From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005\u201331 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studie

Dental Disorders and Salivary Changes in Patients with Laryngopharyngeal Reflux

Background: Laryngopharyngeal reflux (LPR) is a common inflammatory condition of the upper aerodigestive tract tissues related to the effects of gastroduodenal content reflux, characterized by a wide variety of clinical manifestations. The aim of our study was to evaluate the possible association between dental disorders and LRP, focusing on the role of salivary changes. Methods: Patient’s dental status was evaluated according to Schiff Index Sensitivity Scale (SISS), Basic Erosive Wear Examination (BEWE) and Decayed, Missing, and Filled Teeth (DMFT) scores. Reflux-associated symptoms were assessed according to Reflux symptom index (RSI). A qualitative and quantitative examination of saliva was performed. Results: Patients suffering from LPR had a higher incidence of dental disorders, regardless the presence of salivary pepsin, and thus, statistically significant higher scores of RSI (p = 0.0001), SISS (p = 0.001), BEWE (p < 0.001) and VAS (p < 0.001). Moreover, they had lower salivary flow compared with healthy patients. Conclusions: The finding of demineralization and dental caries on intraoral evaluation must raise the suspicion of LRP. Reflux treatments should also be aimed at correcting salivary alterations, in order to preserve the buffering capacity and salivary pH, thus preventing mucosal and dental damage

Nigritanine as a new potential antimicrobial alkaloid for the treatment of staphylococcus aureus-induced infections

Staphylococcus aureus is a major human pathogen causing a wide range of nosocomial infections including pulmonary, urinary, and skin infections. Notably, the emergence of bacterial strains resistant to conventional antibiotics has prompted researchers to find new compounds capable of killing these pathogens. Nature is undoubtedly an invaluable source of bioactive molecules characterized by an ample chemical diversity. They can act as unique platform providing new scaffolds for further chemical modifications in order to obtain compounds with optimized biological activity. A class of natural compounds with a variety of biological activities is represented by alkaloids, important secondary metabolites produced by a large number of organisms including bacteria, fungi, plants, and animals. In this work, starting from the screening of 39 alkaloids retrieved from a unique in-house library, we identified a heterodimer β-carboline alkaloid, nigritanine, with a potent anti-Staphylococcus action. Nigritanine, isolated from Strychnos nigritana, was characterized for its antimicrobial activity against a reference and three clinical isolates of S. aureus. Its potential cytotoxicity was also evaluated at short and long term against mammalian red blood cells and human keratinocytes, respectively. Nigritanine showed a remarkable antimicrobial activity (minimum inhibitory concentration of 128 μM) without being toxic in vitro to both tested cells. The analysis of the antibacterial activity related to the nigritanine scaffold furnished new insights in the structure-activity relationships (SARs) of β-carboline, confirming that dimerization improves its antibacterial activity. Taking into account these interesting results, nigritanine can be considered as a promising candidate for the development of new antimicrobial molecules for the treatment of S. aureus-induced infections

Atrial fibrillation pattern, left atrial diameter and risk of cardiovascular events and mortality. A prospective multicenter cohort study.

BACKGROUND There are conflicting evidence on the association between atrial fibrillation (AF) pattern, such as persistent/permanent (Pers/Perm) and paroxysmal (PAF) AF and risk of ischemic events. We investigated if left atrial diameter (LAd) may affect the risk of cardiovascular outcomes according to AF pattern. METHODS Prospective multicenter observational including 1,252 non-valvular AF patients (533 PAF and 719 Pers/Perm AF). Study endpoints were cardiovascular events (CVEs), major adverse cardiac events (MACE) and CV death. LA anteroposterior diameter (LAd) was obtained by transthoracic echocardiography. RESULTS Pers/Perm AF patients had a higher proportion of LAd above median than PAF (≥44 mm, 59.5% vs 37.5% respectively, P < .001). In a mean follow-up of 42.2 ± 31.0 months (4,315 patients/year) 179 CVEs (incidence rate [IR] 4.2%/year), 133 MACE (IR 3.1%/year), and 97 CV deaths (IR 2.2%/year) occurred. Compared to patients with LAd below median, those with LAd above the median had a higher rate of CVEs (log-rank test, P < .001), MACE (log-rank test P < .001), and CV death (log-rank test P < .001). Multivariable Cox regression analysis showed that LAd above the median was associated with CVEs, (HR 1.569, 95% CI 1.129-2.180, P = .007) MACE (HR 1.858, 95% CI 1.257-2.745, P = .002) and CV death (HR 2.106, 95% CI 1.308-3.390, P = .002). The association between LAd and outcomes was evident both in PAF and Pers/Perm AF patients. No association between AF pattern and outcomes was found. CONCLUSION LAd is a simple parameter that can be obtained in virtually all AF patients and can provide prognostic information on the risk of CVEs, MACE and CV death regardless of AF pattern

Naturally-occurring alkaloids of plant origin as potential antimicrobials against antibiotic-resistant infections

Antibiotic resistance is now considered a worldwide problem that puts public health at risk. The onset of bacterial strains resistant to conventional antibiotics and the scarcity of new drugs have prompted scientific research to re-evaluate natural products as molecules with high biological and chemical potential. A class of natural compounds of significant importance is represented by alkaloids derived from higher plants. In this review, we have collected data obtained from various research groups on the antimicrobial activities of these alkaloids against conventional antibiotic-resistant strains. In addition, the structure-function relationship was described and commented on, highlighting the high potential of alkaloids as antimicrobials

The Paradox of Power in CSR: A Case Study on Implementation

Purpose Although current literature assumes positive outcomes for stakeholders resulting from an increase in power associated with CSR, this research suggests that this increase can lead to conflict within organizations, resulting in almost complete inactivity on CSR. Methods A single in-depth case study, focusing on power as an embedded concept. Results Empirical evidence is used to demonstrate how some actors use CSR to improve their own positions within an organization. Resource dependence theory is used to highlight why this may be a more significant concern for CSR. Conclusions Increasing power for CSR has the potential to offer actors associated with it increased personal power, and thus can attract opportunistic actors with little interest in realizing the benefits of CSR for the company and its stakeholders. Thus power can be an impediment to furthering CSR strategy and activities at the individual and organizational level

Urticaria : recommendations from the Italian Society of Allergology, Asthma and Clinical Immunology and the Italian Society of Allergological, Occupational and Environmental Dermatology

Background: Urticaria is a disorder affecting skin and mucosal tissues characterized by the occurrence of wheals, angioedema or both, the latter defining the urticaria-angioedema syndrome. It is estimated that 12-22% of the general population has suffered at least one subtype of urticaria during life, but only a small percentage (estimated at 7.6-16%) has acute urticaria, because it is usually self-limited and resolves spontaneously without requiring medical attention. This makes likely that its incidence is underestimated. The epidemiological data currently available on chronic urticaria in many cases are deeply discordant and not univocal, but a recent Italian study, based on the consultation of a national registry, reports a prevalence of chronic spontaneous urticaria of 0.02% to 0.4% and an incidence of 0.1-1.5 cases/1000 inhabitants/year. Methods: We reviewed the recent international guidelines about urticaria and we described a methodologic approach based on classification, pathophysiology, impact on quality of life, diagnosis and prognosis, differential diagnosis and management of all the types of urticaria. Conclusions: The aim of the present document from the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) is to provide updated information to all physicians involved in diagnosis and management of urticaria and angioedema

Platelet activation is associated with myocardial infarction in patients with pneumonia

BACKGROUND: Troponins may be elevated in patients with pneumonia, but associations with myocardial infarction (MI) and with platelet activation are still undefined.OBJECTIVES: The aim of this study was to investigate the relationship between troponin elevation and in vivo markers of platelet activation in the early phase of hospitalization of patients affected by community-acquired pneumonia.METHODS: A total of 278 consecutive patients hospitalized for community-acquired pneumonia, who were followed up until discharge, were included. At admission, platelet activation markers such as plasma soluble P-selectin, soluble CD40 ligand, and serum thromboxane B2 (TxB2) were measured. Serum high-sensitivity cardiac troponin T levels and electrocardiograms were obtained every 12 and 24 h, respectively.RESULTS: Among 144 patients with elevated high-sensitivity cardiac troponin T, 31 had signs of MI and 113 did not. Baseline plasma levels of soluble P-selectin and soluble CD40 ligand and serum TxB2 were significantly higher in patients who developed signs of MI. Logistic regression analysis showed plasma soluble CD40 ligand (p &lt; 0.001) and soluble P-selectin (p &lt; 0.001), serum TxB2 (p = 0.030), mean platelet volume (p = 0.037), Pneumonia Severity Index score (p = 0.030), and ejection fraction (p = 0.001) to be independent predictors of MI. There were no significant differences in MI rate between the 123 patients (45%) taking aspirin (100 mg/day) and those who were not aspirin treated (12% vs. 10%; p = 0.649). Aspirin-treated patients with MIs had higher serum TxB2 compared with those without MIs (p = 0.005).CONCLUSIONS: MI is an early complication of pneumonia and is associated with in vivo platelet activation and serum TxB2 overproduction; aspirin 100 mg/day seems insufficient to inhibit thromboxane biosynthesis. (MACCE in Hospitalized Patients With Community-acquired Pneumonia; NCT01773863)

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63–1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70–1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19