Pharmaco-epidemiological approaches for the benefit-risk assessment of drugs in the neonatal population

Le informazioni disponibili sul profilo rischio-beneficio dei farmaci nel periodo prenatale e neonatale sono molto limitate, principalmente per la difficoltà nel condurre sperimentazioni cliniche. La ricerca farmaco-epidemiologica può svolgere un importante ruolo nell’aumento delle conoscenze sulla sicurezza d’uso dei farmaci in questa popolazione. Le tematiche di ricerca del presente progetto di Dottorato sono state: (i) impatto dell’esposizione pre-natale a psicofarmaci sullo sviluppo neuro-comportamentale nel bambino, (ii) pattern di utilizzo dei farmaci in neonati prematuri, e (iii) valutazione della funzionalità renale in neonati prematuri e ruolo dei farmaci nell’insorgenza di danno renale. Con il primo studio si è analizzato il database della Société Marcé Francophone presso l’Unità INSERM 1219 (Università di Bordeaux), che include dati collezionati in 10 anni presso le Unità Madre-Figlio del Network Francofono. Le analisi hanno mostrato come, indipendentemente dalla patologia psichiatrica materna, l’esposizione prenatale ad alcune classi di psicofarmaci è stata associata ad alterazioni dello sviluppo neuro-comportamentale nei bambini. Con lo studio di farmaco-utilizzazione in neonati prematuri si è voluto descrivere il reale impiego dei farmaci in questa popolazione, in particolare le associazioni di farmaci nefrotossici. I risultati di questo studio retrospettivo indicano che i neonati prematuri con inferiore peso alla nascita sono stati più frequentemente esposti a combinazioni di farmaci nefrotossici rispetto ad altri neonati; inoltre, sono state identificate le associazioni di principi attivi nefrotossici più utilizzate. Il terzo studio, di natura prospettica, ha coinvolto una coorte di neonati prematuri ricoverati presso la Terapia Intensiva Neonatale, con l’obiettivo di identificare i fattori di rischio correlati ad alterazione della funzione renale. I risultati delle analisi preliminari hanno mostrato come i neonati con alterata funzione renale hanno inferiori peso alla nascita ed età gestazionale e superiore incidenza di sepsi; questi risultati mettono in luce la necessità di nuovi biomarcatori per la diagnosi di danno renale in questa popolazione.The benefit-risk profile of drugs in the prenatal and neonatal period is still largely unexplored, because of the difficulties in performing clinical trials. The pharmaco-epidemiological approach could play and important role in increasing knowledge on the benefit-risk profile of drugs used in this special population. The present thesis addressed three specific aspects: (i) impact of prenatal exposure to psychotropic drugs on developmental skills in babies up to 6 months, (ii) pattern of drug use in neonates born prematurely, and (iii) identification of risk factors, including drugs, for renal damage in preterm neonates. In the first study, the analysis of the database of the Société Marcé Francophone at INSERM Unit 1219 (University of Bordeaux), which included data collected over 10 years in the Mother-Baby Units of the Francophone Network, showed that the prenatal exposure to some classes of psychotropic drugs were associated to alterations of developmental skills in babies, independently from maternal psychiatric diagnosis. With the second study, we aimed at assessing the actual use of drugs in preterm neonates, especially the combination of those drugs with known nephrotoxicity in adults. Results of this retrospective study showed that preterm neonates with lower birth weight were more likely to receive combinations of nephrotoxic agents compared to other neonates; moreover, we identified most commonly reported combination of drugs with known nephrotoxicity. The third study was conducted prospectively in a cohort of preterm neonates admitted to a tertiary-level Neonatal Intensive Care Unit (NICU), aiming at identifying risk factors, especially drugs, for renal function alteration. Preliminary data show that neonates with altered renal function had lower gestational age and lower weight at birth as well as higher frequency of diagnosis of sepsis; these results highlight the need for novel biomarkers to diagnose renal damage in neonates

Risk of pleural mm and residual asbestos burden in the lung: a retrospective case-control study

Introduction Results of Malignant Pleural Mesothelioma (MPM) occurrence (mortality and incidence) by cumulative exposure dose clearly showed a proportional relation of MPM risk with dose, confirmed among studies by fibre burden. We evaluated the association between residual fibre content and MPM risk by circumstance of asbestos exposure. Methods and materials Lung samples obtained from pleuropneumonectomies or autopsies (349 MPMs, and 41 controls) among subjects investigated for probability and circumstance of asbestos exposure were examined through Scanning Electron Microscopy; 291 cases had an occupational asbestos exposure, 38 MPMs a non-occupational exposure (familiar or environmental), whereas among 20 MPM an asbestos exposure was not identified. The MPM risk was evaluated by means of Odds Ratio (OR). Results The residual asbestos fibre burden was higher among MPMs occupationally exposed (Geometric Mean:2.10 Million fibres/gram of dried tissue; 95% CI:1.5–2.58) in comparison with non-occupational (GM:0.66 Mff/gdt; 95% CI:0.47–0.95) or with unknown exposures (GM:0.59 Mff/gdt; 95% CI:0.34– 1.03) and controls (GM:0.26 Mff/gdt; 95% CI:0.20–0.34). Among occupationally exposed, the MPM risk increased according to the asbestos fibre burden reaching an OR of 36.8 (95%CI:11.9–113.5) for concentrations higher than 1 Mff/g dt, compared to the reference level (<0.25 Mff/gdt). Higher ORs were observed at any concentration of amphibole fibres in comparison those for chrysotile fibres. Conclusions The MPM risk was strongly associated to the residual asbestos fibre lung burden. The MPM risk due to non-occupational exposure shows a magnitude comparable with that with unknown asbestos exposures. The residual lung burden of chrysotile is strongly influenced by clearance and time since exposures ceased

Residual fibre lung burden among patients with pleural mesothelioma who have been occupationally exposed to asbestos

Objectives To evaluate the lungs asbestos fibres concentration in participants with malignant pleural mesothelioma (MPM) who have been occupationally exposed. Methods The lung samples were obtained from pleuropneumonectomies or autopsies of 271 male MPMs. The lung samples were examined through scanning electron microscopy. Retrospective assessment was used to assess for asbestos exposure. This study includes 248 MPMs with an occupational exposure defined as either ‘definite’ or ‘probable’ or ‘possible’. Results The participants had finished working in asbestos exposure conditions more than 20 years ago (on average 26.1±11.0 years). The fibre burden resulted with a geometric mean equal to 2.0 (95% CI 1.6 to 2.4) million fibres per gram of dry lung tissue. The burden was higher among participants employed in asbestos textiles industry and in shipyards with insulation material, if compared with construction workers or non-asbestos textile workers or participants working in chemicals or as auto mechanics. 91.3% of MPMs had a detectable amount of amphibole fibres. A strong lung clearance capability was evident among workers exposed to chrysotile fibres. Owing to that, the 1997 Helsinki Criteria for occupational exposure were reached in <35% of cases among participant working in construction, in metallurgical industry, in chemical or textile industry and among those performing brake repair activities. Conclusions The MPM cases are now occurring in Italy in participants who ceased occupational asbestos exposure decades before the analysis. A large majority still shows a residual content of amphibole fibres, but given the lung clearance capability, attribution to occupational exposure cannot rely only on fibres detection

0203 The lung burden of Asbestos Fibres (AF) and Asbestos Bodies (AB) and the risk of mesothelioma (MM) for exposures ceased 30 years ago

Objectives To estimate the risk of MM according to AF and AB in the lungs. Method Freeze dried lung samples from 309 MM and 41 controls have been analysed for AF (Scanning Electronic Microscopy) and AB (Optical Microscopy) from subjects investigated and classified for probability and circumstances of asbestos exposure. Odds Ratios (OR) were obtained using logistic regression. Results 254 (82%) MMs have been classified as occupationally and 25 (8%) as non-occupationally exposed: Geometric Mean (GM) for AF burden was 1 950 000 and 608 000 ff/g dlt, respectively; and 39 300 and 3300 for AB. 75% and 58% of the AF respectively were amphibole. Controls reported a GM of 269 000 AF and 28 of AB g/dlt. For any increase of 100.000 ff/g dlt, we computed an OR of 1.7 (1.3–2.3) for amphibole, 1.1 (1.0–1.3) for chrysotile, among occupational MMs; an OR of 1.3 (1.0–1.7) and 1.1 (1.0–1.1) among non-occupational MMs. The 1997 Helsinki criteria for attribution to occupational exposure would have excluded more than 30% of MMs under study: here occupational exposures ceased on average 26 years before the disease, and therefore clearance and time since last exposure must be taken into account because are relevant determinants of the retained amount of fibres. Conclusions The risk of MM increases with the amount of retained amphibole, and to a lesser extent, of chrysotile fibres. Because occupational and non-occupation asbestos exposures have been to mixture of fibres, the lungs of MM patients are still loaded with amphibole AF

Association between carrier screening and incidence of cystic fibrosis

Context A downward trend in cystic fibrosis (CF) birth incidence has been reported in some areas. Objective To evaluate the association between carrier screening and CF birth incidence. Design, Setting, and Participants In northeastern Italy, CF birth incidence is monitored by means of a long-standing neonatal screening program. In the same area, 2 sections using different carrier detection approaches were identified—the western region, in which CF carrier tests are offered only to relatives of patients or to couples planning in vitro fertilization; and the eastern region, in which carrier testing is offered to relatives and carrier screening to infertile couples and to couples of reproductive age. A total of 779 631 newborns underwent CF neonatal screening between January 1993 and December 2007, of whom 195 had CF detected. Main Outcome Measure Cystic fibrosis birth incidence in the 2 regions. Results A time-related decrease in birth incidence was found, with a mean annual percentage decrease of 0.16 per 10 000 neonates (P < .001). In the western region, 2559 carrier tests were performed, 314 carriers were identified, and 9 carrier couples were detected. In the eastern region, 87 025 carrier tests were performed, 3650 carriers were identified, and 82 carrier couples were detected. The birth rate decrease was greater in the eastern region (decrease rate, 0.24; 95% confidence interval [CI], 0.12-0.36) than in the western region (decrease rate, 0.04; 95% CI, –0.16 to 0.08; P = .01). The increase in the number of screened carriers over time was significantly correlated with the decrease in CF birth incidence (correlation coefficient = −0.53; 95% CI, –0.20 to –0.74; P = .003). Conclusion In northeastern Italy, carrier screening was associated with a decrease in the incidence of CF

Ricostruzione retrospettiva della dose interna in una coorte lavorativa esposta a PFOA

Introduzione La ditta MITENI di Trissino (VI), già attiva fin dal 1960 con il nome RIMAR, è stata la maggiore produttrice di perfluorurati (PF) in Europa. I dipendenti sono stati esposti a sostanze perfluorurate, in particolare a PFOA (acido perfluorottanoico) e le misurazioni delle concentrazioni ematiche cominciate dal 2000 hanno rilevato alti livelli di PFOA tra i lavoratori analizzati (n=123). Sulla base di questi valori, l’obiettivo è di stimare una dose cumulativa sierica di PFOA per tutti circa i 700 soggetti che sono stati dipendenti della ditta RIMAR-MITENI. Metodi Dal 2000 sono disponibili i livelli sierici di PFOA (in ng/mL) dei lavoratori inclusi nella sorveglianza aziendale annuale. Un totale di 693 campioni di sangue sono stati prelevati dal 2000 al 2013 da 123 lavoratori (Media Geometrica (MG): 4003 ng/mL; min-max: 19-91900 ng/mL); i livelli più elevati riguardano gli addetti ai PFOA (MG: 8826 ng/mL), i manutentori (MG: 1970 ng/mL), i magazzinieri (MG: 1107 ng/mL) e i tecnici di laboratorio (MG: 1084 ng/mL). Ogni dipendente è stato classificato in tre categorie mutuamente esclusive: “Ever PF” con 497 misure su 55 lavoratori, “Never PF” con 177 misure e 60 lavoratori ed infine "Uffici" con 19 misure tra 8 lavoratori. Per ogni categoria è stato stimato un modello di regressione lineare robusto ad effetti misti modellando il logaritmo dei valori sierici di PFOA del periodo 2000-2013 ed includendo le covariate più significative. La robustezza è stata ottenuta con uno stimatore di Huber con parametri k=1.345 e s=10 che garantiscono un'efficienza del 95%. Risultati A seconda del modello sono state incluse le covariate risultate significative: l’anno di rilevazione, la durata lavorativa nei PF, in altri dipartimenti o in ufficio; la produzione media annuale di PFOA dell’azienda nel periodo 2000-2013; il tempo dall’ultimo lavoro ai PF; l'assunzione dopo il 2005; lavori occasionali presso il reparto PF ed il lavoro come addetto alla manutenzione. I fattori fissi spiegano una discreta quota di variabilità (R² marginale "Ever PF": 42,1%; "Never PF": 47,6%; "Uffici": 59,1%). Attraverso il calcolo iterativo delle covariate tempo dipendenti è stato possibile stimare la concentrazione sierica di PFOA nel periodo 1970-2013 per tutti i lavoratori. Conclusioni L’attività di ricostruzione retrospettiva della dose di PFOA ha permesso di attribuire ad ogni dipendente RIMAR/MITENI una concentrazione sierica di PFOA permettendo il calcolo di una dose cumulativa. Come conseguenza della presenza di valori anomali, l’utilizzo di modelli robusti porta a minor adattamento del modello ai dati rispetto ai modelli classici, tuttavia le stime sono influenzate in maniera minore dalla presenza di valori anomali

The relationship between vascularity, p53 gene mutations and distant metastatic disease in epithelial ovarian carcinoma

Mutations of the p53 tumor suppressor gene are associated with large differences (>7 vessels/HPF) in Microvessel density (MVD) counts between primary and metastatic tumor sites in patients with epithelial ovarian cancer. These data are consistent with models demonstrating p53 mutation functions directly to influence angiogenesis. This information supports continued therapy and research involving angiogenesis inhibitors in patients with ovarian cancer, especially in the setting of increased differences in MVD between primary and metastatic sites

Island coarsening in one-dimensional models with partially and completely reversible aggregation

Using computer simulations and scaling ideas, we study one-dimensional models of diffusion, aggregation and detachment of particles from islands in the post-deposition regime, i. e. without flux. The diffusion of isolated particles takes place with unit rate, aggregation occurs immediately upon contact with another particle or island, and detachment from an island occurs with rate epsilon = exp(-E/kT), where E is the related energy barrier. In the partially reversible model, dissociation is limited to islands of size larger than a critical value i, while in the completely reversible model there is no restriction to that process (infinite i). Extending previous simulation results for the completely reversible case, we observe that a peaked island size distribution in the intermediate time regime, in which the mean island size is increasing, crosses over to the theoretically predicted exponentially decreasing distribution at long times. It contrasts with the partially reversible model, in which peaked distributions are obtained until the long time frozen state, which is attained with a crossover time $\tau \sim \frac{i^3}{\epsilon}$. The mean island size at saturation varies as $S_{sat}\approx 2i+C\epsilon$ (C constant), while the completely reversible case shows an Ahrrenius dependence of the mean island size, $S\sim \epsilon^{-1/2}$. Thus, for different coverages, the effect of the critical size i on the geometric features is much stronger than that of epsilon, which may be used to infer the relevance of size-dependent detachment rates in real systems and other models.Comment: 14 pages,8 figures, accepted for publication in Physica