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Background. Pulmonary hypertension (PH) is a progressive fatal disease thus, noninvasive prognostic tools are needed to follow these patients. The aim of our study was to evaluate fractional exhaled nitric oxide (FeNO) and exhaled breath temperature (EBT) values in patients with PH from different causes and to correlate them with respiratory functional data. Methods. Twenty-four PH patients underwent spirometry, carbon monoxide diffusion (DLCO) test, transthoracic echocardiography, right-heart catheterization, and FeNO and EBT measurements. Results. We studied 3 groups according to the type of PH: 10 patients with pulmonary arterial hypertension (PAH) (group A), 11 patients with PH due to chronic obstructive pulmonary disease (COPD) (group B), and 3 patients with PH associated with left heart disease (group C). Mean FeNO values tend to be higher in group B (15.0 ± 9.3ppb) compared with other groups (respectively, 9.9 ± 5.7 and 8.5 ± 5.2 ppb in groups A and C; p = 0.271) but no statistical significance has been reached. Mean values of alveolar NO concentration (CANO) were higher in groups A and B compared to group C (respectively, 16.9 ± 12.6; 13.9 ± 6.8; and 6.7 ± 2.0 ppb) (p = 0.045). EBT mean values were significantly lower in group C when compared with other groups (group C: 29.0 +- 1.3°C, groups A and B: 30.9 ± 1.3 and 31.2 ± 1.2°C, respectively: p = 0.041). EBT levels were inversely correlated to mean pulmonary artery pressure (PAPm) levels (Spearman coefficient -0.481; p = 0.017). Conclusions. eNO, CANO, and EBT have been evaluated in three groups of PH patients. Interestingly EBT reduction was correlated with PAPm increase, whereas FeNO was higher in COPD patients and CANO in PAH and COPD groups. Further studies are needed to clarify EBT, FeNO, and CANO roles as biomarkers in the monitoring of patients with PH.

We present a mid-IR ($\lambda \approx$ 8.3 $\mu$m) quantum well infrared photodetector (QWIP) fabricated on a mid-IR transparent substrate, allowing photodetection with illumination from either the front surface or through the substrate. The device is based on a 400 nm-thick GaAs/AlGaAs semiconductor QWIP heterostructure enclosed in a metal-insulator-metal (MIM) cavity and hosted on a mid-IR transparent ZnSe substrate. Metallic stripes are symmetrically patterned by e-beam lithography on both sides of the active region. The detector spectral coverage spans from $\lambda \approx 7.15$ $\mu$m to $\lambda \approx 8.7$ $\mu$m by changing the stripe width L - from L = 1.0 $\mu$m to L = 1.3 $\mu$m - thus frequency-tuning the optical cavity mode. Both micro-FTIR passive optical characterizations and photocurrent measurements of the two-port system are carried out. They reveal a similar spectral response for the two detector ports, with an experimentally measured T$_{BLIP}$ of $\approx$ 200K., Comment: Copyright 2021 Mario Malerba, Mathieu Jeannin, Stefano Pirotta, Lianhe Li, Alexander Giles Davies, Edmund Linfield, Adel Bousseksou, Jean-Michel Manceau and Raffaele Colombelli. This article is distributed under a Creative Commons Attribution (CC BY) License. The following article has been submitted to APL Photonics. After it is published, it will be found at https://aip.scitation.org/journal/app

Obstructive sleep apnea (OSA) and insomnia are the two most common sleep disorders among the general population, and they may often coexist in patients with sleep-disordered breathing (SDB). The higher prevalence of insomnia symptoms in patients with OSA (40–60%) compared to that observed in the general population has thus led researchers to identify a new disorder named comorbid insomnia and OSA (COMISA), whose true burden has been so far largely underestimated. The combined treatment of COMISA patients with positive-airway pressure ventilation (PAP) with cognitive behavioral therapy for insomnia (CBTi) has shown a better patient outcome compared to that obtained with a single treatment. Furthermore, recent evidence has shown that an innovative patient-centered approach taking into consideration patient characteristics, treatment preferences and accessibility to treatment is recommended to optimize clinical management of COMISA patients. However, in this complex mosaic, many other sleep disorders may overlap with COMISA, so there is an urgent need for further research to fully understand the impact of these therapies on outcomes for OSA patients with comorbidity. In light of this need, this review focuses on the major sleep disorders comorbid with OSA and the recent advances in the management of these insomniac patients.

Introduction Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of cardiovascular disease. The endothelial dysfunction likely plays a central role in increasing cardiovascular risk. Objectives This cross-sectional, study investigated the prevalence and extent of endothelial dysfunction in patients with stable COPD. Methods Peripheral arterial tonometry (PAT) was measured by post-ischemic reactive hyperemia index (RHI) in 16 COPD patients, 16 healthy controls and 16 subjects with treated systemic arterial hypertension (AH) and analysed with covariates condition (dyslipidemia, and medications). Results The prevalence of endothelial dysfunction was significantly higher in COPD group than in the other groups. Mean RHI was significantly lower in COPD patients compared with the other groups. At linear regression FEV1 and RHI were directly correlated (Spearman index = 0.553; P = .026). COPD patients in groups C and D according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages showed lower RHI compared with patients classified as A and B (P

Heat dissipation in a plasmonic nanostructure is generally assumed to be ruled only by its own optical response even though also the temperature should be considered for determining the actual energy-to-heat conversion. Indeed, temperature influences the optical response of the nanostructure by affecting its absorption efficiency. Here, we show both theoretically and experimentally how, by properly nanopatterning a metallic surface, it is possible to increase or decrease the light-to-heat conversion rate depending on the temperature of the system. In particular, by borrowing the concept of matching condition from the classical antenna theory, we first analytically demonstrate how the temperature sets a maximum value for the absorption efficiency and how this quantity can be tuned, thus leading to a temperature-controlled optical heat dissipation. In fact, we show how the nonlinear dependence of the absorption on the electron-phonon damping can be maximized at a specific temperature, depending on the system geometry. In this regard, experimental results supported by numerical calculations are presented, showing how geometrically different nanostructures can lead to opposite dependence of the heat dissipation on the temperature, hence suggesting the fascinating possibility of employing plasmonic nanostructures to tailor the light-to-heat conversion rate of the system.

The identification of determinants of attempts to quit smoking and quitting smoking success is crucial for effective smoking prevention and/or cessation programs. Thus, here we have conducted a survey to determine the sociodemographic characteristics of tobacco use and the potential determinants of quitting smoking among a population of 140 subjects&mdash, 101 smokers and 39 ex-smokers&mdash, referred to our clinic for respiratory diseases. Subject characteristics included demographic data, employment and education status, respiratory disease family history, smoking habits, life habits, diet, alcohol intake, and physical activity. In comparison with former smokers, active smokers were younger, lived with at least one smoking family member, and were more frequently exposed to passive smoke. They also displayed a higher coffee consumption, a higher frequency of in-between-meal snacks, and a lower chronic obstructive pulmonary disease (COPD) prevalence. In comparison with subjects who had never attempted to quit smoking, individuals who had attempted to quit smoking were younger, had a lower pack-year median, consumed a higher amount of coffee and alcohol, and conducted regular physical activity. Determinants of successful smoking cessation were older age, lower passive smoking exposure and daily coffee intake, and COPD diagnosis. Overall, our findings underscore the importance of health education in fostering successful smoking cessation in respiratory disease patients.

We developed a technique that enables replacement of a metallic waveguide cladding with a low-index (n≈1.4) material - CaF

Background: Systemic lupus erythematosus (SLE) is a chronic, auto-immune, multi-organ disease that can affect both the skin and the lungs. Malar rash is a common skin manifestation of SLE and is linked to SLE disease activity, whereas lung involvement is a generally negative prognostic factor for these patients. However, a sensitive and non-invasive screening tool for potential lung involvement in SLE patients is still not available. Methods: This study aimed to investigate the relationship between malar rash and airway inflammation in adult SLE patients who were not known to have any lung involvement (clinical or radiologic). The study comprised of the measurement of the concentration of NO in exhaled breath or fraction of exhaled nitric oxide (FeNO) and levels were compared between those with and without malar rash. This tool is considered as a sensitive and non-invasive method that is routinely used in patients with asthma or other respiratory diseases to identify airway inflammation. Results: A total of 125 patients (100 females, 25 males) were enrolled during the study period from January 2011 to December 2014. Patients with malar rash (N = 35) had a significant decrease in serum levels of C4 (p < 0.05) compared to patients without malar rash (N = 90). The mean levels of FeNO in overall patients were 36.44 ± 8.87 ppb. A statistically significant difference in FeNO50 values between patients with malar rash (43.46 ± 6.72 ppb) and without (29.43 ± 3.64 ppb) was found (p < 0.001). FeNO50 values were inversely correlated only with serum C4 (p < 0.01). However, no correlation between FeNO50 values and SLE clinical disease activity scores was found. Conclusions: The presence of a malar rash may predict sub-clinical airway inflammation in SLE patients. Further prospective studies are needed to confirm the usefulness of FeNO measurements in monitoring SLE-associated airway inflammation.

Combining individual drugs in a single inhaler is the most convenient way to deliver triple therapy. A long-acting muscarinic receptor antagonist (LAMA) added to an inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA) fixed-dose combination (FDC) can improve efficacy of pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). New inhaled ICS/LABA/LAMA FDCs, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are in Phase III of clinical development for COPD. Triple inhaled therapy might be particularly useful in patients with severe to very severe COPD, above all in those with peripheral blood or sputum eosinophilia, asthma-COPD overlap syndrome (ACOS) or frequent exacerbators. Future prospective studies should assess efficacy and safety of triple ICS/LABA/LAMA therapy in selected COPD phenotypes.

Background Electronic cigarette (EC) use is an emerging behaviour that has been shown to help smokers to reduce cigarette consumption. The aim of this study was to illustrate long-term changes in exhaled breath measurements and respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to ECs. Materials and methods Prospective evaluation of cigarette consumption, fractional nitric oxide concentration in exhaled breath (FeNO), exhaled carbon monoxide (eCO) and symptom scores was performed in a 1-year randomized, controlled trial of ‘healthy’ smokers receiving 2·4% nicotine, 1·8% nicotine or no nicotine ECs. FeNO and eCO data are presented on the basis of participants’ pooled continuous smoking phenotype classification (failures, reducers and quitters). Results A significant effect of quitting classification was found on FeNo and eCO at all time points (P < 0·0001). Among quitters, FeNO (medians and interquartile range) rose from 5·5 (4·5–6·9) ppb to 17·7 (13·3–18·9) ppb by week 52. Baseline eCO (medians and interquartile range) decreased from 17 (12–20) ppm to 3 (1–4) ppm by week 52. No significant changes in FeNO and eCO levels were observed in failures and reducers. Improvements in FeNO and eCO levels were correlated with attenuations in symptom scores. Conclusions Smokers invited to switch to electronic cigarettes who completely abstained from smoking showed steady progressive improvements in their exhaled breath measurements and symptom scores. FeNo and eCO normalization is highly supportive of improved respiratory health outcomes and adds to the notion that quitting from tobacco smoking can reverse harm in the lung.

COVID-19, a novel severe acute respiratory syndrome (SARS) emerging in China’s Hubei province in late 2019, due to a new coronavirus (SARS-CoV-2), is causing a global pandemic involving many areas of the world, which so far counts more than 43 million cases and more than 1,155,000 deaths worldwide [...]

Besides advanced age and the presence of multiple comorbidities as major contributors to increased risk of severe disease and fatal outcome from Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19), there is now emerging evidence that overweight and obesity predispose to severe symptoms and negative prognosis. Remarkably, the severity of COVID-19 appears to rise with increasing body mass index (BMI). The association between COVID-19 outcomes and overweight/obesity has biological and physiological plausibility. Potential pathophysiological mechanisms that may explain this strong association include the chronic pro-inflammatory state, the excessive oxidative stress response, and the impaired immunity that is commonly reported in these individuals. The role of cytokines, mammalian target of rapamycin (mTOR), and altered natural killer cell polarization in the dangerous liaison between COVID-19 and obesity are discussed here. These pathways can favor and accelerate the deleterious downstream cellular effects of SARS-CoV-2. Moreover, obesity is well known to be associated with reduced lung function and poor response to mechanical ventilation, thus placing these individuals at high risk of severe illness and mortality from COVID-19. Furthermore, obesity may lead to other complications, such as renal failure, cardiovascular dysfunction, hypertension, and vascular damage, which in turn can further accelerate negative clinical outcomes from COVID-19. Obese individuals should be shielded against any potential viral exposure to SARS-CoV-2 with consequential considerations for compulsory protection devices and social distancing. Health care providers should be aware that obesity predisposes to severe symptoms and negative prognosis in COVID-19 patients.

We developed a technique that enables to replace a metallic waveguide cladding with a low-index (n $\sim$ 1.4) material - CaF2 or BaF2 - that in addition is transparent from the mid-IR up to the visible range: elevated confinement is preserved while introducing an optical entryway through the substrate. Replacing the metallic backplane also allows double-side patterning of the active region. Using this approach, we demonstrate strong light-matter coupling between an intersubband transition (lambda $\sim$ 10 microns) and a dispersive resonator, at 300 K and at 78 K. Finally, we evaluate the potential of this approach as a platform for waveguiding in the mid-IR spectral range, with numerical simulations that reveal losses in the 1-10 cm$^{-1}$ range., just accepted in optics express

Chronic obstructive pulmonary disease (COPD) is a common disabling disease characterized by progressive airflow obstruction. Great efforts were spent in the development of drugs able to improve symptoms, quality of life, reduce exacerbations, hospitalizations and the frequency of death of patients with COPD. The cornerstones of treatment are bronchodilator drugs of two different classes: beta agonists and muscarinic antagonists. Currently the Global initiative for COPD suggests the use of long acting beta agonists (LABAs) and long acting muscarinic antagonists (LAMAs) in combination for the majority of COPD patients, thus great interest is associated with the developing of LAMA/LABA fixed combination in the maintenance treatment of stable COPD. Many LAMA/LABA fixed dose combinations have been licensed in different countries and the clinical use of these drugs stimulated the performance of many clinical trials. The purpose of this review is a complete criticism of pharmacological and clinical aspects related to the use of LAMA/LABA single inhalers for the maintenance treatment of stable COPD, with particular mention to the most debated topics and future prospects in the field.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is one of the most frequent diagnoses in patients presenting with acute dyspnoea or respiratory failure. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document, it is defined clinically as acute worsening of respiratory symptoms that result in additional therapies, bronchodilators, corticosteroids and antibiotics being the cornerstone of acute management [1]., In real-life practice, acute exacerbation of COPD is often treated as a cardiopulmonary syndrome http://ow.ly/uAnk30luMYz

Large-scale neural recordings with high spatial and temporal accuracy are instrumental to understand how the brain works. To this end, it is of key importance to develop probes that can be conveniently scaled up to a high number of recording channels. Despite recent achievements in complementary metal-oxide semiconductor (CMOS) multi-electrode arrays probes, in current circuit architectures an increase in the number of simultaneously recording channels would significantly increase the total chip area. A promising approach for overcoming this scaling issue consists in the use of the modular Active Pixel Sensor (APS) concept, in which a small front-end circuit is located beneath each electrode. However, this approach imposes challenging constraints on the area of the in-pixel circuit, power consumption and noise. Here, we present an APS CMOS-probe technology for Simultaneous Neural recording that successfully addresses all these issues for whole-array read-outs at 25 kHz/channel from up to 1024 electrode-pixels. To assess the circuit performances, we realized in a 0.18 μm CMOS technology an implantable single-shaft probe with a regular array of 512 electrode-pixels with a pitch of 28 μm. Extensive bench tests showed an in-pixel gain of 45.4 ± 0.4 dB (low pass, F-3 dB = 4 kHz), an input referred noise of 7.5 ± 0.67 μVRMS (300 Hz to 7.5 kHz) and a power consumption

Electrophysiological signals in the brain are distributed over broad spatial and temporal scales. Monitoring these signals at multiple scales is fundamental in order to decipher how brain circuits operate and might dysfunction in disease. A possible strategy to enlarge the experimentally accessible spatial and temporal scales consists in combining the use of multiple probes with different resolutions and sensing areas. Here, we propose a neural recording system capable of simultaneous and synchronous acquisitions from a new generation of high-resolution CMOS probes (512 microelectrodes, 25 kHz/electrode whole-array sampling frequency) as well as from a custom-designed CMOS-based headstage. While CMOS probes can provide recordings from a large number of closely spaced electrodes on single-shaft devices, the CMOS-based headstage can be used to interface the wide range of available intra- or epi-cortical passive electrode array devices. The current platform was designed to simultaneously manage high-resolution recordings from up to four differently located CMOS probes and from a single 36-channels low-resolution passive electrode array device. The design, implementation, and performances for both ICs and for the FPGA-based interface are presented. Experiments on retina and neuronal culture preparations demonstrate the recording of neural spiking activity for both CMOS devices and the functionality of the system.

Substrate-integrated multielectrode arrays (MEAs) enable multisite, long-term, and label-free sensing and actuation of neuronal electrical signals in reduced cell culture models for network electrophysiology. Conventional, thin-film fabricated passive MEAs typically provide a few tens of electrode sites. New generations of active CMOS-based high-resolution arrays provide the capabilities of simultaneous recordings from thousands of neurons over fields of view of several square millimeters, yet allowing extracellular electrical imaging to be achieved down to the subcellular scale. In turn, such advancement in chip-based electrical readouts can significantly complement recently developed biotechnological and bimolecular techniques for neurobiology applications. Here, we describe (1) a simple method to fabricate passive MEAs and (2) protocols for preparing and growing primary rat hippocampal neuronal cultures and human iPS-derived neurons on MEAs. The aim is to provide reliable protocols for initiating the reader to this technology and for stimulating their further development and experimental use in neurobiology.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease characterized by progressive loss of lung function and poor prognosis. The so-called acute exacerbation of IPF (AE-IPF) may lead to severe hypoxemia requiring mechanical ventilation in the intensive care unit (ICU). AE-IPF shares several pathophysiological features with acute respiratory distress syndrome (ARDS), a very severe condition commonly treated in this setting. A review of the literature has been conducted to underline similarities and differences in the management of patients with AE-IPF and ARDS. During AE-IPF, diffuse alveolar damage and massive loss of aeration occurs, similar to what is observed in patients with ARDS. Differently from ARDS, no studies have yet concluded on the optimal ventilatory strategy and management in AE-IPF patients admitted to the ICU. Notwithstanding, a protective ventilation strategy with low tidal volume and low driving pressure could be recommended similarly to ARDS. The beneficial effect of high levels of positive end-expiratory pressure and prone positioning has still to be elucidated in AE-IPF patients, as well as the precise role of other types of respiratory assistance (e.g., extracorporeal membrane oxygenation) or innovative therapies (e.g., polymyxin-B direct hemoperfusion). The use of systemic drugs such as steroids or immunosuppressive agents in AE-IPF is controversial and potentially associated with an increased risk of serious adverse reactions. Common pathophysiological abnormalities and similar clinical needs suggest translating to AE-IPF the lessons learned from the management of ARDS patients. Studies focused on specific therapeutic strategies during AE-IPF are warranted.

Substrate-integrated multielectrode arrays (MEAs) enable multisite, long-term, and label-free sensing and actuation of neuronal electrical signals in reduced cell culture models for network electrophysiology. Conventional, thin-film fabricated passive MEAs typically provide a few tens of electrode sites. New generations of active CMOS-based high-resolution arrays provide the capabilities of simultaneous recordings from thousands of neurons over fields of view of several square millimeters, yet allowing extracellular electrical imaging to be achieved down to the subcellular scale. In turn, such advancement in chip-based electrical readouts can significantly complement recently developed biotechnological and bimolecular techniques for neurobiology applications. Here, we describe (1) a simple method to fabricate passive MEAs and (2) protocols for preparing and growing primary rat hippocampal neuronal cultures and human iPS-derived neurons on MEAs. The aim is to provide reliable protocols for initiating the reader to this technology and for stimulating their further development and experimental use in neurobiology.

Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting β2-adrenoceptor agonists (LABA) and inhaled corticosteroids (ICS). Inhaled pharmacological treatment can improve patients’ daily symptoms and reduce decline of pulmonary function and acute exacerbation rate. Treatment with all three inhaled drug classes is reserved for selected, more severe, patients with COPD when symptoms are not sufficiently controlled by dual LABA/LAMA therapy and exacerbations are frequent. This review focuses on the role of single-inhaler triple therapy with once-daily fluticasone furoate/umeclidinium/vilanterol fixed-dose combination, which is in phase III clinical development for maintenance treatment of severe-to-very severe COPD. In this review, we summarize evidence providing the rationale for its use in COPD and discuss the gaps to be filled in this pharmacotherapeutic area.

Plasmonic metamolecules have received much interest in the last years because they can produce a wide spectrum of different hybrid optical resonances. Most of the configurations presented so far, however, considered planar resonators lying on a dielectric substrate. This typically yields high damping and radiative losses, which severely limit the performance of the system. Here we show that these limits can be overcome by considering a 3D arrangement made from slanted nanorod dimers extruding from a silver baseplate. This configuration mimics an out-of-plane split ring resonator capable of a strong near-field interaction at the terminations and a strong diffractive coupling with nearby nanostructures. Compared to the corresponding planar counterparts, higher values of electric and magnetic fields are found (about a factor 10 and a factor 3, respectively). High-quality-factor resonances (Q ≈ 390) are produced in the mid-IR as a result of the efficient excitation of collective modes in dimer arrays.

Display Omitted An approach for the fabrication of hybrid nanostructures has been proposed.ZnO flowers have been grown selectively on the top of gold nanopillars.Raman analysis have shown that ZnO presents a wurtzite structure.Such systems could find application in photocatalysis or energy harvesting. We fabricated flower-like shaped ZnO nanorods on the apexes of hollow gold nanopillars by Focused Ion Beam lithography and hydrothermal growth. The hollow nanopillar geometry was defined on a photoresist by ion-beam induced inversion and subsequently metalized. Then the bottom section of the pillars was protected by a second resist coating, exposing only the nanopillar tips for hydrothermal growth of ZnO. The wurtzite crystalline structure of the ZnO nanorods that composes the flowers was confirmed by Raman spectroscopy. Such novel 3D hybrid metal semiconductor nanostructures are promising materials for catalysis and energy harvesting.

The chemical environment of cells is an extremely complex and multifaceted system that includes many types of proteins, lipids, nucleic acids and various other components. With the final aim of studying these components in detail, we have developed multiband plasmonic antennas, which are suitable for highly sensitive surface enhanced Raman spectroscopy (SERS) and are activated by a wide range of excitation wavelengths. The three-dimensional hollow nanoantennas were produced on an optical resist by a secondary electron lithography approach, generated by fast ion-beam milling on the polymer and then covered with silver in order to obtain plasmonic functionalities. The optical properties of these structures have been studied through finite element analysis simulations that demonstrated the presence of broadband absorption and multiband enhancement due to the unusual geometry of the antennas. The enhancement was confirmed by SERS measurements, which showed a large enhancement of the vibrational features both in the case of resonant excitation and out-of-resonance excitation. Such characteristics indicate that these structures are potential candidates for plasmonic enhancers in multifunctional opto-electronic biosensors.

Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation, with an abnormal pulmonary and systemic inflammatory response to tobacco smoking. Systemic inflammation promotes atherosclerosis, to treat the complications of which beta-blockers are paramount. In the COPD setting, however, the use of beta-blockers has been limited by fears that they could adversely affect lung function. However, by controlling adrenergic drive and reducing the heart rate, beta-blockers could reduce the risk of arrhythmias and sudden death among COPD patients. Thus, beta-blocker use is strongly supported by evidence in COPD patients with history of myocardial infarction, but warrants consideration in other cardiovascular comorbidities. Studies specifically designed to ascertain the role of beta-blockers in patients with COPD with cardiovascular conditions are still needed, because the majority of the current evidence is based on retrospective observational studies.

Understanding the interplay among the spectrum of electrophysiological signals in the brain, distributed over broad spatial and temporal scales, is fundamental to decipher how brain circuits operate and might dysfunction in disease. Here, we present a multiscale recording system for simultaneous and synchronous acquisitions from a new generation of im-plantable CMOS active probes (single-shaft, 512 microelectrodes, 25 kHz/electrode full-array sampling) as well as from implantable conventional electrode array probes interfaced with a custom-designed CMOS-based headstage. The platform can manage highresolution recordings from up to 4 differently located probes, and one 36-channels low-resolution passive electrode array. As presented here, and prior to complete in-vivo validation, the design and recording performance of high- and low-density electrode array ICs were experimentally tested ex-vivo on retinal whole-mounts.

The electro-magnetic field generated within and around dissipative nano-structures upon light radiation is intimately associated to the formation of localized heat sources. In turn, this phenomenon determines localized temperature variations, effect which can be exploited for applications such as photocatalysis [1], nanochemistry [2] or sensor devices [3]. Here we show how the geometrical characteristics of plasmonic nano-structures can indeed be used to modulate the temperature response. The idea is that when metallic structures interact with an electromagnetic field they heat up due to Joule effect. The corresponding temperature variation modifies the optical response of the structure [4,5] and thus its heating process. The key finding is that, depending on the structures geometry, absorption efficiency can either increase or decrease with temperature. Since absorption relates to the thermal energy dissipation and thus to temperature increase, the mechanism leads to positive or negative loops. Consequently, not only an error would be made by neglecting the role of temperature, but it would be not even possible to know, a priori, if the error is towards higher or lower absorption values. Our model can be utilized to study opto-thermal phenomena when high temperature or high intensity sources are employed. [1] M. Honda et al., Appl. Phys. Lett. 104, 061108 (2014) [2] G. Baffou et al., Chem. Soc. Rev. 43, 3898 (2014) [3] S. Ozdemir et al., J. Lightwave Tech. 21, 805 (2003) [4] A. Alabastri et al., ACS Photonics 2, 115 (2015) [5] A. Alabastri et al., Materials 6, 4879 (2013)

Dupilumab (REGN668/SAR231893), produced by a collaboration between Regeneron and Sanofi, is a monoclonal antibody currently in phase III for moderate-to-severe asthma. Dupilumab is directed against the α-subunit of the interleukin (IL)-4 receptor and blocks the IL-4 and IL-13 signal transduction. Areas covered: Pathophysiological role of IL-4 and IL-13 in asthma; mechanism of action of dupilumab; pharmacology of IL-4 receptor; phase I and phase II studies with dupilumab; regulatory affairs. Expert opinion: Patients with severe asthma who are not sufficiently controlled with standard-of-care represent the target asthma population for dupilumab. If confirmed, efficacy of dupilumab in both eosinophilic and non-eosinophilic severe asthma phenotype might represent an advantage over approved biologics for asthma, including omalizumab, mepolizumab, and reslizumab. Head-to-head studies to compare dupilumab versus other biologics with different mechanism of action are required. Pediatric studies with dupilumab are currently lacking and should be undertaken to assess efficacy and safety of this drug in children with severe asthma. The lack of preclinical data and published results of the completed four phase I studies precludes a complete assessment of the pharmacological profile of dupilumab. Dupilumab seems to be generally well tolerated, but large studies are required to establish its long-term safety and tolerability.

The cancer stem cell (CSC) model is describing tumors as a hierarchical organized system and CSCs are suggested to be responsible for cancer recurrence after therapy. The identification of specific markers of CSCs is therefore of paramount importance. Here, we show that high levels of lipid droplets (LDs) are a distinctive mark of CSCs in colorectal (CR) cancer. This increased lipid content was clearly revealed by label-free Raman spectroscopy and it directly correlates with well-accepted CR-CSC markers as CD133 and Wnt pathway activity. By xenotransplantation experiments, we have finally demonstrated that CR-CSCs overexpressing LDs retain most tumorigenic potential. A relevant conceptual advance in this work is the demonstration that a cellular organelle, the LD, is a signature of CSCs, in addition to molecular markers. A further functional characterization of LDs could lead soon to design new target therapies against CR-CSCs. Stem Cells 2015;33:35–44

In this work we show the effect of high temperature on the plasmonic properties of metallic nanorods. Within this context, the dielectric function of metal has been modified to keep into account both the electron–electron and electron–phonon temperature dependent scattering mechanisms. In fact, the mentioned damping processes are very sensible to temperature variation. It is found that the damping modifications due to temperature change substantially modify both the near and far field optical response of metallic nanorods. Furthermore, the response alteration can be very different depending on the rod aspect ratio, suggesting the need of accurate investigations when metallic nanostructures are to be employed within high-temperature environments or under high intensity irradiation. In this regard, by taking into account different nanorods aspect ratio and incident powers, we provide detailed calculations showing the error committed in evaluating absorption, scattering efficiencies, and near-field enhanceme...

Chronic obstructive pulmonary disease (COPD) is characterized by large phenotype variability, reflected by a highly variable response to pharmacological treatment. Nevertheless, current guidelines suggest that patients with COPD of similar severity should be treated in the same way. The phenotype-based pharmacotherapeutic approach proposes bronchodilators alone in the nonfrequent exacerbator phenotype and a combination of bronchodilators and inhaled corticosteroids in patients with asthma-COPD overlap syndrome (ACOS) and moderate-to-severe exacerbator phenotype. The clinical importance of phenotypes is changing the paradigm of COPD management from evidence-based to personalized medicine. However, the personalized pharmacological strategy of COPD has to be validated in future clinical studies.

Tailored hydrophobic and oleophobic surfaces are exploited for controlling the wetting behaviour and evaporation process of solution dropped on them. This enables molecules and nano-objects that are dissolved in water or organic solvents to be delivered and arranged in a well-defined 2D layout.

Chronic Obstructive Pulmonary Disease (COPD) is defined as a disease characterized by persistent, progressive airflow limitation. Recent studies have underlined that COPD is correlated to many systemic manifestations, probably due to an underlying pattern of systemic inflammation. In COPD fractional exhaled Nitric Oxide (FeNO) levels are related to smoking habits and disease severity, showing a positive relationship with respiratory functional parameters. Moreover FeNO is increased in patients with COPD exacerbation, compared with stable ones. In alpha-1 antitrypsin deficiency, a possible cause of COPD, FeNO levels may be monitored to early detect a disease progression. FeNO measurements may be useful in clinical setting to identify the level of airway inflammation,per seand in relation to comorbidities, such as pulmonary arterial hypertension and cardiovascular diseases, either in basal conditions or during treatment. Finally, some systemic inflammatory diseases, such as psoriasis, have been associated with higher FeNO levels and potentially with an increased risk of developing COPD. In these systemic inflammatory diseases, FeNO monitoring may be a useful biomarker for early diagnosis of COPD development.

Diacylglycerol kinases (DGKs) play a key role in phosphoinositide signaling by removing diacylglycerol and generating phosphatidic acid. Besides the well-documented role of DGKα and DGKζ as negative regulators of lymphocyte responses, a robust body of literature points to those enzymes, and specifically DGKα, as crucial regulators of leukocyte function. Upon neutrophil stimulation, DGKα activation is necessary for migration and a productive response. The role of DGKα in neutrophils is evidenced by its aberrant behavior in juvenile periodontitis patients, which express an inactive DGKα transcript. Together with in vitro experiments, this suggests that DGKs may represent potential therapeutic targets for disorders where inflammation, and neutrophils in particular, plays a major role. In this paper we focus on obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), but also rare genetic diseases such as alpha-1-antitrypsin deficiency. Indeed, the biological role of DGKα is understudied outside the T lymphocyte field. The recent wave of research aiming to develop novel and specific inhibitors as well as KO mice will allow a better understanding of DGK’s role in neutrophilic inflammation. Better knowledge and pharmacologic tools may also allow DGK to move from the laboratory bench to clinical trials.

Asthma is a chronic airway inflammatory disease associated with airway hyperresponsiveness which affects subjects with genetic predisposition. An association has been reported between some polymorphisms in various cytokine genes and asthma. Most of them are single nucleotide polymorphisms (SNPs). These polymorphisms are detected in the protein coding sequence or in the promoter region thus influencing cytokine production. We investigated the involvement of SNP mapping in 5 cytokine genes in mild to severe asthmatics of Italian Caucasians. The frequency of alleles and genotypes, relatively to 10 allelic specificities of the cytokine genes, was defined in 57 asthmatics and in 124 control subjects by a Polymerase Chain Reaction-Sequence Specific Primer method. TNF-alpha -308A and TNF-alpha -238A allele frequencies were higher in asthmatics than in controls (p less than 0.001). Significant differences in the frequency of IL-4 -590T allele and of IL-4Ralpha +1902A allele were also detected in asthmatics in comparison with controls (pless than 0.001 and p=0.005, respectively). Similarly, IL-1alpha -889C allele was present in 84.1 percent of asthmatics and in 70.2 percent of controls (p=0.013). Furthermore, the IL-4Ralpha +1902A/A and IL-1alpha -889C/C homozygous conditions and the TNF-alpha -308G/A, TNF-alpha -238G/A, IL-4 -590T/C and IL-10 -1082G/A heterozygous conditions were significantly associated with asthma (p less than 0.05). ACA haplotype of IL-10 was observed only in asthmatic patients. This study reports, for the first time, the frequency of 10 different single nucleotide polymorphisms in 5 cytokine genes in the Italian Caucasians. Furthermore, we also indicate that in our population some single nucleotide polymorphisms are associated with mild to severe bronchial asthma.

Metallic nanostructures can be utilized as heat nano-sources which can find application in different areas such as photocatalysis, nanochemistry or sensor devices. Here we show how the optical response of plasmonic structures is affected by the increase of temperature. In particular we apply a temperature dependent dielectric function model to different nanoparticles finding that the optical responses are strongly dependent on shape and aspect-ratio. The idea is that when metallic structures interact with an electromagnetic field they heat up due to Joule effect. The corresponding temperature increase modifies the optical response of the particle and thus the heating process. The key finding is that, depending on the structures geometry, absorption efficiency can either increase or decrease with temperature. Since absorption relates to thermal energy dissipation and thus to temperature increase, the mechanism leads to positive or negative loops. Consequently, not only an error would be made by neglecting temperature but it would be not even possible to know, a priori, if the error is towards higher or lower values.

The optical properties of metallic nano-structures are intimately related to their temperature variation, characteristics which can be exploited for applications such as photocatalysis [1], nanochemistry [2] or sensor devices [3]. Here we show how the geometrical characteristics of the nano-structure, which are related to the structure optical response [4, 5], can in fact be used to modulate the temperature response. The idea is that when metallic structures interact with an electromagnetic field they heat up due to Joule effect. The corresponding temperature increase modifies the optical response of the structure and thus its heating process. The key finding is that, depending on the structures geometry, absorption efficiency can either increase or decrease with temperature. Since absorption relates to the thermal energy dissipation and thus to temperature increase, the mechanism leads to positive or negative loops. Consequently, not only an error would be made by neglecting the role of temperature, but it would be not even possible to know, a priori, if the error is towards higher or lower absorption values. The model, which does not require any fitting parameter, can be utilized to study opto-thermal phenomena when high temperature or high intensity sources are employed.

Background The presence of virus and bacteria in the airways of subjects with asthma is common and seems to be associated with a deterioration due to the disease. The microbiologic study of airways in asthma is foreseen by guidelines with induced sputum that is often ineffective and contraindicated in severe asthma. Aim To analyze the fungal microbiome in the exhaled breath condensate (EBC) of subjects with asthma by evaluating a possible correlation with anthropometric and asthma severity data. Methods We enrolled 47 consecutive subjects with asthma (28 with atopic asthma and 19 with nonatopic asthma) and 20 controls. Enrolled subjects underwent EBC and sputum collection. Fungal microbiome was assessed by culture on EBC and sputum samples by using Czapek yeast extract agar. Results A fungal colonization in the EBC of 70% of enrolled subjects with asthma was detected (none detected in the controls). An overlap of fungal microbiome in EBC and sputum was observed (100% of overlap). Fungal colonization was higher in subjects without atopic, obesity, and severe and uncontrolled asthma. Conclusion When considering the high morbidity and mortality of patients with severe asthma in whom we found an important fungal airways colonization, we support the use of the analysis of exhaled fungal microbiome in these subjects.

Background Severe asthma might be associated with overexpression of T h 17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways. Objective To study IL-17–related cytokines in nasal/bronchial biopsies from controls and mild asthmatics (MAs) to severe asthmatics (SAs) in relation to exacerbation rate. Methods Inflammatory cells and IL-17A + , IL-17F + , IL-21 + , IL-22 + , and IL-23 + cells were examined by immunohistochemistry in cryostat sections of bronchial/nasal biopsies obtained from 33 SAs (21 frequent exacerbators [FEs]), 31 MAs (3 FEs), and 14 controls. IL-17F protein was also measured by ELISA in bronchial/nasal lysates and by immunohistochemistry in bronchial tissue obtained from subjects who died because of fatal asthma. Immunofluorescence/confocal microscopy was used for IL-17F colocalization. Results Higher number ( P + , IL-17F + , and IL-21 + cells in bronchial biopsies and higher numbers ( P + and IL-21 + cells in nasal biopsies were observed in SAs compared with MAs. Bronchial IL-17F + cells correlated with bronchial neutrophils ( r = 0.54), exacerbation rate ( r = 0.41), and FEV 1 ( r = −0.46). Nasal IL-17F + cells correlated with bronchial IL-17F ( r = 0.35), exacerbation rate ( r = 0.47), and FEV 1 ( r = −0.61). FEs showed increased number of bronchial neutrophils/eosinophils/CD4 + /CD8 + cells and bronchial/nasal IL-17F + cells. Receiver operating characteristic curve analysis evidenced predictive cutoff values of bronchial neutrophils and nasal/bronchial IL-17F for discriminating between asthmatics and controls, between MAs and SAs and between FEs and non-FEs. IL-17F protein increased in bronchial/nasal lysates of SAs and FEs and in bronchial tissue of fatal asthma. IL-17F colocalized in CD4 + /CD8 + cells. Conclusions IL-17–related cytokines expression was amplified in bronchial/nasal mucosa of neutrophilic asthma prone to exacerbation, suggesting a pathogenic role of IL-17F in FEs.

Objective Platelet activation in COPD patients is associated with an increased risk of cardiovascular events. We aimed at assessing the mean platelet volume (MPV), as an index of platelet activation, in COPD patients both when stable or during acute exacerbation (AE). Research design and methods A total of 478 patients (75 with AE) and 72 age-matched healthy controls were enrolled. Medical history, comorbidities, medications, pulmonary function tests, MPV and blood cell count, erythrocyte sedimentation rate (ERS) and C-reactive protein (CRP) were recorded. Results MPV was higher in COPD than in controls (8.7 ± 1.1 fL and 8.4 ± 0.8 fL respectively, p = 0.025) and increased with the severity of the disease as assessed by post-bronchodilator forced expiratory volume in the first second (FEV1) categorized I to IV (p > 0.05). MPV was higher in COPD patients during AE compared with stable condition (8.7 ± 1.0 fL and 8.9 ± 1.0 fL, p = 0.021). MPV ≥10.5 fL correlated with the presence of at least one co-existing cardiovascular disease (p = 0.008). No correlation was observed between MPV and CRP or ERS in patients or in controls. A negative correlation was found between platelet count and MPV in COPD patients. Limitations The retrospective design did not allow the assessment of a clear cause-effect relationship between MPV and all the pathophysiological factors considered. Conclusions Elevated MPV is associated with lower platelet count and with cardiovascular comorbidity in COPD patients. MPV is higher in more severe COPD and during AE. Present findings warrant future studies to confirm a possible clinically relevant role for platelet activation in cardiovascular risk in the COPD population.

Ageing population is constantly increasing due to rising life expectancy; consequently, the percentage of the elderly patients with asthma is increasing, as well. Fractional exhaled nitric oxide (FeNO) is a biomarker of lung inflammation, and currently it is widely used in clinical practice for asthma diagnosis and monitoring. Yet, there are no data about normal values of FeNO in patients of more than 65 years of age with normal lung function. The aim of this study was to establish adult FeNO reference values for subjects older than 65 years, according to the international guidelines. FeNO was measured in 303 healthy, nonsmoking adults more than 65 years of age, with normal spirometry values measured using the online single-breath technique. The results were analyzed by chemiluminescent detection. The FeNO levels obtained range from 5.00 to 29.9 ppb, with a mean value of 12.48 ± 2.80 ppb. A significant association of FeNO levels with age (p

Background: Forced expiratory flow at 25 and 75% of the pulmonary volume (FEF25-75%) might be considered as a marker of early airway obstruction. FEF25-75% impairment might suggest earlier asthma recognition in symptomatic subjects even in the absence of other abnormal spirometry values. Objectives: The study was designed in order to verify whether FEF25-75% impairment in a cohort of subjects with asthma-like symptoms could be associated with the risk of bronchial hyperresponsiveness (BHR) and with airway inflammation expressed as fractional exhaled nitric oxide (FeNO) and eosinophil counts in induced sputum. Methods: Four hundred adults with a history of asthma-like symptoms (10.5% allergic) underwent spirometry, determination of BHR to methacholine (PD20FEV1), FeNO analysis and sputum induction. FEF25-75% Results: All subjects had normal FVC, FEV1 and FEV1/FVC, while FEF25-75% was abnormal in 27.5% of them. FEF25-75% (z-score) was associated with PD20FEV1 (p < 0.001), FeNO (p < 0.001) and sputum eosinophils (p < 0.001). Patients with abnormal FEF25-75% showed higher levels of FeNO and eosinophils in induced sputum than did patients with normal FEF25-75% (p < 0.01 and p < 0.01, respectively). Subjects with abnormal FEF25-75% had an increased probability of being BHR positive (OR = 13.38; 95% CI: 6.7-26.7; p < 0.001). Conclusions: Our data show that abnormal FEF25-75% might be considered an early marker of airflow limitation associated with eosinophilic inflammation and BHR in subjects with asthma-like symptoms, indicating a role for FEF25-75% as a predictive marker of newly diagnosed asthma.

High aspect ratio metal nanostructures have been the subject of a number of studies in the past, due to their pronounced resonances in the infrared that can be exploited to enhance vibrational spectroscopies. In this work, we investigate the nonlinear optical response of both individual and closely-packed assemblies of vertical hollow Ag nanopillars upon excitation with ultrafast laser pulses. In particular, the analysis of their nonlinear emission spectra evidences an intense two photon photoluminescence (TPPL) emission and a neat signature of second harmonic generation (SHG). Given the relatively low background, this pronounced nonlinear emission could be employed as a local probe for analytes trapped at the surface of the nanopillar or flowing through it. For this reason, these nanostructures may become appealing building blocks in multi-purpose devices for nonlinear photonics and sensing.

Although historically considered a neglected disease, bronchiectasis has become a disease of renewed interest over recent decades in light of an increase in prevalence and a substantial burden on healthcare systems. In 2010, the British Thoracic Society (BTS) published guidelines on the management of bronchiectasis in adults, along with specific quality standards. To date, these represent the only quality standards available in Europe. These have been tested over a number of years in the UK with progressive improvements in the standard of care. No national guidelines are available in Italy and no indications on which guideline should be followed have been given by the Italian Society of Respiratory Medicine (SIP). There are limited published data on the quality of bronchiectasis care in Europe outside of the UK. The BTS standards have not been tested in continental Europe or in Italy, where information on characteristics and management of bronchiectasis patients are lacking.

Various nanoplasmonic devices were fabricated using top-down method such as electron beam lithography, electroplating and focused ion beam techniques. These substrates were investigated after depositing the molecules from dye to protein, using chemisorptions techniques. Theoretical simulations were also performed on these model nanostructures in order to understand the electrical field distribution. Furthermore, the future prospects of these nanostructures were also mentioned in this report. Various nanoplasmonic devices can be fabricated using top-down methods such as electron beam lithography, electroplating and focused ion beam techniques. The substrates can be investigated after depositing the molecules from the dye to the protein, using chemisorptions techniques. Theoretical simulations are presented on these model nanostructures in order to understand the electrical field distribution.

In this paper we present numerical FDTD calculations, optimizing experimental setup conditions for surface plasmon polariton (SPP) generation. The simulation considers a silver nanocone placed on a Si"3N"4 membrane, and studies the effects on the apex for a linearly polarized Gaussian light beam impinging from below or from the side of the cone. Radially polarized focused beams already proved to generate efficiently SPPs; in this work, we show that also linear polarization leads to an efficient generation of SPPs on the cone surface, as long as tilt angle and numeric aperture are optimized. In particular, we show that our setup conditions and proposed device, designed for a @l=633nm linearly polarized He-Ne laser, can enhance the incoming electric field up to 150 times at the apex of the cone.

Crohn's Disease is an inflammatory bowel disease associated with a variety of systemic manifestations, including large and small airway involvement. The latter is most often a subclinical one, and requires expensive and invasive diagnostic approaches. Nitric Oxide (NO) can be detected non-invasively in the exhaled air (eNO) and be considered as a surrogate marker of airway inflammation. eNO tested at multiple expiratory flows can be used to distinguish the alveolar concentration of NO (CalvNO) from the total amount of fractional eNO (FeNO). The aim of our study is to compare FeNO and concentration of alveolar nitric oxide (CalvNO) levels and to assess their relationship with pulmonary involvement in Crohn's patients differing in clinical stage and therapeutic regimens versus a group of healthy subjects. Thirty Crohn's patients not showing clinical evidence of pulmonary diseases and 21 non-smoking, non-atopic healthy controls were enrolled. FeNO (14.9±10.2 ppb vs 10.1±6.3 ppb, p=0.049) and CaIvNO (4.4±2.2 ppb vs 2.6±1.9; p=0.006) values were found to be significantly higher in Crohn's patients than in healthy controls. Both FeNO and CaIvNO correlated positively with the Crohn's Disease Activity Index. In conclusion, our results for FeNO and CaIvNO confirm the presence of subclinical pulmonary involvement in Crohn's disease. eNO measurement may be of clinical value in the follow-up of Crohn's patients.