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BACKGROUND: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS: We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS: Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS: Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.

Endothelial hemoglobin (Hb)α regulates endothelial nitric oxide synthase (eNOS) biochemistry. We hypothesized that Hb could also be expressed and biochemically active in the ciliated human airway epithelium. Primary human airway epithelial cells, cultured at air–liquid interface (ALI), were obtained by clinical airway brushings or from explanted lungs. Human airway Hb mRNA data were from publically available databases; or from RT-PCR. Hb proteins were identified by immunoprecipitation, immunoblot, immunohistochemistry, immunofluorescence and liquid chromatography- mass spectrometry. Viral vectors were used to alter Hbβ expression. Heme and nitrogen oxides were measured colorimetrically. Hb mRNA was expressed in human ciliated epithelial cells. Heme proteins (Hbα, β, and δ) were detected in ALI cultures by several methods. Higher levels of airway epithelial Hbβ gene expression were associated with lower FEV1 in asthma. Both Hbβ knockdown and overexpression affected cell morphology. Hbβ and eNOS were apically colocalized. Binding heme with CO decreased extracellular accumulation of nitrogen oxides. Human airway epithelial cells express Hb. Higher levels of Hbβ gene expression were associated with airflow obstruction. Hbβ and eNOS were colocalized in ciliated cells, and heme affected oxidation of the NOS product. Epithelial Hb expression may be relevant to human airways diseases.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 infection, has led to a pandemic of acute respiratory illness. Pharmacologic treatments for COVID-19 have included treatments that target infection prevention, prevention of viral replication, reduce inflammation, and manage symptoms of respiratory failure caused by the disease. This is a review of key pharmacologic treatments for COVID-19 based on peer-reviewed articles from 2020.

Despite early diagnosis of cystic fibrosis (CF) through newborn screening, a substantial proportion of infants and young children with CF still demonstrate physiologic and structural evidence of lung disease progression, such as obstructive airway disease and bronchiectasis. The growing availability of highly effective CF transmembrane conductance regulatory modulator therapy to the vast majority of people with CF has led to the potential to alter the natural history of CF lung disease, but to assess the full impact of these therapies on CF lung disease and to help guide treatment, sensitive measures of early and mild disease are needed. Chest imaging using computed tomography or magnetic resonance imaging is one approach, but technologic barriers and/or concern about exposure to ionizing radiation may limit its use. However, advances in physiologic measurement techniques and exhaled breath analysis offer another option for assessment of CF lung disease.

Pneumonia is a significant risk for critically ill, mechanically ventilated (CIMV) patients. Diagnosis of pneumonia generally requires a combination of clinician-guided diagnoses and clinical scoring systems. Exhaled breath condensate (EBC) can be safely collected non-invasively from CIMV patients. Hundreds of biomarkers in EBC are associated with acute disease states, including pneumonia. We evaluated cytokines in EBC from CIMV patients and hypothesized that these biomarkers would correlate with disease severity in pneumonia, sepsis, and death. EBC IL-2 levels were associated with chest radiograph severity scores (odds ratio = 1.68; 95% confidence interval = 1.09–2.60; P = 0.02). EBC TNF-α levels were also associated with pneumonia (odds ratio = 3.20; 95% confidence interval = 1.19–8.65; P = 0.02). The techniques and results from this study may be useful for all mechanically ventilated patients.

BACKGROUND: Intravenous formulations of epoprostenol are frequently delivered via nebulizer to treat pulmonary hypertension in acutely ill patients. Although their efficacy as pulmonary vasodilators has been shown to be comparable to inhaled nitric oxide, the local effects of these formulations within the airways have not been determined. We hypothesized that the alkaline diluents of these compounds would lead to increased airway epithelial cell death and ciliary cessation. METHODS: Human bronchial epithelial cells were exposed to epoprostenol in glycine and arginine diluents or control fluid. Ciliary beat frequency, lactate dehydrogenase, and total RNA levels were measured before and after exposure. Results were compared between exposure and control groups. RESULTS: Ciliary beat frequency ceased immediately after exposure to epoprostenol with both diluents. Lactate dehydrogenase levels increased by 200% after exposure to epoprostenol and glycine diluent (P = .002). Total RNA levels were undetectable after exposure to epoprostenol and arginine, indicating complete cell death and lysis (P = .015). Ciliary beat frequency ceased after 30 s of exposure to epoprostenol and glycine (P = .008). There was no difference between cells exposed to epoprostenol and those exposed only to diluent. CONCLUSIONS: Exposure to intravenous formulations of epoprostenol in glycine and arginine caused increased cell death and ciliary cessation in bronchial epithelial cells. These findings suggest that undesired local effects may occur when these compounds are delivered as inhaled aerosols to patients.

Asthma is an obstructive airway disease affecting children and adults throughout the world. It is a heterogeneous disease with a variety of causes and treatments. Research in the diagnosis, treatment, and management of asthma is ongoing, and there were > 8,000 publications on asthma in 2019. This paper reviews several research articles about asthma from 2019 that are most relevant for practicing respiratory therapists caring for patients with asthma.

Normal breathing for healthy humans is taken for granted; it occurs without conscious effort using ambient (1-atmosphere) pressure with 21% oxygen (O(2)) concentration. The body automatically adjusts for stress, exercise, altitude, and mild disease by increasing the volume and frequency of breathing. Longer term adaptations for exercise and altitude include increases in red blood cell counts and higher concentrations of capillaries in muscle tissue. When more challenging external environmental conditions or pulmonary illnesses exceed the capability for these adaptations, the human system requires technology to maintain sufficient ventilation to preserve life. On the environmental side there are two conditions to be addressed: toxicity of the surrounding atmosphere and changes in external pressure and O(2) concentration. On the medical side, mechanisms for assisting breathing include O(2) supplementation at ambient pressure, positive pressure/flow without additional O(2), or a combination of both. This overview describes the various technologies applied to maintaining a safe breathing environment. Topics for environmental intervention include filter-based and flowing air-supply masks for toxic environments (occupational and laboratory protection), and on-demand gas supply systems for firefighters, self-contained underwater breathing apparatus (SCUBA) divers, and altitude (high performance aircraft, spacecraft) applications. The topics for medical intervention include nasal cannula, continuous positive airway pressure (CPAP), and medical ventilators. The primary purpose of this article is to provide a basic understanding of normal human breathing and the adaptation of breathing in different environments using available technologies.

Pulmonary hypertension is a life-threatening condition that affects people of all ages that can occur as an idiopathic disorder at birth or as part of a variety of cardiovascular and infectious disorders. It is commonly treated with inhaled pulmonary vasodilators such as nitric oxide and less frequently using formulations and analogs of prostacyclin. To minimize systemic effects and preserve pulmonary vasodilation, vasodilators are often administered directly into the airway. Nitric oxide is the only USA Food and Drug Administration-approved inhaled pulmonary vasodilator that can be used during mechanical ventilation. Over the past two decades, interest has grown in the use of aerosolized prostacyclin and prostacyclin analogs for the treatment of pulmonary hypertension during mechanical ventilation. Clinicians who administer inhaled prostacyclin may not have a clear understanding of its risks because of the lack of data from large clinical trials examining safety and efficacy; moreover, its safe use remains poorly documented. The off-label use of drugs is legitimate, but prescribers must recognize the potential complications and liability in doing so. This manuscript aims to address potential problems related to the aerosol administration of pulmonary vasodilators in the mechanically ventilated neonatal patient.

Mechanical ventilation is frequently used in pediatric patients to ensure adequate gas exchange, ameliorate respiratory distress, and enable resolution of pulmonary or other disorders. However, a number of important challenges remain in the pediatric population because there is a paucity of large-scale randomized controlled trials to generate data and inform clinical practice. This review summarizes a number of discoveries and advances that have been made in pediatric mechanical ventilation from June 2017 to December 2018.

The mechanisms by which transepithelial pressure changes observed during exercise and airway clearance can benefit lung health are challenging to study. Here, we have studied 117 mature, fully ciliated airway epithelial cell filters grown at air-liquid interface grown from 10 cystic fibrosis (CF) and 19 control subjects. These were exposed to cyclic increases in apical air pressure of 15 cmH2O for varying times. We measured the effect on proteins relevant to lung health, with a focus on the CF transmembrane regulator (CFTR). Immunoflourescence and immunoblot data were concordant in demonstrating that air pressure increased F508Del CFTR expression and maturation. This effect was in part dependent on the presence of cilia, on Ca2+ influx, and on formation of nitrogen oxides. These data provide a mechanosensory mechanism by which changes in luminal air pressure, like those observed during exercise and airway clearance, can affect epithelial protein expression and benefit patients with diseases of the airways.

A number of clinical scoring systems for asthma management have been described in the literature over the last four decades.[1][1] These systems are largely used to index severity of disease, quantify changes in disease status, and predict outcomes. Resulting scores can then be used to triage

Exhaled breath condensate (EBC) is a promising source of biomarkers of lung disease. EBC research and utility has increased substantially over the past 2 decades. This review summarizes many of the factors regarding the composition of EBC, its collection, and analysis for the utility of both clinicians and researchers.

BACKGROUND: Tissue factor (TF) canonically functions as the initiator of the coagulation cascade. TF levels are increased in inflamed airways and seem to be important for tumor growth and metastasis. We hypothesized that airway epithelia release TF as part of a wound repair program. OBJECTIVES: The goal of this study was to evaluate whether airway epithelia release TF in response to pro-inflammatory stimuli and to investigate roles of TF in cell growth and repair. METHODS: Airway epithelial cells were exposed to 10 μg/mL of lipopolysaccharide or 1 ng/mL of transforming growth factor β (TGF-β). TF and TGF-β messenger RNA and protein were measured in cell lysate and culture media, respectively. Signaling pathways were evaluated by using selective agonists and inhibitors. Airway epithelia were mechanically injured in the presence of TF and tissue factor pathway inhibitor to investigate their roles in wound repair. RESULTS: TF protein levels increased in cell media after exposure to lipopolysaccharide (P < .01) but only in growing cells, and this action was blocked when exposed to an extracellular signal-regulated kinase inhibitor or a “small” worm phenotype and mothers against Decapentaplegic inhibitor. TF protein also increased in the presence of TGF-β (P < .05). Exposure to TF pathway inhibitor decreased the rate of cell growth by 60% (P < .05), and exposure to TF increased the rate of airway healing after injury by 19% (P < .05). CONCLUSIONS: Growing airway epithelia release TF when exposed to lipopolysaccharide or TGF-β. TF reduces wound-healing time in airway epithelia and therefore may be important to airway recovery after injury.

Exhaled breath is a robust matrix of biomarkers divided between three fractions – gaseous breath, volatile breath, and breath condensate. Breath is collected non-invasively through bags (for gaseous breath), cold condensation chambers (breath condensate), and adsorbent traps (volatile breath). Due to the incredibly dilute nature of breath matrices, breath biomarker analysis requires precise analytical techniques, highly sensitive technology and often challenges the limit of detection of even the most advanced assays. Interest and advances in breath collection, analysis, and use have increased in recent years largely due to advances in analytical technology. Approved and validated breath tests are available as tools for researchers and clinicians. Novel development is ongoing. This article reviews the current applications for exhaled breath biomarkers.

To better understand the impact of hypoxia and hyperoxia on neonatal morbidity and mortality, we examined the number of hypoxia and hyperoxia events as well as percentage of time spent outside oxygen saturation targets in relationship to threshold retinopathy of prematurity (tROP) and mortality in preterm infants.Saturation data in 2-second sampling from pulse oximeters was prospectively collected in a single NICU. Average SaO2, low and high saturation events, duration of events, and percentage of time infants spent outside of oxygen saturation range were collected and analyzed continuously during the hospitalization.102 infants1500g or32 weeks gestation were enrolled. There were 125, 112, and 43 hypoxia events/day and 106, 80, and 34 hyperoxia events/day for tROP (N=8), non-survivor (N=16) and non-tROP patients (N=78), respectively. Infants were outside saturation targets for 2:35, 1:38, and 1:03 (hypoxia) and 2:02, 1:25, and 0:38 hours/day (hyperoxia) for tROP, non-survivor and non-tROP, respectively. Time spent outside saturation range (hypoxia, hyperoxia and total time) for the hospital course was higher in tROP (P≤0.006) and non-survivor (P≤0.005) compared with non-tROP patients. The three groups defined themselves in the first 10 days after birth, with regard to duration of hypoxia (P=0.0003), hyperoxia (P=0.0004) and total time outside the targeted saturation range (P=0.0006).Information such as the duration and number of hypoxia and hyperoxia events, as well as total time outside the targeted saturation range, could be factored into assessing clinical interventions and research studies in the prevention, treatment and evaluation of neonatal outcomes.

Structural imaging research offers excellent translational benefits when non-human primate (NHP) models are employed. In this paper, we will discuss the development of anatomical MR imaging protocols for two important applications of structural imaging in NHPs: studies of genetic variability in brain morphology and longitudinal imaging of fetal brain maturation trends. In contrast with imaging studies of adult humans, structural imaging in the NHPs is challenging due to a comparatively small brain size (2- to 200-fold smaller volume, depending on the species). This difference in size is further accentuated in NHP studies of brain development in which fetal brain volumes are 10-50% of their adult size. The sizes of cortical gyri and sulci scale allometrically with brain size. Thus, achieving spatial sampling that is comparable to that of high-quality human studies (approximately 1.0 mm(3)) requires a brain-size-adjusted reduction in the sampling volumes of from 500-to-150 microm(3). Imaging at this spatial resolution while maintaining sufficient contrast and signal to noise ratio necessitates the development of specialized MRI protocols. Here we discuss our strategy to optimize the protocol parameters for two commonly available structural imaging sequences: MPRAGE and TrueFisp. In addition, computational tools developed for the analysis of human structural images were applied to the NHP studies. These included removal of non-brain tissues, correction for RF inhomogeneity, spatial normalization, building of optimized target brain and analysis of cerebral gyrification and individual cortical variability. Finally, recent findings in the genetics of cerebral gyrification and tracking of maturation trends in the fetal, newborn and adult brain are described.

In the search for bioactive sphingosine 1-phosphate (S1P) receptor ligands, a series of 2-amino-2-heterocyclic-propanols were synthesized. These molecules were discovered to be substrates of human-sphingosine kinases 1 and 2 (SPHK1 and SPHK2). When phosphorylated, the resultant phosphates showed varied activities at the five sphingosine-1-phosphate (S1P) receptors (S1P(1-5)). Agonism at S1P(1) was displayed in vivo by induction of lymphopenia. A stereochemical preference of the quaternary carbon was crucial for phosphorylation by the kinases and alters binding affinities at the S1P receptors. Oxazole and oxadiazole compounds are superior kinase substrates to FTY720, the prototypical prodrug immunomodulator, fingolimod (FTY720). The oxazole-derived structure was the most active for human SPHK2. Imidazole analogues were less active substrates for SPHKs, but more potent and selective agonists of the S1P(1) receptor; additionally, the imidazole class of compounds rendered mice lymphopenic.

We searched MEDLINE, CINAHL, and Cochrane Library database for articles published between January 1990 and December 2012. The update of this clinical practice guideline is based on 237 clinical trials, 54 reviews, and 23 meta-analyses on blood gas analysis (BGA) and hemoximetry. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation scoring system. BGA and hemoximetry are recommended for evaluating a patient's ventilatory, acid-base, and/or oxygenation status. BGA and hemoximetry are suggested for evaluating a patient's response to therapeutic interventions. BGA and hemoximetry are recommended for monitoring severity and progression of documented cardiopulmonary disease processes. Hemoximetry is recommended to determine the impact of dyshemoglobins on oxygenation. Capillary BGA is not recommended to determine oxygenation status. Central venous BGA and hemoximetry are suggested to determine oxygen consumption in the setting of early goal-directed therapies. For the assessment of oxygenation, a peripheral venous P(O2) is not recommended as a substitute for an arterial blood measurement (P(aO2)). It is not recommended to use venous P(CO2) and pH as a substitute for arterial blood measurement of P(aCO2) and pH. It is suggested that hemoximetry is used in the detection and evaluation of shunts during diagnostic cardiac catheterization.

BACKGROUND: Airway acidification plays a role in disorders of the pulmonary tract. We hypothesized that the inhalation of alkalinized glycine buffer would measurably alkalinize the airways without compromising lung function or causing adverse events. We evaluated the safety of an inhaled alkaline glycine buffer in both healthy subjects and in subjects with stable obstructive airway disease. METHODS: This work includes 2 open-label safety studies. The healthy controls were part of a phase 1 safety study of multiple inhalations of low-dose alkaline glycine buffer; nebulized saline was used as a comparator in 8 of the healthy controls. Subsequently, a phase 2 study in subjects with stable obstructive airway disease was completed using a single nebulized higher-dose strategy of the alkaline inhalation. We studied 20 non-smoking adults (10 healthy controls and 10 subjects with obstructive airway disease), both at baseline and after inhalation of alkaline buffer. We used spirometry and vital signs as markers of clinical safety. We used changes in fraction of exhaled nitric oxide (NO) and exhaled breath condensate (EBC) pH as surrogate markers of airway pH modification. RESULTS: Alkaline glycine inhalation was tolerated by all subjects in both studies, with no adverse effects on spirometric parameters or vital signs. Airway alkalinization was confirmed by a median increase in EBC pH of 0.235 pH units (IQR 0.56–0.03, P = .03) in subjects after inhalation of the higher-dose alkaline buffer (2.5 mL of 100 mmol/L glycine). CONCLUSIONS: Alkalinization of airway lining fluid is accomplished with inhalation of alkaline glycine buffer and causes no adverse effects on pulmonary function or vital signs.

Airway pH is central to the physiologic function and cellular biology of the airway. The causes of airway acidification include (1) hypopharyngeal gastric acid reflux with or without aspiration through the vocal cords, (2) inhalation of acid fog or gas (such as chlorine), and (3) intrinsic airway acidification caused by altered airway pH homeostasis in infectious and inflammatory disease processes. The recognition that relevant airway pH deviations occur in lung diseases is opening doors to new simple and inexpensive therapies. This recognition has resulted partly from the ability to use exhaled breath condensate as a window on airway acid-base balance.

The standard organization of psychiatric inpatient care at our hospital involved consultations with various specialist physicians visiting the psychiatry wards to assess patients' medical needs and to provide appropriate interventions. We thought that this type of clinical care pathway might not be leading to the best integration and timeliness of patient care, the most efficient use of specialist resources, or the least cost to the health care system.To initiate a protocol that would involve an FP visiting all the psychiatry wards daily (on weekdays) to conduct medical consultations. We hoped this program would improve the timeliness and integration of patient care, reduce patients' length of stay in hospital, and alter the pattern of specialist consultations.The FP consulted on patients referred by psychiatrists and registered psychiatric nurses; carried out assessments; initiated treatment of commonmedical problems; referred to other specialists when necessary; and made arrangements for follow-up care as appropriate.The FP consultations improved patient care in several ways, was highly valued by staff, and modified the pattern of specialist consultations on participatingpsychiatry wards.

Exhaled breath condensate (EBC) pH serves as a surrogate marker of airway lining fluid (ALF) pH and can be used to evaluate airway acidification (AA). AA is known to be present in acute respiratory distress syndrome (ARDS) and can be evaluated via continuous EBC pH measurement during mechanical ventilation. Lung recruitment maneuvers (LRMs) are utilized in the treatment of ARDS, however, their impact on EBC pH has never been explored. Here we described the acute effects of two commonly used LRMs on EBC pH. In a prospective, non-randomized, serial exposure study, 10 intubated pediatric subjects with acute respiratory distress syndrome sequentially underwent: a period of baseline ventilation, sustained inflation (SI) maneuver of 40 cm H2O for 40 s, open lung ventilation, staircase recruitment strategy (SRS) (which involves a systematic ramping of plateau pressures in 5 cm H2O increments, starting at 30 cm H2O), and PEEP titration. Maximum lung recruitment during the SRS is defined as a PaO2 + PaCO2 of 400 mmHg. Following lung recruitment, PEEP titration was conducted from 20 cm H2O in 2 cm H2O decrements until a PaO2 + PaCO2 was 380 and then increased by 2 cm H2O. EBC pH, arterial blood gases, lung mechanics, hemodynamics, and function residual capacity were obtained following each phase of the LRM and observational period. Seven out of 10 patients were able to reach maximum lung recruitment. Baseline EBC pH (6.38 ± 0.37) did not correlate with disease severity defined by PaO2/FiO2 ratio or oxygenation index (OI). Average EBC pH differed between phases and decreased after LRM (p = 0.001). EBC pH is affected by LRMs. EBC acidification following LRMs may represent a washout effect of opening acidic lung units and ventilating them or acute AA resulting from LRM.

The relevance of allergic sensitization, as judged by titers of serum IgE antibodies, to the risk of an asthma exacerbation caused by rhinovirus is unclear.We sought to examine the prevalence of rhinovirus infections in relation to the atopic status of children treated for wheezing in Costa Rica, a country with an increased asthma burden.The children enrolled (n= 287) were 7 through 12 years old. They included 96 with acute wheezing, 65 with stable asthma, and 126 nonasthmatic control subjects. PCR methods, including gene sequencing to identify rhinovirus strains, were used to identify viral pathogens in nasal washes. Results were examined in relation to wheezing, IgE, allergen-specific IgE antibody, and fraction of exhaled nitric oxide levels.Sixty-four percent of wheezing children compared with 13% of children with stable asthma and 13% of nonasthmatic control subjects had positive test results for rhinovirus (P.001 for both comparisons). Among wheezing subjects, 75% of the rhinoviruses detected were group C strains. High titers of IgE antibodies to dust mite allergen (especially Dermatophagoides species) were common and correlated significantly with total IgE and fraction of exhaled nitric oxide levels. The greatest risk for wheezing was observed among children with titers of IgE antibodies to dust mite of 17.5 IU/mL or greater who tested positive for rhinovirus (odds ratio for wheezing, 31.5; 95% CI, 8.3-108; P.001).High titers of IgE antibody to dust mite allergen were common and significantly increased the risk for acute wheezing provoked by rhinovirus among asthmatic children.