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The self-assembly of highly functionalized phenanthrene-DNA conjugates into supramolecular nanostructures is presented. DNA oligomers modified with phenanthrene residues at the 3'-end and internal positions self-assemble into spherical nanostructures. The nanospheres exhibit light-harvesting properties. Upon irradiation of phenanthrene, the excitation energy is transferred along phenanthrene units, resulting in phenanthrene-pyrene exciplex formation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.)

People with long COVID may suffer from a wide range of ongoing symptoms including fatigue, exertional dyspnea, reduced exercise performance, and others. In particular, impaired exercise performance is a condition that can be recovered in many people through an individualized physical exercise training program. However, clinical experience has shown that the presence of post-exertional malaise (PEM) is a significant barrier to physical exercise training in people with long COVID. Currently, there is no guideline or consensus available on how to apply exercise training in this cohort. Therefore, we conducted a literature review in the PubMed library using the following search terms: "COVID", "post-COVID", "long COVID" and "exercise" searching for studies from January 2020 to January 2024. Data from 46 trials were included. Exercise training regimes were very heterogeneous and none of these studies reported on the management of PEM in the context of an exercise training program. Based on the feedback from an additional survey that was answered by 14 international experts in the field of exercise training in long COVID, combined with the authors´ own extensive practical experience, a best practice proposal for exercise training recommendations has been developed. This proposal differentiates exercise procedures according to the presence of no, mild/moderate or severe PEM in people with long COVID. These recommendations may guide allied healthcare professionals worldwide in initiating and adjusting exercise training programs for people with long COVID, stratified according to the presence and severity of PEM., (© 2024. The Author(s).)

Background: Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide ( P aCO 2 ), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved P aCO 2 ., Methods: We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on P aCO 2 , HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in P aCO 2 ., Findings: Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14 versus ≥14 cmH 2 O) and with lower adherence (<5 versus ≥5 h·day -1 ) had less improvement in P aCO 2 (mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival. P aCO 2 improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in P aCO 2 ., Interpretation: With greater pressure support and better daily NIV usage, a larger improvement in P aCO 2 and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal P aCO 2 ., Competing Interests: Conflict of interest: T. Raveling reports a travel grant from Breas Medical. N.S. Hill reports consulting fees from Philips, consulting fees and payments from Fisher & Paykel, and participates in boards of Breas and Philips. C. Casanova reports consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini and Novartis, and participates in boards of AstraZeneca and GlaxoSmithKline. E. Clini reports consulting fees from Chiesi Italia and Novartis, payments from AstraZeneca, Boehringer Ingelheim and GaxoSmithKline, and meeting/travel support from Boehringer Ingelheim and Chiesi. T. Köhnlein reports support from Grifols Deutschland GmbH. P.B. Murphy reports grants and payments from Fisher & Paykel, Resmed, Breas Medical and Philips Respironics, and payments from Chiesi and Genzyme. M.L. Duiverman reports grants from Resmed, Philips, Lowenstein, Vivisol, Sencure and Fisher & Paykel, and payments from Chiesi and Breas Medical. P.J. Wijkstra reports grants from Resmed, and grants and consulting fees from Philips., (Copyright ©The authors 2024.)

Introduction: SARS-CoV-2 infections can result in a broad spectrum of symptoms from mild to life-threatening. Long-term consequences on lung function are not well understood yet., Methods: In our study, we have examined 134 post-COVID patients (aged 54.83 ± 14.4 years) with dyspnea on exertion as a leading symptom 6 weeks to 24 months after a SARS-CoV-2 infection for bronchodilator responsiveness during their stay in our pulmonary rehabilitation clinic., Results: Prior to bronchial dilation, 6 out of 134 patients (4.47%) presented an FEV1/FVC ratio below lower limit of normal (Z-score = -1.645) indicative of an obstructive airway disease. Following inhalation of a β2-adrenergic agonist we measured a mean FEV1 increase of 181.5 mL in our cohort, which was significantly elevated compared to a historical control group (ΔFEV1 = 118 mL). 28.7% of the patients showed an increase greater than 200 mL and 12% displayed a significant bronchodilation response (&gt;200 mL ΔFEV1 and &gt;12% FEV1 increase). Interestingly, no significant difference in bronchial dilation effect was observed when comparing patients hospitalized and those non-hospitalized during the course of their SARS-CoV-2 infection., Conclusion: Our data provide evidence for increased prevalence of obstructive ventilatory defects and increased bronchodilator responsiveness in patients with persisting symptoms after COVID-19. Depending on the extent of this complication, post-COVID patients may benefit from an adapted β2-inhalation therapy including subsequent reevaluation., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: People with very severe chronic obstructive pulmonary disease (COPD) using nocturnal non-invasive ventilation (NIV) for chronic hypercapnic respiratory failure (CHRF) experience reduced exercise capacity and severe dyspnoea during exercise training (ET). The use of NIV during ET can personalise training during pulmonary rehabilitation (PR) but whether high-intensity NIV (HI-NIV) during exercise is accepted and improves outcomes in these extremely physically limited patients is unknown. The aim of this trial was to determine if ET with HI-NIV during PR was more effective than without at improving exercise capacity and reducing dyspnoea during exercise., Methods: Patients with COPD, CHRF and nocturnal-NIV were randomised to supervised cycle-ET as part of PR with HI-NIV or without (control). Primary outcome was change in cycle endurance time (ΔCET time ), while secondary outcomes were dyspnoea at isotime during the cycle endurance test and during ET-sessions and for the HI-NIV group, post-trial preferred exercising method., Results: Twenty-six participants (forced expiratory volume in 1 s 22±7%pred, PaCO 2 51±7 mm Hg) completed the trial (HI-NIV: n=13, ET: IPAP 26±3/EPAP 6±1 cm H 2 O; control n=13). At completion of a 3 week ET-programme, no significant between-group differences in ΔCET time were seen (HI-NIV-control: Δ105 s 95% CI (-92 to 302), p=0.608). Within-group ΔCET time was significant (HI-NIV: +246 s 95% CI (61 to 432); control: +141 s 95% CI (60 to 222); all p<0.05). The number of responders (Δ>minimal important difference (MID) 101 s : n=53.8%) was the same in both groups for absolute ΔCET time and 69.2% of control and 76.9% of the HI-NIV group had a %change>MID 33% .Compared with control, the HI-NIV group reported less isotime dyspnoea (Δ-2.0 pts. 95% CI (-3.2 to -0.8), p=0.005) and during ET (Δ-3.2 pts. 95% CI (-4.6 to -1.9), p<0.001). Most of the HI-NIV group (n=12/13) preferred exercising with NIV., Conclusion: In this small group of patients with very severe COPD requiring nocturnal NIV, participation in an ET-programme during PR significantly improved exercise capacity irrespective of HI-NIV use. Reported dyspnoea was in favour of HI-NIV., Trial Registration Number: NCT03803358., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The SARS-CoV-2 pandemic has not only caused millions of deaths but left also millions of people with persistent symptoms behind. These long-term COVID-19 sequelae cause a considerable burden on individuals´ health, healthcare systems, and economies worldwide given the high rate of SARS-CoV-2 infections. Therefore, rehabilitative interventions and strategies are needed to counteract the post COVID-19 sequelae. The importance of rehabilitation for patients with persistent COVID-19 symptoms has been recently also highlighted in a Call for Action by the World Health Organisation. Based on previously published research, but also in line with clinical experience, COVID-19 is not one specific disease but rather presents in different phenotypes that vary in their pathophysiological mechanisms, symptomatic manifestations, and potential interventional approaches. This review provides a proposal for differentiating post COVID-19 patients in non-organ-specific phenotypes that may help clinicians to evaluate patients and to plan therapeutic options. Furthermore, we present current unmet needs and suggest a potential pathway for a specific rehabilitation approach in people with persistent post-COVID symptoms., (© 2023. The Author(s).)

Background: Evidence suggests that patients with COPD struggle to maintain improved physical activity (PA) after completing pulmonary rehabilitation (PR). Smartphone applications (apps) providing a comprehensive training programme have conferred healthy benefits. This study was conducted to determine whether regular usage of an app maintains PA following PR., Methods: Patients with stage II-IV COPD were enrolled in a 6-month trial following PR. After the screening period, participants were randomised into the Kaia COPD app group (intervention group (IG)) or the control group (CG). The primary outcome was PA (daily steps), measured using an activity tracker. Secondary outcomes included the COPD Assessment Test (CAT), the Chronic Respiratory Disease Questionnaire (CRQ) and the 1 min Sit-to-Stand Test (STST)., Results: Sixty participants completed the study. The median steps from baseline to 6 months were significantly different between the groups, in favour of the IG (-105.3, IQR -1970.1 to 2105.8, vs CG -1173.0, IQR -3813.1 to -93.8; p=0.007). CAT was significantly decreased in the IG (15.1±8.6 vs 19.7±6.4, p=0.02), whereas the CRQ subdomains for dyspnoea (4.5±1.7 vs 3.7±1.3, p=0.033) and fatigue (4.5±1.4 vs 3.5±1.3, p=0.028) improved significantly in the IG. The STST at 6 months was not significant. Sleep duration and sleep efficiency showed no significant differences between the two groups at any time., Conclusions: A comprehensive program by using the Kaia app following PR maintained PA and improved symptoms in patients with COPD at 6 months. The app might be an important accessory tool for enhanced COPD care., Trial Registration Number: DRKS00017275., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: In patients with COPD, oxygen (O 2 )-supplementation via a constant flow oxygen system (CFOS) can result in insufficient oxygen saturation (SpO 2 <90%) during exercise. An automatically titrating O 2 -system (ATOS) has been shown to be beneficial compared with an untitrated CFOS, however, it is unknown if ATOS is superior to CFOS, titrated during exercise as stipulated by guidelines. The aim was to investigate the effects of ATOS compared with titrated CFOS on walking capacity in people with hypoxaemic COPD., Methods: Fifty participants completed this prospective randomised controlled, double-blind, crossover trial. Participants performed two endurance shuttle walk tests (ESWTs) with: (1) exercise titrated CFOS (ESWT CFOS ) and (2) ATOS targeting an SpO 2 of 92% (ESWT ATOS ). Primary outcome measure was walking time. Secondary measures were SpO 2 , transcutaneous-PCO 2 (TcPCO 2 ), respiratory rate (RR), heart rate (HR) at isotime (end of shortest ESWT) with blood gases and dyspnoea at rest and end exercise., Results: Participants (median (IQR): age 66 (59, 70) years, FEV 1 28.8 (24.8, 35.1) % predicted, PO 2 54.7 (51.0, 57.7) mm Hg, PCO 2 44.2 (38.2, 47.8) mm Hg) walked significantly longer with ESWT ATOS in comparison to ESWT CFOS (median effect (95% CI) +144.5 (54 to 241.5) s, p<0.001). At isotime, SpO 2 was significantly higher (+3 (95% CI 1 to 4) %, p<0.001) with ATOS while TcPCO 2 , RR and HR were comparable. End exercise, PO 2 (+8.85 (95% CI 6.35 to 11.9) mm Hg) and dyspnoea (-0.5 (95% CI -1.0 to -0.5) points) differed significantly in favour of ATOS (each p<0.001) while PCO 2 was comparable., Conclusion: In patients with hypoxaemia with severe COPD the use of ATOS leads to significant, clinically relevant improvements in walking endurance time, SpO 2 , PO 2 and dyspnoea with no impact on PCO 2 ., Trial Registration Number: NCT03803384., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The perceptions of using noninvasive ventilation (NIV) during exercise in patients with COPD who are naïve to NIV is unknown. The present study aimed to examine the perceptions of using NIV during exercise in people with COPD and to determine the relationship between patient perceptions with both baseline patient characteristics and exercise outcomes., Methods: During a trial examining the effect of NIV during exercise on dynamic hyperinflation in people with COPD who were naïve to NIV, participants completed a 5-point Likert scale questionnaire (scored strongly disagree -2 to strongly agree +2) before and after using NIV during exercise and a semi-structured interview after using NIV during exercise., Results: Eighteen participants, mean age (SD) 69 (7) y, FEV 1 /FVC 0.44 (0.08), FEV 1 39 (7)% predicted, completed the study. Prior to exercise with NIV, participants were neutral about NIV, (mean [SD]) (0.67[0.84]). After exercise with NIV, participants felt that NIV made breathing easier (1.00 [0.77]) and that it helped exercise (1.06 [0.64]). There were moderate correlations between feeling that NIV was comfortable or effective and a change in exercise endurance time (ρ = - 0.588, P = .02), isotime inspiratory capacity (ρ = 0.488, P = .03), and measures of resting hyperinflation (ρ = 0.603, \ P = .02). Interviews revealed that despite feeling comfortable using NIV during exercise, NIV might be too complicated for patients to manage outside a supervised environment., Conclusions: Individuals with COPD, naïve to NIV, and using NIV during exercise for the first time reported a positive effect of NIV on breathlessness and exercise performance. Participants' perceived benefit of NIV correlated moderately with increased endurance time and resting hyperinflation and with a reduction in dynamic hyperinflation during exercise, suggesting that patient reports could also aid selection of those who will benefit from NIV during exercise., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2022 by Daedalus Enterprises.)

Background: During exercise, dynamic hyperinflation (DH), measured by a reduction in inspiratory capacity (IC), increases exertional dyspnea and reduces functional capacity in many patients with severe COPD. Although noninvasive ventilation (NIV) during exercise can improve exercise duration, the effect on DH is unclear., Research Questions: In people with COPD, resting hyperinflation, and evidence of DH during exercise, does bilevel NIV during exercise reduce DH and increase endurance time compared with exercise with no NIV, and does NIV with an individually titrated expiratory positive airway pressure (T-EPAP) reduce DH and increase exercise endurance time more than NIV with standardized EPAP (S-EPAP) of 5 cm H 2 O?, Study Design and Methods: A randomized crossover trial in which investigators and participants were blinded between NIV interventions was performed. Participants (N = 19; FEV 1 of 1.02 ± 0.24 L (39% ± 6% predicted) completed three constant work rate endurance cycle tests in random order-no NIV, NIV with S-EPAP, and NIV with T-EPAP-during exercise. Primary outcomes were isotime IC and exercise endurance time. Outcome measures from each intervention were compared at isotime and at end exercise by using a linear mixed-model analysis., Results: Compared with no NIV, isotime IC and endurance time were greater with both NIV with S-EPAP (mean difference: 95% CI, 0.19 L [0.10-0.28]; 95% CI, 153 s [24-280], respectively) and T-EPAP (95% CI, 0.22 L [0.13-0.32]; 95% CI, 145 s [28-259], respectively). There was no difference between NIV with S-EPAP and NIV with T-EPAP., Interpretation: In people with COPD and DH during exercise, NIV during exercise reduced DH and increased cycle endurance time. An S-EPAP of 5 cm H 2 O was adequate to obtain these benefits., Trial Registry: Australian New Zealand Clinical Trials Registry; No.: ACTRN12613000804785; URL: http://www.anzctr.org.au., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Bioelectrical impedance analysis (BIA) can be used to estimate Fat-Free Mass Index (FFMI). However, the use of directly measured BIA variables, such as phase angle (PhA), has gained attention. The frequency of low FFMI and PhA and its associations with exercise capacity and health-related quality of life (HRQL) in patients with idiopathic pulmonary fibrosis (IPF) have been scarcely studied., Objectives: To investigate the frequency of low FFMI and PhA and their associations with exercise capacity and HRQL in patients with IPF., Methods: Patients underwent assessment of lung function, body composition, exercise capacity by the 6 min walk distance (6MWD), and HRQL by the Medical Outcomes Study Short-Form 36-item Questionnaire (SF-36). Patients were classified as presenting normal or low PhA or FFMI, accordingly to the 10th percentiles of age-sex-body mass index (BMI)-specific reference values., Results: 98 patients (84 males, age: 68±8 years, forced vital capacity: 64%±18%predicted) were included. 24 patients presented low PhA. They were characterised by worse lung function, exercise capacity and HRQL compared with patients with normal PhA. 10 patients presented low FFMI, but despite differences in body composition, no differences were found between these patients and patients with normal FFMI. In a single regression analysis, age, lung function and body composition variables (except FFMI) were related to 6MWD and SF-36 Physical Summary Score (R²=0.06-0.36, p<0.05). None of the variables were related to SF-36 Mental Summary Score., Conclusion: One-fourth of the patients with IPF with normal to obese BMI present abnormally low PhA. Patients classified as low PhA presented worse lung function, exercise capacity and HRQL., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In the light of missing randomised controlled trials, some arguments suggest that pulmonary rehabilitation has beneficial effects beyond natural recovery https://bit.ly/3ze2xvw., Competing Interests: Conflict of interest: R. Gloeckl has nothing to disclose. Conflict of interest: D. Leitl has nothing to disclose. Conflict of interest: I. Jarosch has nothing to disclose. Conflict of interest: T. Schneeberger has nothing to disclose. Conflict of interest: C. Nell has nothing to disclose. Conflict of interest: N. Stenzel has nothing to disclose. Conflict of interest: A. Daher has nothing to disclose. Conflict of interest: M. Dreher has nothing to disclose. Conflict of interest: C.F. Vogelmeier has nothing to disclose. Conflict of interest: K. Kenn has nothing to disclose. Conflict of interest: A.R. Koczulla has nothing to disclose., (Copyright ©The authors 2021.)

Background: Cognitive impairment might interfere with the efficacy of Pulmonary Rehabilitation (PR) in Chronic Obstructive Pulmonary Disease (COPD). We aimed to identify differential responses to PR between cognitively impaired (CI) and cognitively normal (CN) COPD patients by assessing health status and exercise capacity., Methods: Sixty patients (FEV 1 : 47 ± 15%) were classified as CI or CN according to the Montreal Cognitive Assessment (MoCA ≤25points) and completed a 3-week inpatient PR program. Cognitive function (neuropsychological battery), health-status (36-Item Short Form Survey [SF-36]), and exercise capacity (6-min walk test [6MWT], cycle-endurance test [CET]) were assessed before and after PR. Responsiveness to PR was estimated by mean change (delta-value [Δ]) and the d-Effect Size (ES)., Results: Twenty-five COPD patients (42%) presented evidence of mild CI prior to PR. Both, CI and CN patients significantly improved global cognitive function, health status (the majority of SF-36 components), and exercise capacity (6MWT and cycle endurance) in response to PR. Compared to CN, CI patients did not improve SF-36 subdomains of "role emotional" and "bodily pain", and demonstrated a lower magnitude of improvement in 6MWT ([Δ]: 25 m; ES: 0.21) compared to CN ([Δ]: 46 m; ES: 0.54)., Conclusions: PR has favorable effects on global cognitive function, health status, and exercise capacity in both CI and CN COPD patients. There was no concrete evidence to indicate interference of cognitive impairment to PR effectiveness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Pulmonary rehabilitation (PR) has been shown to be an effective intervention in patients with very severe chronic obstructive pulmonary disease (COPD) awaiting lung transplantation (LTx). The objective of this study was to characterize the prevalence of acute exacerbations (AEs) during PR and their impact on the outcomes of pre-LTx PR., Methods: In this retrospective analysis, 559 patients with COPD awaiting LTx who were referred to a 4-wk inpatient PR program were evaluated. A total of 114 patients (20%) acquired an AE during PR and continued in an adapted fashion. Pulmonary function testing, 6-min walk test (6MWT), and a health-related quality-of-life questionnaire (SF-36) were administered on admission and on discharge of PR., Results: Following PR, both groups, patients with and without AE, increased their 6MWT significantly (P < .001) to a clinically relevant amount (58 ± 72 and 52 ± 64 m, respectively). The sum scores of the SF-36 also improved significantly without any between-group differences. No observed changes were different between the two groups. No relevant predictors for PR outcomes could be detected by logistic regression., Conclusions: Our data show that patients with end-stage COPD listed for LTx can achieve clinically relevant improvements in functional exercise capacity and quality of life even if they develop an AE during PR., Competing Interests: Conflicts of Interest: None., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) can result in a large variety of chronic health issues such as impaired lung function, reduced exercise performance and diminished quality of life. Our study aimed to investigate the efficacy, feasibility and safety of pulmonary rehabilitation in COVID-19 patients and to compare outcomes between patients with a mild/moderate and a severe/critical course of the disease., Methods: Patients in the post-acute phase of a mild to critical course of COVID-19 admitted to a comprehensive 3-week inpatient pulmonary rehabilitation programme were included in this prospective, observational cohort study. Several measures of exercise performance (6-min walk distance (6MWD)), lung function (forced vital capacity (FVC)) and quality of life (36-question short-form health survey (SF-36)) were assessed before and after pulmonary rehabilitation., Results: 50 patients were included in the study (24 with mild/moderate and 26 with severe/critical COVID-19). On admission, patients had a reduced 6MWD (mild: median 509 m, interquartile range (IQR) 426-539 m; severe: 344 m, 244-392 m), an impaired FVC (mild: 80%, 59-91%; severe: 75%, 60-91%) and a low SF-36 mental health score (mild: 49 points, 37-54 points; severe: 39 points, 30-53 points). Patients attended a median (IQR) 100% (94-100%) of all provided pulmonary rehabilitation sessions. At discharge, patients in both subgroups improved in 6MWD (mild/moderate: +48 m, 35-113 m; severe/critical: +124 m, 75-145 m; both p<0.001), FVC (mild/moderate: +7.7%, 1.0-17.8%, p=0.002; severe/critical: +11.3%, 1.0-16.9%, p<0.001) and SF-36 mental component (mild/moderate: +5.6 points, 1.4-9.2 points, p=0.071; severe/critical: +14.4 points, -0.6-24.5, p<0.001). No adverse event was observed., Conclusion: Our study shows that pulmonary rehabilitation is a feasible, safe and effective therapeutic option in COVID-19 patients independent of disease severity., Competing Interests: Conflict of interest: R. Gloeckl has nothing to disclose. Conflict of interest: D. Leitl has nothing to disclose. Conflict of interest: I. Jarosch has nothing to disclose. Conflict of interest: T. Schneeberger has nothing to disclose. Conflict of interest: C. Nell has nothing to disclose. Conflict of interest: N. Stenzel has nothing to disclose. Conflict of interest: C.F. Vogelmeier has nothing to disclose. Conflict of interest: K. Kenn has nothing to disclose. Conflict of interest: A.R. Koczulla has nothing to disclose., (Copyright ©The authors 2021.)

Background: Whole-body vibration training (WBV) performed on a vibration platform can significantly improve physical performance in patients with chronic obstructive pulmonary disease. It has been suggested that an important mechanism of this improvement is based on an improvement in balance. Therefore, the aim of this study was to investigate the effects of WBV compared to conventional balance training., Methods: 48 patients with severe COPD (FEV 1 : 37 ± 7%predicted) and low exercise performance (6 min walk distance (6MWD): 55 ± 10%predicted) were included in this randomized controlled trial during a 3 week inpatient pulmonary rehabilitation. All patients completed a standardized endurance and strength training program. Additionally, patients performed 4 different balance exercises 3x/week for 2 sets of 1 min each, either on a vibration platform (Galileo) at varying frequencies (5-26 Hz) (WBV) or on a conventional balance board (BAL). The primary outcome parameter was the change in balance performance during a semi tandem stance with closed eyes assessed on a force measurement platform. Muscular power during a countermovement jump, the 6MWD, and 4 m gait speed test (4MGST) were secondary outcomes. Non-parametric tests were used for statistical analyses., Results: Static balance performance improved significantly more (p = 0.032) in favor of WBV (path length during semi-tandem stand: - 168 ± 231 mm vs. + 1 ± 234 mm). Muscular power also increased significantly more (p = 0.001) in the WBV group (+ 2.3 ± 2.5 W/kg vs. - 0.1 ± 2.0 W/kg). 6MWD improved to a similar extent in both groups (WBV: 48 ± 46 m, p < 0.001 vs. BAL: 38 ± 32 m; p < 0.001) whereas the 4MGST increased significantly only in the WBV-group (0.08 ± 0.14 m/s 2 , p = 0.018 vs. 0.01 ± 0.11 m/s 2 , p = 0.71)., Conclusions: WBV can improve balance performance and muscular power significantly more compared to conventional balance training., Trial Registration: Clinical-Trials registration number: NCT03157986; date of registration: May 17, 2017. https://clinicaltrials.gov/ct2/results?cond=&term=NCT03157986&cntry=&state=&city=&dist  = .

Introduction: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are the most critical events for patients with COPD that have a negative impact on patients' quality of life, accelerate disease progression, and can result in hospital admissions and death. Although there is no distinct definition or detailed knowledge about AECOPD, it is commonly used as primary outcome in clinical studies. Furthermore, it may be difficult in clinical practice to differentiate the worsening of symptoms due to an AECOPD or to the development of heart failure. Therefore, it is of major clinical importance to investigate the underlying pathophysiology, and if possible, predictors of an AECOPD and thus to identify patients who are at high risk for developing an acute exacerbation., Methods and Analysis: In total, 355 patients with COPD will be included prospectively to this study during a 3-week inpatient pulmonary rehabilitation programme at the Schoen Klinik Berchtesgadener Land, Schoenau am Koenigssee (Germany). All patients will be closely monitored from admission to discharge. Lung function, exercise tests, clinical parameters, quality of life, physical activity and symptoms will be recorded, and blood samples and exhaled air will be collected. If a patient develops an AECOPD, there will be additional comprehensive diagnostic assessments to differentiate between cardiac, pulmonary or cardiopulmonary causes of worsening. Follow-up measures will be performed at 6, 12 and 24 months.Exploratory data analyses methods will be used for the primary research question (screening and identification of possible factors to predict an AECOPD). Regression analyses and a generalised linear model with a binomial outcome (AECOPD) will be applied to test if predictors are significant., Ethics and Dissemination: This study has been approved by the Ethical Committee of the Philipps University Marburg, Germany (No. 61/19). The results will be presented in conferences and published in a peer-reviewed journal., Trial Registration Number: NCT04140097., Competing Interests: Competing interests: For CS: consultancy and research funding, Hycor Biomedical, Bencard Allergie and Thermo Fisher Scientific; research funding, Mead Johnson Nutrition (MJN)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of layered perovskites is an important strategy to improve the stability of hybrid perovskite materials and their optoelectronic devices. However, tailoring their properties requires accurate structure determination at the atomic scale, which is a challenge for conventional diffraction-based techniques. We demonstrate the use of nuclear magnetic resonance (NMR) crystallography in determining the structure of layered hybrid perovskites for a mixed-spacer model composed of 2-phenylethylammonium (PEA + ) and 2-(perfluorophenyl)ethylammonium (FEA + ) moieties, revealing nanoscale phase segregation. Moreover, we illustrate the application of this structure in perovskite solar cells with power conversion efficiencies that exceed 21%, accompanied by enhanced operational stability.

Something simple, like changing a nasal cannula for a technologically superior one, can improve exercise capacity and oxygenation in patients with IPF. There is a need to develop improved cannulas for comfort and patient acceptance. https://bit.ly/2NelacE., Competing Interests: Conflict of interest: T. Schneeberger has nothing to disclose. Conflict of interest: D. Leitl has nothing to disclose. Conflict of interest: R. Gloeckl has nothing to disclose. Conflict of interest: I. Jarosch has nothing to disclose. Conflict of interest: D. Reimann has nothing to disclose. Conflict of interest: W. Hitzl has nothing to disclose. Conflict of interest: R. Koczulla has nothing to disclose. Conflict of interest: K. Kenn has nothing to disclose., (Copyright ©ERS 2020.)

Background: Increasing physical activity (PA) is considered to be an important factor for the efficient management of chronic obstructive pulmonary disease (COPD). Successful methods required to achieve improvements in PA following pulmonary rehabilitation (PR), however, are rarely reported. Therefore, we will conduct this trial to evaluate the effectiveness of using a COPD management program delivered to the patient via the KAIA COPD app, a mobile medical application, after the completion of PR., Methods: This is the protocol for a randomized, controlled, open-label, multicentered trial that will be carried out at inpatient PR hospital centers in Germany and Switzerland. The interventions will involve the use of the KAIA COPD app program (Arm 1) or an active comparator, i.e., usual care (Arm 2). Patients completing an in-hospital PR program and consenting to participate in the study will be screened with the inclusion and exclusion criteria and enrolled in the study. After fulfilling the screening requirements, the patients will be randomized into one of the two arms with parallel group assignment in a 1:1 ratio. The training program will be delivered to the participants grouped in Arm 1 via the KAIA COPD app and to participants grouped in Arm 2 via the regular recommendations or standard of care by the PI. In total, 104 participants will be included in the trial. The treatment period will last for 24 weeks. Electronic versions of questionnaires will be used to collect patient-reported assessments remotely. The primary outcome measure is the change in physical activity of the intervention group in comparison to the control group, measured over 1 week as the mean steps per day with a Polar A 370 activity tracker, from baseline (end of PR) to the 6-month follow-up. The secondary outcome measures are functional exercise capacity, health status, sleep quality, exacerbation rate, and depression and anxiety symptoms assessed at several intervals., Discussion: This study seeks to prove the effects of the KAIA COPD mobile application in COPD patients after PR. The app offers educational, exercise training plus activity monitoring and motivational programs that can be easily implemented in the patient's home setting, enabling patients to maintain the effects that are typically elicited in the short term after pulmonary rehabilitation for the long term., Trial Registration: German Clinical Trials Register ( DRKS00017275 ). Protocol version 2.0 dated 3 June 2019.

The recommendation for pulmonary rehabilitation (PR) in idiopathic pulmonary fibrosis (IPF) is weak with low-quality evidence. Therefore, the aim of this study is to investigate short-term PR effects and their maintenance after a 3-month follow-up. Fifty-four IPF patients were randomized into a group receiving a 3-week comprehensive, inpatient PR ( n = 34, FVC: 74 ± 19% pred.) or usual care (UC) ( n = 17, FVC: 72 ± 20%pred.). Outcomes were measured at baseline (T1), after intervention (T2), and 3 months after T2 (T3). A 6-min walk distance (6MWD) was used as the primary outcome and chronic respiratory disease questionnaire (CRQ) scores as the secondary outcome. Change in 6MWD from T1 to T2 (Δ = 61 m, 95% CI (18.5-102.4), p = 0.006) but not from T1 to T3 (∆ = 26 m, 95% CI (8.0-61.5), p = 0.16) differed significantly between groups. Higher baseline FVC and higher anxiety symptoms were significant predictors of better short-term 6MWD improvements. For the change in CRQ total score, a significant between-group difference from T1 to T2 (∆ = 3.0 pts, 95% CI (0.7-5.3), p = 0.01) and from T1 to T3 (∆ = 3.5 pts, 95% CI (1.5-5.4), p = 0.001) was found in favour of the PR group. To conclude, in addition to the short-term benefits, inpatient PR is effective at inducing medium-term quality of life improvements in IPF. PR in the early stages of the disease seems to provoke the best benefits.

Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Numerous studies have reported positive effects of exercise training in patients with interstitial lung disease (ILD) on physical capacity and quality of life. However, evidence is rare on the effects of specific forms of training and further pathophysiological mechanisms in these patients., Objectives: In this multicenter study we aimed to explore the clinical effects of whole-body vibration training (WBVT) in patients with ILD on various outcome measures, including proinflammatory cytokines and myostatin., Methods: We randomly assigned 26 patients with different forms of multidisciplinary confirmed fibrotic ILDs either to the WBVT group (n = 11; 55% male, 61 ± 14 years old, forced vital capacity 83.2 ± 29.3% predicted, 6-min walking distance [6MWD] 478 ± 79 m) performing 3 months of a standardized training (3 times per week), or to a control training group (CTG, n = 15; 60% male, 63 ± 9 years old, FVC 74.6 ± 20.5% predicted, 6MWD 455 ± 85 m) performing sham WBV training. Training in the two groups was performed on a GalileoTM vibration plate (6-20 vs. 5 Hz). The functional assessments before and after the intervention period included pulmonary function, 6MWD test, chair rise test, ultrasonographic measurement of quadriceps muscle thickness (cross-sectional area), quality of life questionnaires, and serum samples., Results: We observed a significant increase in 6MWD (∆Training = 30 m [12-67], p = 0.024) and a decrease of myostatin (∆Training = -465 pg/mL [-713 to -166], p = 0.008) in the WBVT group. In contrast, no significant differences were observed in the CTG., Conclusions: The present study demonstrates that WBVT is able to significantly increase 6MWD and decrease myostatin in patients with fibrotic ILDs. Therefore, WBVT seems to be a beneficial and feasible training modality in ILD patients. Clinical Trial Registry: German Clinical Trials Registry (DRKS00012930)., (© 2020 S. Karger AG, Basel.)

Background: Pulmonary rehabilitation (PR) following lung transplantation (LTx) is considered part of the optimal treatment in chronic obstructive pulmonary disease (COPD) for favourable post-operative outcomes. We investigated the effects of a PR intervention in the post-transplant phase with regard to lung function, exercise responses and cognitive function in COPD LTx recipients., Methods: 24 COPD LTx recipients (mean±sd forced expiratory volume in 1 s 75±22% predicted) were assigned to a comprehensive 3-week inpatient PR programme. Changes from PR admission to discharge in lung function variables, 6-min walk test-derived outcomes and cognitive function were assessed and examined for several factors. The magnitude of changes was interpreted by effect size (ES)., Results: In response to the PR intervention, LTx recipients had improved lung function with regard to diffusing capacity of the lung for carbon monoxide (+4.3%; p=0.012) and static hyperinflation (residual volume/total lung capacity -2.3%; p=0.017), increased exercise capacity (6-min walk test +86 m; p<0.001), and had small to large improvements (ES range 0.23-1.00; all p≤0.34) in 50% of the administered cognitive tests. Learning skills and memory ability presented the greatest benefits (ES composite scores 0.62 and 0.31, respectively), which remained similar after stratification by single or bilateral LTx and sex., Conclusions: PR is an effective treatment for LTx recipients in the post-transplant phase, improving lung function, exercise responses, and domains of cognitive function of learning, memory and psychomotor speed. PR may facilitate the course of post-operative treatment and should be recommended in LTx., Competing Interests: Conflict of interest: V. Andrianopoulos has nothing to disclose. Conflict of interest: R. Gloeckl has nothing to disclose. Conflict of interest: M. Boensch has nothing to disclose. Conflict of interest: K. Hoster has nothing to disclose. Conflict of interest: T. Schneeberger has nothing to disclose. Conflict of interest: I. Jarosch has nothing to disclose. Conflict of interest: R.A. Koczulla has nothing to disclose. Conflict of interest: K. Kenn has nothing to disclose.

Background: Supplemental oxygen is a recommended therapy option in stable hypoxemic COPD patients. Often, supplemental oxygen is provided by continuous flow (CF). However, demand oxygen delivery systems (DODS) that provide an oxygen bolus only during inspiration have gained increasing use as they prolong oxygen cylinder life (beside battery life). However, there is a lack of evidence if different DODS and CF devices are equivalent., Methods: Seventy hypoxemic COPD patients (FEV 1 32 ± 9% predicted, PaO 2 56±7 mmHg) on long-term oxygen therapy were included in this prospective single-blinded, randomized cross-over trial. Following an initial incremental shuttle walk test, patients performed 3 endurance shuttle walk tests (ESWT) at 85% of their maximum walking speed in random order with: (A) CF (ESWT-CF), (B) a DODS based on liquid oxygen (ESWT-DL) and (C) an DODS oxygen concentrator (ESWT-DC). The primary outcome was oxygen saturation (SpO 2 ) at ESWT isotime. Secondary outcomes were total ESWT duration, heart rate (HR) and breathing frequency (BF) at isotime and dyspnea at end-exercise., Results: SpO 2 at ESWT isotime was not clinically different between devices: 90 ± 4% (CF), 89 ± 5% (DL) and 90 ± 5% (DC). However, 20% of the patients showed a ≥4% lower oxygen desaturation while using a DODS device. Secondary outcomes were similar under the three conditions., Conclusion: Oxygen supplementation via DODS (based on liquid oxygen or as a concentrator) yielded comparable physiological effects during standardized walking in stable hypoxemic COPD patients like CF. However, 20% of patients showed a clinically relevant lower oxygen saturation while using a DODS device. Therefore, we suggest individual testing of oxygen saturation of DODS suitability., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Long-term oxygen therapy (LTOT) is an established treatment for patients with chronic hypoxemia. Its scientific basis is derived mainly from two trials from the early 1980s that showed a survival advantage for patients with chronic obstructive pulmonary disease (COPD) treated with LTOT. Robust data are not available for other diseases associated with hypoxemia., Methods: This review is based on pertinent publications retrieved by a selective search in PubMed., Results: The use of LTOT for 15 to 16 hours per day (or, better, 24 hours per day) is recommended in current guidelines for patients with chronic hypoxemia (PaO2 ≤ 55 mm Hg) because this treatment was found to be associated with a lower mortality rate compared to no LTOT (33% vs. 55%, p <0.05) based on data from the early 1980s. In the short term, oxygen administration to a hypoxemic patient can improve oxygen saturation by nine percentage points and improve physical performance to a clinically relevant extent (6-minute walking test: + 37 m, p <0.001). The available data do not support the use of LTOT for normoxemic patients. LTOT should only be administered for strict indications, in accordance with the guidelines, and only in a form suitable for the individual patient. Skin burns can occur as a side effect of LTOT because of contact explosions with any type of fire., Conclusion: The acquisition of further robust data would be desirable, particularly with respect to patient-relevant outcome parameters including quality of life, performance status, and mortality. Moreover, the German guidelines on oxygen therapy need to be updated.

Background: This study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD., Methods: 219 patients with COPD (FEV 1 : 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H 2 O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time., Findings: No significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI -13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI -1.5 to -0.01, p=0.049) were observed in the intervention group., Interpretation: Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results., Competing Interests: Competing interests: AM acknowledges a previous (now expired) beneficial interest in the POWERbreathe inspiratory muscle trainers in the form of a share of royalty income to the University of Birmingham, and a potential share of royalty income to Brunel University. In the past, she has also provided consultancy services to POWERbreathe International, but no longer does so. She is named on two patents relating to POWERbreathe products, including the device used in the present study, as well as being the author of two books on inspiratory muscle training. FM reports research support from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Grifols and Novartis, advisory board participation for Boehringer Ingelheim and GlaxoSmithKline, and speaking engagements for Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Grifols and Novartis., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Chronic obstructive pulmonary disease (COPD) is a common condition that is becoming increasingly prevalent. It affects 13.2% of the population over age 40 in Germany. In 2020, it will be the third most common cause of morbidity and mortality around the world. It markedly impairs the quality of life of those who suffer from it and presents a major economic challenge to the health-care system., Methods: This review is based on pertinent publications retrieved by a selective literature search and on the authors' clinical experience., Results: Pulmonary rehabilitation (PR) for patients with COPD is supported by evidence on the highest level. It is associated with statistically significant (p <0.001) and clinically relevant improvement in physical performance (6-minute walk distance: + 44 m; 95% confidence interval [33; 55]), shortness of breath (Chronic Respiratory Disease Questionnaire: +0.79 points [0.56; 1.03]), and the quality of life (Saint George´s Respiratory Questionnaire: -6.9 points [-9.3; -4.5]). The benefits of PR are especially evident after an acute exacerbation of COPD: it significantly lowers the rate of readmission to the hospital (odds ratio 0.22 [0.08; 0.58], p = 0.002) and improves physical performance ability (6-minute walk distance: + 62 m [38; 86] and the quality of life (Saint George´s Respiratory Questionnaire: -7.8 points [-12.1; -3.5]; p <0.001 for both)., Conclusion: PR is an effective and cost-effective therapeutic intervention that improves physical performance ability, shortness of breath, and the quality of life in patients with COPD, but it has not yet been fully implemented as recommended in the relevant guidelines. There is a need for targeted, problem-oriented referral to a range of PR programs with problem-specific content. The necessary outpatient PR structures still need to be established in Germany.

Background: Several studies have shown that whole-body vibration training (WBVT) improves exercise capacity in patients with severe COPD. The aim of this study was to investigate the determinants of improved exercise capacity following WBVT., Methods: Seventy-four COPD patients (FEV 1 : 34 ± 9%predicted) were recruited during a 3-week inpatient pulmonary rehabilitation (PR) program. Conventional endurance and strength exercises were supplemented with self-paced dynamic squat training sessions (4bouts*2min, 3times/wk). Patients were randomly allocated to either a WBVT-group performing squat training on a side-alternating vibration platform (Galileo) at a high intensity (24-26 Hz) or a control group performing squat training without WBVT., Results: Patients in the WBVT group significantly improved postural balance in several domains compared to the control-group (i.e. tandem stance: WBVT +20% (95%CI 14 to 26) vs. control -10% (95%CI 6 to 15), p < 0.001; one-leg stance: WBVT +11% (95%CI 4 to 19) vs. control -8% (95%CI -19 to 3), p = 0.009). Six-minute walk distance and muscle power but not muscle strength were also significantly improved compared to control group., Conclusions: Implementation of WBVT improves postural balance performance and muscle power output. The neuromuscular adaptation related to improved balance performance may be an important mechanism of the improvement in exercise capacity after WBVT especially in COPD patients with impaired balance performance and low exercise capacity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Pulmonary rehabilitation (PR) following lung transplantation (LTx) has been shown to be effective with regard to exercise capacity and health-related quality of life (HRQL). However, outcome data is limited with respect to LTx as a population. Differences concerning the effects of PR in patients with single LTx (SLTx) or double LTx (DLTx) have not been studied yet., Objectives: The aim was to compare possible differences concerning PR outcomes between SLTx and DLTx., Methods: In a retrospective analysis (period: 1997-2016), data from 722 patients with either chronic obstructive pulmonary disease (COPD; SLTx: n = 129, FEV1 51 ± 17% pred.; DLTx: n = 204, FEV1 74 ± 20% pred.) or interstitial lung disease (ILD; SLTx: n = 135, FVC 58 ± 18% pred.; DLTx: n = 254, FVC 63 ± 18% pred.) after LTx were included. All patients underwent a specialized inpatient PR program. The data of the 6-minute walk distance (6MWD) and HRQL (physical [PCS] and mental [MCS] component summary of the SF- 36 questionnaire) were analyzed., Results: Independently from the procedure and pretransplant diagnosis, patients significantly (p < 0.05) improved the 6MWD without any differences between SLTx and DLTx (COPD: SLTx: +109 ± 68 m, DLTx: +117 ± 82 m; ILD: SLTx: +115 ± 80 m, DLTx: +132 ± 77 m). The PCS (COPD: SLTx: +9 ± 9 points, DLTx: +7 ± 9 points; ILD: SLTx: +6 ± 9 points, DLTx: +9 ± 9 points) and MCS (COPD: SLTx: +8 ± 15 points, DLTx: +7 ± 15 points; ILD: SLTx: +10 ± 13 points, DLTx: +8 ± 12 points) also improved significantly without any group differences., Conclusions: LTx patients with a pretransplant diagnosis of COPD or ILD all benefitted significantly and with clinical relevance with regard to exercise capacity and HRQL from an inpatient PR performed within 1 year postoperatively. PR outcomes were similar regardless of SLTx or DLTx., (© 2017 S. Karger AG, Basel.)

Background: Transcutaneous carbon-dioxide partial-pressure (T C PCO 2 ) can be reliably measured and may be of clinical relevance in COPD. Changes in T C PCO 2 and exercise-induced hypercapnia (EIH) during six-minute walk test (6MWT) need further investigation. We aimed (1) to define patterns of T C PCO 2 trends during 6MWT and (2) to study determinants of CO2-retention and EIH., Methods: Sixty-two COPD patients (age: 63±8years, FEV1: 33±10%pred.) were recruited and T C PCO2 was recorded by SenTec digital-monitoring-system during 6MWT., Results: Half of patients (50%) exhibited CO 2 -retention (T C PCO 2 [Δ]>4mmHg); 26% preserved and 24% reduced T C PCO 2 . Nineteen (31%) patients presented EIH (T C PCO 2 >45mmHg). EIH was associated to higher baseline-P C CO 2 , worse FEV1, lower inspiratory-pressures, underweight/normal BMI, and pre-walk dyspnea. Stronger determinants of CO 2 -retention were FEV1 and pre-walk dyspnea, whereas baseline-P C CO 2 and pre-walk dyspnea better predict EIH., Conclusions: PCO 2 response to 6MWT is highly heterogeneous; however, very low FEV1 and elevated baseline-P C CO 2 together with pre-walk dyspnea increase the risk for CO 2 -retention and EIH. Overweight-BMI seems to carry a protective effect against EIH in very severe COPD., (Copyright © 2016 Elsevier B.V. All rights reserved.)