Covid-19 and the role of smoking: the protocol of the multicentric prospective study COSMO-IT (COvid19 and SMOking in ITaly).

The emergency caused by Covid-19 pandemic raised interest in studying lifestyles and comorbidities as important determinants of poor Covid-19 prognosis. Data on tobacco smoking, alcohol consumption and obesity are still limited, while no data are available on the role of e-cigarettes and heated tobacco products (HTP). To clarify the role of tobacco smoking and other lifestyle habits on COVID-19 severity and progression, we designed a longitudinal observational study titled COvid19 and SMOking in ITaly (COSMO-IT). About 30 Italian hospitals in North, Centre and South of Italy joined the study. Its main aims are: 1) to quantify the role of tobacco smoking and smoking cessation on the severity and progression of COVID-19 in hospitalized patients; 2) to compare smoking prevalence and severity of the disease in relation to smoking in hospitalized COVID-19 patients versus patients treated at home; 3) to quantify the association between other lifestyle factors, such as e-cigarette and HTP use, alcohol and obesity and the risk of unfavourable COVID-19 outcomes. Socio-demographic, lifestyle and medical history information will be gathered for around 3000 hospitalized and 700-1000 home-isolated, laboratory-confirmed, COVID-19 patients. Given the current absence of a vaccine against SARS-COV-2 and the lack of a specific treatment for -COVID-19, prevention strategies are of extreme importance. This project, designed to highly contribute to the international scientific debate on the role of avoidable lifestyle habits on COVID-19 severity, will provide valuable epidemiological data in order to support important recommendations to prevent COVID-19 incidence, progression and mortality

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Long-Term Response to PD-1 and CTLA-4 Blockade in an SCLC Patient with Negative PD-L1 Expression on Biopsy: A Case Report

Despite recent advances in the availability of new therapeutic agents, small-cell lung cancer (SCLC) remains an aggressive disease with a poor prognosis. While immune checkpoint inhibition has revolutionized the treatment of non-small cell histologies, results in SCLC have shown overall less favorable evolution, and despite initial data from different trials showing potential for development, the lack of reliable biomarkers for patient selection is a major hindrance to their use. Most notably, programmed death-ligand 1 (PD-L1) expression does not appear to play a key role in SCLC responsiveness to immune checkpoint inhibition. While other biomarkers such as tumor mutational burden (TMB) have been suggested to be more relevant, literature data are not univocal on this subject. We report here on a 58-year-old patient with metastatic PD-L1-negative SCLC treated in an advanced and symptomatic setting who obtained a complete and sustained clinical and radiological response to the combination of nivolumab and ipilimumab. We also discuss the impact of treatment-related adverse events, such as autoimmune hypothyroidism, gastroenteric toxicity and pneumonitis, on his quality of life. This case, while it exemplifies the potential of immune checkpoint inhibition in SCLC, highlights the need for a deeper understanding of the mechanisms underlying its efficacy in order to identify patients who are more likely to benefit from treatment

Prognostic implication of PD-L1 in early-stage non-small cell lung cancer: a retrospective single-centre study

BACKGROUND: The prognostic role of programmed death-ligand 1 (PD-L1) expression in patients with localised and locally advanced non-small cell lung cancer has not been fully elucidated. This information could help to better interpret recent and upcoming results of phase III adjuvant or neoadjuvant anti-PD-1/PD-L1 immunotherapy studies. METHODS: In a cohort of 146 patients with early or locally advanced non-small cell lung cancer treated with curative intent (by surgery or radiotherapy), we investigated the prognostic value of PD-L1 expression and its correlation with other biological and clinical features. PD-L1 expression was stratified by quartiles. Primary endpoints were overall and disease-free survival. We also analysed the prognostic impact of the presence of actionable mutations, implemented treatment modality and completion of the treatment plan. Neither type of patient received neoadjuvant or adjuvant immunotherapy or target therapy. RESULTS: Of the 146 selected patients, 32 (21.9%) presented disease progression and 15 died (10.3%) at a median follow-up of 20 months. In a univariable analysis, PD-L1 expression ≥25% was associated with significantly lower disease-free survival (hazard ratio [HR]) 1.9, 95% confidence interval [CI] 1.0–3.9, p= 0.049). PD-L1 expression ≥50% did not lead to disease-free survival or overall survival benefits (HR 1.2 and 1.1, respectively; 95% CI 0.6–2.6 and 0.3–3.4, respectively; pnot significant). In a multivariate analysis, a stage >I (HR 2.7, 95% CI 1.2–6, p = 0.012) and having an inoperable tumour (HR 3.2, 95% CI 1.4–7.4, p = 0.005) were associated with lower disease-free survival. CONCLUSION: The population of patients with early-stage non-small cell lung cancer and PD-L1 expression ≥25% who were treated with curative intent during the pre-immunotherapy era exhibited a worse prognosis. This finding provides justification for the utilisation of adjuvant immunotherapy in this subgroup of patients, based on the current evidence derived from disease-free survival outcomes. However, for patients with PD-L1 expression <25%, opting to wait for the availability of the overall survival results may be a prudent choice

Le garanzie fondamentali dell\u2019immigrato in Europa

Il volume contiene una riflessione collettiva sulle garanzie fondamentali dell\u2019immigrato in Europa. Esso fornisce agli operatori, agli studiosi e a quanti intendono approfondire il tema dell\u2019immigrazione un\u2019analisi del processo di progressivo arricchimento del sistema di protezione dei diritti fondamentali dei migranti, determinato dalle sentenze della Corte di giustizia dell\u2019Unione europea e dal dialogo che tale organo giurisdizionale ha intrattenuto con la Corte EDU. L\u2019opera mira anzitutto a far emergere il processo di elevazione delle garanzie avvenuto in favore delle diverse categorie di migranti a seguito dell\u2019intervento della Corte di giustizia. In alcuni casi, l\u2019accrescimento delle garanzie in questione \ue8 avvenuto sulla scia di importanti pronunce della Corte EDU, che hanno trainato la Corte di giustizia verso il superamento o il ridimensionamento di criteri stabiliti nel diritto derivato. La giurisprudenza relativa al regolamento Dublino rappresenta un chiaro esempio di questa dinamica. Il volume si propone pertanto anche di chiarire se il dialogo tra le due Corti europee in questo settore lascia presagire uno \u201cscavalcamento\u201d della Corte di giustizia da parte della Corte EDU nella tutela dei diritti fondamentali dei migranti oppure se tale dialogo avverr\ue0 \u2013 in linea con quanto accaduto pi\uf9 di frequente \u2013 secondo una dinamica di \u201creciproca contaminazione\u201d, nel rispetto delle peculiarit\ue0 dei rispettivi sistemi. Per meglio raggiungere gli obiettivi proposti i contributi che compongono il volume sono stati suddivisi in tre parti. Dopo talune indispensabili valutazioni di carattere generale sull\u2019evoluzione della politica comune dell\u2019immigrazione, il libro esamina, nell\u2019ordine, le garanzie di tipo sostanziale in favore dei migranti, la tutela degli status e delle relazioni familiari degli stranieri e, ancora, le garanzie procedurali e processuali offerte ai cittadini di Paesi terzi, a seconda della condizione (di soggiorno regolare, irregolare o di protezione internazionale) in cui essi si trovano. Vengono infine tratte le debite conclusioni

Leptogenesis via varying Weinberg operator

The Weinberg operator is a well-known solution to explain light neutrino masses. This operator violates lepton number and can provide non-equilibrium dynamics in the early Universe due to the suppression of tiny neutrino masses. A lot of underlying symmetries proposed in the lepton sector strongly motivate the existence of phase transitions at high scale. During the phase transition, the coupling of the Weinberg operator may be time-dependent, and the lepton asymmetry is generated by the interference of Weinberg operators at different times. This mechanism does not require any explicit new particles beyond the standard model or seesaw models