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Luigino Calzetta,1 Angelo Coppola,2 Beatrice Ludovica Ritondo,3 Matteo Matino,3 Alfredo Chetta,1 Paola Rogliani2,3 1Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy; 2Division of Respiratory Medicine, University Hospital “Policlinico Tor Vergata”, Rome, Italy; 3Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, ItalyCorrespondence: Paola Rogliani Department of Experimental MedicineUniversity of Rome “Tor Vergata”, Via Montpellier 1, Rome 00133, ItalyTel +39 06 2090 4656Email paola.rogliani@uniroma2.itAbstract: Long-acting muscarinic receptor antagonists (LAMAs) are the cornerstone for the treatment of chronic obstructive pulmonary disease (COPD); furthermore, tiotropium is approved as add-on therapy in severe asthmatic patients. Accumulating evidence suggests that LAMAs may modulate airway contractility and airway hyperresponsiveness not only by blocking muscarinic acetylcholine receptors (mAchRs) expressed on airway smooth muscle but also via anti-inflammatory mechanisms by blocking mAchRs expressed on inflammatory cells, submucosal glands, and epithelial cells. The aim of this systematic review, performed according to the PRISMA-P guidelines, was to provide a synthesis of the literature on the anti-inflammatory impact of muscarinic receptor antagonists in the airways. Most of the current evidence originates from studies on tiotropium, that demonstrated a reduction in synthesis and release of cytokines and chemokines, as well as the number of total and differential inflammatory cells, induced by different pro-inflammatory stimuli. Conversely, few data are currently available for aclidinium and glycopyrronium, whereas no studies on the potential anti-inflammatory effect of umeclidinium have been reported. Overall, a large body of evidence supports the beneficial impact of tiotropium against airway inflammation. Further well-designed randomized controlled trials are needed to better elucidate the anti-inflammatory mechanisms leading to the protective effect of LAMAs against exacerbations via identifying suitable biomarkers.Keywords: muscarinic receptor antagonist, LAMA, tiotropium, inflammation, systematic review

Praised for saving China from a demographic catastrophe or blamed as a violation of a basic human right, the one child family policy is reaching its 25th year and a recent law has confirmed this demographic strategy for the future. The government decision to limit the number of children to one per couple, taken in 1979, was a response to the threat that the country's massive demographic growth cast on the future of economic development and of living conditions of the Chinese people. The goal set to limit the total population to about 1.2 billion for the year 2000 and to significantly reduce the natural increase rate.

Introduction: According to Global Initiative for Asthma (GINA) guidelines, long-acting muscarinic antagonists (LAMAs) should be considered as add-on therapy in patients with asthma that remains uncontrolled, despite treatment with medium-dose (MD) or high-dose (HD) inhaled corticosteroids (ICS)/long-acting β 2 -agonist (LABA) combinations. In patients ≥ 18 years, LAMA may be added in triple combination with an ICS and a LABA. To date, the precise efficacy of triple ICS/LABA/LAMA combination remains uncertain concerning the impact on exacerbation risk in patients with uncontrolled asthma. Therefore, an umbrella review was performed to systematically summarize available data on the effect of triple ICS/LABA/LAMA combination on the risk of asthma exacerbation., Methods: An umbrella review has been performed according to the PRIOR statement., Results: The overall results obtained from 5 systematic reviews and meta-analyses suggest that triple ICS/LABA/LAMA combination reduces the risk of asthma exacerbation. HD-ICS showed a greater effect particularly in reducing severe asthma exacerbation, especially in patients with evidence of type 2 inflammation biomarkers., Conclusions: The findings of this umbrella review suggest an optimization of ICS dose in triple ICS/LABA/LAMA combination, based on the severity of exacerbation and type 2 biomarkers expression.

Aim: The aim of this study was to detect predisposing CV risks factors and ECGs changes in COVID-19 patients., Methods: The study population included 60 noncritically ill patients with COVID-19 pneumonia admitted to our hospital between 16 March and 11 May 2020. Electrographic changes, evaluated from ECGs acquired at admission and at 7 days after starting COVID-19 therapy, were analysed. We also compared 45 patients without CV involvement with 15 patients with new onset of cardiac adverse events during hospitalization., Results: ECGs under treatment showed a lower heart rate (HR) (69.45 ± 8.06 vs 80.1 ± 25.1 beats/min, P = 0,001) and a longer QRS (102.46 ± 15.08 vs 96.75 ± 17.14, P = 0.000) and QT corrected (QTc) interval (452.15 ± 37.55 vs 419.9 ± 33.41, P = 0,000) duration than ECGs before therapy. Fifteen patients (25%) showed clinical CV involvement. Within this group, female sex, lower ejection fraction (EF), low serum haemoglobin, high Troponin I levels (TnI), low lymphocytes count, high serum IL-6 levels, or use of Tocilizumab (TCZ) were more represented., Conclusions: Patients admitted for SARS-CoV2 infection and treated with anti-COVID-19 drug therapy develop ECG changes such as reduction in HR and increase in QRS duration and QTc interval. One in four patients developed CV events. Gender, EF, heamoglobin values, TnI, lymphocytes count, IL-6 and use of TCZ can be considered as predisposing factors for CV involvement., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Introduction: The relationship between dyspnea and COVID-19 is unknown. In COVID-19 patients, the higher prevalence of neurological symptoms and the lack of dyspnea may suggest common underlying pathogenetic mechanisms. The aim of this preliminary study is to address whether there is a lack of dyspnea in COVID-19 patients and if there is a relationship between neurological symptoms and the perception of dyspnea., Methods: A structured interview regarding the occurrence of subjective neurological symptoms was performed and coupled with a questionnaire about the intensity and qualities of dyspnea. Respiratory rate (RR) and an arterial blood gas on room air were concurrently evaluated., Results: Twenty-two patients (age 68.4 ± 13.9 years, 13 males and 9 females) were included and divided into two groups according to the Borg dyspnea scale: dyspneic patients BU ≥ 1(DYSP) and non-dyspneic patients BU < 1 (NDYSP). The prevalence of dyspnea overall was 31.8%. The prevalence of neurological symptoms, dyspnea descriptors, RR, pH, PaCO 2 , PaO 2 , or lactate was similar between groups., Conclusion: This study confirms that the prevalence of dyspnea is low in non-severe COVID-19 patients, but contrary to our hypothesis of a relationship between shortness of breath and neurological symptoms, we have not been able to find any evidence of an impairment in dyspnea perception, either in the DYSP or NDYSP group.

Background: An abnormal intestinal permeability could contribute to establish an altered sensitivity to food-allergen., Aim: To evaluate the intestinal permeability in subjects with adverse reactions to food on allergen-free diet., Subjects: Twenty-one patients with food allergy and 20 with food hypersensitivity on allergen-free diet were enrolled and divided in four groups according to the seriousness of their referred clinical symptoms when they were on a free diet., Methods: Intestinal permeability was evaluated by Lactulose/Mannitol ratio urinary detection determined by anion-exchange chromatography., Results: Statistically significant different Lactulose/Mannitol ratio was evidenced in subjects with food allergy (p=0.003) or hypersensitivity (p=0.0008) compared to control patients. The correlation between Lactulose/Mannitol ratio and the seriousness of clinical symptoms, by using Spearman test, was statistically significant for food allergy (p=0.0195) and hypersensitivity (p=0.005) patients., Conclusions: The present data demonstrate that impaired intestinal permeability, measured in our conditions, is present in all subjects with adverse reactions to food. In addition, for the first time, we report a statistically significant association between the severity of referred clinical symptoms and the increasing of Intestinal Permeability Index. These data reveal that intestinal permeability is not strictly dependent on IgE-mediated processes but could better be related to other mechanisms involved in early food sensitisation, as breast-feeding, or microbial environment that influence the development of oral tolerance in early infancy.

Recent data show that monocyte chemotactic peptide-1 (MCP-1), a chemotactic factor specific for monocytes, may play a central role in regulating the activation of these cells. For this reason, the production of MCP-1 in peripheral blood mononuclear cell (PBMC) cultures of eight healthy subjects, six chronic uraemic subjects under conservative treatment and six chronic uraemic patients undergoing haemodialysis (HD), was assessed. In the latter group of individuals, complement-activating membranes such as cuprophan (CU) were used for 1 month followed by biocompatible non-complement-activating membranes, like polymethylmetacrylate (PMMA) for the next 30 days. The chemotactic index (CI) elicited by PBMC supernatants from patients undergoing dialysis was found to be significantly higher than that obtained by supernatants recovered from normal subjects or uraemic patients on conservative therapy. Furthermore, the CI from PBMC supernatants having had contact with CU membranes was higher than that obtained from PBMC activated by PMMA. Finally, the increased chemotactic ability in the supernatants was closely correlated with the augmented MCP-1 gene expression and production, as assessed by in vitro hybridization studies.