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The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18–65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35–70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI −1·50 g/L per year [SE 0·22]; placebo −2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI −0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (−1·45 g/L per year [SE 0·23]) than in the placebo group (−2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06–1·42], p=0·03), but was not at FRC alone (A1PI −1·54 g/L per year [0·24]; placebo −2·02 g/L per year [0·26]; difference 0·48 g/L per year [–0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. CSL Behring.

Generativity is defined as an individual’s concern for and actions dedicated toward the well-being of others, especially youth and subsequent generations. It is a key stage of psychological development from midlife to older age and can be a guiding concept for promoting engagement of older adults in productive and contributive activities, which benefit their well-being. This study examined the longitudinal association between generativity and higher-level functional capacity (HLFC) decline in older Japanese adults. The two-year longitudinal data of 879 older adults aged 65–84 years were analyzed. Participants’ HLFC and generativity were assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence and the Revised Japanese version of the Generativity Scale, respectively. The binary logistic regression analysis results showed that a higher generativity score was negatively associated with HLFC decline, indicating that generativity effectively prevents HLFC decline over 2 years. On adding the interaction term between generativity and sex to examine whether the protective effect of generativity differed by sex, we found that generativity was especially effective in protecting the HLFC decline in men with higher generativity. The study results highlight the importance of promoting engagement of older adults in generative activities to maintain their HLFC.

Nutritional factors, including low protein intake and poor dietary variety, affect age-associated impairment in physical performance resulting in physical frailty. This cross-sectional study investigated the association between intake frequency of major high protein foods and both physical performance and higher-level functional capacity using the food frequency score (FFS) and high protein food frequency score (PFFS) among community-dwelling older adults. The data of 1185 older adults categorized into quartiles based on FFS and PFFS were analyzed. After adjusting for covariates, FFS and PFFS were significantly associated with physical performance [FFS, usual gait speed (p for trend = 0.007); PFFS, usual gait speed (p for trend < 0.001), maximum gait speed (p for trend = 0.002), timed up and go (p for trend = 0.025)], and higher-level functional capacity [FFS (p for trend < 0.001); PFFS (p for trend < 0.001)]. After excluding PFFS data, the participants’ scores were associated with only higher-level functional capacity. Multi-regression analysis with higher-level functional capacity as the covariate showed that FFS and PFFS were significantly correlated with physical performance. Hence, improving food intake frequency, particularly that of high protein foods, and dietary variety may help maintain higher-level functional capacity and physical performance in community-dwelling older adults.

Iron deficiency anemia (IDA) in heart failure (HF) is associated with poor functional capacity. Several studies reported the benefit of iron therapy in HF with IDA on improving functional capacity. Therefore, we attempt to investigate the effect of oral iron supplementation on functional capacity in HF patients with IDA. A double blind randomized controlled trial was conducted in National Cardiovascular Center Harapan Kita Hospital Universitas Indonesia. A total of 54 HFREF patients with IDA were enrolled and randomized to either oral Ferrous Sulphate (FS) 200 mg three times a day or placebo with 1:1 ratio for 12 weeks. Primary outcome was functional capacity measured by a six-minute walk test. There were 41 participants completed the study (FS n = 22, placebo n = 19). Ferrous sulphate significantly improved functional capacity changes (46.23 ± 35 m vs -13.7 ± 46 m, p < 0.001, CI -86.8 to -33.2) compared with placebo groups respectively after 12 weeks intervention. Oral FS supplementation for 12 weeks significantly improved functional capacity in HF patients with IDA. clinicaltrials.gov, NCT02998697. Registered 14 December 2016 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02998697.

Currently, no clinical studies have compared the inspiratory and expiratory volumes of unilateral lung or of each lobe among supine, standing, and sitting positions. In this prospective study, 100 asymptomatic volunteers underwent both low-radiation-dose conventional (supine position, with arms raised) and upright computed tomography (CT) (standing and sitting positions, with arms down) during inspiration and expiration breath-holds and pulmonary function test (PFT) on the same day. We compared the inspiratory/expiratory lung/lobe volumes on CT in the three positions. The inspiratory and expiratory bilateral upper and lower lobe and lung volumes were significantly higher in the standing/sitting positions than in the supine position (5.3–14.7% increases, all P < 0.001). However, the inspiratory right middle lobe volume remained similar in the three positions (all P > 0.15); the expiratory right middle lobe volume was significantly lower in the standing/sitting positions (16.3/14.1% decrease) than in the supine position (both P < 0.0001). The Pearson’s correlation coefficients ( r ) used to compare the total lung volumes on inspiratory CT in the supine/standing/sitting positions and the total lung capacity on PFT were 0.83/0.93/0.95, respectively. The r values comparing the total lung volumes on expiratory CT in the supine/standing/sitting positions and the functional residual capacity on PFT were 0.83/0.85/0.82, respectively. The r values comparing the total lung volume changes from expiration to inspiration on CT in the supine/standing/sitting positions and the inspiratory capacity on PFT were 0.53/0.62/0.65, respectively. The study results could impact preoperative CT volumetry of the lung in lung cancer patients (before lobectomy) for the prediction of postoperative residual pulmonary function, and could be used as the basis for elucidating undetermined pathological mechanisms. Furthermore, in addition to morphological evaluation of the chest, inspiratory and expiratory upright CT may be used as an alternative tool to predict lung volumes such as total lung capacity, functional residual capacity, and inspiratory capacity in situation in which PFT cannot be performed such as during an infectious disease pandemic, with relatively more accurate predictability compared with conventional supine CT.

Background: Obesity is associated with increased prevalence and incidence of asthma, but the mechanism is unknown. Obesity reduces lung volumes, which can increase airway responsiveness, and increases resistive and elastic work of breathing, which can increase dyspnea. Objective: To determine if the intensity of dyspnea due to airway narrowing or if airway responsiveness is increased in obese, non-asthmatic subjects. Subjects: Twenty-three obese (BMI (body mass index) ⩾30 kg m −2 ) and 26 non-obese (BMI <30 kg m −2 ) non-asthmatic subjects, aged between 18 and 70 years. Methods: High-dose methacholine challenge was used to determine the sensitivity and the maximal response to methacholine. Respiratory system resistance (Rrs) and reactance were measured, using the forced oscillation technique, as indicators of resistive and elastic loads during challenge. Perception of dyspnea was measured by the Borg score during challenge. Static lung volumes were measured by body plethysmography. Results: Static lung volumes were reduced in the obese subjects. There were no significant differences in the sensitivity or maximal response to methacholine between obese and non-obese subjects. The magnitude of change in Rrs was similar in both groups, but obese subjects had more negative reactance after challenge ( P =0.002) indicating a greater elastic load. The intensity of dyspnea was greater in obese subjects ( P =0.03). Conclusions: Obesity reduces lung volumes, but does not alter the sensitivity or maximal response to methacholine. However, obese subjects have enhanced perception of dyspnea, associated with greater apparent stiffness of the respiratory system, and may therefore be at greater risk of symptoms.

Background Exercise training provides benefits for individuals with cystic fibrosis; however, the optimal program is unclear. High-intensity interval training is safe and effective for improving ‘functional capacity’ in these individuals with peak rate of O 2 uptake typically referenced. The ability to adjust submaximal rate of oxygen uptake (V̇O 2 kinetics) might be more important for everyday function because maximal efforts are usually not undertaken. Moreover, the ability of high-intensity training to accelerate V̇O 2 kinetics for individuals with cystic fibrosis could be enhanced with O 2 supplementation during training. Methods Nine individuals with cystic fibrosis completed incremental cycling to limit of tolerance followed by 8 weeks of high-intensity interval cycling (2 sessions per week x ~ 45 min per session) either with ( n  = 5; O2+) or without (AMB) oxygen supplementation (100%). Each session involved work intervals at 70% of peak work rate followed by 60 s of recovery at 35%. For progression, duration of work intervals was increased according to participant tolerance. Results Both groups experienced a significant increase in work-interval duration over the course of the intervention (O2+, 1736 ± 141 v . 700 ± 154 s; AMB, 1463 ± 598 v . 953 ± 253 s; P  = 0.000); however, the increase experienced by O2+ was greater ( P  = 0.027). During low-intensity constant-work-rate cycling, the V̇O 2 mean response time was shortened post compared to pre training (O2+, 34 ± 11 v . 44 ± 9 s; AMB, 39 ± 14 v . 45 ± 17 s; P  = 0.000) while during high-intensity constant-work-rate cycling, time to exhaustion was increased (O2+, 1628 ± 163 v . 705 ± 133 s; AMB, 1073 ± 633 v . 690 ± 348 s; P  = 0.002) and blood [lactate] response was decreased (O2+, 4.5 ± 0.9 v . 6.3 ± 1.4 mmol . L − 1 ; AMB, 4.5 ± 0.6 v . 5.2 ± 1.4 mmol . L − 1 ; P  = 0.003). These positive adaptations were similar regardless of gas inspiration during training. Conclusion Eight weeks of high-intensity interval training for patients with cystic fibrosis accelerated V̇O 2 kinetics and increased time to exhaustion. This provides some evidence that these patients may benefit from this type of exercise. Trial registration This study was retrospectively registered in the ISRTCN registry on 22/06/2019 (# ISRCTN13864650 ).

Established methods of measuring functional residual capacity (FRC) involve sophisticated equipment and elaborate procedures. Here we present a new method based on CO 2 rebreathing that has a simple fast procedure and only requires end‐tidal CO 2 monitoring. Ten healthy subjects with diverse anthropometric and respiratory parameters were studied in the sitting position. Reference FRC (RefFRC) and tidal volume (TV) were measured with a Cosmed Quark PFT/DLCO unit using the single‐breath methane dilution technique in combination with spirometry. Rebreathing through an external dead space of precisely known volume and recording the rising end‐tidal CO 2 value of the first two breaths allows the determination of effective lung volume (ELV) and the calculation of FRC. Two sets of measurements were made on each subject 15 min apart. Bland–Altman analysis of a comparison between FRC and RefFRC showed a mean bias of 0.04 L, with limits of agreement (LoA, 95% CI) of −1.24 to +1.32 L and a percentage error (PE) of 0.54. When the mean value of two observations from a subject (meanFRC) was compared to RefFRC we obtained a mean bias of −0.08 L, LoA (95% CI) of –0.88 to +0.72 L and PE of 0.23. The FRC data obtained demonstrate good absolute accuracy. An average of repeated measurements improves precision indicating that a criterion for exchangeability with the reference method can be met. The simplicity of the equipment and the procedure could make this method attractive in the pre‐operative and the post‐operative settings, as well as in out‐of‐hospital applications. What is the central question of this study? Can functional residual capacity (FRC) be determined at bedside using a short CO 2 rebreathing manoeuvre? What is the main finding and its importance? FRC can be determined in this way, provided that the size of the dead space volume is adequately chosen and is precisely known. The importance of this finding is that such a simple method could allow a more routine use of FRC measurements in pre‐operative assessments and in out of hospital environments, for instance in the management of lung diseases.

Background Mechanical power increases with positive end-expiratory pressure (PEEP). However, its injurious potential may depend on the available lung gas volume, which can be modified by alveolar recruitment. We investigated how PEEP-induced recruitment affects mechanical power. Methods We analyzed previously collected data on 20 patients with acute respiratory distress syndrome who underwent a decremental PEEP trial (15–5 cmH₂O). End-expiratory lung volume and respiratory mechanics were measured to quantify recruited volume, functional residual capacity (FRC), and the recruitment-to-inflation (R/I) ratio. Absolute power and power normalized to aerated lung volume (FRC + recruited volume) were calculated at each PEEP level. Patients were classified as having higher or lower recruitability according to the cohort median recruited volume accrued between PEEP 5 and 15 cmH₂O, expressed as a fraction of FRC (median 0.42). Results Absolute mechanical power increased linearly with rising PEEP (approximately + 1 J/min per cmH₂O), from 20 [16–23] J/min at 5 cmH₂O, to 31 [28–33] J/min at 15 cmH₂O, irrespective of recruitability (low recruitability: + 1.12 J/min per cmH₂O, p < 0.001; high recruitability: + 0.96 J/min per cmH₂O, p < 0.001, p for interaction = 0.12). Normalized power increased in patients with lower recruitability (+ 0.43 J/min/L per cmH 2 O, p < 0.001) but decreased in those with higher recruitability (− 0.33 J/min/L per cmH 2 O, p < 0.001; p for interaction < 0.001). The reduction in normalized power was strongly related to PEEP-induced recruitment, expressed as recruited volume/FRC (− 102% per unit, R 2  = 0.75, p < 0.001), and to R/I ratio (− 38% per unit, R 2  = 0.69, p < 0.001). Associations with PEEP-related changes in compliance (R 2  = 0.40, p = 0.003) and PaO₂/FiO₂ (R 2  = 0.33, p = 0.008) were weaker. In the multivariate model, PEEP-induced recruitment (p = 0.002) and compliance changes (p = 0.011) remained independent predictors of normalized power changes. Conclusions Absolute mechanical power increases with higher PEEP, but power per aerated lung decreases when PEEP produces substantial recruitment. PEEP-induced increases in absolute power do not necessarily imply a higher mechanical load per alveolar unit. Recruited volume and compliance changes are the main physiological determinants of this effect. Among bedside tools, the R/I ratio best identifies whether and to what extent PEEP will reduce or increase mechanical power per alveolar unit.