Happy birthday to the Italian Territorial Emergency Service (118): Thirty years of your valuable service

Sunday 27th March 2022 marked 30 years of activity of the Italian Territorial Emergency Service, also known as "118", which was officially set up in Italy on 27th March 1992 by a presidential decree, with the aim of creating a single number for sanitary emergencies that would operate 24 hours a day, seven days a week, free of charge throughout the country. [...

miR-382-5p Controls Hematopoietic Stem Cell Differentiation Through the Downregulation of MXD1

microRNAs are key regulators of gene expression that control stem cell fate by posttranscriptional downregulation of hundreds of target genes through seed pairing in their 3' untranslated region. In fact, miRNAs tightly regulate fundamental stem cell processes, like self-renewal, proliferation, and differentiation; therefore, miRNA deregulation may contribute to the development of solid tumors and hematological malignancies. miR-382-5p has been found to be upregulated in patients with myeloid neoplasms, but its role in normal hematopoiesis is still unknown. In this study, we demonstrated that miR-382-5p overexpression in CD34(+) hematopoietic stem/progenitor cells (HSPCs) leads to a significant decrease of megakaryocyte precursors coupled to increase of granulocyte ones. Furthermore, by means of a computational analysis using different prediction algorithms, we identified several putative mRNA targets of miR-382-5p that are downregulated upon miRNA overexpression (ie, FLI1, GATA2, MAF, MXD1, RUNX1, and SGK1). Among these, we validated MXD1 as real target of miR-382-5p by luciferase reporter assay. Finally, we showed that MXD1 knockdown mimics the effects of miR-382-5p overexpression on granulocyte and megakaryocyte differentiation of CD34(+) cells. Overall, our results demonstrated that miR-382-5p expression favors the expansion of granulocyte lineage and impairs megakaryocyte commitment through MXD1 downregulation. Therefore, our data showed for the first time that the miR-382-5p/MXD1 axis plays a critical role in myelopoiesis by affecting the lineage choice of CD34(+) HSPCs

Transient global amnesia: Isolated event or healthy predictor? Clinical experience of an Italian Emergency Department

Transient global amnesia (TGA) is a clinical syndrome characterized by reversible anterograde amnesia, in which the patient is alert, self-awareness appears intact and other neurological symptoms are absent. The diagnosis is based on the following criteria: i) witnessed event; ii) acute onset of anterograde amnesia; iii) no accompanying neurological symptoms; iv) no alteration of consciousness; v) no epileptic features; vi) resolution within 24 hours; vii) exclusion of other causes. We conducted a cohort study at the Department of Emergency Medicine on 119 patients with TGA diagnosis from 2010 to 2014, with follow-up evaluation by telephone interview. The objectives of our study were to evaluate the frequency of subsequent episodes, to identify predisposing factors, and to investigate whether TGA is a possible predictor of neurological disease. The frequency of comorbidity in our population was in line with literature. We observed a recurrence rate of 9.5%, with a prevalence for the male gender, while no other factor correlates with TGA recurrence. TGA was not a predictor of further neurological diseases. In conclusion, TGA is a benign pathology with a low probability of relapse. Accordingly, management in Emergency Department should be based on a correct initial clinical classification for rapid discharge

Endoscopic management of Zenker's diverticulum: stapling vs. Z-POEM

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Prognostic value of lung ultrasound score performed in the Emergency Department in COVID-19 patients: a prospective multicenter study in central Italy

Lung ultrasound (LUS) is an essential tool for respiratory disease differential diagnosis at Emergency Department (ED), due to easy applicability and safety. During Sars-Cov 2 pandemic, LUS was widely used in every setting. This study aims to demonstrate the prognostic role of LUS independently of other factors and the identification of an LUS score cut-off to be applied in the ED. A multi-center prospective study was conducted on 285 patients, 123 from Pisa University Hospital, 162 from S. Maria Misericordia Hospital of Perugia. All patients received LUS examination by expert sonographers within 48 hours of admission with the same methodology. Univariate logistic analysis demonstrated that LUS is a mortality predictor, OR 2.8 (CL1.5-5.1). Using LUS score cut-off 1.3, the OR was 6.7 (CL2.7-1.6). In multivariate logistic analysis, LUS score significantly predicted death, independently of other factors. ROC curves comparison demonstrated that the introduction of LUS score <1.3 to a multifactorial model improved the association with mortality (AUC 0.76vs0.84, p=0.04). LUS combined with clinical, anamnestic, laboratory, and blood gas parameters, would allow an effective prognostic stratification in Sars-Cov2 patients at ED

Role of TGF-\u3b21/miR-382-5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro-inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2, MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR-382-5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR-382-5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR-382-5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR-382-5p. Subsequently, we confirmed miR-382-5p/SOD2 interaction by luciferase assay and we showed that miR-382-5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR-382-5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro-inflammatory cytokine transforming growth factor-\u3b21 (TGF-\u3b21) is a key player in PMF pathogenesis, we further investigated the effect of TGF-\u3b21 on ROS and miR-382-5p levels. Our data showed that TGF-\u3b21 treatment enhances miR-382-5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF-\u3b21 signaling in PMF CD34+ cells by galunisertib significantly reduced miR-382-5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF-\u3b21/miR-382-5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF-\u3b21 in PMF patients. Database linking: GEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464

Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial.

PURPOSE: MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations. PATIENTS AND METHODS: Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 &gt;2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts. RESULTS: From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts. CONCLUSIONS: Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed

Estimated pulse wave velocity improves risk stratification for all-cause mortality in patients with COVID-19

Accurate risk stratification in COVID-19 patients consists a major clinical need to guide therapeutic strategies. We sought to evaluate the prognostic role of estimated pulse wave velocity (ePWV), a marker of arterial stiffness which reflects overall arterial integrity and aging, in risk stratification of hospitalized patients with COVID-19. This retrospective, longitudinal cohort study, analyzed a total population of 1671 subjects consisting of 737 hospitalized COVID-19 patients consecutively recruited from two tertiary centers (Newcastle cohort: n = 471 and Pisa cohort: n = 266) and a non-COVID control cohort (n = 934). Arterial stiffness was calculated using validated formulae for ePWV. ePWV progressively increased across the control group, COVID-19 survivors and deceased patients (adjusted mean increase per group 1.89 m/s, P &lt; 0.001). Using a machine learning approach, ePWV provided incremental prognostic value and improved reclassification for mortality over the core model including age, sex and comorbidities [AUC (core model + ePWV vs. core model) = 0.864 vs. 0.755]. ePWV provided similar prognostic value when pulse pressure or hs-Troponin were added to the core model or over its components including age and mean blood pressure (p &lt; 0.05 for all). The optimal prognostic ePWV value was 13.0 m/s. ePWV conferred additive discrimination (AUC: 0.817 versus 0.779, P &lt; 0.001) and reclassification value (NRI = 0.381, P &lt; 0.001) over the 4C Mortality score, a validated score for predicting mortality in COVID-19 and the Charlson comorbidity index. We suggest that calculation of ePWV, a readily applicable estimation of arterial stiffness, may serve as an additional clinical tool to refine risk stratification of hospitalized patients with COVID-19 beyond established risk factors and scores

Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients

Transtorno bipolar em crianças: análise de relato de caso 2018-2023

O transtorno bipolar em crianças é uma realidade clínica que demanda atenção especializada. A compreensão dos sintomas, fatores de risco, prevalência e desafios diagnósticos é fundamental para proporcionar intervenções precoces e adequadas, visando melhorar a qualidade de vida desses jovens e reduzir o impacto a longo prazo dessa condição psiquiátrica. Trata-se de um estudo cujo objetivo foi objetivo revisar relatos de caso publicados entre 2018 e 2023 sobre transtorno bipolar em crianças, identificando o estado da arte desses estudos. Para isso, se realizou uma revisão sistemática de literatura utilizando as bases de dados Medical Literature Analysis and Retrieval System Online (MEDLINE), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) e Scientific Electronic Library Online (SCIELO). Com a análise e interpretação qualitativa dos resultados, a principal conclusão deste estudo é que o transtorno bipolar na infância é uma condição complexa, manifestando-se com comportamentos consistentes com o Transtorno de Conduta e sendo influenciado por fatores ambientais, familiares e genéticos. O tratamento eficaz requer uma abordagem multidisciplinar, integrando intervenções farmacológicas e não farmacológicas, personalizadas conforme as necessidades individuais. A supervisão familiar é crucial para a adesão ao tratamento, mas reconhece-se a necessidade contínua de pesquisa para aprimorar as estratégias terapêuticas diante da diversidade de casos