti B e il loro differenziamento a GC in vitro ed in vivo. Questi risultati evidenziano la funzione soppressiva della PGE2 sullo sviluppo di GC nei TLS associati al PDAC, offrendo un target promettente per modulare la risposta dei linfociti B come approccio immunoterapeutico
The Effect of a Manni Telescopic Herbst Appliance with Four Miniscrews (STM4) on the Treatment of a Class II Division I Malocclusion: A 3D Finite Element Study
Get PDFAim: Class II Division I malocclusion poses significant challenges in orthodontics. The combination of a Herbst appliance and miniscrew anchorage emerged as a practical solution to improve skeletal and dental outcomes. This study employed finite element analysis to evaluate the biomechanical effects of a miniscrew-supported Herbst appliance on mandibular advancement and dentition movement. Methods: High-definition CBCT scans captured the maxilla and mandible’s detailed dental anatomy. The scans were stored in DICOM format for seamless integration with Mimics software (Mimics Innovation Suite research version 21.0, Materialise NV, Leuven, Belgium) for 3D reconstruction and model refinement. The appliance, designed with a maxillary fixed palatal arch and mandibular acrylic splint connected by telescoping rods, incorporated titanium TADs and elastic chains. STL models were optimized in Geomagic x Design for finite element analysis in Abaqus, assigning validated mechanical properties for materials. Tetrahedral meshing and realistic boundary conditions simulated biomechanical interactions. Tetrahedral C3D4 elements were used for meshing, ensuring a balance between computational efficiency and detailed anatomical representation. Tetrahedral meshing and realistic boundary conditions simulated biomechanical interactions. Dynamic simulations in CATIA evaluated mandibular movement. FEA analyzed displacement across dentoalveolar structures along the X, Y, and Z axes to assess treatment efficacy and biomechanical stability. Results: The Z displacement analysis revealed that the incisal edges of the lower central, lateral, and canines shifted lingually by 0.41, 0.4, and 0.47 mm, respectively. Additionally, the apices of the lower central, lateral, and canines displaced backwards by 0.05 mm, 0.05 mm, and 0.07 mm, respectively. Conclusions: The appliance facilitated mandibular advancement, bodily retracted the lower incisors, well-controlled the upper ones, and mesial-tipped the upper posterior teeth. In contrast with traditional functional appliances, it caused the lower anterior teeth to move backwards, while skeletal anchorage overcame some shortcomings of nonsurgical treatments. This method might be a good treatment option for growing skeletal Class II patients
The Invention of Philosophical Rationality: An Introduction to Philosophy by Way of the Presocratics
No full textNascita della filosofia come razionalità scientifica nei Presocratic
Autoimmune Pancreatitis Mimicking a Pancreatic Neuroendocrine Tumor: A Case Report with a Literature Review
No full textAutoimmune pancreatitis (AIP) is a rare chronic pancreatitis subtype that often mimics pancreatic cancer due to the overlapping clinical and radiological features, posing significant diagnostic challenges. Similarly, distinguishing AIP from pancreatic neuroendocrine neoplasms (PanNENs), which present with nonspecific symptoms, adds complexity to clinical evaluations. We present the case of a 46-year-old male with recurrent acute idiopathic pancreatitis. Abdominal computed tomography (CT) revealed a 25 mm hypodense mass in the pancreatic tail with mild arterial contrast enhancement. Magnetic resonance imaging (MRI) showed the mass to be hypointense on T2-weighted sequences, with no diffusion restriction and an enhancement pattern akin to normal pancreatic tissue. The endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) was inconclusive. Gallium-68 DOTATATE positron emission tomography–CT (Ga-68 DOTATATE PET-CT) showed an increased tracer uptake, leading to a distal pancreatectomy with a splenectomy. Histopathology demonstrated chronic sclerotic pancreatitis with inflammatory infiltrates. Elevated serum IgG4 levels confirmed the diagnosis of type 1 AIP Differentiating AIP from pancreatic malignancies, including PanNENs, is both critical and complex. This case highlights a misdiagnosis of PanNENs in a patient with focal AIP, where neuroendocrine hyperplasia and islet cell clusters within fibrotic areas mimicked PanNENs, even on Ga-68 PET-CT. The findings emphasize the potential for false positives with Ga-68 DOTATATE PET-CT and the importance of integrating clinical, radiological, and histological data for an accurate diagnosis
Decongestion and Outcomes in Patients Hospitalized for Acute Heart Failure: Insights From the RELAX-AHF-2 Trial
Get PDFBackground: The prognostic importance of residual congestion after acute heart failure (AHF) hospitalization is still debated. Objectives: The authors aimed to assess the impact of residual congestion in a large cohort of patients with AHF enrolled in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF) trial. Methods: Residual congestion was assessed at day 5 after admission among hospitalized patients using an established composite congestion score (CCS) based on the presence of orthopnea, peripheral edema, and increased jugular venous pressure, ranging from 0 to 8 points. The primary endpoint was a composite of cardiovascular death or rehospitalization for heart failure or renal failure at 180 days. Results: Among the 5,900 AHF patients included in this analysis, 3,380 (57.3%) had at least 1 sign of congestion (ie, CCS ≥1) and 1,066 (18.1%) had a CCS ≥3 at day 5 after admission. Patients with residual congestion at day 5 were more symptomatic, had more comorbidities, received higher doses of loop diuretic agents in-hospital, albeit with lower diuretic response, were less likely to have hemoconcentration, and were more likely to have worsening renal function at day 5. After multivariable adjustment for clinically meaningful variables, any sign of residual congestion and CCS ≥3 at day 5 were both independently associated with a higher risk of the primary endpoint (adjusted HR: 1.32 [95% CI: 1.15-1.51]; P < 0.001 and adjusted HR: 1.62 [95% CI: 1.39-1.88]; both P < 0.001). Conclusions: Among patients with AHF who were still hospitalized at day 5, residual congestion was common and independently associated with worse outcome. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778