The patient journey in Chronic Obstructive Pulmonary Disease (COPD): a human factors qualitative international study to understand the needs of people living with COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common condition that causes irreversible airway obstruction. Fatigue and exertional dyspnoea, for example, have a detrimental impact on the patient's daily life. Current research has revealed the need to empower the patient, which can result in not only educated and effective decision-making, but also a considerable improvement in patient satisfaction and treatment compliance. The current study aimed to investigate the perspectives and requirements of people living with COPD to possibly explore new ways to manage their disease. METHODS: Adults with COPD from 8 European countries were interviewed by human factor experts to evaluate their disease journey through the gathering of information on the age, performance, length, and impact of diagnosis, symptoms progression, and family and friends' reactions. The assessment of present symptoms, services, and challenges was performed through a 90-min semi-structured interview. To identify possible unmet needs of participants, a generic thematic method was used to explore patterns, themes, linkages, and sequences within the data collected. Flow charts and diagrams were created to communicate the primary findings. Following analysis, the data was consolidated into cohesive insights and conversation themes relevant to determining the patient's unmet needs. RESULTS: The 62, who voluntarily accepted to be interviewed, were patients (61% females, aged 32-70 years) with a COPD diagnosis for at least 6 months with stable symptoms of different severity. The main challenges expressed by the patients were the impact on their lifestyle, reduced physical activity, and issues with their mobility. About one-fourth had challenges with their symptoms or medication including difficulty in breathing. Beyond finding a cure for COPD was the primary goal for patients, their main needs were to receive adequate information on the disease and treatments, and to have adequate support to improve physical activity and mobility, helpful both for patients and their families. CONCLUSIONS: These results could aid in the creation of new ideas and concepts to improve our patient's quality of life, encouraging a holistic approach to people living with COPD and reinforcing the commitment to understanding their needs.

Preclinical Assessment of Nebulized Surfactant Delivered through Neonatal High Flow Nasal Cannula Respiratory Support.

High-flow nasal cannula (HFNC) is a non-invasive respiratory support (NRS) modality to treat premature infants with respiratory distress syndrome (RDS). The delivery of nebulized surfactant during NRS would represent a truly non-invasive method of surfactant administration and could reduce NRS failure rates. However, the delivery efficiency of nebulized surfactant during HFNC has not been evaluated in vitro or in animal models of respiratory distress. We, therefore, performed first a benchmark study to compare the surfactant lung dose delivered by commercially available neonatal nasal cannulas (NCs) and HFNC circuits commonly used in neonatal intensive care units. Then, the pulmonary effect of nebulized surfactant delivered via HFNC was investigated in spontaneously breathing rabbits with induced respiratory distress. The benchmark study revealed the surfactant lung dose to be relatively low for both types of NCs tested (Westmed NCs 0.5 ± 0.45%; Fisher & Paykel NCs 1.8 ± 1.9% of a nominal dose of 200 mg/kg of Poractant alfa). The modest lung doses achieved in the benchmark study are compatible with the lack of the effect of nebulized surfactant in vivo (400 mg/kg), where arterial oxygenation and lung mechanics did not improve and were significantly worse than the intratracheal instillation of surfactant. The results from the present study indicate a relatively low lung surfactant dose and negligible effect on pulmonary function in terms of arterial oxygenation and lung mechanics. This negligible effect can, for the greater part, be explained by the high impaction of aerosol particles in the ventilation circuit and upper airways due to the high air flows used during HFNC.

Lung Deposition of Surfactant Delivered via a Dedicated Laryngeal Mask Airway in Piglets.

It is unknown if the lung deposition of surfactant administered via a catheter placed through a laryngeal mask airway (LMA) is equivalent to that obtained by bolus instillation through an endotracheal tube. We compare the lung deposition of surfactant delivered via two types of LMA with the standard technique of endotracheal instillation. 25 newborn piglets on continuous positive airway pressure support (CPAP) were randomized into three groups: 1-LMA-camera (integrated camera and catheter channel; catheter tip below vocal cords), 2-LMA-standard (no camera, no channel; catheter tip above the glottis), 3-InSurE (Intubation, Surfactant administration, Extubation; catheter tip below end of endotracheal tube). All animals received 100 mg·kg-1 of poractant alfa mixed with 99mTechnetium-nanocolloid. Surfactant deposition was measured by gamma scintigraphy as a percentage of the administered dose. The median (range) total lung surfactant deposition was 68% (10-85), 41% (5-88), and 88% (67-92) in LMA-camera, LMA-standard, and InSurE, respectively, which was higher (p < 0.05) in the latter. The deposition in the stomach and nasopharynx was higher with the LMA-standard. The surfactant deposition via an LMA was lower than that obtained with InSurE. Although not statistically significant, introducing the catheter below the vocal cords under visual control with an integrated camera improved surfactant LMA delivery by 65%.

Extended Pharmacopeial Characterization of Surfactant Aerosols Generated by a Customized eFlow Neos Nebulizer Delivered through Neonatal Nasal Prongs.

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 63-74% of the nominal dose), with aerodynamic characteristics displaying mass median aerodynamic diameters ranging between 2.52 and 2.81 µm. 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.

In Vitro Performance of an Investigational Vibrating-Membrane Nebulizer with Surfactant under Simulated, Non-Invasive Neonatal Ventilation Conditions: Influence of Continuous Positive Airway Pressure Interface and Nebulizer Positioning on the Lung Dose.

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 (100-600 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% ± 2.8 vs. 2.3% ± 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 µm 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.

AC and Phase Sensing of Nanowires for Biosensing.

Silicon nanowires are label-free sensors that allow real-time measurements. They are economical and pave the road for point-of-care applications but require complex readout and skilled personnel. We propose a new model and technique for sensing nanowire sensors using alternating currents (AC) to capture both magnitude and phase information from the sensor. This approach combines the advantages of complex impedance spectroscopy with the noise reduction performances of lock-in techniques. Experimental results show how modifications of the sensors with different surface chemistries lead to the same direct-current (DC) response but can be discerned using the AC approach.

Long-term outcome of inflammatory bowel diseases with cytomegalovirus colitis: effect of antiviral treatment.

OBJECTIVE: The role of cytomegalovirus (CMV) reactivation in the outcome of inflammatory bowel diseases (IBDs) is unclear. Uncertainties remain on the treatment of CMV infection, especially in patients with a viral load just above the normal value in the blood or with very few positive cells in colonic biopsies. This retrospective cohort study reports the long-term outcome of 38 active IBD patients with CMV infection, 13 of whom received an antiviral treatment. PATIENTS AND METHODS: Thirty patients with ulcerative colitis (UC) and eight patients with Crohn's colitis with active colitis and CMV infection, diagnosed by detection of at least one CMV inclusion by histology and immunohistochemistry and/or with the CMV antigen test or the CMV DNA test, were studied. Their clinical history at 6 months and up to 1 year following hospital discharge was reviewed. Clinical remission at hospital discharge and recurrences requiring new treatments or colectomy were considered major outcomes of the study. The features of treated and untreated patients were compared using the Fisher exact test and the Student t-test. RESULTS: All patients showed rare CMV inclusions, and only three had positive blood CMV PCR. Thirteen patients received antiviral treatment, whereas 25 patients did not. No patient underwent colectomy during the hospitalization. The 12-month cumulative rate of clinical relapse requiring new treatment or colectomy was 23% in patients treated with antivirals and 50% in untreated patients (P=0.165). However, in patients with UC and in those with steroid-dependent/refractory disease, antiviral treatment was associated with a significantly higher clinical remission rate at 12 months (77.8 vs. 45%, P=0.049, and 77.8 vs. 19.4%, P=0.038, respectively). CONCLUSION: In IBD patients with active CMV colitis, antiviral treatment seems to have a marginal impact in the short term, during the treatment of the acute phase, but it may have some beneficial effect in maintaining remission up to 1 year of follow-up in patients with UC and steroid-dependent/refractory disease.

ABO histo-blood group might modulate predisposition to Crohn's disease and affect disease behavior.

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.

Crohn's disease loci are common targets of protozoa-driven selection.

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.

Thin film polycrystalline silicon nanowire biosensors.

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. Antibody-functionalized nanowire sensors were used to detect the proteins interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) over a wide range of concentrations, demonstrating excellent sensitivity and selectivity, exemplified by a detection sensitivity of 10 fM in the presence of a 100,000-fold excess of a nontarget 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 low-cost mass production, providing a realistic route to the realization of disposable nanoelectronic point-of-care (PoC) devices.

Horizontal nDEP cages within open microwell arrays for precise positioning of cells and particles.

We present the structure of an open microwell, i.e. a microwell open at both the top and bottom ends, which enables single-cells to be handled, processed and recovered after the experiment. The microwell has a novel architecture which allows particles to be trapped and forced to interact by means of a cylindrical negative dielectrophoretic cage. Particles are aligned along a horizontal axis where the electric field minimum is placed. Arrays of open microwells are fabricated using flexible printed circuit board (PCB) technology providing cheap and disposable devices. Levitation and precise positioning of both polystyrene beads and K562 cells were experimented, confirming the results of physical simulations. Assessment of cell viability after 20 min exposure to the electric field was performed through a standard calcein-release assay.