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BACKGROUND: Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking. OBJECTIVE: To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down. METHODS: In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator). RESULTS: Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59–1.78] and 1.29 [95% CI, 0.65–2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers. CONCLUSIONS: In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.

Pediatric optic neuritis (ON) is a rare disease that has not been well characterized. The Pediatric ON Prospective Outcomes Study (PON1) was the first prospective study to our knowledge aiming to evaluate visual acuity (VA) outcomes, including VA, recurrence risk, and final diagnosis 2 years after enrollment.Nonrandomized observational study at 23 pediatric ophthalmology or neuro-ophthalmology clinics in the United States and Canada.A total of 28 (64%) of 44 children initially enrolled in PON1 (age 3-16 years) who completed their 2-year study visit.Participants were treated at the investigator's discretion.Age-normal monocular high-contrast VA (HCVA). Secondary outcomes included low-contrast VA (LCVA), neuroimaging findings, and final diagnoses.A total of 28 participants completed the 2-year outcome with a median enrollment age of 10.3 years (range, 5-15); 46% were female, and 68% had unilateral ON at presentation. Final 2-year diagnoses included isolated ON (n = 11, 39%), myelin oligodendrocyte glycoprotein-associated demyelination (n = 8, 29%), multiple sclerosis (MS) (n = 4,14%), neuromyelitis optica spectrum disease (NMOSD) (n = 3, 11%), and acute disseminated encephalomyelitis (n = 2, 7%). Two participants (7%; 95% confidence interval [CI], 1-24) had subsequent recurrent ON (plus 1 participant who did not complete the 2-year visit); all had MS. Two other participants (7%) had a new episode in their unaffected eye. Mean presenting HCVA was 0.81 logarithm of the minimum angle of resolution (logMAR) (∼20/125), improving to 0.14 logMAR (∼20/25Despite poor VA at presentation, most children had marked improvement in VA by 6 months that was maintained over 2 years. Associated neurologic autoimmune diagnoses were common. Additional episodes of ON occurred in 5 (18%) of the participants (3 relapses and 2 new episodes).

A test of suppression was developed to provide a standardized approach to detecting and grading density of suppression in children with intermittent exotropia when manifestly exotropic. This new Office Suppression Test is a three-step procedure to grade suppression on a 4-point scale (from 0 for "negligible suppression" to 3 for "dense suppression"). The test was performed in 57 children 3-13 years of age with intermittent exotropia (distance angle of 16Δ-35Δ, with spontaneous tropia) during enrollment in a randomized trial. Of the 57 children, 51 could complete testing: 28 (55%) had dense suppression, 12 (24%) had moderate suppression, 5 (10%) had mild suppression, and 6 (12%) had negligible suppression. In a subgroup of 20 untreated children, suppression was evaluated again at 8 weeks. There was moderate agreement between suppression scores at baseline and at 8 weeks (weighted κ = 0.65 [95% CI, 0.45-0.84]).

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p, Haemoglobin is nonlinearly associated with clinical outcomes in COPD, with increased morbidity at either extreme of the observed range, suggesting that therapeutic correction of anaemia might be most beneficial if targeting normal haemoglobin values https://bit.ly/3ovl7Lt

Introduction: We evaluated risk factors and demographic characteristics of associated with mild cognitive impairment (MCI) in patients with COPD. Methods: 220 individuals with COPD enrolled in a cohort study designed to evaluate anxiety conducted at 16 clinical centers. Cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA), a cutoff score of Results: The median age was 65 years and 54% of participants were male. 119(54%) of participants had MCI as classified by MoCA. In multivariable logistic regression, higher odds ratios (OR) (95% confidence interval) for MCI (MoCA) Conclusions: COPD patients commonly screen positive for MCI. Characteristics associated with MCI included age, African-American race, sleep disturbance and persistent phlegm.

To characterize a cohort of children with airflow limitation resistant to bronchodilator (BD) therapy.Pulmonary function tests performed in children 6-17 years of age at 15 centers in a clinical research consortium were screened for resistant airflow limitation, defined as a post-BD FEV582 children were identified. Median age was 13 years (IQR: 11, 16), 60% were males; 62% were Caucasian, 28% were African-American; 19% were obese; 32% were born prematurely and 21% exposed to second hand smoke. Pulmonary diagnoses included asthma (93%), prior significant pneumonia (28%), and bronchiectasis (5%). 65% reported allergic rhinitis, and 11% chronic sinusitis. Subjects without a history of asthma had significantly lower post-BD FEVThe most prevalent diagnosis in children with BD-resistant airflow limitation is asthma. Allergic rhinitis and premature birth are common co-morbidities. Children without a history of asthma, as well as those with asthma but no allergic rhinitis, had lower pulmonary function. Children with BD-resistant airflow limitation may represent a sub-group of children with persistent obstruction and high risk for life-long airway disease.

Increasing stress on the global water supply necessitates the measurement of water consumption as a sustainability metric to evaluate energy production, including the production of transportation fuels (gasoline, diesel, jet fuel) at petroleum refineries. This study estimated refinery water consumption for petroleum fuels by considering three typical refinery configurations (cracking, light coking, and heavy coking) that process different crude qualities (e.g., American Petroleum Institute Gravity (API) gravity and sulfur content). The results showed that refinery water consumption was 0.34, 0.44, and 0.47 bbl water/bbl crude (L water/L crude) for cracking, light coking, and heavy coking configurations, respectively. The water consumption for a specific refinery product was estimated using an energy allocation approach at the process unit level. The results indicated that gasoline production consumes the largest amount of water, 0.60–0.71 gal water/gal gasoline (0.60–0.71 L water/L gasoline), due to the energy-intensive (and thus water-intensive) processing of gasoline components (mainly sourced from alkylation, reformer, and fluid catalytic cracking units). In contrast, jet fuel production consumes the least water, 0.09 gal water/gal jet fuel, for all three refinery configurations, because it is sourced directly from the crude distillation unit with minimal post-treating. The consumption of diesel is most sensitive to refinery configuration with 0.20, 0.30, and 0.40 gal water/gal diesel (L water/L diesel) for cracking, light coking and heavy coking configurations, respectively. This is mainly because as configuration complexity increases to process heavier and sourer crudes, a sizable burden of hydrogen production from steam methane reforming unit is allocated to diesel fuel production (including diesel sulfur removal). The trend of water consumption associated with these refinery products is consistent with the energy consumption for their production.

BACKGROUND: Diffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown. OBJECTIVE: The goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging. METHODS: Data for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV(1) > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV(1) ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV(1) percent predicted among other confounders. RESULTS: In multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P < .001]; St. George’s Respiratory Questionnaire, 1.67 [P < .001]; Medical Outcomes Study Short Form 36 Physical Function, –0.89 [P < .001]), exercise performance (6-min walk distance, –45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV(1) alone, or both Dlco and FEV(1) were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes). CONCLUSIONS: Impairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD.

© 2019 Asian Pacific Society of Respirology Background and objective: The reduction of forced expiratory volume in 1 s (FEV1) in response to methacholine challenge in asthma may reflect two components: airway narrowing, assessed by the change in FEV1/forced vital capacity (FVC), and airway closure, assessed by the change in FVC. The purpose of this study was to determine the degree and determinants of airway closure in response to methacholine in a large group of asthmatic patients participating in studies conducted by the American Lung Association-Airways Clinical Research Centers (ALA-ACRC). Methods: We used the methacholine challenge data from participants in five studies of the ALA-ACRC to determine the closing index, defined as the contribution of airway closure to the decrease in FEV1, and calculated as %ΔFVC/%ΔFEV1. Results: There were a total of 936 participants with asthma, among whom the median closing index was 0.67 relative to that of a published healthy population of 0.54. A higher closing index was associated with increased age (10-year increments) (0.04, 95% CI = 0.02, 0.05, P < 0.005) and obesity (0.07, 95% CI = 0.03, 0.10, P < 0.001). There was no association between the closing index and asthma control. Conclusion: Our findings confirm that airway closure in response to methacholine occurs in a large, diverse population of asthmatic participants, and that increased airway closure is associated with older age and obesity. These findings suggest that therapies targeting airway closure may be important in patients with a high closing index.

This study examines the association of myelin oligodendrocyte glycoprotein immunoglobulin G–associated disorder with pediatric optic neuritis to guide prognosis and treatment.

Rationale: Anxiety is a common comorbidity of chronic obstructive pulmonary disease (COPD) that is associated with higher morbidity and mortality. We evaluated three anxiety screening questionnaires: the Generalized Anxiety Disorder 7-Item Scale (GAD-7), the Hospital Anxiety and Depression Scale Anxiety subscale (HADS-A), and the Anxiety Inventory for Respiratory Disease (AIR). Objectives: To evaluate and compare the test performance characteristics of three anxiety screening questionnaires, using the Mini-International Neuropsychiatric Interview (MINI), version 7.0, as the “gold standard.” Methods: Individuals with COPD were recruited at 16 centers. The MINI and questionnaires were administered by trained research coordinators at an in-person visit and readministered by telephone 2–4 weeks later. A composite score for the presence of any Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) anxiety disorder was computed, based on the MINI as the gold standard, compared with a participant screening positive on self-report measures for these analyses. Results: Two hundred and twenty eligible individuals with COPD were enrolled; 219 completed the study. Eleven percent were identified as having a DSM-V anxiety disorder, based on the MINI. Elevated anxiety symptoms based on questionnaires were 38% for the AIR, 30% for the GAD-7, and 20% for the HADS-A. Area under the receiver operating characteristic curve (AUC) was highest for the GAD-7 (0.78; 95% confidence interval [CI], 0.69–0.87), followed by the HADS-A (0.74; 95% CI, 0.64–0.84) and the AIR (0.66; 95% CI, 0.56–0.76). The AUC for the GAD-7 was significantly greater than for the AIR (P = 0.014). Sensitivity was not statistically different among the questionnaires: 77% for the GAD-7, 63% for the HADS-A, and 66% for the AIR. The HADS-A had the highest specificity, 85%, which was significantly higher than that of the GAD-7 (77%; P

Background Chronic lung disease such as asthma or COPD may be exacerbated by electronic nicotine device (ENDS) use. Despite this, little is known about the extent to which adults with chronic lung disease use ENDS and what factors are associated with use. Methods We analyzed data from the second wave of the Population Assessment of Tobacco and Health (PATH) study. The PATH study recruited 28,362 U.S. adults over the age of 18 using a multi-stage randomized sampling protocol. Our analysis was restricted to adults who reported being treated for COPD or asthma in the past 12 months (N=1,748). Among these individuals, we examined prevalence of ever and current ENDS use, intensity of use, and motivations for use. Results Approximately one-quarter (24.72%) of individuals being treated for COPD or asthma reported ever using ENDS; 4.09% were established users and 3.99% were experimental users. Established e-cigarette users were more likely to be white and younger. The average number of puffs from an e-cigarette on the last day used was 18.05. Key motivations for ENDS use among this population include: perceptions of less harm to the user (79.72%) and to other people (78.84%), because they can be used in places where people can't smoke (74.2%), perceptions that they help people quit smoking (73.94%), perceived acceptability to non-smokers than cigarettes (70.37%), and appealing flavors (64.0%). Conclusions A significant number of individuals being treated for lung disease have or are currently using ENDS, and many of these individuals use these products for health-related concerns. Healthcare providers treating these patients should ask about ENDS use and offer counseling and treatment to help these individuals become tobacco free.

Brown RH, Henderson RJ, Sugar EA, Holbrook JT, Wise RA, on behalf of the American Lung Association Airways Clinical Research Centers. Reproducibility of airway luminal size in asthma measured by HRCT. J Appl Physiol 123: 876–883, 2017. First published July 13, 2017; doi:10.1152/japplphysiol.00307.2017.—High-resolution CT (HRCT) is a well-established imaging technology used to measure lung and airway morphology in vivo. However, there is a surprising lack of studies examining HRCT reproducibility. The CPAP Trial was a multicenter, randomized, three-parallel-arm, sham-controlled 12-wk clinical trial to assess the use of a nocturnal continuous positive airway pressure (CPAP) device on airway reactivity to methacholine. The lack of a treatment effect of CPAP on clinical or HRCT measures provided an opportunity for the current analysis. We assessed the reproducibility of HRCT imaging over 12 wk. Intraclass correlation coefficients (ICCs) were calculated for individual airway segments, individual lung lobes, both lungs, and air trapping. The ICC [95% confidence interval (CI)] for airway luminal size at total lung capacity ranged from 0.95 (0.91, 0.97) to 0.47 (0.27, 0.69). The ICC (95% CI) for airway luminal size at functional residual capacity ranged from 0.91 (0.85, 0.95) to 0.32 (0.11, 0.65). The ICC measurements for airway distensibility index and wall thickness were lower, ranging from poor (0.08) to moderate (0.63) agreement. The ICC for air trapping at functional residual capacity was 0.89 (0.81, 0.94) and varied only modestly by lobe from 0.76 (0.61, 0.87) to 0.95 (0.92, 0.97). In stable well-controlled asthmatic subjects, it is possible to reproducibly image unstimulated airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability. NEW & NOTEWORTHY There is a surprising lack of studies examining the reproducibility of high-resolution CT in asthma. The current study examined reproducibility of airway measurements. In stable well-controlled asthmatic subjects, it is possible to reproducibly image airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability.

Background Because respiratory tract infections (RTIs) precede most exacerbations, a better understanding of the risk factors of RTIs and RTI-associated exacerbations in patients with asthma is a pressing public health need. Obesity in patients with asthma is associated with worse asthma control and higher asthma-associated health care utilization, but its effect on RTI risk is unknown. Objective We aimed to study the association of body mass index (BMI) classification on the risk of self-reported RTIs and related asthma morbidity among adults and children with asthma. Methods This post hoc analysis of 5 large asthma trials involving 747 children and 1287 adults compared BMI classification, defined as lean, overweight, and obese based on age-appropriate BMI and BMI-percentile conventions. The primary outcome was rate of visits with RTIs. Secondary asthma outcomes included upper respiratory infection (URI) severity, systemic steroid use, and health care contact. Results Children had 1.4 times the rate of RTI compared with adults (95% confidence interval 1.27-1.56). In all participants, BMI classification did not affect the rate of visits with RTI. In children, BMI classification did not affect URI severity, all-cause asthma events, or RTI-associated asthma events. However, in adults, higher BMI classification was associated with an increase in moderate/severe URI (P = .02). Adults with higher BMI classification also had increased rates of all-cause and RTI-associated asthma exacerbations requiring systemic steroids and health care contact. Conclusions BMI classification was not associated with an increased risk of RTIs in children or adults. In adults only, obesity was associated with increased URI severity and all-cause and RTI-associated asthma morbidity.

Susac Syndrome (SS) and multifocal motor neuropathy (MMN) are rare autoimmune neurological conditions which can affect women of childbearing years. The effect of pregnancy on these disorders is poorly characterised. We report a case of SS first manifesting in pregnancy with challenges in diagnosis and management and a poor clinical outcome, and a case of MMN manifesting in pregnancy then relapsing in a subsequent pregnancy. A summary of other cases in the literature and the postulated underlying immune mechanisms is presented.

Smoking asthmatics respond worse to existing asthma therapies and have more asthma symptoms and exacerbations.We evaluated the Asthma Control Test (ACT) for assessing asthma control among smokers.Adults with asthma who smoked were enrolled and followed for 6 weeks. The statistical properties, validity, and responsiveness of the ACT were evaluated. Physician global assessment (GS) of asthma was the "gold standard."A total of 151 participants were enrolled: 52% female and 48% male. The median (interquartile ranges) was 35 (27, 43) years for age, 11 (7, 18) for pack-years, and 16 (13, 20) for the ACT score. Participants self-identified as African American (49%), non-Hispanic whites (38%), and Hispanic whites (11%). Participants were classified as well controlled (24%), not well controlled (42%), or very poorly controlled (34%) at enrollment. Cronbach's alpha (95% confidence interval [CI]) for the ACT at enrollment was 0.81 (0.76, 0.85). The intraclass correlation coefficient (95% CI) for agreement of scores at enrollment and 6 weeks was 0.68 (0.57, 0.78) in participant with stable asthma (n = 93). ACT scores were associated with GS (P.001). Area under the receiver operating characteristic (ROC) curve (95% CI) for an ACT cutoff score of ≤19 (not well controlled) was 0.76 (0.67, 0.84). The ACT score with the maximum area under the ROC curve was 18.6.The ACT questionnaire was reliable and discriminated between levels of asthma control in smoking asthmatics with similar sensitivity and specificity as nonsmoking asthmatics, which confirms its value as a tool for the management of asthma in this prevalent but understudied subgroup of subjects.

Inductive programming systems characteristically exhibit an exponential explosion in search time as one increases the size of the programs to be generated. As a way of overcoming this, we introduce incremental learning, a process in which an inductive programming system automatically modifies its inductive bias towards some domain through solving a sequence of gradually more difficult problems in that domain. We demonstrate a simple form of incremental learning in which a system incorporates solution programs into its background knowledge as it progresses through a sequence of problems. Using a search-based inductive functional programming system modelled on the MagicHaskeller system of Katayama [4], we perform a set of experiments comparing the performance of inductive programming with and without incremental learning. Incremental learning is shown to produce a performance improvement of at least a factor of thirty on each of the four problem sequences tested. We describe how, given some assumptions, inductive programming with incremental learning can be shown to have a polynomial, rather than exponential, time complexity with respect to the size of the program to be generated. We discuss the difficulties involved in constructing suitable problem sequences for our incremental learning system, and consider what improvements can be made to overcome these difficulties.

Receiver structures are developed to implement homodyne detection operating near the quantum limit and optimal bandwidth efficiency using monolithic laser diodes. The homodyne receiver approaches examined used NRZ and RZ formats and AM and PM subcarriers. Signalling schemes using subcarriers or Manchester BPSK can achieve a factor of 20-27 relaxation in laser linewidth requirements by minimizing the spectral overlap between the data modulation and the phase tracking loop. It is shown that Manchester BPSK (with 0.5 dB carrier leakage) can achieve 2.5 dB better receiver sensitivity than heterodyne BPSK with better bandwidth efficiency and an overall IF linewidth requirement of 390 kHz for a Gbps data rate and 0.5 dB phase tracking penalty at BER of 10 exp -6. For 1 dB carrier leakage, the IF linewidth requirement relaxes to 830 kHz. The feasibility of homodyne BPSK receivers with monolithic laser diode sources is established.

Experimental measurements of direct detection receiver sensitivity for state of the art radiation hardened silicon avalanche photodiodes are compared with simulation results and show excellent agreement, generally within less than 0.25 dB. It is shown that for low preamp thermal noise and zero source laser extinction ratio, the McIntyre gain statistics of the APD result in receiver sensitivity as much as 2 dB better than predicted by Gaussian statistics. However, for larger preamp noise and finite laser extinction ratios there is very little difference between Gaussian and McIntyre sensitivity predictions. A binary PPM receiver sensitivity of -52 dBm for 10 exp -6 bit error rate at 220 Mbps was measured with a laser extinction ratio of 13.2 percent, corresponding to 102 photoelectrons per bit.