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The delivery of nebulized medications to preterm infants during Non-Invasive Ventilation (NIV) remains an unmet clinical need. In this regard, the effective delivery of nebulized surfactant has been particularly investigated in preclinical and clinical studies. In this work, we investigated the feasibility of delivering nebulized surfactant through various commercially available nasal prong types. We first performed a compendial characterization of surfactant aerosols generated by the eFlow Neos nebulizer, customized to be used in neonates, determining the amount of surfactant delivered by the device as well as the aerodynamic characteristics of surfactant aerosols. Additionally, we extended the compendial characterization by testing the effect of different nasal prong types on the estimated lung dose using a realistic Continuous Positive Airway Pressure (CPAP) circuit that included a cast of the upper airways of a preterm neonate. The compendial characterization of surfactant aerosols delivered through different nasal prongs achieved relatively high delivered surfactant doses (in the range 63&ndash, 74% of the nominal dose), with aerodynamic characteristics displaying mass median aerodynamic diameters ranging between 2.52 and 2.81 &micro, m. Nevertheless, when using a representative in vitro setup mimicking NIV in a clinical setting, significant differences were observed in terms of the estimated lung dose accounting for up to two-fold differences (from 10% to 20% estimated lung deposition of the nominal dose) depending on the chosen nasal prong type. Considering that surfactant lung deposition rates are correlated with therapeutic efficacy, this study points out the relevance of choosing the appropriate NIV interface to maximize the lung dose of nebulized medications.

Background Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. Methods Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100–600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. Results Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 μm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). Conclusions The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016–004547-36). Electronic supplementary material The online version of this article (10.1186/s12931-019-1096-9) contains supplementary material, which is available to authorized users.

Non-invasive delivery of nebulized surfactant has been a long-pursued goal in neonatology. Our aim was to evaluate the performance of an investigational vibrating-membrane nebulizer in a realistic non-invasive neonatal ventilation circuit with different configurations. Surfactant (aerosols were generated with a nebulizer in a set-up composed of a continuous positive airway pressure (CPAP) generator with a humidifier, a cast of the upper airway of a preterm infant (PrINT), and a breath simulator with a neonatal breathing pattern. The lung dose (LD), defined as the amount of surfactant collected in a filter placed at the distal end of the PrINT cast, was determined after placing the nebulizer at different locations of the circuit and using either infant nasal mask or nasal prongs as CPAP interfaces. The LD after delivering a range of nominal surfactant doses (100&ndash, 600 mg/kg) was also investigated. Surfactant aerosol particle size distribution was determined by laser diffraction. Irrespective of the CPAP interface used, about 14% of the nominal dose (200 mg/kg) reached the LD filter. However, placing the nebulizer between the Y-piece and the CPAP interface significantly increased the LD compared with placing it 7 cm before the Y-piece, in the inspiratory limb. (14% &plusmn, 2.8 vs. 2.3% &plusmn, 0.8, nominal dose of 200 mg/kg). The customized eFlow Neos showed a constant aerosol generation rate and a mass median diameter of 2.7 &mu, m after delivering high surfactant doses (600 mg/kg). The customized eFlow Neos nebulizer showed a constant performance even after nebulizing high doses of undiluted surfactant. Placing the nebulizer between the Y-piece and the CPAP interface achieves the highest LD under non-invasive ventilation conditions.

Previous studies indicated that a few risk variants for autoimmune diseases are subject to pathogen-driven selection. Nonetheless, the proportion of risk loci that has been targeted by pathogens and the type of infectious agent(s) that exerted the strongest pressure remain to be evaluated. We assessed whether different pathogens exerted a pressure on known Crohn's disease (CD) risk variants and demonstrate that these single-nucleotide polymorphisms (SNPs) are preferential targets of protozoa-driven selection (P = 0.008). In particular, 19% of SNPs associated with CD have been subject to protozoa-driven selective pressure. Analysis of P values from genome-wide association studies (GWASs) and meta-analyses indicated that protozoan-selected SNPs display significantly stronger association with CD compared with nonselected variants. This same behavior was not observed for GWASs of other autoimmune diseases. Thus, we integrated selection signatures and meta-analysis results to prioritize five genic SNPs for replication in an Italian cohort. Three SNPs were significantly associated with CD risk, and combination with meta-analysis results yielded P values < 4 × 10 −6 . The bona fide risk alleles are located in ARHGEF2, an interactor of NOD2, NSF, a gene involved in autophagy, and HEBP1, encoding a possible mediator of inflammation. Pathway analysis indicated that ARHGEF2 and NSF participate in a molecular network, which also contains VAMP3 (previously associated to CD) and is centered around miR-31 (known to be disregulated in CD). Thus, we show that protozoa-driven selective pressure had a major role in shaping predisposition to CD. We next used this information for the identification of three bona fide novel susceptibility loci.

Background and aims ABO encodes a glycosyltranferase which determines the major human histo-blood group. The FUT2 fucosyltransferase allows expression of ABO antigens on the gastrointestinal mucosa and in bodily secretions (secretor phenotype). A nonsense allele in FUT2 represents a susceptibility variant for Crohn's disease, and both the secretor and ABO blood group status affect the composition of the gut microbiota. Thus, we evaluated if variants in ABO might represent good candidates as Crohn's disease susceptibility loci. Methods We recruited two case–control cohorts, from Italy (n = 1301) and Belgium (n = 2331). Subjects were genotyped for one SNP in FUT2 and two variants in ABO . Results No effect on Crohn's disease risk was detected for ABO variants, whereas an association was observed between the FUT2 polymorphism and Crohn's disease susceptibility in the Belgian sample, but not in the Italian cohort. The effect of histo-blood groups was evaluated using group O as the reference. Most non-O groups had odds ratios (ORs) higher than 1 in both cohorts, and combined analysis of the two samples indicated a predisposing effect for the A and B groups (OR = 1.17, 95% CI: 1.02–1.32 and OR = 1.33, 95% CI: 1.09–1.58, respectively). In Crohn's disease patients, the non-O blood group and the non-secretor status were associated with higher risk of developing a stricturing or penetrating disease. Conclusions ABO histo-blood group might confer susceptibility to Crohn's disease and modulate disease severity.

Polysilicon nanowire biosensors have been fabricated using a top-down process and were used to determine the binding constant of two inflammatory biomarkers. A very low cost nanofabrication process was developed, based on simple and mature photolithography, thin film technology and plasma etching, enabling an easy route to mass manufacture. Antibodyfunctionalized nanowire sensors were used to detect the proteins interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) over a wide range of concentrations, demonstrating excellent sensitivity and selectivity, exemplified by a detection sensitivity of 10fM in the presence of a 100,000-fold excess of a non-target protein. Nanowire titration curves gave antibody-antigen dissociation constants in good agreement with low-salt enzyme-linked immunosorbent assays (ELISAs). This fabrication process produces high-quality nanowires that are suitable for lowcost mass production, providing a realistic route to the realization of disposable nanoelectronic Point-of-Care (PoC) devices.

Background: Crohn’s disease (CD) is associated with penetrating complications such as phlegmons and intra-abdominal abscesses. As the management of the patients influenced by the presence of such complications, a readily available tool for the diagnosis of extramural complications in CD is needed. Preliminary findings suggest that the assessment of vascularity within intra-abdominal masses may distinguish between phlegmons and abscesses. Aim of our study was to evaluate the use of contrast enhanced ultrasound (CEUS) to distinguish between phlegmons and intra-abdominal abscesses in CD patients as a point-of-care technique. Methods: From November 2011, consecutive patients with complicated CD were enrolled. Indications of patient assessments by CEUS were symptoms, signs and biochemical exams indicating penetrating behavior (abdominal pain, mass, fever, elevated CRP and leukocytosis). A total of 22 CD pts (14 M; median age 27 yrs, range 18 75; disease duration: median 54 mos, range 1 564; CD site: ileal in 13 pts, ileo-colonic in 9 pts; CD behavior: penetrating in 20 pts, stricturing in 2 pts; previous ileocolonic resection in 9 pts) were included. Clinical evaluation by an IBD expert and other cross sectional imaging techniques (MR and CT) were considered as the standard. Results: CEUS detected abscesses in 9 and phlegmons in 12 pts. One patient had an unspecified lesion that was diagnosed as metastasis by PET. Six out of 9 abscesses were confirmed by CT-Enteroclysis and these pts underwent surgery during the follow up. The remaining 3 pts with abscesses were treated with antibiotics and are still in follow up (17.5 mos). In the phlegmon group, 4 out of 12 patients were evaluated by CT or MRI that confirmed CEUS findings in 3 cases but in one patient a deep abscess was identified and surgery was scheduled. Eight out of 12 pts were clinically followed up (median: 16 mos). Two of these patients developed an abscess after one week from CEUS despite medical treatment. Overall CEUS correctly identified 19 out of 22 lesions (86%) on the basis of cross sectional imaging modalities and clinical follow up used as final diagnosis. Conclusions: CEUS is a non-invasive, radiation free and point-of-care technique able to differentiate phlegmons from abscesses driving a prompt clinical management in complicated CD patients. P255 Computed virtual chromoendoscopy with FICE in the definition of raised dysplastic lesions and pseudopolyps in long-standing ulcerative colitis: a preliminary, prospective, study towards a new classification A. Cassinotti1 *, F. Buffoli2, P. Fociani3, V. Villanacci4, T. Staiano2, M. Fichera1, R. Grassia2, G. Manes1, M. Salemme4, M. Lombardini1, P. Molteni1, G. Sampietro5, D. Foschi5, G. Maconi1, R. de Franchis1, S. Ardizzone1. 1Luigi Sacco University Hospital, Gastroenterology and IBD Unit, Milan, Italy, 2Istituti Ospitalieri Cremona, Endoscopy Unit, Cremona, Italy, 3Luigi Sacco University Hospital, Pathology Unit, Milan, Italy, 4Spedali Civili, Pathology Unit, Brescia, Italy, 5Luigi Sacco University Hospital, General Surgery, Milan, Italy