IRIS UniSR (’Università Vita-Salute San Raffaele)
Not a member yet
54666 research outputs found
Sort by
Early multimodal vasopressor strategy in septic shock (TRICYCLE)—Study protocol for a randomized controlled clinical trial
No full textIntroduction The main mechanism of hypotension in septic shock is persistent vasodilation secondary to vascular hyporeactivity despite high endogenous catecholamine levels and despite endogenous activation of the renin-angiotensin-aldosterone system. The classic stepwise approach involves initiation of norepinephrine, up-titration of the dosage to achieve a specified mean arterial pressure and moving to a second-line vasopressor if the patient remains refractory to norepinephrine. This approach often leads to prolonged states of hypoperfusion and high dose catecholamine exposure and is associated with poor clinical outcomes. Given the multifactorial basis of vasodilation in septic shock there is a strong physiological rationale for the early introduction of a multimodal vasopressor strategy that would provide a more physiologically guided approach. This study will compare the effects of a classic stepwise vs. an early balanced multimodal vasopressor strategy in septic shock. Methods This is a single blind randomized Phase II study. Patients with septic shock will be randomly assigned to control (classic stepwise vasopressor administration, n = 40) versus interventional (balanced multimodal vasopressor administration, n = 40) groups. The study employs a superiority trial design. Patients in the control group will be started on norepinephrine followed by vasopressin. Additional vasoactive drugs will be added as per the clinical team’s decision. In the interventional group, patients will simultaneously receive norepinephrine, angiotensin II and vasopressin at equipotent starting doses. We hypothesize that balanced multimodal vasopressor administration will result in a significant decrease in renin levels compared to the conventional stepwise strategy. Several secondary and exploratory outcome measures will be investigated. Univariate statistical tests with generalized linear modeling will be used to test for significant differences between the groups. Discussion The goal of this randomized controlled trial is to test the clinical efficacy of an early multimodal vasopressor strategy in septic shock. It aims to provide new insights and contribute to improved management of vasodilatory states
Body water distribution, early malnutrition and sarcopenia in ADPKD: insights from a cross sectional study
No full textBackground: Bioelectrical impedance analysis is a non-invasive method used to assess body composition and nutritional status in patients with chronic kidney disease (CKD). However, its reliability in autosomal dominant polycystic kidney disease (ADPKD) remains uncertain due to altered fluid distribution caused by cystic organ enlargement. This cross-sectional study compared bioelectrical impedance analysis-derived body composition and nutritional parameters between patients with ADPKD and those with non-ADPKD CKD. Methods: A total of 218 CKD patients (71 with ADPKD and 147 with non-ADPKD CKD, stages 1–5D) were enrolled. To control for baseline differences, 1:1 propensity score matching was applied. All participants underwent bioelectrical impedance analysis to assess body water compartments, skeletal muscle mass, fat mass, and phase angle. In the ADPKD group, parameters were further analyzed based on the presence of organomegaly, defined as nephromegaly (total kidney volume > 750 mL or kidney length > 16 cm) or hepatomegaly (liver transverse diameter > 25 cm). Results: After matching, two balanced groups of 71 patients each were compared. ADPKD patients showed significantly higher total and extracellular water than controls, both as absolute values normalized to height squared and as a percentage of body weight. Among ADPKD patients, the 41 with organomegaly had significantly lower phase angle, fat mass, fat-free mass, and skeletal muscle mass than the 30 without organomegaly—despite a paradoxical increase in body mass index (BMI). These changes were independent of kidney function. Conclusions: Bioelectrical impedance analysis detected altered fluid distribution and early signs of malnutrition and sarcopenia in ADPKD, supporting the need for proactive nutritional monitoring, especially in patients with organomegaly
Early Intensive Versus Escalation Approach: Ten-Year Impact on Disability in Relapsing Multiple Sclerosis
No full textObjective: To evaluate the long-term impact of early intensive treatment (EIT) versus escalation (ESC) strategies using high-efficacy disease-modifying therapies (HE-DMTs) on disability progression in relapsing multiple sclerosis (RMS). Methods: This observational study included 4878 RMS patients from the Italian Multiple Sclerosis Register. Eligible participants initiated their first disease-modifying therapy (DMT) within 3 years of disease onset and had >= 5 years of follow-up with at least three Expanded Disability Status Scale (EDSS) evaluations. Patients were categorized into the EIT group if they started with HE-DMTs and into the ESC group if HE-DMTs were initiated after >= 1 year of moderate-efficacy therapy. Propensity score matching was performed to balance baseline characteristics. Outcomes included disability trajectories assessed using linear mixed models for repeated measures and risks of confirmed disability accrual (CDA), progression independent of relapse activity (PIRA), and relapse-associated worsening (RAW) evaluated using Cox proportional hazards models. Results: Post-matching analysis of 908 pairs revealed significantly slower disability progression in the EIT group compared to the ESC group. At 10 years, the delta-EDSS difference between groups was -0.63 (95% CI: -0.83 to -0.43; p < 0.0001). ESC was associated with higher risks of CDA (HR 1.36, 95% CI: 1.20-1.54; p < 0.0001), PIRA (HR 1.22, 95% CI: 1.05-1.40; p = 0.0074), and RAW (HR 1.55, 95% CI: 1.17-2.05; p = 0.0021). Interpretation: EIT significantly reduces long-term disability progression in RMS compared to ESC. These findings underscore the potential of EIT to optimize long-term outcomes in RMS patients
Indagare i meccanismi molecolari e immunologici alla base della persistenza dell'HIV
No full textLa principale barriera a una cura sterilizzante è la precoce instaurazione di un serbatoio stabile di cellule infettate da HIV. L’inizio precoce della terapia antiretrovirale (ART) durante l’infezione acuta favorisce il recupero immunologico, riduce la dimensione del serbatoio virale e aumenta la probabilità di controllo virale post-trattamento. Diversi meccanismi contribuiscono al mantenimento del reservoir; la disregolazione dell’espressione di BACH2 e STAT5B è stata associata alla persistenza di HIV nelle cellule T regolatorie. D’altra parte, le cellule mieloidi sono state descritte come potenziali serbatoi dell’infezione. Gli obiettivi di questo studio erano caratterizzare l’infezione da HIV nelle fasi acute e croniche dal punto di vista immunologico, descrivere la dimensione e la competenza replicativa del reservoir, e caratterizzare i profili di integrazione di HIV-1 nell’ambito degli studi PERSHIST e IMMUNERaRe.
Lo studio PERSHIST ha incluso persone adulte con HIV (PLWH) trattate durante l’infezione cronica, con una storia di ART superiore a 15 anni o 5 anni o trattate in fase di infezione acuta. Nello studio IMMUNERaRe, invece, sono stati inclusi solo PLWH che avevano iniziato la ART durante l’AHI. L’analisi citofluorimetrica è stata utilizzata per valutare la composizione relativa delle sottopopolazioni linfocitarie e mieloidi specifiche. L’Intact Proviral DNA Assay è stato impiegato per quantificare e distinguere i provirus deleti da quelli intatti. I trascritti chimerici sono stati rilevati mediante RT-PCR, mentre i siti di integrazione sono stati analizzati tramite Sonicated Linker Mediated-PCR. Le comparazioni tra i gruppi sono state effettuate con test non parametrici.
Abbiamo arruolato 28 persone con HIV nello studio PERSHIST e 89 nello studio IMMUNERaRe. Abbiamo riscontrato una composizione relativa simile delle cellule T-regolatorie convenzionali e non convenzionali e delle compartimentazioni mieloidi con funzioni regolatorie, anche rispetto ai controlli sani. L'IPDA ha rivelato una maggiore quantità di DNA intatto nelle persone con HIV che hanno iniziato la ART in fase cronica (partecipanti a PERSHIST), rispetto a quelle in fase acuta (partecipanti a IMMUNERaRe). BACH2 e, ancora di più, STAT5B sono stati confermati come responsabili dell'integrazione. Abbiamo identificato specifiche interazioni HLA-KIR associate al controllo immunologico in PWH che hanno iniziato ART durante la PHI.
Il nostro lavoro migliora la comprensione dei complessi meccanismi alla base della persistenza dell’HIV e del controllo immunologico in PLWH. L’arricchimento di KIR attivanti nei RR suggerisce un ruolo delle risposte mediate dalle cellule NK nel recupero immunologico.Main barrier to a sterilizing cure is the early establishment of a stable reservoir of HIV infected cells. Starting ART during acute infection supports immunological recovery, reduces the size of the HIV reservoir, and enhances the likelihood of post-treatment viral control. Several mechanisms contribute to maintenance of reservoir; the deregulation of BACH2 and STAT5B expression was shown to contribute to HIV persistence in regulatory T cells. On the other hand, myeloid cells have been described as reservoirs of HIV. We aimed to characterize acute and chronic HIV infection from an immunological perspective, describe the size and replication competence of the reservoir, and characterize the integration profile of HIV-1 in the context of the PERSHIST and in the IMMUNERaRe studies.
Adult people living with HIV (PLWH) treated either in chronic infection (CHI) with history of ART higher than 15 years or 5 years or in acute infection (AHI) were included in the PERSHSIT study, while in the IMMUNERaRe study only PWLH who started ART in AHI were included. Cytofluorimetric analysis was used to assess the relative composition of myeloid and lymphocytic cell subpopulations. Intact proviral DNA assay was used to quantify and distinguish deleted proviruses from intact proviruses. Chimeric transcripts were retrieved by RT-PCR, while integration sites by Sonicated Linker Mediated-PCR. Comparisons among groups were performed by nonparametric tests.
We enrolled 28 PLWH in PERSHIST study and 89 in IMMUNERaRe study. We found similar relative composition of conventional and non-conventional T-regulatory cells and of myeloid compartments with regulatory functions, also when compated to healthy controls. IPDA revealed a greater amount of intact DNA in PLWH who started ART in CHI (PERSHIST participants), as compared to AHI (IMMUNERaRe participants). BACH2 and, even more, STAT5B were confirmed to be culprit of integration. We identified specific HLA-KIR interactions associated with immunological control in PWH starting ART during PHI.
Our work enhances the understanding of the complex mechanisms underlying HIV persistence and immunological control in PLWH. The enrichment of activating KIR in RR suggests a role for NK cell-mediated responses in immune recovery
Transcription Factor EB (TFEB) Expression and Localization in the 3rd-Trimester Preeclamptic and Diabetic Placenta
No full textThe lack of expression of TFEB in 12/13 cases of MVM seems to corroborate the role of TFEB in vascular remodel- ing during placental development. The positivity in VSTB and vessels in cases with mixed MVM and DVM histological features in patients with gestational diabetes may suggest that hypoxic injury is mediated through mechanisms (such as the ALANO pathway) different from those intervening in MVM despite some morpho- logical similarities
Hyaluronic acid: A novel approach in regenerative/reconstructive periodontal therapy?
No full textBackground: Although hyaluronic acid (HA) has long been used for many medical applications, only in recent years has it gained greater popularity in the field of periodontics because of its biological effects during wound healing. Even today, most clinicians are not aware that more than one type of HA exists and that the extent of its biological functions may vary depending upon the particular characteristics of the biomolecule itself. Aim: To review and synthesize the current preclinical and clinical evidence on the biological effects and therapeutic applications of HA in periodontology, with a focus on its role in wound healing and regeneration. Materials and methods: The origin and chemical structure of HA are discussed first, with a focus on the importance of its molecular weight and the possibility of modifying its structure and form. The main biological properties of HA followed by its effects on the cells of periodontal tissues are summarized and followed by the presentation of the results from preclinical studies in animals which have evaluated the effects of HA in various types of defects. Subsequently, the data from clinical studies evaluating the application of HA in nonsurgical periodontal therapy, regenerative periodontal surgery, and mucogingival surgery are summarized, and recommendations for the clinicians are provided. Results: The preclinical and clinical evidence indicates that HA accelerates the wound healing process through inflammatory mechanisms and enhances blood clot stability when applied to the root surface. It also influences the expression of both mineralized tissue markers and cementoblast-specific genes, suggesting a potential role in cementum regeneration. HA strongly promotes osteoprogenitor growth while maintaining stemness, potentially regulating the balance between self-renewal and differentiation during bone regeneration. Additionally, HA enhances periodontal ligament (PDL) cell adhesion and proliferation. It has been shown to improve the proliferative and migratory abilities of cells while inducing the expression of collagen type III alpha 1 (COL3A1) and TGFβ-3 genes, which are characteristic of scarless fetal wound healing. Certain HA formulations upregulate the expression of genes encoding platelet-derived growth factor B (PDGFB), fibroblast growth factor 2 (FGF-2), and epidermal growth factor (EGF), all of which play crucial roles in the healing process. Histologic evidence from animal studies suggests that HA may promote periodontal regeneration when applied both non-surgically and surgically—particularly in intrabony defects, gingival recessions, and, to some extent, in furcation defects. The data from clinical studies revealed that HA leads to statistically significant and clinically relevant improvements of probing depths and clinical attachment levels when used in conjunction with nonsurgical periodontal therapy and surgical therapy in intrabony and recession defects. Conclusion: The available data from preclinical and clinical studies provide robust evidence on the effects of HA to enhance periodontal wound healing and regeneration, and on the improved clinical outcomes when HA is used in conjunction with nonsurgical periodontal therapy and regenerative surgery in intrabony and recession defects
Comprehensive Cardiac Imaging Before and During Microaxial Flow Pump Support for Cardiogenic Shock
No full textThe increasing use of microaxial flow pumps (mAFP) underpins the need for a comprehensive approach to manage critically ill patients in an effort to maximize the benefits of this temporary mechanical circulatory support (tMCS) while minimizing its potential complications. Multimodality cardiac imaging offers an irreplaceable array of tools to address device position, device–heart hemodynamic interaction, myocardial recovery assessment, and identification of complications. This review provides a comprehensive and pragmatic summary of the cardiovascular imaging modalities currently available throughout the pathway of care of mAFP-supported patients, from device insertion, to intensive cardiac care hemodynamic monitoring, weaning guidance, and myocardial recovery assessment. The specific logistical and technical challenges related to pump management and potential interference with the imaging technology performed during mAFP are also discussed. Comprehensive cardiovascular imaging represents a fundamental pillar to ensure the best care to mAFP-supported patients and plays a pivotal role in any successful critical care and tMCS program
Skin Photodamage and Melanomagenesis: A Comprehensive Review
No full textMelanoma, the most aggressive form of skin cancer, still represents a significant and growing public health concern. Ultraviolet radiation (UVR) is considered the primary driver of melanoma, although genetic predisposition also plays a critical role. This review explores the intricate molecular mechanisms by which UVR-induced photodamage contributes to melanoma development. We examine epidemiological evidence linking UV exposure to increased risk, detailing how UVR damage to DNA triggers inflammatory responses and impairs DNA repair mechanisms. Specifically, we discuss the roles of nucleotide excision repair (NER) and base excision repair (BER) in mitigating UV damage. The review further explores diagnostic and surgical implications for melanomas arising on sun-exposed skin. By synthesizing current evidence, this overview aims to deepen understanding of the complex relationship between UVR, photodamage, and melanoma, shedding light on the need for personalized preventive strategies to better stratify the risk and introduce behavioral changes to reduce skin photodamage
The evolving landscape of hormone receptor-positive/HER2-negative metastatic breast cancer (EVOLVE): An Italian Delphi consensus report
No full textBackground: The expanding treatment landscape for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) has led to the emergence of new “grey areas” not covered by international guidelines, where treatment decision making is particularly challenging. Methods: Sixteen relevant statements regarding the management of HR+ /HER2- mBC were formulated by an Executive Board and validated by a Scientific Board, composed by internationally recognized experts in the field of BC. Subsequently, 50 Italian oncologists were surveyed between May 2024 and June 2024 through the modified Delphi method, in order to capture their rate of agreement and disagreement on the proposed statements. Results: The consensus was reached for all 16 statements: 4 were related to resistance and sensitivity to CDK4/6 inhibitors and endocrine therapy, 6 to biomarkers for HR+ /HER2- mBC, and 6 to treatment algorithm of HR+ /HER2- mBC. The Panel critically and comprehensively discussed the most relevant results, especially regarding the statements with lower level of agreement (which ranged from 85.4 % to 100 %). Conclusions: The treatment of HR+ /HER2- mBC is currently being reshaped due to the expansion of its pharmacopoeia, the better understanding of its molecular determinants and the validation of biomarkers for patient selection. This consensus addressed the most controversial questions related to treatment decision and reached the agreement in all statements
Intrinsic disorder and fuzzy interactions drive multiple functions of HMGB1
No full textHMGB1, a multitasking protein, is scrutinized here through the lens of the 'fuzzy interactions' driven by its intrinsically disordered regions (IDRs). Although the multiple intracellular and extracellular functions of this protein have been studied for decades, viewing HMGB1 as fuzzy and dynamic provides a novel perspective. Recent breakthroughs emphasize the crucial role of its IDRs, especially the acidic C-terminal tail, in mediating dynamic multivalent interactions. This fuzziness enables HMGB1 to modulate DNA and chromatin binding, to chaperone other proteins such as p53, and to tune inflammatory signals via receptors such as TLR4 and CXCR4. Understanding the fuzzy nature of HMGB1 unlocks new therapeutic strategies targeting both its structured and unstructured regions to tackle a range of diseases