NMR-Based Metabolomics for the Assessment of Inhaled Pharmacotherapy in Chronic Obstructive Pulmonary Disease Patients.

The aim of this proof-of-concept, pilot study was the evaluation of the effects of steroid administration and suspension of an inhaled corticosteroid (ICS)-long-acting ß2-agonist (LABA) extrafine fixed dose combination (FDC) on metabolomic fingerprints in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that a comprehensive metabolomics approach discriminates across inhaled pharmacotherapies and that their effects on metabolomic signatures depend on the biological fluids analyzed. We performed metabolomics via nuclear magnetic resonance (NMR) spectroscopy in exhaled breath condensate (EBC), sputum supernatants, serum, and urine. Fourteen patients suffering from COPD who were on regular inhaled fluticasone propionate/salmeterol therapy (visit 1) were consecutively treated with 2-week beclomethasone dipropionate/formoterol (visit 2), 4-week formoterol alone (visit 3), and 4-week beclomethasone/formoterol (visit 4). The comprehensive NMR-based metabolomics approach showed differences across all pharmacotherapies and that different biofluids provided orthogonal information. Serum formate was lower at visits 1 versus 3 (P = 0.03), EBC formate was higher at visit 1 versus 4 (P = 0.03), and urinary 1-methyl-nicotinamide was lower at 3 versus 4 visit (P = 0.002). NMR-based metabolomics of different biofluids distinguishes across inhaled pharmacotherapies, provides complementary information on the effects of an extrafine ICS/LABA FDC on metabolic fingerprints in COPD patients, and might be useful for elucidating the ICS mechanism of action.

Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen.

OBJECTIVE: To evaluate the effects of nusinersen on respiratory function of patients with type 1 spinal muscular atrophy. STUDY DESIGN: Observational, longitudinal cohort study. We collected respiratory data from 118 children with type 1 spinal muscular atrophy and differing pulmonary requirements and conducted a semistructured qualitative interview among a subsample of caregivers at baseline, 6 months, and 10 months after the first nusinersen treatment. Patients were stratified according to ventilation modalities and age at study entry. RESULTS: Most patients in our cohort remained stable (84/109 = 77%). More than 80% of the children treated before age 2 years survived, in contrast to the lower survival reported in natural history studies, and did so without tracheostomy or noninvasive ventilation (NIV) ≥16 hours. In those less than 2 years old, only 3 patients shifted from NIV ≤10 hours to NIV >10 hours, and the other 3 reduced the hours of NIV required. Most of the older patients remained stable; this included not only those on tracheostomy or NIV >10 hours but also 75% of those on NIV ≤10 hours. CONCLUSIONS: Our results suggest that nusinersen may produce some improvement in the progression of respiratory impairment, both in terms of survival and need for respiratory support ≥16 hours, especially before the age of 2 years.

Brain regions and functional interactions supporting early word recognition in the face of input variability.

Perception and cognition in infants have been traditionally investigated using habituation paradigms, assuming that babies' memories in laboratory contexts are best constructed after numerous repetitions of the very same stimulus in the absence of interference. A crucial, yet open, question regards how babies deal with stimuli experienced in a fashion similar to everyday learning situations-namely, in the presence of interfering stimuli. To address this question, we used functional near-infrared spectroscopy to test 40 healthy newborns on their ability to encode words presented in concomitance with other words. The results evidenced a habituation-like hemodynamic response during encoding in the left-frontal region, which was associated with a progressive decrement of the functional connections between this region and the left-temporal, right-temporal, and right-parietal regions. In a recognition test phase, a characteristic neural signature of recognition recruited first the right-frontal region and subsequently the right-parietal ones. Connections originating from the right-temporal regions to these areas emerged when newborns listened to the familiar word in the test phase. These findings suggest a neural specialization at birth characterized by the lateralization of memory functions: the interplay between temporal and left-frontal regions during encoding and between temporo-parietal and right-frontal regions during recognition of speech sounds. Most critically, the results show that newborns are capable of retaining the sound of specific words despite hearing other stimuli during encoding. Thus, habituation designs that include various items may be as effective for studying early memory as repeated presentation of a single word.

Newborns are sensitive to multiple cues for word segmentation in continuous speech.

Before infants can learn words, they must identify those words in continuous speech. Yet, the speech signal lacks obvious boundary markers, which poses a potential problem for language acquisition (Swingley, Philos Trans R Soc Lond. Series B, Biol Sci 364(1536), 3617-3632, 2009). By the middle of the first year, infants seem to have solved this problem (Bergelson & Swingley, Proc Natl Acad Sci 109(9), 3253-3258, 2012; Jusczyk & Aslin, Cogn Psychol 29, 1-23, 1995), but it is unknown if segmentation abilities are present from birth, or if they only emerge after sufficient language exposure and/or brain maturation. Here, in two independent experiments, we looked at two cues known to be crucial for the segmentation of human speech: the computation of statistical co-occurrences between syllables and the use of the language's prosody. After a brief familiarization of about 3 min with continuous speech, using functional near-infrared spectroscopy, neonates showed differential brain responses on a recognition test to words that violated either the statistical (Experiment 1) or prosodic (Experiment 2) boundaries of the familiarization, compared to words that conformed to those boundaries. Importantly, word recognition in Experiment 2 occurred even in the absence of prosodic information at test, meaning that newborns encoded the phonological content independently of its prosody. These data indicate that humans are born with operational language processing and memory capacities and can use at least two types of cues to segment otherwise continuous speech, a key first step in language acquisition.

On the edge of language acquisition: inherent constraints on encoding multisyllabic sequences in the neonate brain.

To understand language, humans must encode information from rapid, sequential streams of syllables - tracking their order and organizing them into words, phrases, and sentences. We used Near-Infrared Spectroscopy (NIRS) to determine whether human neonates are born with the capacity to track the positions of syllables in multisyllabic sequences. After familiarization with a six-syllable sequence, the neonate brain responded to the change (as shown by an increase in oxy-hemoglobin) when the two edge syllables switched positions but not when two middle syllables switched positions (Experiment 1), indicating that they encoded the syllables at the edges of sequences better than those in the middle. Moreover, when a 25 ms pause was inserted between the middle syllables as a segmentation cue, neonates' brains were sensitive to the change (Experiment 2), indicating that subtle cues in speech can signal a boundary, with enhanced encoding of the syllables located at the edges of that boundary. These findings suggest that neonates' brains can encode information from multisyllabic sequences and that this encoding is constrained. Moreover, subtle segmentation cues in a sequence of syllables provide a mechanism with which to accurately encode positional information from longer sequences. Tracking the order of syllables is necessary to understand language and our results suggest that the foundations for this encoding are present at birth.

Newborn's brain activity signals the origin of word memories.

Recent research has shown that specific areas of the human brain are activated by speech from the time of birth. However, it is currently unknown whether newborns' brains also encode and remember the sounds of words when processing speech. The present study investigates the type of information that newborns retain when they hear words and the brain structures that support word-sound recognition. Forty-four healthy newborns were tested with the functional near-infrared spectroscopy method to establish their ability to memorize the sound of a word and distinguish it from a phonetically similar one, 2 min after encoding. Right frontal regions--comparable to those activated in adults during retrieval of verbal material--showed a characteristic neural signature of recognition when newborns listened to a test word that had the same vowel of a previously heard word. In contrast, a characteristic novelty response was found when a test word had different vowels than the familiar word, despite having the same consonants. These results indicate that the information carried by vowels is better recognized by newborns than the information carried by consonants. Moreover, these data suggest that right frontal areas may support the recognition of speech sequences from the very first stages of language acquisition.

TRITRIAL: The Impact of Fixed Triple Therapy with Beclometasone/Formoterol/Glycopyrronium on Health Status and Adherence in Chronic Obstructive Pulmonary Disease in an Italian Context of Real Life.

Purpose: The TRITRIAL study assessed the effects of beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) fixed combination in patients with chronic obstructive pulmonary disease (COPD) in a real-world setting, focusing on patient's experience and perspective through the use of patients reported outcomes. Patients and Methods: TRITRIAL was a multicenter, prospective, observational study conducted on patients with moderate-severe COPD treated with BDP/FF/G fixed therapy for 12 months. The main objective was to evaluate the impact of BDP/FF/G on health status through the COPD Assessment Test (CAT) score. Additional assessments included adherence and satisfaction, measured by the TAI-10/12 questionnaire and a specifically designed eight-item questionnaire, quality of life through the EQ-5D-5L test, sleep quality through the COPD and Asthma Sleep Impact Scale (CASIS), as well as safety and disease-related outcomes. Results: Data from 655 patients were analyzed in the study. The mean total CAT score significantly improved (from 22.8 at baseline to 18.1 at 6 months and 16.5 at 12 months; p < 0.0001), as well as all the eight CAT sub-items, which decreased on average by 0.5-0.9 points during the study. Adherence and usability of the inhaler also improved during the study, with a decrease in poor compliance (from 30.1% to 18.3%) and an increase in good compliance (from 51.8% to 58.3%) according to the TAI score. Patients also benefited from significantly improved quality of life (EQ Index from 0.70 to 0.80; EQ-5D VAS score from 55.1 to 63.1) and sleep quality (CASIS score from 41.1 to 31.8). Finally, patients reported a significant reduction in exacerbation during the study. Conclusion: TRITRIAL showed that the BDP/FF/G fixed combination is effective and safe in patients with moderate-severe COPD and poorly controlled disease, improving patients' HRQoL, sleep quality, adherence and inhaler usability and reducing COPD symptoms and the risk of exacerbation in a real-life setting.

Cause-specific mortality of very preterm infants and antenatal events.

OBJECTIVE: To assess the relationship between antenatal factors and cause-specific risk of death in a large area-based cohort of very preterm infants. STUDY DESIGN: The ACTION (Accesso alle Cure e Terapie Intensive Ostetriche e Neonatali) study recruited during an 18-month period all infants 22-31 weeks' gestational age admitted to neonatal care in 6 Italian regions (n=3040). We analyzed the data of 2974 babies without lethal or acutely life-threatening malformations. Cause-specific risks of death adjusted for competing causes were calculated, and region-stratified multiple Cox regression analyses were used to study the association between cause-specific mortality and infants' characteristics, pregnancy complications, antenatal steroids, and place of birth. RESULTS: Deaths attributable to respiratory problems and intraventricular hemorrhage prevailed in the first 2 weeks of life, and those attributable to infections and gastrointestinal diseases afterwards. Antepartum hemorrhage was associated with respiratory deaths (hazard ratio [HR] 1.6, 95% CI 1.1-2.4), and maternal infection with deaths attributable to asphyxia (HR 32.5, 95% CI 4.1-259.4) and to respiratory problems (HR 2.8, 95% CI 1.6-5.2). Preterm premature rupture of membranes increased the likelihood of deaths due to neonatal infection (HR 1.8, 95% CI 1.0-3.1), and preterm labor/contractions of those due to respiratory (HR 1.5, 95% CI 1.1-2.0) and gastrointestinal diseases (HR 5.8, 95% CI 2.1-16.3). In addition, a birth weight z-score<-1 was associated with increasing hazards of death resulting from asphyxia, late infections, respiratory, and gastrointestinal diseases. CONCLUSIONS: Different complications of pregnancy lead to different cause-specific mortality patterns in very preterm infants.

Pregnancy disorders leading to very preterm birth influence neonatal outcomes: results of the population-based ACTION cohort study.

BACKGROUND: We examined the relationships between -pregnancy disorders leading to very preterm birth -(spontaneous preterm labor, prelabor premature rupture of -membranes (PPROM), hypertension/preeclampsia, -intrauterine growth restriction (IUGR), antenatal hemorrhage, and maternal -infection), both in isolation and grouped together as -"disorders of placentation" (hypertensive disorders and IUGR) vs. -"presumed infection/inflammation" (all the others), and several unfavorable neonatal outcomes. METHODS: We examined a population-based prospective cohort of 2,085 singleton infants of 23-31 wk gestational age (GA) born in six Italian regions (the Accesso alle Cure e Terapie Intensive Ostetriche e Neonatali (ACTION) study). RESULTS: Neonates born following disorders of placentation had a higher GA and better overall outcomes than those born following infection/inflammation. After adjustment for GA, however, they showed higher risk of mortality (odds ratio, OR: 1.4; 95% confidence interval, CI: 1.0-2.0), bronchopulmonary dysplasia (BPD) (OR: 2.5; CI: 1.8-3.6), and retinopathy of prematurity (ROP) (OR: 2.0; CI: 1.1-3.5), especially in growth-restricted infants, and a lower risk of intraventricular hemorrhage (IVH) (OR: 0.5; CI: 0.3-0.8) and periventricular leukomalacia (PVL) (OR: 0.6; CI: 0.4-1.1) as compared with infants born following -infection/inflammation disorders. CONCLUSION: Our data confirm the hypothesis that, in very preterm infants, adverse outcomes are both a function of immaturity (low GA) and of complications leading to preterm birth. The profile of risk is different in different pregnancy disorders.

The neonate brain detects speech structure.

What are the origins of the efficient language learning abilities that allow humans to acquire their mother tongue in just a few years very early in life? Although previous studies have identified different mechanisms underlying the acquisition of auditory and speech patterns in older infants and adults, the earliest sensitivities remain unexplored. To address this issue, we investigated the ability of newborns to learn simple repetition-based structures in two optical brain-imaging experiments. In the first experiment, 22 neonates listened to syllable sequences containing immediate repetitions (ABB; e.g., "mubaba," "penana"), intermixed with random control sequences (ABC; e.g., "mubage," "penaku"). We found increased responses to the repetition sequences in the temporal and left frontal areas, indicating that the newborn brain differentiated the two patterns. The repetition sequences evoked greater activation than the random sequences during the first few trials, suggesting the presence of an automatic perceptual mechanism to detect repetitions. In addition, over the subsequent trials, activation increased further in response to the repetition sequences but not in response to the random sequences, indicating that recognition of the ABB pattern was enhanced by repeated exposure. In the second experiment, in which nonadjacent repetitions (ABA; e.g., "bamuba," "napena") were contrasted with the same random controls, no discrimination was observed. These findings suggest that newborns are sensitive to certain input configurations in the auditory domain, a perceptual ability that might facilitate later language development.

The Impact of Fixed Triple Therapy with Beclometasone/Formoterol/Glycopyrronium on Health Status and Adherence in Chronic Obstructive Pulmonary Disease (COPD) in an Italian Context of Real Life: The TRITRIAL Study Protocol.

BACKGROUND: The fixed triple combination Beclometasone dipropionate/Formoterol fumarate/Glycopyrronium (BDP/FF/G, Trimbow®), an extrafine formulation in a unique pressurized metered dose inhaler, is indicated for the maintenance treatment in adult patients with moderate to severe COPD, not adequately treated by ICS/LABA or LABA/LAMA. Besides the evidence from three randomized controlled trials, the impact of fixed triple therapy has not been extensively evaluated in a real-world population of COPD patients. TRITRIAL (TRIple Therapy in Real life: Impact on Adherence and HeaLth status) is a non-interventional study to assess the effect of BDP/FF/G in a real world setting in Italy. DESIGN: TRITRIAL is a 12-month, multicenter, cohort, prospective, longitudinal observational study. Two follow-up visits will be performed at 6 and 12 months, respectively. The study includes the collection of anamnestic clinical and functional data before the start of BDP/FF/G. The study is built for digital conduction, from signature of the informed consent on a dedicated web platform, to the collection of questionnaires and clinical data on the eCRF. POPULATION: A total of 800 patients with COPD ranging from Global Initiative for Obstructive Lung Disease (GOLD) stages 2 to 4, receiving therapy with BDP/FF/G according to the Summary of Product Characteristics and local clinical practice, will be recruited. All concomitant therapies will be permitted for the duration of the study. EVALUATIONS: The primary endpoint is the change of CAT score at 12 months versus baseline. Secondary endpoints are adherence, health-related quality of life, sleep quality, disease-related outcomes (lung function and COPD exacerbations), device usability, economic resources consumption, and safety. CONCLUSION: TRITRIAL study is expected to give relevant information about effectiveness of BDP/FF/G fixed triple therapy in a real-life setting of patients with COPD, where adherence, usability of inhalers and patient's preference of the device are crucial factors for the success of the therapy.

Obstructive sleep apnea in sarcoidosis and impact of cpap treatment on fatigue.

RATIONALE: An increased incidence of Obstructive Sleep Apnea (OSA) in sarcoidosis has been described in small sample size studies. Fatigue is common in sarcoidosis and OSA could be a relevant, treatable comorbidity. To date, the effect of Continuous Positive Airway Pressure (CPAP) on fatigue has never been assessed. OBJECTIVES: To investigate the prevalence of OSA in sarcoidosis, fatigue status and daytime sleepiness in patients of our center. To explore the effect of CPAP in fatigue and daytime sleepiness after 3 months using validated questionnaires. METHOD: Single group, one center, open-label prospective cohort study. MEASUREMENTS AND MAIN RESULT: We enrolled 68 patients and OSA was diagnosed in 60 (88.2%): 25 (36.8%) were mild while 35 (51.5%) were moderate-to-severe. 38 (55.9%) patients received CPAP but only 20 (30.9%) were compliant at 3-month evaluation. Questionnaires demonstrated fatigue in 34 (50%) and daytime sleepiness in 21 (30.9%). In multivariate regression analysis, Scadding stage and FAS behave as predictors of Apnea-Hypopnea Index (AHI) severity while sleepiness and steroids weren't associated. FAS score (ΔFAS = 6.3; p = 0.001) and ESS score (ΔESS = 2.8; p = 0.005) improved after three months of CPAP. CONCLUSIONS: OSA is highly prevalent in patients affected by sarcoidosis. ESS questionnaire is not reliable for OSA screening and other pre-test probability tool should be evaluated in further studies. CPAP leads to a significative reduction of fatigue and daytime sleepiness at three-month. Further studies are needed to confirm the high prevalence of OSA in sarcoidosis and the positive role of CPAP in fatigue. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 169-178).

Current and Future Idiopathic Pulmonary Fibrosis Therapy.

The last years have led to advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF), mainly through the discovery of new pathological pathways and drugs and better design of clinical trials. The objective of this review is both to describe the current therapies approved for the treatment of IPF and the emerging therapeutic approaches. Currently, nintedanib and pirfenidone are the basis of IPF therapy, based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease progression. Nonetheless, the ideal IPF therapy is still lacking and trials are underway to test new therapeutic targets. The near future could bring to clinicians and patients a combined therapeutic strategy, hitting the disease from several simultaneous pathways and hopefully leading to clinical stabilization or improvement.

Breathomics for Assessing the Effects of Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With COPD.

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting ß2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics. Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 µg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 µg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 µg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 µg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured. Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25-75% and FEV1/FVC (P = 0.008-0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01). Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.

New treatment directions for IPF: current status of ongoing and upcoming clinical trials.

INTRODUCTION: The main objective of this review is to explore the wide and expanding field of new clinical trials in IPF. Recent trials have confirmed the efficacy of the approved drugs pirfenidone and nintedanib; nonetheless, the discovery of new biological pathways has opened new horizons in this field. Areas covered: New strategies against matrix deposition are under study and so is for the role of immunity and autoimmunity. Recent advances in the use of stem cells are opening new possibilities for the recovery of damaged lung tissues. The role of microbioma is under investigation in order to evaluate the use of antibiotics in IPF treatment. Analysing all the new and the upcoming clinical trials, we are trying to offer a comprehensive view of the emerging new frontiers in the treatment of IPF. Expert commentary: The key points for the ongoing and upcoming clinical trials will be to avoid previous mistakes and to choose carefully both study populations and efficacy endpoints. The exciting possibility to enrol patients with progressive lung fibrosis, both idiopathic and not, could be a next step forward. How the existing therapies will fit in a futurist scenario of personalized medicine is still a challenge.

Investigational drugs for idiopathic pulmonary fibrosis.

INTRODUCTION: IPF is a specific form of chronic fibrosing interstitial pneumonia of unknown cause, characterized by progressive worsening in lung function and an unfavorable prognosis. Current concepts on IPF pathogenesis are based on a dysregulated wound healing response, leading to an over production of extracellular matrix. Based on recent research however, several other mechanisms are now proposed as potential targets for novel therapeutic strategies. Areas covered: This review analyzes the current investigational strategies targeting extracellular matrix deposition, tyrosine-kinase antagonism, immune and autoimmune response, and cell-based therapy. A description of the pathogenic rationale implied in each novel therapeutic approach is summarized. Expert opinion: New IPF drugs are being evaluated in the context of phase 1 and 2 clinical trials. Nevertheless, many drugs that have shown efficacy in preclinical studies, failed to exhibit the same positive effect when translated to humans. A possible explanation for these failures might be related to the known limitations of animal models of the disease. The recent development of 3D systems composed of cells from individual patients that recreate an ex-vivo model of IPF, could lead to significant improvements in disease pathogenesis and treatment. New drugs could be tested on more genuine models and clinicians could tailor therapy based on patient's response.

In vivo measure of neonate brain optical properties and hemodynamic parameters by time-domain near-infrared spectroscopy.

By exploiting a multichannel portable instrument for time-domain near-infrared spectroscopy (TD-NIRS), we characterized healthy neonates' brains in term of optical properties and hemodynamic parameters. In particular, we assessed the absolute values of the absorption and reduced scattering coefficients at two wavelengths, together with oxy-, deoxy- and total hemoglobin concentrations, and the blood oxygen saturation of the neonates' brains. In this study, 33 healthy full-term neonates were tested, obtaining the following median values: 0.28 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; 5.8 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; 72% for [Formula: see text]. In general, the agreement of these values with the sparse existing literature appears not always consistent. These findings demonstrate the first measurements of optical properties of the healthy neonate brain using TD-NIRS and show the need for clarification of optical properties across methods and populations.

Electronic Nose and Exhaled Breath NMR-based Metabolomics Applications in Airways Disease.

Breathomics, the multidimensional molecular analysis of exhaled breath, includes analysis of exhaled breath with gas-chromatography/mass spectrometry (GC/MS) and electronic noses (e-noses), and metabolomics of exhaled breath condensate (EBC), a non-invasive technique which provides information on the composition of airway lining fluid, generally by high-resolution nuclear magnetic resonance (NMR) spectroscopy or MS methods. Metabolomics is the identification and quantification of small molecular weight metabolites in a biofluid. Specific profiles of volatile compounds in exhaled breath and metabolites in EBC (breathprints) are potentially useful surrogate markers of inflammatory respiratory diseases. Electronic noses (e-noses) are artificial sensor systems, usually consisting of chemical cross-reactive sensor arrays for characterization of patterns of breath volatile compounds, and algorithms for breathprints classification. E-noses are handheld, portable, and provide real-time data. E-nose breathprints can reflect respiratory inflammation. E-noses and NMR-based metabolomics of EBC can distinguish patients with respiratory diseases such as asthma, COPD, and lung cancer, or diseases with a clinically relevant respiratory component including cystic fibrosis and primary ciliary dyskinesia, and healthy individuals. Breathomics has also been reported to identify patients affected by different types of respiratory diseases. Patterns of breath volatile compounds detected by e-nose and EBC metabolic profiles have been associated with asthma phenotypes. In combination with other -omics platforms, breathomics might provide a molecular approach to respiratory disease phenotyping and a molecular basis to tailored pharmacotherapeutic strategies. Breathomics might also contribute to identify new surrogate markers of respiratory inflammation, thus, facilitating drug discovery. Validation in newly recruited, prospective independent cohorts is essential for development of e-nose and EBC NMRbased metabolomics techniques.

Liquid chromatography-mass spectrometry measurement of leukotrienes in asthma and other respiratory diseases.

Leukotrienes (LTs), including cysteinyl-LTs (LTC4, LTD4 and LTE4) and LTB4, are potent inflammatory lipid mediators which have been involved in the pathophysiology of respiratory diseases. LC-MS/MS techniques for measuring LT concentrations in sputum supernatants, serum, urine and exhaled breath condensate (EBC) have been developed. In asthmatic adults, reported LTB4 and LTE4 concentrations in sputum range from 79 to 7,220 pg/ml and from 11.9 to 891 pg/ml, respectively. Data on sputum LT concentrations in healthy subjects are not available. In EBC, reported LTE4 concentrations range from 38 to 126 pg/ml (95% CI) in adult asthma patients and from 34 to 48 pg/ml in healthy subjects. LTB4 concentrations in EBC range from 175 to 315 pg/ml (interquartile range) in asthmatic children, and from 25 to 245 pg/ml in healthy children. Enabling an accurate quantitative assessment of LTs in biological fluids, LC-MS/MS techniques provide a valuable tool for exploring the pathophysiological role of LTs in respiratory disease and might be useful for assessing the effects of therapeutic intervention. This review presents the analytical aspects of the LC-MS/MS techniques for measuring LT concentrations in biological fluids and discusses their potential utility for the assessment of airway inflammation and monitoring of pharmacological treatment in patients with asthma phenotypes and other respiratory diseases.