The total-breath method yields higher values of DLCO and TLC than the conventional method.

BACKGROUND: The 2017 ATS/ERS technical standard for measuring the single-breath diffusing capacity (DLCO) proposed the "rapid-gas-analyzer" (RGA) or, equivalently, "total-breath" (TB) method for the determination of total lung capacity (TLC). In this study, we compared DLCO and TLC values estimated using the TB and conventional method, and how estimated TLC using these two methods compared to that determined by body plethysmography. METHOD: A total of 95 people with COPD (GOLD grades 1-4) and 23 healthy subjects were studied using the EasyOne Pro (ndd Medical Technologies, Switzerland) and Master Screen Body (Vyaire Medical, Höchberg, Germany). RESULTS: On average the TB method resulted in higher values of DLCO (mean ± SD Δ = 0.469 ± 0.267; 95%CI: 0.420; 0.517 mmol*min-1*kPa-1) and TLC (Δ = 0.495 ± 0.371; 95%CI: 0.427; 0.562 L) compared with the conventional method. In healthy subjects the ratio between TB and conventional DLCO was close to one. TLC estimated using both methods was lower than that determined by plethysmography. The difference was smaller for the TB method (Δ = 1.064 ± 0.740; 95%CI: 0.929; 1.199 L) compared with the conventional method (Δ = 1.558 ± 0.940; 95%CI: 1.387; 1.739 L). TLC from body plethysmography could be estimated as a function of TB TLC and FEV1 Z-Score with an accuracy (normalized root mean square difference) of 9.1%. CONCLUSION: The total-breath method yielded higher values of DLCO and TLC than the conventional analysis, especially in subjects with COPD. TLC from the total-breath method can also be used to estimate plethysmographic TLC with better accuracy than the conventional method. The study is registered under clinicaltrial.gov NCT04531293.

Improving asthma outcomes: Clinicians' perspectives on peripheral airways.

Disease of the peripheral (or small) airways is fundamental in asthma, being closely related to symptoms (or lack of control of them), airway hyperresponsiveness, spirometric abnormalities, risk of loss of control, or exacerbations and inflammation. Current technology now allows routine measurement of peripheral airway function. Having a working concept of peripheral airways disease in asthma is arguably very useful to clinicians and beneficial to patients because it allows a more comprehensive assessment of asthma severity (rather than just symptoms alone, which is the norm), tracking of progress or deterioration, and assessing response to treatment. Oscillometry is a sensitive way to monitor the peripheral airways, whereas multiple breath nitrogen washout parameters are excellent measures of future risk. In the longer term, physiologic measurements will be crucial in research to define causes and find new disease-modifying treatments.

Quantification of smooth muscle in human airways by polarization-sensitive optical coherence tomography requires correction for perichondrium.

Quantifying airway smooth muscle (ASM) in patients with asthma raises the possibility of improved and personalized disease management. Endobronchial polarization-sensitive optical coherence tomography (PS-OCT) is a promising quantitative imaging approach that is in the early stages of clinical translation. To date, only animal tissues have been used to assess the accuracy of PS-OCT to quantify absolute (rather than relative) ASM in cross sections with directly matched histological cross sections as validation. We report the use of whole fresh human and pig airways to perform a detailed side-by-side qualitative and quantitative validation of PS-OCT against gold-standard histology. We matched and quantified 120 sections from five human and seven pig (small and large) airways and linked PS-OCT signatures of ASM to the tissue structural appearance in histology. Notably, we found that human cartilage perichondrium can share with ASM the properties of birefringence and circumferential alignment of fibers, making it a significant confounder for ASM detection. Measurements not corrected for perichondrium overestimated ASM content several-fold (P < 0.001, paired t test). After careful exclusion of perichondrium, we found a strong positive correlation (r = 0.96, P < 0.00001) of ASM area measured by PS-OCT and histology, supporting the method's application in human subjects. Matching human histology further indicated that PS-OCT allows conclusions on the intralayer composition and in turn potential contractile capacity of ASM bands. Together these results form a reliable basis for future clinical studies.NEW & NOTEWORTHY Polarization-sensitive optical coherence tomography (PS-OCT) may facilitate in vivo measurement of airway smooth muscle (ASM). We present a quantitative validation correlating absolute ASM area from PS-OCT to directly matched histological cross sections using human tissue. A major confounder for ASM quantification was observed and resolved: fibrous perichondrium surrounding hyaline cartilage in human airways presents a PS-OCT signature similar to ASM for birefringence and optic axis orientation. Findings impact the development of automated methods for ASM segmentation.

Association of novel adult cough subclasses with clinical characteristics and lung function across six decades of life in a prospective, community-based cohort in Australia: an analysis of the Tasmanian Longitudinal Health Study (TAHS).

BACKGROUND: Cough is a common yet heterogeneous condition. Little is known about the characteristics and course of cough in general populations. We aimed to investigate cough subclasses, their characteristics from childhood across six decades of life, and potential treatable traits in a community-based cohort. METHODS: For our analysis of the Tasmanian Longitudinal Health Study (TAHS), a prospective, community-based cohort study that began on Feb 23, 1968, and has so far followed up participants in Tasmania, Australia, at intervals of 10 years from a mean age of 7 years to a mean age of 53 years, we used data collected as part of the TAHS to distinguish cough subclasses among current coughers at age 53 years. For this analysis, participants who answered Yes to at least one cough-related question via self-report questionnaire were defined as current coughers and included in a latent class analysis of cough symptoms; participants who answered No to all nine cough-related questions were defined as non-coughers and excluded from this analysis. Two groups of longitudinal features were assessed from age 7 years to age 53 years: previously established longitudinal trajectories of FEV1, forced vital capacity [FVC], FEV1/FVC ratio, asthma, and allergies-identified via group-based trajectory analysis or latent class analysis-and symptoms at different timepoints, including asthma, current productive cough, ever chronic productive cough, current smoking, and second-hand smoking. FINDINGS: Of 8583 participants included at baseline in the TAHS, 6128 (71·4%) were traced and invited to participate in a follow-up between Sept 3, 2012, and Nov 8, 2016; 3609 (58·9%) of these 6128 returned the cough questionnaire. The mean age of participants in this analysis was 53 years (SD 1·0). 2213 (61·3%) of 3609 participants were defined as current coughers and 1396 (38·7%) were categorised as non-coughers and excluded from the latent class analysis. 1148 (51·9%) of 2213 participants in this analysis were female and 1065 (48·1%) were male. Six distinct cough subclasses were identified: 206 (9·3%) of 2213 participants had minimal cough, 1189 (53·7%) had cough with colds only, 305 (13·8%) had cough with allergies, 213 (9·6%) had intermittent productive cough, 147 (6·6%) had chronic dry cough, and 153 (6·9%) had chronic productive cough. Compared with people with minimal cough, and in contrast to other cough subclasses, people in the chronic productive cough and intermittent productive cough subclasses had worse lung function trajectories (FEV1 persistent low trajectory 2·9%, 6·4%, and 16·1%; p=0·0011, p<0·0001; FEV1/FVC early low-rapid decline trajectory 2·9%, 12·1%, and 13·0%; p=0·012, p=0·0007) and a higher prevalence of cough (age 53 years 0·0%, 32·4% [26·1-38·7], and 50·3% [42·5-58·2]) and asthma (age 53 years 6·3% [3·7-10·6], 26·9% [21·3-33·3], and 41·7% [24·1-49·7]) from age 7 years to age 53 years. INTERPRETATION: We identified potential treatable traits for six cough subclasses (eg, asthma, allergies, and active and passive smoking for productive cough). The required management of productive cough in primary care (eg, routine spirometry) might differ from that of dry cough if our findings are supported by other studies. Future population-based studies could apply our framework to address the heterogeneity and complexity of cough in the community. FUNDING: The National Health and Medical Research Council of Australia, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, Victorian Asthma Foundation, Queensland Asthma Foundation, Tasmanian Asthma Foundation, The Royal Hobart Hospital Research Foundation, the Helen MacPherson Smith Trust, GlaxoSmithKline, and the China Scholarship Council.

Preclinical investigations on broccoli-derived sulforaphane for the treatment of ophthalmic disease.

Vision loss causes a significant burden on individuals and communities on a financial, emotional and social level. Common causes include age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and retinitis pigmentosa (RP; also known as 'rod-cone dystrophy'). As the population continues to grow and age globally, an increasing number of people will experience vision loss. Hence, there is an urgent need to develop therapies that can curb early pathological events. The broccoli-derived compound, sulforaphane (SFN), is reported to have multiple health benefits and modes of action. In this review, we outline the preclinical findings on SFN in ocular diseases and discuss the future clinical testing of this compound.

Functional lung imaging using novel and emerging MRI techniques.

Respiratory diseases are leading causes of death and disability in the world. While early diagnosis is key, this has proven difficult due to the lack of sensitive and non-invasive tools. Computed tomography is regarded as the gold standard for structural lung imaging but lacks functional information and involves significant radiation exposure. Lung magnetic resonance imaging (MRI) has historically been challenging due to its short T2 and low proton density. Hyperpolarised gas MRI is an emerging technique that is able to overcome these difficulties, permitting the functional and microstructural evaluation of the lung. Other novel imaging techniques such as fluorinated gas MRI, oxygen-enhanced MRI, Fourier decomposition MRI and phase-resolved functional lung imaging can also be used to interrogate lung function though they are currently at varying stages of development. This article provides a clinically focused review of these contrast and non-contrast MR imaging techniques and their current applications in lung disease.

Implementation of a fully integrated CM direct compression and coating process at a commercial pharmaceutical facility - Part 2: PAT and RTD results for normal operational conditions batches.

This is the second of two articles detailing the continuous manufacturing (CM) development and implementation activities for an marketed product which have been realized in novel, qualified equipment, using validated control strategy elements to enable manufacture of batches under current good manufacturing practices (cGMP) and compliant with data integrity principles. Here, the application of process analytical technologies (PAT) and automation tools on batches produced under normal operational conditions is reviewed. The results from residence time distribution (RTD) models for predicting API concentration, in-line near infrared (NIR) testing of blend uniformity (BU) and at-line NIR spectroscopy analysis of core tablet concentration and tablet identity for real-time release testing (RTRT) are discussed. The influences of process equipment and design choices on NIR and RTD model variability, as well as the use of the PAT tools for monitoring the evolving properties understanding of CM process development, such as overcoming flow instabilities, is described. Results demonstrate that the RTD and NIR models developed and validated are robust to operating conditions and are critical for assuring steady state control of the continuous manufacturing process. Finally, the NIR and RTD model lifecycle, including procedures for necessary and normal model upgrades in a cGMP production environment, are presented.

Assessing the calculation of conductive and acinar ventilatory heterogeneity indices Scond and Sacin from multiple-breath washout data.

Sensor errors resulting in elevated values of N2 concentration [N2] in commercial multiple-breath washout (MBW) devices have been shown to prolong the washout and result in erroneously high functional residual capacity (FRC) and lung clearance index (LCI) values. The errors also affect the indices of conductive and acinar ventilatory heterogeneity (Scond and Sacin) although the mechanism by which this change in values occurs remains unclear. Exploring these effects also provides a timely opportunity to examine the appropriateness of the algorithm used to calculate these indices. Using a two-compartment model with differing specific ventilation (SV) such that the lower SV unit empties late, noise-free MBW were simulated both corrected and uncorrected for the recent sensor error. Scond was calculated using regression of normalized phase III slope (SnIII) against lung turnover (TO) from a TO range starting at 1.5 and ending at an upper turnover (TOupper) between 4 and 8 (default 6) over a range of simulated values. The principal effect of the sensor error was that as the MBW proceeded the phase III slope of successive breaths was normalized by an increasingly overestimated [N2], resulting in SnIII values that fell precipitously at high TO, greatly reducing Scond. Reanalysis of previously published data and of simulated data showed a large proportional bias in Scond, whereas Sacin was only minimally affected. In adult subject data, reducing TOupper below 5.5 was associated with a large drop of up to ∼60% in Scond calculated from data corrected for sensor error. Raising the upper TO limit elevated Scond by ∼20% but with a large concomitant increase in variability. In contrast to Scond, Sacin was relatively unaffected by changes in TOupper with changes of <3%. This work serves to emphasize that the upper limit of TO of 6 represents an appropriate upper limit for the calculation of Scond.NEW & NOTEWORTHY Sensor errors that elevated values of N2 concentration in commercial multiple-breath washout (MBW) devices resulted in errors in calculated parameters including Scond and Sacin. We examined the mechanism of the change in values produced by these errors and explored the appropriateness of the calculation of Scond and Sacin. This work serves to emphasize that the current algorithm in use is appropriate for the calculation of Scond and Sacin.

Associations of physical activity levels, and attitudes towards physical activity with blood pressure among adults with high blood pressure in Bangladesh.

BACKGROUND: Physical activity is important for the control of high blood pressure (hypertension). We aimed to investigate the associations of current physical activity levels, sedentary time, knowledge of and attitude towards physical activity with blood pressure in people with hypertension in a rural area in Bangladesh. METHODS: A total of 307 adults aged 30 to 75 years with hypertension were recruited from the Banshgram Union of Narial district as part of a cluster-randomized control trial. Current blood pressure was measured as the outcome variable. Associated variables included physical activity at work, travel to and from places, recreational activity, metabolic equivalent task (MET)-min, sedentary time, and awareness of and attitudes towards physical activity. Rasch analysis was used to compute a combined score from the five awareness of and attitudes towards physical activity items and categorized into 0-40 (towards negative attitude), 41-60 score (mixed attitude) and 61-100 (positive attitude). We used a generalised linear model to analyze the data. RESULTS: Participants (n = 68, 22.1%) who engaged in vigorous-intensity physical activity that causes large increases in breathing or heart rate like carrying or lifting heavy loads, digging or construction work for at least 10 minutes continuously had lower systolic blood pressure (SBP) (mean (95% confidence interval (CI)), 143.6 (140.1, 147.2)) compared to those who did not take part in a vigorous-intensity physical activity (mean (95% CI), 150 (147.6, 152.3)). MET-min less than 600 min/week was significantly associated with higher SBP 153.8 (148.1, 159.6) than MET-min 600-2999 min/week 148.0 (143.0, 152.9) and MET-min>3000 min/week 146.9 (144.5, 149.3), p = 0.001 for trend. Sitting time more than four hours a day was associated with higher DBP 91.4 (89.7, 93.0) compared to those who had sitting time less than fours a day 88.6 (87.1, 90.1). People with positive attitudes were associated with a reduced SBP of 10.6 (0.36, 20.8) mmHg and DBP 5.88 (0.47, 11.3) compared to the people who had a negative attitude towards taking part in physical activity. CONCLUSIONS: Participating in high physical activity and positive attitudes towards physical activity were associated with lower blood pressure levels. Physical activity awareness programs should be implemented to increase awareness of health benefits and increase participation in high physical activity.

Lifetime spirometry patterns of obstruction and restriction, and their risk factors and outcomes: a prospective cohort study.

BACKGROUND: Interest in lifetime lung function trajectories has increased in the context of emerging evidence that chronic obstructive pulmonary disease (COPD) can arise from multiple disadvantaged lung function pathways, including those that stem from poor lung function in childhood. To our knowledge, no previous study has investigated both obstructive and restrictive lifetime patterns concurrently, while accounting for potential overlaps between them. We aimed to investigate lifetime trajectories of the FEV1/forced vital capacity (FVC) ratio, FVC, and their combinations, relate these combined trajectory groups to static lung volume and gas transfer measurements, and investigate both risk factors for and consequences of these combined trajectory groups. METHODS: Using z scores from spirometry measured at ages 7, 13, 18, 45, 50, and 53 years in the Tasmanian Longitudinal Health Study (n=2422), we identified six FEV1/FVC ratio trajectories and five FVC trajectories via group-based trajectory modelling. Based on whether trajectories of the FEV1/FVC ratio and FVC were low (ie, low from childhood or adulthood) or normal, four patterns of lifetime spirometry obstruction or restriction were identified and compared against static lung volumes and gas transfer. Childhood and adulthood characteristics and morbidities of these patterns were investigated. FINDINGS: The prevalence of the four lifetime spirometry patterns was as follows: low FEV1/FVC ratio only, labelled as obstructive-only, 25·8%; low FVC only, labelled as restrictive-only, 10·5%; both low FEV1/FVC ratio and low FVC, labelled as mixed, 3·5%; and neither low FEV1/FVC ratio nor low FVC, labelled as reference, 60·2%. The prevalence of COPD at age 53 years was highest in the mixed pattern (31 [37%] of 84 individuals) followed by the obstructive-only pattern (135 [22%] of 626 individuals). Individuals with the mixed pattern also had the highest prevalence of parental asthma, childhood respiratory illnesses, adult asthma, and depression. Individuals with the restrictive-only pattern had lower total lung capacity and residual volume, and had the highest prevalence of childhood underweight, adult obesity, diabetes, cardiovascular conditions, hypertension, and obstructive sleep apnoea. INTERPRETATION: To our knowledge, this is the first study to characterise lifetime phenotypes of obstruction and restriction simultaneously using objective data-driven techniques and unique life course spirometry measures of FEV1/FVC ratio and FVC from childhood to middle age. Mixed and obstructive-only patterns indicate those who might benefit from early COPD interventions. Those with the restrictive-only pattern had evidence of true lung restriction and were at increased risk of multimorbidity by middle age. FUNDING: National Health and Medical Research Council of Australia, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, The Victorian, Queensland & Tasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, and GlaxoSmithKline.

Post-operative, inpatient rehabilitation after lung transplant evaluation (PIRATE): A feasibility randomized controlled trial.

BACKGROUND: Postoperative rehabilitation is crucial following lung transplantation (LTx); however, it is unclear whether intensive rehabilitation is feasible to deliver in the acute setting. We aimed to establish the feasibility and safety of intensive acute physiotherapy post-LTx. METHODS: This feasibility trial randomized 40 adults following bilateral sequential LTx to either standard (once-daily) or intensive (twice-daily) physiotherapy. Primary outcomes were feasibility (recruitment and delivery of intensive intervention) and safety. Secondary outcomes included six-minute walk test; 60-second sit-to-stand; grip strength; physical activity; pain; EQ-5D-5L; length of stay; and readmissions. Data were collected at baseline, week 3, and week 10 post-LTx. ClinicalTrials.gov #NCT03095859. RESULTS: Of 83 LTx completed during the trial, 49% were eligible and 48% provided consent. Median age was 61 years {range 18-70}; waitlist time 85 days [IQR 35-187]. Median time to first mobilization was 2 days [2-3]. Both groups received a median of 10 [7-14] standard interventions post-randomization. A median of 9 [6-18] individual intensive interventions were attempted (86% successful), the most common barrier being medical procedures/investigations (67%). No intervention-related adverse events or between-group differences in secondary outcomes were observed. CONCLUSIONS: Acute, intensive physiotherapy was feasible and safe post-LTx. This trial provides data to underpin definitive trials to establish efficacy.

Small airways dysfunction is associated with increased exacerbations in patients with asthma.

There is a poor understanding of why some patients with asthma experience recurrent exacerbations despite high levels of treatment. We compared measurements of peripheral ventilation heterogeneity and respiratory system mechanics in participants with asthma who were differentiated according to exacerbation history, to ascertain whether peripheral airway dysfunction was related to exacerbations. Three asthmatic groups: "stable" (no exacerbations for >12 mo, n = 18), "exacerbation-prone" (≥1 exacerbation requiring systemic corticosteroids within the last 12 mo, but stable for ≥1-mo, n = 9), and "treated-exacerbation" (exacerbation requiring systemic corticosteroids within the last 1 mo, n = 12) were studied. All participants were current nonsmokers with <10 pack yr smoking history. Spirometry, static lung volumes, ventilation heterogeneity from multibreath nitrogen washout (MBNW), and respiratory system mechanics from oscillometry were measured. The exacerbation-prone group compared with the stable group had slightly worse spirometry [forced expired volume in 1 s or FEV1 z-score -3.58(1.13) vs. -2.32(1.06), P = 0.03]; however, acinar ventilation heterogeneity [Sacin z-score 7.43(8.59) vs. 3.63(3.88), P = 0.006] and respiratory system reactance [Xrs cmH2O·s·L-1 -2.74(3.82) vs. -1.32(1.94), P = 0.01] were much worse in this group. The treated-exacerbation group had worse spirometry but similar small airway function, compared with the stable group. Patients with asthma who exacerbate have worse small airway function as evidenced by increases in Sacin measured by MBNW and ΔXrs from oscillometry, both markers of small airway dysfunction, compared with those that do not.NEW & NOTEWORTHY This study assessed the relationship between peripheral airway function, measured by multiple breath nitrogen washout and oscillometry impedance, and exacerbation history. We found that those with a history of exacerbation in the last year had worse peripheral airway function, whereas those recently treated for an asthma exacerbation had peripheral airway function that was comparable to the stable group. These findings implicate active peripheral airway dysfunction in the pathophysiology of an asthma exacerbation.

Childhood 'bronchitis' and respiratory outcomes in middle-age: a prospective cohort study from age 7 to 53 years.

BACKGROUND: Chronic bronchitis in childhood is associated with a diagnosis of asthma and/or bronchiectasis a few years later, however, consequences into middle-age are unknown. OBJECTIVE: To investigate the relationship between childhood bronchitis and respiratory-related health outcomes in middle-age. DESIGN: Cohort study from age 7 to 53 years. SETTING: General population of European descent from Tasmania, Australia. PARTICIPANTS: 3202 participants of the age 53-year follow-up (mean age 53, range 51-55) of the Tasmanian Longitudinal Health Study cohort who were born in 1961 and first investigated at age 7 were included in our analysis. STATISTICAL METHODS: Multivariable linear and logistic regression. The association between parent reported childhood bronchitis up to age 7 and age 53-year lung conditions (n=3202) and lung function (n=2379) were investigated. RESULTS: Among 3202 participants, 47.5% had one or more episodes of childhood bronchitis, classified according to severity based on the number of episodes and duration as: 'non-recurrent bronchitis' (28.1%); 'recurrent non-protracted bronchitis' (18.1%) and 'recurrent-protracted bronchitis' (1.3%). Age 53 prevalence of doctor-diagnosed asthma and pneumonia (p-trend <0.001) and chronic bronchitis (p-trend=0.07) increased in accordance with childhood bronchitis severities. At age 53, 'recurrent-protracted bronchitis' (the most severe subgroup in childhood) was associated with doctor-diagnosed current asthma (OR 4.54, 95% CI 2.31 to 8.91) doctor-diagnosed pneumonia (OR=2.18 (95% CI 1.00 to 4.74)) and, paradoxically, increased transfer factor for carbon monoxide (z-score +0.51 SD (0.15-0.88)), when compared with no childhood bronchitis. CONCLUSION: In this cohort born in 1961, one or more episodes of childhood bronchitis was a frequent occurrence. 'Recurrent-protracted bronchitis', while uncommon, was especially linked to multiple respiratory outcomes almost five decades later, including asthma, pneumonia and raised lung gas transfer. These findings provide insights into the natural history of childhood 'bronchitis' into middle-age.