Improvement In Airway Function Research Articles

Functional evaluation of Septal L-strut extension graft in East Asians

BackgroundThe septal L-strut extension graft (SLEG) consists of anterior extended spreader graft and caudal septal extension graft. SLEG is used to increase the anterocaudal projection from a low-profile nose by creating the de-novo septum. This retrospective study verified the effectiveness of SLEG in improving the nasal function in East Asians. MaterialsMedical records of patients who underwent septorhinoplasty with SLEG were retrospectively reviewed. The clinical features showed under-projected lower two-thirds of the nose with septal deviation, saddle nose, and short nose. We analyzed the post-operative changes in the NOSE score and variables of nasal geometry measured using acoustic rhinometry through long-term follow-up. ResultsPatients were divided into two groups, those who underwent SLEG with turbinoplasty (Group A) and SLEG alone (group B). The NOSE scores decreased significantly in groups A and B, and the improvement was statistically more significant in Group A (p < 0.05). Acoustic rhinometry showed an increase in nasal cavity volume (VOL1) on the deviated side in Group A, and an increase in minimal cross-sectional area 1 (MCA1) on the deviated side in Group B (p < 0.05). The non-deviated side did not show significant reduction in MCA1 and VOL1 after SLEG with or without turbinoplasty. Thus, SLEG, by itself, improved airway function in East Asians. ConclusionsSLEG has proven to be valuable in improving nasal function.

Content analysis of AI-generated (ChatGPT) responses concerning orthodontic clear aligners.

To assess the accuracy of ChatGPT answers concerning orthodontic clear aligners. A cross-sectional content analysis of ChatGPT generated responses to queries related to clear aligner treatment (CAT) was undertaken. A total of 111 questions were generated by three orthodontists based on a set of predefined domains and subdomains. The artificial intelligence (AI)-generated (ChatGPT) answers were extracted and their accuracy was determined independently by five orthodontists. The accuracy of answers was assessed using a prepiloted four-point scale scoring rubric. Descriptive statistics were performed. The total mean accuracy score for the entire set was 2.6 ± 1.1. It was noted that 58% of the AI-generated answers were scored as objectively true, 18% were selected facts, 9% were minimal facts, and 15% were false. False claims included the ability of CAT to reduce the need for orthognathic surgery (4.0 ± 0.0), improve airway function (3.8 ± 0.5), achieve root parallelism (3.6 ± 0.5), alleviate sleep apnea (3.8 ± 0.5), and produce more stable results compared to fixed appliances (3.8 ± 0.5). The overall level of accuracy of ChatGPT responses to questions concerning CAT was suboptimal and lacked citations to relevant literature. Ability of the software to offer current and precise information was limited. Therefore, clinicians and patients must be mindful of false claims and relevant facts omitted in the answers generated by ChatGPT.

Active cycle of breathing technique for cystic fibrosis.

People with cystic fibrosis (CF) experience chronic airway infections as a result of mucus buildup within the lungs. Repeated infections often cause lung damage and disease. Airway clearance therapies aim to improve mucus clearance, increase sputum production, and improve airway function. The active cycle of breathing technique (ACBT) is an airway clearance method that uses a cycle of techniques to loosen airway secretions including breathing control, thoracic expansion exercises, and the forced expiration technique. This is an update of a previously published review. To compare the clinical effectiveness of ACBT with other airway clearance therapies in CF. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched clinical trials registries and the reference lists of relevant articles and reviews. Date of last search: 29 March 2021. We included randomised or quasi-randomised controlled clinical studies, including cross-over studies, comparing ACBT with other airway clearance therapies in CF. Two review authors independently screened each article, abstracted data and assessed the risk of bias of each study. We used GRADE to assess our confidence in the evidence assessing quality of life, participant preference, adverse events, forced expiratory volume in one second (FEV1) % predicted, forced vital capacity (FVC) % predicted, sputum weight, and number of pulmonary exacerbations. Our search identified 99 studies, of which 22 (559 participants) met the inclusion criteria. Eight randomised controlled studies (259 participants) were included in the analysis; five were of cross-over design. The 14 remaining studies were cross-over studies with inadequate reports for complete assessment. The study size ranged from seven to 65 participants. The age of the participants ranged from six to 63 years (mean age 18.7 years). In 13 studies follow up lasted a single day. However, there were two long-term randomised controlled studies with follow up of one to three years. Most of the studies did not report on key quality items, and therefore, have an unclear risk of bias in terms of random sequence generation, allocation concealment, and outcome assessor blinding. Due to the nature of the intervention, none of the studies blinded participants or the personnel applying the interventions. However, most of the studies reported on all planned outcomes, had adequate follow up, assessed compliance, and used an intention-to-treat analysis. Included studies compared ACBT with autogenic drainage, airway oscillating devices (AOD), high-frequency chest compression devices, conventional chest physiotherapy (CCPT), positive expiratory pressure (PEP), and exercise. We found no difference in quality of life between ACBT and PEP mask therapy, AOD, other breathing techniques, or exercise (very low-certainty evidence). There was no difference in individual preference between ACBT and other breathing techniques (very low-certainty evidence). One study comparing ACBT with ACBT plus postural exercise reported no deaths and no adverse events (very low-certainty evidence). We found no differences in lung function (forced expiratory volume in one second (FEV1) % predicted and forced vital capacity (FVC) % predicted), oxygen saturation or expectorated sputum between ACBT and any other technique (very low-certainty evidence). There were no differences in the number of pulmonary exacerbations between people using ACBT and people using CCPT (low-certainty evidence) or ACBT with exercise (very low-certainty evidence), the only comparisons to report this outcome. There is little evidence to support or reject the use of the ACBT over any other airway clearance therapy and ACBT is comparable with other therapies in outcomes such as participant preference, quality of life, exercise tolerance, lung function, sputum weight, oxygen saturation, and number of pulmonary exacerbations. Longer-term studies are needed to more adequately assess the effects of ACBT on outcomes important for people with cystic fibrosis such as quality of life and preference.

Feasibility and acceptability of home monitoring with portable spirometry in young adults with asthma

Objective Self-monitoring asthma control is a key component of asthma management. Few studies have reported usability and acceptability of portable spirometry among young adults with asthma. Portable spirometry offers a practical solution to monitoring airway narrowing at home. The purpose of this paper was to determine if self-administered spirometry is feasible and acceptable in young adults with asthma and whether regular monitoring resulted in improved airway function as measured by forced expiratory volume in one second (FEV1). Methods Sixty-seven young adults (18–26 years) with self-reported asthma participated in a clinical trial during wildfire season which measured FEV1 as an outcome measure. Data was collected at baseline, week 4, and week 8 using a portable spirometer linked to a smartphone application. A subset of intervention participants completed spirometry twice daily. Acceptability of self-administered spirometry was evaluated after the trial among participants that volunteered to submit a survey and be interviewed. Results At baseline, all 67 participants (100.0%) completed their scheduled spirometry readings which declined to 94.0% (n = 63) at week 4 and 86.6% (n = 58) at week 8. Daily readings were completed 83.2% of the time in the mornings and 84.3% of the time in the evenings. Mean FEV1 values were lower than predicted values, but above the lower limit of expected. FEV1 remained steady throughout the study period. Over two-thirds of participants used the notes feature in the application and described symptoms, asthma triggers, mitigating actions and test-taking issues. Conclusions Young adults in our sample were highly compliant with regular, self-administered spirometry.

Supplemental treatment to atropine improves the efficacy to reverse nerve agent induced bronchoconstriction

Exposure to highly toxic organophosphorus compounds causes inhibition of the enzyme acetylcholinesterase resulting in a cholinergic toxidrome and innervation of receptors in the neuromuscular junction may cause life-threatening respiratory effects. The involvement of several receptor systems was therefore examined for their impact on bronchoconstriction using an ex vivo rat precision-cut lung slice (PCLS) model. The ability to recover airways with therapeutics following nerve agent exposure was determined by quantitative analyses of muscle contraction.PCLS exposed to nicotine resulted in a dose-dependent bronchoconstriction. The neuromuscular nicotinic antagonist tubocurarine counteracted the nicotine-induced bronchoconstriction but not the ganglion blocker mecamylamine or the common muscarinic antagonist atropine. Correspondingly, atropine demonstrated a significant airway relaxation following ACh-exposure while tubocurarine did not. Atropine, the M3 muscarinic receptor antagonist 4-DAMP, tubocurarine, the β2-adrenergic receptor agonist formoterol, the Na+-channel blocker tetrodotoxin and the K+ATP-channel opener cromakalim all significantly decreased airway contractions induced by electric field stimulation. Following VX-exposure, treatment with atropine and the Ca2+-channel blocker magnesium sulfate resulted in significant airway relaxation. Formoterol, cromakalim and magnesium sulfate administered in combinations with atropine demonstrated an additive effect.In conclusion, the present study demonstrated improved airway function following nerve agent exposure by adjunct treatment to the standard therapy of atropine.

Pinus sylvestris L. and Syzygium aromaticum (L.) Merr. & L. M. Perry Essential Oils Inhibit Endotoxin-Induced Airway Hyperreactivity despite Aggravated Inflammatory Mechanisms in Mice.

Scots pine (SO) and clove (CO) essential oils (EOs) are commonly used by inhalation, and their main components are shown to reduce inflammatory mediator production. The aim of our research was to investigate the chemical composition of commercially available SO and CO by gas chromatography–mass spectrometry and study their effects on airway functions and inflammation in an acute pneumonitis mouse model. Inflammation was evoked by intratracheal endotoxin and EOs were inhaled three times during the 24 h experimental period. Respiratory function was analyzed by unrestrained whole-body plethysmography, lung inflammation by semiquantitative histopathological scoring, myeloperoxidase (MPO) activity and cytokine measurements. α-Pinene (39.4%) was the main component in SO, and eugenol (88.6%) in CO. Both SO and CO significantly reduced airway hyperresponsiveness, and prevented peak expiratory flow, tidal volume increases and perivascular edema formation. Meanwhile, inflammatory cell infiltration was not remarkably affected. In contrast, MPO activity and several inflammatory cytokines (IL-1β, KC, MCP-1, MIP-2, TNF-α) were aggravated by both EOs. This is the first evidence that SO and CO inhalation improve airway function, but enhance certain inflammatory parameters. These results suggest that these EOs should be used with caution in cases of inflammation-associated respiratory diseases.

Development of Inhaled GABAA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders.

We report the modification of MIDD0301, an imidazodiazepine GABAA receptor (GABAAR) ligand, using two alkyl substituents. We developed PI310 with a 6-(4-phenylbutoxy)hexyl chain as used in the long-acting β2-agonist salmeterol and PI320 with a poly(ethylene glycol) chain as used to improve the brain:plasma ratio of naloxegol, a naloxone analogue. Both imidazodiazepines showed affinity toward the GABAAR binding site of clonazepam, with IC50 values of 576 and 242 nM, respectively. Molecular docking analysis, using the available α1β3γ2 GABAAR structural data, suggests binding of the diazepine core between the α1+/γ2- interface, whereas alkyl substituents are located outside the binding site and thus interact with the protein surface and solvent molecules. The physicochemical properties of these compounds are very different. The solubility of PI310 is low in water. PEGylation of PI320 significantly improves aqueous solubility and cell permeability. Neither compound is toxic in HEK293 cells following exposure at >300 μM for 18 h. Ex vivo studies using guinea pig tracheal rings showed that PI310 was unable to relax the constricted airway smooth muscle. In contrast, PI320 induced muscle relaxation at organ bath concentrations as low as 5 μM, with rapid onset (15 min) at 25 μM. PI320 also reduced airway hyper-responsiveness in vivo in a mouse model of steroid-resistant lung inflammation induced by intratracheal challenge with INFγ and lipopolysaccharide (LPS). At nebulized doses of 7.2 mg/kg, PI320 and albuterol were equally effective in reducing airway hyper-responsiveness. Ten minutes after nebulization, the lung concentration of PI320 was 50-fold that of PI310, indicating superior availability of PI320 when nebulized as an aqueous solution. Overall, PI320 is a promising inhaled drug candidate to quickly relax airway smooth muscle in bronchoconstrictive disorders, such as asthma. Future studies will evaluate the pharmacokinetic/pharmacodynamic properties of PI320 when administered orally.

Sophora flavescens Alkaloids and Corticosteroid Synergistically Augment IL-10/IL-5 Ratio with Foxp3-Gene-Epigenetic Modification in Asthma PBMCs.

BackgroundIt has been demonstrated that ASHMI (antiasthma-simplified herbal medicine intervention) can improve airway function and reduce inflammation in human asthmatic patients with high safety and tolerability. In addition, ASHMI significantly suppresses Th2 cytokine production and increases Th1 cytokine production in treating asthma.ObjectiveAllergic asthma is associated with dysregulation of cytokines. We focused on IL-5 and IL-10 as signature Th2 and Treg cytokines to characterize ASHMI immunomodulatory components.MethodsThe effects of ASHMI and individual herbal constituents on IL-5 and IL-10 production by PBMCs from asthmatic subjects were determined ex vivo. Sophora flavescens (SF)-F2, containing alkaloid compounds, effects on PBMC IL-10 and IL-5 production in the presence or absence of dexamethasone (Dex), and on DNA methylation levels at the foxp3 gene promoter were determined.ResultsThe ratio of anti-CD3/CD28 stimulated IL-10/IL-5 production by PBMCs from asthmatic subjects was significantly reduced compared to healthy subjects. In PBMCs from asthmatic subjects, ASHMI significantly reduced IL-5 production and increased IL-10 secretion in a dose-dependent manner (p < 0.05–0.01). SF-F2 was most effective in increasing IL-10, whereas SF-F4 (flavonoid compounds) was most effective in suppressing IL-5 production. Dex-treated PBMCs from asthma subjects showed a trend of increasing ratio of IL-10/IL-5 while demonstrating reduced levels in both IL-5 and IL-10 (p < 0.05). Co-culture with Dex and SF-F2 significantly prevented Dex suppression of IL-10, while retained Dex-suppression of IL-5 production, and increased IL-10/IL-5 ratio by Dex. Co-culture with SF-F2 and Dex significantly reduced DNA methylation levels at the foxp3 gene promoter at CpG−126.ConclusionThe SF alkaloid-rich fraction may be responsible for ASHMI induction of IL-10 production by PBMCs and plays a synergistic effect with Dex for augmenting IL-10/IL-5 ratio.

From the pages of AllergyWatch: August 2021

For this issue of “From the Pages of AllergyWatch,” I have chosen 3 recent reviews focusing on publications on upper airway allergies, the emphasis of this issue of Annals of Allergy, Asthma & Immunology. The first, reviewed by Dr Lee, presents data revealing half of patients with chronic rhinosinusitis without nasal polyps have type 2 inflammation. The next study, also reviewed by Dr Lee, reports improvement in airway function with environmental controls with pest management. The third review, by Dr Joshi, evaluates the effect of high-efficiency particulate air (HEPA) filtration on fine particles and the impact on airway inflammation in children with asthma.

Obstructive sleep Apnea's association with the cervical spine abnormalities, posture, and pain: a systematic review

ObjectivesWhile obstructive sleep apnea (OSA) is associated with several chronic health conditions such as hypertension, obesity, and chronic hypoxia, there is limited information on its association with neuromuscular and spinal pathologies that may be of interest to a musculoskeletal (MSK) medicine or pain management clinician. The objective of this study was to perform a systematic literature review to examine the association between OSA and cervical spine pathologies, postural changes, and pain. DesignWe systematically reviewed PubMed and Embase databases up to 4/15/2019. We included studies that explored associations between OSA and a) pain, b) postural characteristics or changes, or c) cervical spine morphology. Systematic reviews, meta-analysis, randomized control trials, cohort studies, and case–control studies were included. Case reports, narrative reviews or expert opinion papers were excluded. From the articles that met selection criteria, information regarding type, direction and magnitude of such associations was extracted. The OSA-pain association studies were further divided into 3 subgroups: neuropathic, temporomandibular, and chronic pain. Results21 articles that met our study criteria were selected for this review. Two studies were on cervical spine pathologies, eight on postural changes, and eleven on pain associated with OSA. Exploring the association between OSA and cervical spine pathologies, postural changes, and pain in this systematic review we found: (1) Cervical spine lesions, fusions, and abnormalities that reduce retropharyngeal space are associated with OSA, likely by way of worsening posture and decreasing range of motion. (2) Head extension and anteriorization are associated with OSA likely as a compensatory mechanism. Extension may improve airway function, while anteriorization helps to maintain visual sense. (3) Head-of-bed-elevation may improve OSA symptoms and can possibly supplement other conservative treatment measures. (4) Neuropathic pain is associated with OSA, likely by way of inflammatory pathways. (5) Oral appliance use (eg mandibular advancement/protruding device) in OSA likely contributes to transient temporomandibular pain. (6) There is little association between OSA and chronic pain prevalence. (7) Increased pain intensity and decreased pain tolerance are somewhat associated with OSA, likely by way of hypoxemia and sleep fragmentation. ConclusionsClinicians in MSK and pain medicine need to consider these associations and consider obtaining imaging studies and/or making referrals for management of their OSA to better provide appropriate care to these patients.

Counter Autografting of Dorsal Septum in Crooked Nose.

The nasal septum plays an important role in nasal form and function. In this study, we describe a novel, alternative septoplasty approach that results in an aesthetically acceptable dorsal profile and improves airway function in patients with a crooked nose. This study enrolled 26 patients who presented with crooked noses between 2012 and 2017. All patients underwent open rhinoplasty under general anesthesia. During correction of the cartilaginous part, a dorsal strip from the deviated septum was prepared and inverted in a 180° fashion to exert a counter-force to correct the remaining septum and fixed by suturation. This maneuver allowed application of the maximum possible force in the opposite direction to reset the deviation by its own force. The approach was used successfully in 26 patients with severe nasal septal deviations in the caudal septum and dorsal angulation of the nasal shape. There was no case of hematoma, synechia, septal perforation, dorsal irregularity, or saddle deformity. Temporary nasal obstruction occurred in 4 patients but improved in all of them by the third postoperative month. One patient had a recurrence of the septal deviation, dorsal angulation, and persistent nasal obstruction, which were treated by revision nasal valve surgery 14months postoperatively. There was no subsequent recurrence during the long-term follow-up. The improvement between the preoperative and postoperative 12-month deviation angle measurements, Nasal Obstruction and Septoplasty Effectiveness (NOSE) scores were significant (P < 0.05), Improvement in the NOSE score correlated strongly and significantly with deviation angle changes and patient satisfaction. Our counter-autografting technique in septoplasty is safe and effective in the correction of severe dorsal and/or caudal deviations, as long as the severely angulated cartilage septum remains in one piece after careful dissection. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Nebulized Delivery of Albuterol during Exercise is Safe and Effective in Individuals with Cystic Fibrosis, but does not Augment Bronchodilation or Drug Delivery

ObjectiveExercise is a cornerstone of therapeutic intervention for individuals with cystic fibrosis (CF). However, daily breathing treatments (e.g. chest physiotherapy and inhalation of nebulized albuterol) typically last ~90 minutes, providing a time‐barrier to completing daily exercise. Thus, the purpose of our study was to determine the effects of a combination therapy (exercise and nebulized albuterol) on airway function and bronchodilator delivery. We tested the hypotheses that combination therapy (exercise + nebulized albuterol) would 1) augment the bronchodilator effect compared to either intervention alone, and 2) increase the plasma concentration of albuterol compared to nebulized albuterol alone.MethodsParticipants with CF (n=9, 5 female, 25±2yrs, forced expiratory volume in 1 second (FEV1) =82±5%predicted) first completed a screening visit (V̇O2max test, cycle ergometer) and then three study visits in a randomized order. During each study visit, participants completed measures of airway function [FEV1 and forced expiratory flow from 25–75% of forced vital capacity (FEF25–75)], and a blood draw (n=8) to determine plasma albuterol concentration. Participants then completed one of three interventions [albuterol only, (A): 2.5mg nebulized albuterol over 15min; exercise only (E): 30min cycling exercise at 50% of peak watts; albuterol and exercise (A+E): 30min cycling exercise at 50% of peak watts with 2.5mg nebulized albuterol nebulized over the last 15min of cycling). Airway function and plasma albuterol were measured at 0, 15, 30, 45, 60, 90, 120, 180, and 240min after the intervention. Additional plasma albuterol measures were taken 5, and 6hrs post intervention. Data are mean±SD.ResultsDelivery of nebulized albuterol during exercise did not augment or prolong the bronchodilator effect compared to exercise or albuterol alone. The transient improvement in airway function during the interventions—increase in FEV1 (time=0.050, intervention p=0.166, interaction p=0.135) or increase in FEF25–75 (time p=0.001, intervention p=0.207, interaction p=0.990) — was not different between the three interventions. Delivery of nebulized albuterol during exercise did not increase the plasma concentration of albuterol compared to nebulized albuterol alone. The maximum plasma concentration of albuterol (Cmax) and the area under the curve (AUC) of albuterol concentration over time were not different between interventions (Cmax= 2.57±1.60 vs. 2.56±1.13ng·mL−1, p=0.982; AUC0–6hrs= 6.1±3.6 vs. 6.9±3.3hr·ng·mL−1, p=0.188; A vs. A+E interventions, respectively).ConclusionsDelivery of nebulized albuterol during moderate intensity exercise did not significantly alter bronchodilator effects or plasma levels of albuterol compared to albuterol or exercise alone. These data suggest that delivery of nebulized albuterol during exercise is safe and effective, but does not augment bronchodilator effects or drug delivery. This combination intervention (A+E) may be a time efficient method for individuals with cystic fibrosis to gain therapeutic effects of exercise and breathing treatments.Support or Funding InformationF32 HL131151, Cystic Fibrosis Research Inc.

History and Evolution of Orthognathic Surgery at Chang Gung Craniofacial Center: Lessons Learned From 35-Year Experience.

Modern orthognathic surgery (OGS) was established on the basis of contributions from multidisciplinary centers worldwide. This study reports the history and evolution of OGS at the Chang Gung Craniofacial Center (CGCC) and identifies the lessons learned from 35 years of experience. The total number of OGS procedures managed by the CGCC multidisciplinary team between 1981 and 2016 was determined. The database of the senior author (Y.-R.C.) was reviewed for consecutive OGS procedures performed between 2003 and 2016. A literature review was also performed to retrieve the contributions from the total CGCC team. The 35 years of experience at a single center and 13-year experience of a single surgeon corresponded to 8073 and 2883 OGS procedures, respectively. Moreover, 53 peer-reviewed articles were reviewed. Teamwork (plastic surgeons, orthodontists, and anesthetists) ensured an optimal balance between occlusion functional and facial aesthetic outcomes, with patient safety ensured and a minimum of OGS-related complications. Progression from the conventional orthodontics-first approach to the surgery-first OGS approach decreased the overall treatment time. Transition from 1-jaw to 2-jaw surgery enabled more consistent aesthetic outcomes to be achieved. Conversion from the 2-splint to the single-splint technique enabled development of a more precise tridimensional simulation plan and surgical execution, including in challenging scenarios such as malocclusion associated with facial asymmetry. Clockwise pitch rotation of the maxillomandibular complex has been designed for facial aesthetic purposes in class III malocclusion, whereas counterclockwise pitch rotation of the maxillomandibular complex improves airway function in those with sleep apnea. The lessons learned from experience and outcome-based articles reveal that OGS has successfully evolved at the CGCC, with a balance being achieved between functional and aesthetic outcomes and effective decreases in the burden of care (ie, morbidity, complications, and treatment time).

EFFICACY OF NEBULIZED ARFORMOTEROL FOR THE TREATMENT OF PATIENTS WITH COPD: A ROLE FOR LONG-ACTING BRONCHODILATORS IN TREATING LONG-TERM CARE PATIENTS WITH COPD

SESSION TITLE: Monday Electronic Posters 4 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM PURPOSE: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and increased health care resource utilization in long-term care (LTC) nursing home facilities in the US. Although GOLD guidelines recommend the use of long-acting bronchodilators (LABDs) for the treatment of COPD, as they are more effective and convenient than regular treatment with short-acting bronchodilators (SABDs), a large proportion of nursing home residents with a diagnosis of COPD do not receive any respiratory medication. Arformoterol tartrate (ARF; 15 μg twice daily [BID]) is a nebulized long-acting beta2-agonist (LABA) indicated for the maintenance treatment of bronchoconstriction in patients with COPD; ARF should not be used as rescue medication. In this post-hoc analysis, the efficacy of ARF was assessed in older COPD patients and in patients with very severe COPD. METHODS: Data from two identical, 12-week, multicenter, double-dummy, randomized Phase III trials (NCT00685841 and NCT00064402) evaluating improvement in airway function with ARF treatment in patients with COPD were pooled for analysis. Patients (n=1456; mean predicted forced expiratory volume in 1 second [FEV1]=40.6% [standard deviation: 12.8]) received nebulized ARF 15 μg BID, 25 μg BID, or 50 μg once daily (QD), salmeterol 42 μg BID (via metered dose inhaler), or placebo BID for 12 weeks. In order to assess the efficacy of ARF in patients with COPD representative of an LTC population, an analysis of improvement in airway function (as measured by FEV1) was performed comparing ARF 15 ug BID with placebo (BID) in a subset of patients defined by age (≥75 years; n=160) and baseline COPD disease severity (FEV1 <30% predicted; n=410). RESULTS: In the overall study population, the median % change in FEV1 was 2.05% among patients receiving placebo and 12.72% in patients treated with ARF 15 μg BID. In patients ≥75 years of age, the median % change in FEV1 was −5.22% in patients receiving placebo compared with 18.62% improvement in patients treated with ARF 15 μg BID. In patients with severe COPD disease (<30% FEV1 % predicted), the median % change in FEV1 was 5.13% among patients receiving placebo compared with 22.58% in patients treated with ARF 15 μg BID. CONCLUSIONS: Despite the recommendations for use of LABDs by GOLD guidelines, many LTC nursing home residents with COPD do not receive any respiratory medications. In this post-hoc analysis of patients with COPD representative of nursing facility residents (≥75 years of age; severe baseline disease), treatment with ARF 15 μg BID resulted in greater improvements in lung function when compared with placebo. CLINICAL IMPLICATIONS: LABDs such as ARF should be considered as a treatment option for residents in an LTC setting with a diagnosis of COPD. DISCLOSURES: Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/11/2019 by Thomas Goodin, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/12/2019 by Ayca Ozol-Godfrey, source=Admin input, value=Salary Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/13/2019 by Barry Price, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Inc. Please note: >$100000 Added 03/14/2019 by Shahin Sanjar, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Inc. Please note: $20001 - $100000 Added 03/11/2019 by Sanjay Sharma, source=Web Response, value=Salary Removed 03/11/2019 by Sanjay Sharma, source=Web Response Employee relationship with Sunovion Pharmaceuticals, Inc. Please note: >$100000 Added 03/11/2019 by Sanjay Sharma, source=Web Response, value=Salary

AN ASSESSMENT OF TIME TO ONSET OF BRONCHODILATION FOLLOWING TREATMENT WITH NEBULIZED ARFORMOTEROL IN PATIENTS WITH COPD

SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM PURPOSE: Short and long-acting beta2-agonists are commonly utilized for the treatment of chronic obstructive pulmonary disease (COPD). Arformoterol tartrate (ARF; 15 μg twice daily [BID]) is a long-acting beta2-agonist (LABA) approved for the long-term maintenance treatment of bronchoconstriction in patients with COPD; ARF should not be used as rescue medication. ARF exhibits a rapid onset of action, producing significant bronchodilation and a long duration of effect. The time to onset of bronchodilation following treatment with nebulized ARF was assessed in COPD patients stratified by baseline forced expiratory volume in 1 second (FEV1) % predicted. METHODS: Data from two identical, 12-week, randomized Phase III trials (NCT00685841 and NCT00064402) evaluating improvement in airway function with ARF treatment in patients with COPD were pooled for analysis. Patients (n=1456; mean predicted FEV1=40.6% [standard deviation: 12.8]) received nebulized ARF 15 μg BID, 25 μg BID, or 50 μg once daily (QD), salmeterol 42 μg BID (using a metered dose inhaler), or placebo BID for 12 weeks. The time to onset was determined from serial spirometry assessments performed immediately and at 15 and 40 minutes, 1, 2, 3, 4, 5, 6, 8, 10, 12, 23, and 24 hours post-first dose. Time to onset of bronchodilation was defined as the time at which the linear interpolated value of FEV1 is equal to 12% change from baseline. The median time to onset, following administration of the first dose, was estimated using the Kaplan-Meier method. RESULTS: Across ARF treatment groups, time to onset of bronchodilation was quicker in the groups with the lowest baseline FEV1 % predicted. The median time to onset of bronchodilation for the approved ARF 15 μg BID dose, stratified by baseline FEV1 % predicted (<30, ≥30-<50, and ≥50), was 1.8, 3.6, and 42.2 minutes, respectively. The median time to onset was longer for placebo (122.1, 290.3, N/A) and salmeterol (14.6, 16.0, 43.7) groups by baseline FEV1 % predicted (<30, ≥30-<50, and ≥50, respectively) compared with ARF 15 μg BID. CONCLUSIONS: In this post-hoc analysis, median time to onset of bronchodilation in patients with COPD was shorter following treatment with nebulized ARF 15 μg BID than with placebo or salmeterol, regardless of baseline FEV1 % predicted. Notably, patients with COPD treated with nebulized ARF 15 μg BID demonstrated a rapid time to onset in patients with a baseline FEV1 % predicted <50%. CLINICAL IMPLICATIONS: Bronchodilators are essential in the management of COPD symptoms. These data highlight the rapid onset of bronchodilation observed with ARF 15 μg BID compared to placebo or salmeterol in all patients, independent of baseline disease severity. The observed differences between the clinically approved LABAs, ARF 15 ug BID and salmeterol 50 ug QD, may be due to dosing frequency, receptor uptake or mode of delivery. DISCLOSURES: Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/11/2019 by Thomas Goodin, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/12/2019 by Ayca Ozol-Godfrey, source=Admin input, value=Salary Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/13/2019 by Barry Price, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Inc. Please note: >$100000 Added 03/14/2019 by Shahin Sanjar, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Inc. Please note: $20001 - $100000 Added 03/11/2019 by Sanjay Sharma, source=Web Response, value=Salary Removed 03/11/2019 by Sanjay Sharma, source=Web Response Employee relationship with Sunovion Pharmaceuticals, Inc. Please note: >$100000 Added 03/11/2019 by Sanjay Sharma, source=Web Response, value=Salary

Mandibular distraction osteogenesis versus sagittal split ramus osteotomy in managing obstructive sleep apnea: A randomized clinical trial

PurposeTo compare mandibular distraction osteogenesis (MDO) to sagittal split ramus osteotomy (SSRO) to treat moderate-to-severe obstructive sleep apnea (OSA), and their surgical morbidities and skeletal stability. Materials and methodsA randomized clinical trial was conducted on non-syndromic adult patients with apnea-hypopnea index (AHI) 15 or above to receive MDO or SSRO as part or whole skeletal advancement surgery. Post-operative 1 year OSA cure rate (AHI < 5/hour) and treatment success rate (50% reduction of AHI and AHI< 20/hour) were compared. Polysomnography were conducted pre-operatively and post-operatively up to 2 years. Surgical morbidities and skeletal stability were analyzed. ResultsEighteen patients (9 in each group) were recruited. Patient recruitment was terminated after two major complications in the MDO group. The OSA cure rate and treatment success rate showed no statistical difference between MDO group or SSRO group at post-operative 1 year. Major complication rate was 44.4% in the MDO group and 0 in the SSRO group. No statistical difference was found in skeletal stability between the two groups. ConclusionBoth MDO and SSRO were highly effective to treat moderate-to-severe OSA. MDO had a high major complication rate and was not superior than SSRO in airway function improvement and skeletal stability.

Reboxetine and hyoscine butylbromide improve upper airway function during nonrapid eye movement and suppress rapid eye movement sleep in healthy individuals.

Recent findings indicate that noradrenergic and antimuscarinic processes are crucial for sleep-related reductions in pharyngeal muscle activity. However, there are few human studies. Accordingly, this study aimed to determine if a combined noradrenergic and antimuscarinic intervention increases pharyngeal dilator muscle activity and improves airway function in sleeping humans. Genioglossus (GG) and tensor palatini electromyography (EMG), pharyngeal pressure, upper airway resistance, and breathing parameters were acquired in 10 healthy adults (5 female) during two overnight sleep studies after 4 mg of reboxetine (REB) plus 20 mg of hyoscine butylbromide (HBB) or placebo using a double-blind, placebo-controlled, randomized, cross-over design. Compared with placebo, peak and tonic GG EMG were lower (Mean ± SD: 83 ± 73 vs. 130 ± 75, p = 0.021 and 102 ± 102 vs. 147 ± 123 % wakefulness, p = 0.021, respectively) but the sleep-related reduction in tensor palatini was less (Median [25th, 75th centiles]: 53[45, 62] vs. 34[28, 38] % wakefulness, p = 0.008) with the drug combination during nonrapid eye movement (non-REM) sleep. These changes were accompanied by improved upper airway function including reduced pharyngeal pressure swings, airway resistance, respiratory load compensation, and increased breathing frequency during N2. REB and HBB significantly reduced rapid eye movement sleep compared with placebo (0.6 ± 1.1 vs. 14.5 ± 6.8 % total sleep time, p < 0.001). Contrary to our hypothesis, GG muscle activity (% wakefulness) during non-REM sleep was lower with REB and HBB. However, sleep-related reductions in tensor palatini activity were less and upper airway function improved. These findings provide mechanistic insight into the role of noradrenergic and antimuscarinic processes on upper airway function in humans and have therapeutic potential for obstructive sleep apnea. Australian New Zealand Clinical Trials Registry, https://www.anzctr.org.au, trial ID: ACTRN12616000469415.

Detrimental role of type I interferon signaling in respiratory syncytial virus infection

Abstract Respiratory Syncytial Virus (RSV), the primary cause of lower respiratory tract infections in young children, is a poor inducer of type I interferons (IFN) and is resistant to its canonical antiviral activity. Paradoxically, increased type I IFN has been observed in some studies to correlate with more severe disease in RSV-infected children. Previously, we have shown that a pathogenic reactive oxygen species (ROS) production in the course of RSV infection is caused by a progressive reduction in nuclear and cellular levels of the transcription factor NF-E2-related factor 2 (NRF2), the primary regulator of antioxidant enzyme (AOE) gene expression. Thus, the goal of this study was to determine the contribution of type I IFN to lung innate/inflammatory responses, modulation of AOE expression, and airway disease in experimental RSV infection. Using either IFN alpha/beta receptor knockout mice or IFNAR neutralizing antibody, we found that IFN signaling blockade attenuated RSV-mediated NRF2 degradation and rescued AOE levels (i.e. SOD 1 and Catalase) in the lung, resulting in improved airway function and clinical disease. We also showed that NRF2/AOE rescue in mice lacking IFN signaling is due to the reduced expression of the promyelocytic leukemia protein (PML), a key component of PML nuclear bodies. In addition, levels of RSV-induced pro-inflammatory cytokines including IL-1α/β, IL-6, IL-12(p40), TNF-α, and the chemokines CXCL1, CCL2, 3, 4, and 5 were also reduced in IFN deficient mice. In conclusion, this data shows for the first time that IFN type I signaling plays a critical role in enhancing RSV-mediated airway disease through an innate immune pathways that involve the PML-NRF2-AOE axis.

Abstract: Incidence of Secondary Midface Advancement at the Time of Skeletal Maturity in Patients with a History of Early Le Fort III Distraction Osteogenesis

INTRODUCTION: Le Fort III distraction osteogenesis is commonly recommended for children with syndromic craniosynostosis to reduce exorbitism, improve airway function, and decrease dysmorphism. This purpose of this study is to report on the long-term clinical outcomes of patients with syndromic craniosynostosis who have undergone early primary subcranial Le Fort III distraction osteogenesis and who have been followed longitudinally through skeletal maturity. METHODS: Retrospective review of all patients who underwent Le Fort III distraction osteogenesis between the ages of 3 to 11 years and were followed throughout development with longitudinal dental, medical, radiographic, and photographic evaluations conducted through skeletal maturity and beyond. Inclusion criteria entailed having preoperative medical photographs and cephalometric studies at 6 months and 1, 5, and 10 years postoperatively after the primary Le Fort III distraction osteogenesis as well as cephalometric documentation 6 months and 1 year after the secondary midface advancement after skeletal maturity. RESULTS: 17 patients fulfilled inclusion criteria with a mean age of 5.7 years at the time of initial Le Fort III distraction. The mean advancement of Point A was 14.9mm anteriorly and 2.7 mm inferiorly along the x- and y-axis, respectively. Orbitale moved 10.5mm anteriorly and 2.2mm inferiorly along the x- and y-axis, respectively. At 10 years postoperatively Point A moved 3.4 mm anterior along the x-axis and 4.7mm inferiorly along the y-axis, while orbitale moved 0.4mm posteriorly and 3 mm inferiorly along the x- and y-axis, respectively. At the time skeletal maturity there was a return of occlusal disharmony from normal mandibular growth and a return of proptosis due to remodeling of orbitale inferiorly, and the lateral orbital rim posteriorly, while the globe continued to grow in the anterior vector. All but one study patient underwent or is scheduled to undergo a secondary midface advancement at the Le Fort III and Le Fort I level after skeletal maturity was attained. CONCLUSION: The data demonstrates that patients who undergo early Le Fort III distraction osteogenesis before the age of mixed dentition will still most likely need a secondary midface advancement after skeletal maturity is reached given that there is a small degree of anterior growth at the level of the maxilla and no anterior growth at orbitale over time.

Rutin has anti-asthmatic effects in an ovalbumin-induced asthmatic mouse model

Purpose: To investigate the anti-asthmatic effects of the flavonoid rutin in an ovalbumin (OVA)-induced asthmatic mouse model. Methods: Asthma was induced by OVA induction. Effects of rutin (25–100 mg/kg BW) on interleukins (IL)-4, IL-5, and IL-13 and interferon (IFN)-γ in bronchoalveolar lavage fluid (BALF) and serum OVAspecific IgE levels were assessed by enzyme linked immunosorbent assay (ELISA). Airway hyperresponsiveness (AHR) was measured by determining lung compliance and airway resistance. Expression levels of p-I-κBα, p-NF-κB p65, TNF-α, and Foxp3 were also assessed. The CD4 + CD25 + Foxp3 + T regulatory cell population was determined by flow cytometry. Results: Rutin significantly ( p < 0.05) decreased Th2 cytokines (IL-4, IL-5, IL-13), whereas it enhanced IFN-γ levels in BALF. Decreased OVA-specific serum IgE was also observed with improved lung histology. Rutin was effective in reducing AHR and regulating the expression levels of p-I-κBα, p-NF-κB p65, and TNF α, and also increased the CD4 + CD25 + Foxp3 + Treg cell population and Foxp3 mRNA and protein levels. Conclusion: Rutin effectively suppresses OVA-induced asthma and improves airway function by suppressing inflammatory mediators and inflammatory cell infiltration. Keywords: Asthma, CD4 + CD25 + , Cytokines, Inflammation, Ovalbumin, Rutin, Protein levels