IRIS UniSR (’Università Vita-Salute San Raffaele)
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CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming
Get PDFChronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8+ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4+ T cell receptor transgenic mice to show that CD4+ effector T cells can prevent and reverse the CD8+ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8+ T cell function and suppresses viral replication. CD4+ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4+ T cells license Kupffer cells via CD40–CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4+ T cell pool, while IL-27 is essential for CD8+ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8+ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infectio
Serious complications associated with nasogastric, orogastric or enteral tube misplacement over the decades: a systematic review
Get PDFBackground: Gastrointestinal tube (GIT) insertion is common in surgical, medical and intensive care unit settings, with approximately 170,000 annual insertions in the UK alone. Despite its apparent simplicity, GIT placement can lead to acute complications, ranging from mucosal lesions to life-threatening conditions. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching on PubMed, Cochrane, EMBASE and Scopus, all case reports and series describing harm from nasogastic, orogastric, or enteral tube placement. Results: A total of 148 studies reported acute GIT complications in 168 patients (70 patients received an enteral feeding tube). The number of publications increased over time. Half (91 patients, 52%) of the displacements involved the respiratory tract, but other organs were also affected, including the brain (33 patients, 20%), gastrointestinal tract (23 patients, 14%) and intravascular system (6 patients, 4%). Brain misplacement had the highest mortality (60.6%), while for respiratory tract misplacement mortality was 20.9%. Mortality was high in emergency department procedures and acute trauma, while it was low when enteral feeding tubes were involved. Only 30% of the manuscripts reported adherence to guidelines, which was associated with a trend towards decreased mortality. Conclusions: Our findings identify an increasing reporting of GIT misplacement complications and emphasize a variety of involved anatomical sites, from the well-known brain, respiratory tract, and pleural space mispositioning, to gastrointestinal and abdomen perforation, to the extremely uncommon spleen and intravascular mispositioning. The importance of implementing standardized protocols and maintaining heightened clinical vigilance is crucial to mitigate complications related to GIT misplacement. The PROSPERO Registration: PROSPERO CRD42024491074
Temporal Validation of an FDG-PET-Radiomic Model for Distant-Relapse-Free-Survival After Radio-Chemotherapy for Pancreatic Adenocarcinoma
No full textBackground/Objectives: Pancreatic cancer is a very aggressive disease with a poor prognosis, even when diagnosed at an early stage. This study aimed to validate and refine a radiomic-based [18F]FDG-PET model to predict distant relapse-free survival (DRFS) in patients with unresectable locally advanced pancreatic cancer (LAPC). Methods: A Cox regression model incorporating two radiomic features (RFs) and cancer stage (III vs. IV) was temporally validated using a larger cohort (215 patients treated between 2005–2022). Patients received concurrent chemoradiotherapy with capecitabine and hypo-fractionated Intensity Modulated Radiotherapy (IMRT). Data were split into training (145 patients, 2005–2017) and validation (70 patients, 2017–2022) groups. Seventy-eight RFs were extracted, harmonized, and analyzed using machine learning to develop refined models. Results: The model incorporating Statistical-Percentile10, Morphological-ComShift, and stage demonstrated moderate predictive accuracy (training: C-index = 0.632; validation: C-index = 0.590). When simplified to include only Statistical-Percentile10, performance improved slightly in the validation group (C-index = 0.601). Adding GLSZM3D-grayLevelVariance to Statistical-Percentile10, while excluding Morphological-ComShift, further enhanced accuracy (training: C-index = 0.654; validation: C-index = 0.623). Despite these refinements, all versions showed similar moderate ability to stratify patients into risk classes. Conclusions: [18F]FDG-PET radiomic features are robust predictors of DRFS after chemoradiotherapy in LAPC. Despite moderate performance, these models hold promise for patient risk stratification. Further validation with external cohorts is ongoing
Digital remote monitoring of people with multiple sclerosis
No full textIntroduction: Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects over 2.8 million people globally, leading to significant motor and non-motor symptoms. Effective disease monitoring is critical for improving patient outcomes but is often hindered by the limitations of infrequent clinical assessments. Digital remote monitoring tools leveraging big data and AI offer new opportunities to track symptoms in real time and detect disease progression. Methods: This narrative review explores recent advancements in digital remote monitoring of motor and non-motor symptoms in MS. We conducted a PubMed search to collect original studies aimed at evaluating the use of AI and/or big data for digital remote monitoring of pwMS. We focus on tools and techniques applied to data from wearable sensors, smartphones, and other connected devices, as well as AI-based methods for the analysis of big data. Results: Wearable sensors and machine learning algorithms show significant promise in monitoring motor symptoms, such as fall risk and gait disturbances. Many studies have demonstrated their reliability not only in clinical settings and for independent execution of motor assessments by patients, but also for passive monitoring during everyday life. Cognitive monitoring, although less developed, has seen progress with AI-driven tools that automate the scoring of neuropsychological tests and analyse passive keystroke dynamics. However, passive cognitive monitoring is still underdeveloped, compared to monitoring of motor symptoms. Some preliminary evidence suggests that application of AI and big data to other understudied aspects of MS (namely sleep and circadian autonomic patterns) may provide novel insights. Conclusion: Advances in AI and big data offer exciting possibilities for improving disease management and patient outcomes in MS. Digital remote monitoring has the potential to revolutionize MS care by providing continuous, long-term granular data on both motor and non-motor symptoms. While promising results have been demonstrated, larger-scale studies and more robust validation are needed to fully integrate these tools into clinical practice and generalise their results to the wider MS population
Seeing structure, losing sight: The case for morphological thinking in the age of integration
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Identification, characterisation and outcomes of pre-atrial fibrillation in heart failure with reduced ejection fraction
No full textAims: Atrial fibrillation (AF) in heart failure with reduced ejection fraction (HFrEF) has prognostic implications. Using a machine learning algorithm (FIND-AF), we aimed to explore clinical events and the cardiac magnetic resonance (CMR) characteristics of the pre-AF phenotype in HFrEF. Methods and results: A cohort of individuals aged ≥18 years with HFrEF without AF from the MATCH 1 and MATCH 2 studies (2018–2024) stratified by FIND-AF score. All received cardiac magnetic resonance using Cvi42 software for volumetric and T1/T2. The primary outcome was time to a composite of MACE inclusive of heart failure hospitalisation, myocardial infarction, stroke and all-cause mortality. Secondary outcomes included the association between CMR findings and FIND-AF score. Of 385 patients [mean age 61.7 (12.6) years, 39.0% women] with a median 2.5 years follow-up, the primary outcome occurred in 58 (30.2%) patients in the high FIND-AF risk group and 23 (11.9%) in the low FIND-AF risk group (hazard ratio 3.25, 95% CI 2.00–5.28, P < 0.001). Higher FIND-AF score was associated with higher indexed left ventricular mass (β = 4.7, 95% CI 0.5–8.9), indexed left atrial volume (β = 5.9, 95% CI 2.2–9.6), higher indexed left ventricular end-diastolic volume (β = 9.55, 95% CI 1.37–17.74, P = 0.022), native T1 signal (β = 18.0, 95% CI 7.0–29.1) and extracellular volume (β = 1.6, 95% CI 0.6–2.5). Conclusions: A pre-AF HFrEF subgroup with distinct CMR characteristics and poor prognosis may be identified, potentially guiding interventions to reduce clinical events
Recall vaccination increases detectable B-cell reactivity in persons with multiple sclerosis treated with ocrelizumab
No full textBACKGROUND: Utility of repeated boosts of anti-SARS-CoV-2 vaccination in persons with MS (pwMS) treated with ocrelizumab is questioned. OBJECTIVE: Investigate antiviral antibody and T-cell responses after mRNA vaccination for SARS-CoV-2 in ocrelizumab-treated pwMS. METHODS: Peripheral blood mononuclear cells were stimulated with SARS-CoV-2 peptide pools and T-cell reactivity was assessed by ELISPOT for IFN-γ detection, and by multiparametric flow cytometry analyses for assessment and characterization of T-cell activation. Anti-SARS-CoV-2 spike and nucleocapsid antibodies were analyzed in plasma of pwMS using two commercial platforms. RESULTS: ELISPOT assay against the spike protein of SARS-CoV-2 showed that COVID vaccination with mRNA results in the development of a robust specific T-cell reactivity that is sustained over repeated cycles of vaccination and tends to decline 2 years after last boost. Flow cytometry analysis following stimulation with SARS-CoV-2 peptide pools confirmed the presence of CD8+ T memory stem cells. CD8+ T memory stem cells, in particular, increased after repeated boosts of vaccination, as occurred for anti-SARS-CoV-2 antibodies. CONCLUSIONS: Repeated cycles of vaccination increase T and B-cell reactivity against SARS-CoV-2
Evaluation of respiratory virus transmissibility and resilience from fomites: the case of 11 SARS-CoV-2 clinical isolates
Get PDFThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic, significantly impacting social and economic aspects of society. While belonging to the Coronaviridae family, SARS-CoV-2 exhibited unique characteristics that facilitated its widespread transmission and pathogenicity. This study aimed to investigate the molecular characterization and infection kinetics of emerging SARS-CoV-2 variants, focusing on four key virological aspects: viral entry mechanisms, replication dynamics, immune evasion strategies, and surface persistence. We isolated 11 SARS-CoV-2 variants from clinical samples and conducted in vitro studies using Calu-3 cell lines and pseudovirus systems to explore viral entry. Whole-genome sequencing identified mutations linked to increased replication and enhanced immune evasion, particularly through the inhibition of interferon responses. Additionally, persistence studies on common environmental surfaces (copper, aluminum, and plastic) revealed that certain variants, such as G446S, contributed to increased viral stability, suggesting potential for indirect transmission beyond direct person-to-person contact. Furthermore, we evaluated the effectiveness of “green” disinfectants, including tea tree oil and quercetin-based compounds, which demonstrated viral load reductions of over 95% within minutes, outperforming conventional alcohol- and UV-based disinfection methods. Notably, two influenza virus isolates belonging to highly divergent subtypes are sanitized as well while showing different persistence surface profiles compared to SARS-CoV-2. These findings highlight the evolutionary strategies employed by SARS-CoV-2 to ensure transmission, its ability to adapt under selective pressure, and the importance of ongoing surveillance of emerging variants. Moreover, the efficacy of environmentally sustainable disinfectants presents a promising strategy for reducing viral transmission in both clinical and community settings
Personalized therapy in multiple sclerosis: an Italian Delphi consensus
Get PDFObjective: The increasing availability of disease-modifying therapies (DMTs) may provide more personalized treatment options for multiple sclerosis (MS) based on various factors, including patients’ characteristics, prognostic indicators, comorbidities, and safety. In Italy, recent efforts focused on promoting interdisciplinary, patient-centered care and equitable access to optimized therapies, as reported in the 2023 Barometer of Multiple Sclerosis and Related Diseases from the Italian Multiple Sclerosis Association. A key challenge is ensuring equitable access to homogeneous and personalized therapeutic strategies. Materials and methods: Using a Delphi methodology, a panel of Italian neurologists with expertise in MS evaluated consensus on specific aspects of MS treatments, including personalized therapy, patient involvement in decision-making, treatment flexibility, self-management of therapies, perception of treatment efficacy and safety and therapeutic sequence management. Results: Of 166 votes, 116 statements reached consensus (68% positive, 2% negative), representing 70% of the total, whereas 50 (30%) highlighted areas of non-consensus. The findings emphasize the central role of neurologists, the importance of personalized therapy, the inclusion of patients in therapeutic choices to enhance adherence and quality of life, and managing both quality of life and caregiver burden. Most high-efficacy disease-modifying therapies (HE DMTs), like cladribine and anti-CD20 therapies, recognized for their efficacy and convenience of administration, received positive consensus, emphasizing their perceived value in individualized treatment approaches. Conclusions: This research highlights best practices and provides a roadmap for improving patient outcomes through tailored, well-communicated therapeutic strategies