Identificazione della collusione negli appalti pubblici: un approccio con effetti fissi

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SNPs inFAM13AandIL2RBgenes are associated with FeNO in adult subjects with asthma

Nitric oxide has different roles in asthma as both an endogenous modulator of airway function and a pro-inflammatory mediator. Fractional exhaled nitric oxide (FeNO) is a reliable, quantitative, non-invasive, simple, and safe biomarker for assessing airways inflammation in asthma. Previous genome-wide and genetic association studies have shown that different genes and single nucleotide polymorphisms (SNPs) are linked to FeNO. We aimed at identifying SNPs in candidate genes or gene regions that are associated with FeNO in asthma. We evaluated 264 asthma cases (median age 42.8 years, female 47.7%) who had been identified in the general adult population within the Gene Environment Interactions in Respiratory Diseases survey in Verona (Italy; 2008-2010). Two hundred and twenty-one tag-SNPs, which are representative of 50 candidate genes, were genotyped by a custom GoldenGate Genotyping Assay. A two-step association analysis was performed without assuming ana priorigenetic model: step 1) a machine learning technique [Gradient Boosting Machine (GBM)] was used to select the 15 SNPs with the highest variable importance measure; step 2) the GBM-selected SNPs were jointly tested in a linear regression model with natural log-transformed FeNO as the normally distributed outcome and with age, sex, and the SNPs as covariates. We replicated our results within an independent sample of 296 patients from the European Community Respiratory Health Survey III. We found that SNP rs987314 in family with sequence similarity 13 member A (FAM13A) and SNP rs3218258 in interleukin 2 receptor subunit beta (IL2RB) gene regions are significantly associated with FeNO in adult subjects with asthma. These genes are involved in different mechanisms that affect smooth muscle constriction and endothelial barrier function responses (FAM13A), or in immune response processes (IL2RB). Our findings contribute to the current knowledge on FeNO in asthma by identifying two novel SNPs associated with this biomarker of airways inflammation

Subjects who developed SARS-CoV-2 specific IgM after vaccination show a longer humoral immunity and a lower frequency of infection

Background: We have previously shown that eliciting SARS-CoV-2-specific IgM after vaccination is associated with higher levels of SARS-CoV-2 neutralizing IgG. This study aims to assess whether IgM development is also associated with longer-lasting immunity. Methods: We analysed anti-SARS-CoV-2 spike protein IgG and IgM (IgG-S, IgM-S), and anti-nucleocapsid IgG (IgG-N) in 1872 vaccinees at different time points: before the first dose (D1; w0), before the second dose (D2; w3) at three (w6) and 23 weeks (w29) after D2; moreover, 109 subjects were further tested at the booster dose (D3, w44), at 3 weeks (w47) and 6 months (w70) after D3. Two-level linear regression models were used to evaluate the differences in IgG-S levels. Findings: In subjects who had no evidence of a previous infection at D1 (non-infected, NI), IgM-S development after D1 and D2 was associated with higher IgG-S levels at short (w6, p < 0.0001) and long (w29, p < 0.001) follow-up. Similar IgG-S levels were observed after D3. The majority (28/33, 85%) of the NI subjects who had developed IgM-S in response to vaccination did not experience infection. Interpretation: The development of anti-SARS-CoV-2 IgM-S following D1 and D2 is associated with higher IgG-S levels. Most individuals who developed IgM-S never became infected, suggesting that IgM elicitation may be associated with a lower risk of infection. Funding: "Fondi Ricerca Corrente" and "Progetto Ricerca Finalizzata" COVID-2020 (Italian Ministry of Health); FUR 2020 Department of Excellence 2018-2022 (MIUR, Italy); the Brain Research Foundation Verona

The Exposome Approach in Allergies and Lung Diseases: Is It Time to Define a Preconception Exposome?

Emerging research suggests environmental exposures before conception may adversely affect allergies and lung diseases in future generations. Most studies are limited as they have focused on single exposures, not considering that these diseases have a multifactorial origin in which environmental and lifestyle factors are likely to interact. Traditional exposure assessment methods fail to capture the interactions among environmental exposures and their impact on fundamental biological processes, as well as individual and temporal factors. A valid estimation of exposure preconception is difficult since the human reproductive cycle spans decades and the access to germ cells is limited. The exposome is defined as the cumulative measure of external exposures on an organism (external exposome), and the associated biological responses (endogenous exposome) throughout the lifespan, from conception and onwards. An exposome approach implies a targeted or agnostic analysis of the concurrent and temporal multiple exposures, and may, together with recent technological advances, improve the assessment of the environmental contributors to health and disease. This review describes the current knowledge on preconception environmental exposures as related to respiratory health outcomes in offspring. We discuss the usefulness and feasibility of using an exposome approach in this research, advocating for the preconception exposure window to become included in the exposome concept

ASSOCIATION BETWEEN CANDIDATE GENE POLYMORPHISMS AND ASTHMA SEVERITY IN ADULTS. A BAYESIAN ANALYSIS.

Introduzione Diversi geni sono associati con misure di gravit\ue0 dell'asma, definite secondo classificazioni categoriali. Tuttavia, \ue8 preferibile utilizzare misure continue di gravit\ue0 della malattia in quanto permettono di catturare l'eterogeneit\ue0 dei fenotipi e permettono di aumentare la potenza in studi di associazione. Inoltre, a causa della complessit\ue0 dei processi patologici legati all'asma, \ue8 preferibile utilizzare modelli statistici che testano contemporaneamente l'effetto di tutte le varianti genetiche e che hanno una maggiore potenza nell'identificare fenotipi associati alle varianti genetiche, rispetto ai modelli che considerano una sola variante alla volta.ObiettiviLa tesi si pone i seguenti obiettivi: (i) identificare misure continue di gravit\ue0 dell'asma (Studio 1) e (ii) valutare l'associazione tra tali misure e polimorfismi a singolo nucleotide (SNP) in geni candidati (Studio 2) in soggetti asmatici adulti della popolazione generale.Al fine del raggiungimento di tali obiettivi sono stati utilizzati i dati raccolti nello studio \u201cGene Environment Interactions in Respiratory Diseases\u201d (GEIRD, 2007-2010), basato su un disegno multi-caso/controllo innestato in una coorte dove i casi e i controlli sono stati identificati attraverso un processo di screening in due fasi (questionario + stadio clinico) all\u2019interno di coorti preesistenti e di nuovi campioni probabilistici della popolazione generale italiana.Studio 1Al fine di identificare misure continue di gravit\ue0 dell\u2019asma, sono state considerate le informazioni riguardanti i sintomi respiratori, il trattamento con farmaci antiasmatici e la funzionalit\ue0 polmonare di 520 casi di asma (et\ue0 20-64) identificati in sette centri italiani (Ancona, Pavia, Salerno, Sassari, Terni, Torino e Verona). Per identificare le variabili che rappresentano la stessa dimensione della gravit\ue0 dell'asma, \ue8 stata utilizzata un\u2019analisi fattoriale esplorativa (EFA) e l'informazione contenuta in tali variabili \ue8 stata poi sintetizzata mediante un\u2019analisi fattoriale multipla (MFA).Le variabili riguardanti i sintomi respiratori e il trattamento con farmaci antiasmatici sono state sintetizzate in una misura di gravit\ue0 (STS) che varia su una scala continua con range 0-10: il valore 0 indica assenza di sintomi e di trattamento con farmaci antiasmatici; il valore 10 indica la presenza di sintomi con la massima frequenza e la massima intensit\ue0 del trattamento. I risultati mostrano che STS correla positivamente con la classificazione della gravit\ue0 dell'asma indicata dalle linee guida internazionali Global Initiative for Asthma (GINA), calcolata nei 137 casi di asma che riportano la diagnosi di un medico (coefficiente di Spearman = 0.91, p-value 0 vs STS = 0). Quattro SNP sono risultate associate ad un aumento dello score STS nell\u2019asma sintomatica (E[STS], se STS> 0), ovvero: rs573122 nel gene FCER1A (media = 0,166, intervallo di credibilit\ue0 = [0,020, 0,320]), rs676750 nel gene CHML (media = -0,248, intervallo di credibilit\ue0 = [-0,434, -0,072]), rs4334089 nel gene VDR (media = -0,255, intervallo di credibilit\ue0 = [-0,456, -0,059]) e rs11080344 nel gene NOS2 (media = -0,224, intervallo di credibilit\ue0 = [-0,390, -0,064]).ConclusioniLo score STS \ue8 una misura di gravit\ue0 dell'asma negli adulti che risulta essere valida e replicabile, e che potrebbe essere utilizzata in studi epidemiologici. Tale misura \ue8 stata applicata in una analisi di associazione genetica, la quale ha evidenziato che cinque SNP (localizzate nei geni FCER1A, CHML, VDR e NOS2) potrebbero avere un ruolo nella gravit\ue0 della malattia nei soggetti asmatici adulti.Introduction Different genes are associated with categorical classifications of asthma severity. However, continuous measures of disease severity should be used to catch the heterogeneity of asthma phenotypes and to increase the power in association studies. Furthermore, due to the complex pathological processes involved in asthma, statistical models that simultaneously test the effect of all variants have a better performance and they gain power in identifying phenotypes associated to genetic variants, as compared to statistical models that consider a single variant at a time. AimsThis thesis is aimed at (i) providing continuous measures of asthma severity (Study-line 1) and (ii) evaluating the association between disease severity and single nucleotide polymorphisms (SNPs) in candidate gene regions (Study-line 2), in adult patients with ever asthma from the general population.Data from the Gene Environment Interactions in Respiratory Diseases study (GEIRD, 2007-2010), which is an Italian, population-based, (multi)case-control study on respiratory health, were used.Study-line 1Respiratory symptoms, anti-asthmatic treatment and lung function were measured on 520 cases of asthma (aged 20-64) in seven Italian centres (Ancona, Pavia, Salerno, Sassari, Terni, Torino and Verona). The variables that represent the same dimension of asthma severity were identified through an exploratory factor analysis (EFA) and were summarized through a multiple factor analysis (MFA). Only respiratory symptoms and anti-asthmatic treatment were summarized in a continuous score (STS). STS ranges from 0 (no symptoms/treatment) to 10 (maximum symptom frequency and treatment intensity). STS was positively correlated with the Global INitiative for Asthma (GINA) classification of asthma severity computed on the 137 cases with a doctor's diagnosis (Spearman\u2019s coefficient=0.91, p-value0 vs STS=0), whereas four SNPs were associated with an increased STS in symptomatic asthma (i.e. E[STS] if STS>0): rs573122 in FCER1A (mean = 0.166, credible interval = [0.020, 0.320]), rs676750 in CHML (mean = -0.248, credible interval = [-0.434, -0.072]), rs4334089 in VDR (mean = -0.255, credible interval = [-0.456, -0.059]) and rs11080344 in NOS2 (mean = -0.224, credible interval = [-0.390, -0.064]).ConclusionsSTS is a valid and replicable measure of asthma severity in adults, which could be used in epidemiological studies. An application of this score in a genetic association analysis shows that five SNPs (in FCER1A, CHML, VDR and NOS2) could play a role in disease severity among adults with ever asthma

DEFINIZIONE DI UNO SCORE CONTINUO DI GRAVIT\uc0 DELL\u2019ASMA

Introduzione. Si \ue8 ancora lontani da una definizione condivisa di gravit\ue0 dell\u2019asma. La tendenza \ue8 quella di sintetizzare caratteristiche fisiopatologiche individuali in un numero esiguo di livelli1 che, per l\u2019eterogeneit\ue0 della malattia, pu\uf2 causare perdita di informazioni. Obiettivo. Definire uno score su scala continua che catturi tutti gli aspetti di gravit\ue0 dell\u2019asma in soggetti caratterizzati sia dall\u2019attivit\ue0 che dalla non attivit\ue0 della malattia. Metodi. 334 soggetti (20-64 anni) asmatici identificati in un campione casuale della popolazione generale di Verona nell\u2019ambito dello studio GEIRD2 (2008-2010). Lo score di gravit\ue0 \ue8 stato ottenuto mediante un\u2019Analisi delle Componenti Principali non lineare (NLPCA) implementata in due step. Le informazioni cliniche riguardanti la bronchite cronica, i sintomi asmatiformi riportati negli ultimi 12 mesi, la loro riacutizzazione e l\u2019attivit\ue0 della malattia (asma attiva/non attiva) sono state sintetizzate nella dimensione \u201csintomi\u201d. Lo score unidimensionale di gravit\ue0 dell\u2019asma \ue8 stato ottenuto da una seconda NLPCA, come combinazione non lineare dello score \u201csintomi\u201d e di due variabili indicanti i livelli di trattamento farmacologico e di funzionalit\ue0 respiratoria (FR). La concurrent validity \ue8 stata verificata mediante il confronto con lo score proposto dalle linee guida GINA definito su 4 livelli di gravit\ue0 crescente (ottenuti dalla combinazione della frequenza dei sintomi, della riduzione della FR e degli step di trattamento)3, e con gli indici sintetici di stato fisico e psicologico del questionario SF364 (valori bassi = stato peggiore). Risultati. Lo score di gravit\ue0 dell\u2019asma \ue8 una variabile continua con distribuzione Quasi-Gamma (0=asma non attiva, assenza di sintomi, nessun trattamento, funzionalit\ue0 respiratoria normale; 16=asma attiva, massima presenza di sintomi, massimo trattamento, ostruzione non lieve del flusso respiratorio). \uc8 correlato positivamente con la serie ordinata dei livelli di gravit\ue0 come in Figura (\u3c1-Spearman= 0.82, p<0.001), e negativamente con gli indici di stato fisico (\u3c1-Spearman= -0.22, p<0.001) e psicologico (\u3c1-Spearman= -0.18, p=0.001) dell\u2019SF36. Conclusioni. Lo score di gravit\ue0 dell\u2019asma proposto \ue8 un indicatore sintetico sia delle misurazioni cliniche e fisiologiche del soggetto sia del trattamento a cui esso \ue8 sottoposto e, per la sua natura continua, ha il vantaggio di essere altamente informativo

Fetal Exposure to Maternal Pregnancy Complications and Respiratory Health in Childhood

Background: A number of studies have highlighted that prenatal adverse events can affect the offspring's health status. We evaluated whether pregnancy complications might affect the respiratory health of the offspring during infancy and childhood. Methods: In 2006, all the children (3-14 years, N = 3,907) living in the Viadana district (Mantua, Italy) were surveyed through a parental questionnaire about pregnancy complications (hypertensive disorders, febrile infections, gynecological infections) and early-life and current respiratory diseases. Hospital discharge records for respiratory diseases were obtained for a 6-year follow-up period (2007-2012). Association estimates were adjusted for maternal smoking during pregnancy, maternal age at delivery, type and term of delivery, and other potential confounders. Results: A total of 3,617 (93%) children were included in the analyses. Pregnancy complications were significantly associated with higher risk of respiratory diseases during infancy and childhood. In particular, children exposed to gynecological infections were more likely to have bronchitis [odds ratio (OR): 1.48, 95% confidence interval (95% CI): 1.04-2.10], pneumonia (OR: 2.05, 95% CI: 1.10-3.81), and wheezing (OR: 1.49, 95% CI: 1.00-2.23) at 0-2 years; to report asthma (OR: 3.57, 95% CI: 1.59-8.04) and cough/phlegm (OR: 2.68, 95% CI: 1.67-4.31) at the time of the survey; and to be hospitalized for respiratory diseases (hospitalization hazard ratio: 1.74, 95% CI: 1.02-2.97) in the 6-year follow-up. There was a significant association between febrile infections and wheezing in infancy, even in children whose mothers did not use paracetamol or antibiotics during pregnancy. Conclusions: This observational study suggests that pregnancy complications, especially gynecological infections, might affect the offspring's respiratory health throughout infancy and childhood