Applying Nuclear Forward Scattering as In Situ and Operando Tool for the Characterization of FeN4 Moieties in the Hydrogen Evolution Reaction.

Nuclear forward scattering (NFS) is a synchrotron-based technique relying on the recoil-free nuclear resonance effect similar to Mössbauer spectroscopy. In this work, we introduce NFS for in situ and operando measurements during electrocatalytic reactions. The technique enables faster data acquisition and better discrimination of certain iron sites in comparison to Mössbauer spectroscopy. It is directly accessible at various synchrotrons to a broad community of researchers and is applicable to multiple metal isotopes. We demonstrate the power of this technique with the hydrogen evolution mechanism of an immobilized iron porphyrin supported on carbon. Such catalysts are often considered as model systems for iron-nitrogen-carbon (FeNC) catalysts. Using in situ and operando NFS in combination with theoretical predictions of spectroscopic data enables the identification of the intermediate that is formed prior to the rate-determining step. The conclusions on the reaction mechanism can be used for future optimization of immobilized molecular catalysts and metal-nitrogen-carbon (MNC) catalysts.

Physical Activity, Depression and Quality of Life in COPD - Results from the CLARA II Study.

Background: Symptoms of depression, pain and limitations in physical activity may affect quality of life in COPD patients independent from their respiratory burden. We aimed to analyze the associations of these factors in outpatients with COPD in Austria in a stable phase of disease. Methods: We conducted a national, cross-sectional study among patients with COPD. For depression, the Patient Health Questionnaire-9 (PHQ-9) and for respiratory symptoms the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) were used along with 10-point scales for physical activity and pain. Results: After exclusion of 211 patients due to non-obstructive spirometry or missing data, 630 patients (62.5% men; mean age 66.8 ± 8.6 (SD) years; mean FEV1%pred. 54.3 ± 16.5 (SD)) were analyzed. Of these, 47% reported one or more exacerbations in the previous year, 10.4% with hospitalization. A negative depression score was found in 54% and a score suggesting severe depression (PHQ-9 score ≥ 15) in 4.7%. In a multivariate linear regression model, self-reported pain, dyspnea, and number of exacerbations were predictors for higher PHQ-9-scores. A negative pain score was found in 43.8%, and a score suggesting severe pain in 2.9% (8-10 points of 10-point scale). Patients reporting severe pain were more often female, had more exacerbations, and reported more respiratory and depressive symptoms, a lower quality of life, and less physical activity. About 46% of patients rated their physical activity as severely impaired. These patients were significantly older, had more exacerbations, concomitant heart disease, a higher pain and depression score, and a lower quality of life (SGRQ-C - total score and all subscores). Conclusions: In Austria, nearly half of stable COPD outpatients reported symptoms of depression, which were associated with lower levels of self-reported physical activity, more pain, and respiratory symptoms. The associations were particularly strong for depression with SGRQ-C.

Towards the definition of metrics for the assessment of operational design domains.

Background: The Operational Design Domain (ODD) of an automated driving function defines on which roads and under which environmental conditions the function is safe to operate. It plays an important role in definition, safety analysis and validation of automated driving. In many cases, users want to determine metrics about ODDs, or about ODDs in combination with other work products, like collections of validation scenarios. Such metrics could answer questions such as what percentage of the road network of a given region is inside the ODD. While language formats to specify ODDs have emerged over the last few years, a solid methodology on how to calculate different sorts of metrics is still ONThe roadmap for the future. Methods: This contribution suggests metrics for ODDs that are mathematically built upon a notion of ontologies, and ODDs as multi-dimensional cross-products of sets, using standard arithmetic and set operations. To illustrate the idea, a couple of possible metrics for ODDs are derived as examples and discussed in the light of some real-world use cases. Results: To illustrate the application of a ODD metric, we apply an analysis of a sample trip and calculate the theoretical availability of variants of an automated driving system with different ODDs. Conclusions: The metrics presented and the shown sample application present an important next step in discussions around ODDs of Automated Driving Systems. They make it possible to not only consider an ODD specification as a reference for a single system, but allow comparing systems with different ODDs, judging the maturity of a system with a certain ODD, or provide indicators how usable a system is within a real-word application.

The Impact of Exercise Training and Supplemental Oxygen on Peripheral Muscles in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

OBJECTIVE: Exercise training is a cornerstone of the treatment of chronic obstructive pulmonary disease, whereas the related interindividual heterogeneity in skeletal muscle dysfunction and adaptations are not yet fully understood. We set out to investigate the effects of exercise training and supplemental oxygen on functional and structural peripheral muscle adaptation. METHODS: In this prospective, randomized, controlled, double-blind study, 28 patients with nonhypoxemic chronic obstructive pulmonary disease (forced expiratory volume in 1 second, 45.92% ± 9.06%) performed 6 wk of combined endurance and strength training, three times a week while breathing either supplemental oxygen or medical air. The impact on exercise capacity, muscle strength, and quadriceps femoris muscle cross-sectional area (CSA) was assessed by maximal cardiopulmonary exercise testing, 10-repetition maximum strength test of knee extension, and magnetic resonance imaging, respectively. RESULTS: After exercise training, patients demonstrated a significant increase in functional capacity, aerobic capacity, exercise tolerance, quadriceps muscle strength, and bilateral CSA. Supplemental oxygen affected significantly the training impact on peak work rate when compared with medical air (+0.20 ± 0.03 vs +0.12 ± 0.03 W·kg -1 , P = 0.047); a significant increase in CSA (+3.9 ± 1.3 cm 2 , P = 0.013) was only observed in the training group using oxygen. Supplemental oxygen and exercise-induced peripheral desaturation were identified as significant opposing determinants of muscle gain during this exercise training intervention, which led to different adaptations of CSA between the respective subgroups. CONCLUSIONS: The heterogenous functional and structural muscle adaptations seem determined by supplemental oxygen and exercise-induced hypoxia. Indeed, supplemental oxygen may facilitate muscular training adaptations, particularly in limb muscle dysfunction, thereby contributing to the enhanced training responses on maximal aerobic and functional capacity.

Operando studies of Mn oxide based electrocatalysts for the oxygen evolution reaction.

Inspired by photosystem II (PS II), Mn oxide based electrocatalysts have been repeatedly investigated as catalysts for the electrochemical oxygen evolution reaction (OER), the anodic reaction in water electrolysis. However, a comparison of the conditions in biological OER catalysed by the water splitting complex CaMn4Ox with the requirements for an electrocatalyst for industrially relevant applications reveals fundamental differences. Thus, a systematic development of artificial Mn-based OER catalysts requires both a fundamental understanding of the catalytic mechanisms as well as an evaluation of the practicality of the system for industrial scale applications. Experimentally, both aspects can be approached using in situ and operando methods including spectroscopy. This paper highlights some of the major challenges common to different operando investigation methods and recent insights gained with them. To this end, vibrational spectroscopy, especially Raman spectroscopy, absorption techniques in the bandgap region and operando X-ray spectroelectrochemistry (SEC), both in the hard and soft X-ray regime are particularly focused on here. Technical challenges specific to each method are discussed first, followed by challenges that are specific to Mn oxide based systems. Finally, recent in situ and operando studies are reviewed. This analysis shows that despite the technical and Mn specific challenges, three specific key features are common to most of the studied systems with significant OER activity: structural disorder, Mn oxidation states between III and IV, and the appearance of layered birnessite phases in the active regime.

Substituent Effects in Iron Porphyrin Catalysts for the Hydrogen Evolution Reaction.

For a future hydrogen economy, non-precious metal catalysts for the water splitting reactions are needed that can be implemented on a global scale. Metal-nitrogen-carbon (MNC) catalysts with active sites constituting a metal center with fourfold coordination of nitrogen (MN4 ) show promising performance, but an optimization rooted in structure-property relationships has been hampered by their low structural definition. Porphyrin model complexes are studied to transfer insights from well-defined molecules to MNC systems. This work combines experiment and theory to evaluate the influence of porphyrin substituents on the electronic and electrocatalytic properties of MN4 centers with respect to the hydrogen evolution reaction (HER) in aqueous electrolyte. We found that the choice of substituent affects their utilization on the carbon support and their electrocatalytic performance. We propose an HER mechanism for supported iron porphyrin complexes involving a [FeII (P⋅)]- radical anion intermediate, in which a porphinic nitrogen atom acts as an internal base. While this work focuses on the HER, the limited influence of a simultaneous interaction with the support and an aqueous electrolyte will likely be transferrable to other catalytic applications.

Clinical, imaging, and blood biomarkers to assess 1-year progression risk in fibrotic interstitial lung diseases-Development and validation of the honeycombing, traction bronchiectasis, and monocyte (HTM)-score.

Introduction: Progression of fibrotic interstitial lung disease (ILD) leads to irreversible loss of lung function and increased mortality. Based on an institutional ILD registry, we aimed to evaluate biomarkers derived from baseline patient characteristics, computed tomography (CT), and peripheral blood for prognosis of disease progression in fibrotic ILD patients. Methods: Of 209 subsequent ILD-board patients enregistered, 142 had complete follow-up information and were classified fibrotic ILD as defined by presence of reticulation or honeycombing using a standardized semi-quantitative CT evaluation, adding up typical ILD findings in 0-6 defined lung fields. Progression at 1 year was defined as relative loss of ≥10% in forced vital capacity, of ≥15% in diffusion capacity for carbon monoxide, death, or lung transplant. Two-thirds of the patients were randomly assigned to a derivation cohort evaluated for the impact of age, sex, baseline lung function, CT finding scores, and blood biomarkers on disease progression. Significant variables were included into a regression model, its results were used to derive a progression-risk score which was then applied to the validation cohort. Results: In the derivation cohort, age, monocyte count ≥0.65 G/L, honeycombing and traction bronchiectasis extent had significant impact. Multivariate analyses revealed the variables monocyte count ≥0.65 G/L (1 point) and combined honeycombing or traction bronchiectasis score [0 vs. 1-4 (1 point) vs. 5-6 lung fields (2 points)] as significant, so these were used for score development. In the derivation cohort, resulting scores of 0, 1, 2, and 3 accounted for 1-year progression rates of 20, 25, 46.9, and 88.9%, respectively. Similarly, in the validation cohort, progression at 1 year occurred in 0, 23.8, 53.9, and 62.5%, respectively. A score ≥2 showed 70.6% sensitivity and 67.9% specificity, receiver operating characteristic analysis for the scoring model had an area under the curve of 71.7%. Conclusion: The extent of honeycombing and traction bronchiectasis, as well as elevated blood monocyte count predicted progression within 1 year in fibrotic ILD patients.

Durvalumab after Sequential High Dose Chemoradiotherapy versus Standard of Care (SoC) for Stage III NSCLC: A Bi-Centric Trospective Comparison Focusing on Pulmonary Toxicity.

Introduction: The standard of care (SoC) for unresectable stage III non-small-cell lung cancer (NSCLC) is durvalumab maintenance therapy after concurrent chemoradiation in patients with PD-L1 > 1%. However, the concurrent approach is only amenable for about one-third of patients due to co-morbidities. Although sequential regimens are usually not regarded as curative, these schedules applied in a dose-escalated manner may be similarly radical as SoC. As combining high-dose radiation and durvalumab remains a question of debate this retrospective bi-center study aims to evaluate pulmonary toxicity after high-dose chemoradiotherapy beyond 70 Gy compared to SoC. Patients and Methods: Patients with NSCLC stage III received durvalumab after either sequential high-dose chemoradiation or concomitant SoC. Chemotherapy consisted of platinum combined with either pemetrexed, taxotere, vinorelbine, or gemcitabine. The primary endpoint was short-term pulmonary toxicity occurring within six months after the end of radiotherapy (RT). Results: A total of 78 patients were eligible for this analysis. 18F-FDG-PET-CT, cranial MRT, and histological/cytological verification were mandatory in the diagnostic work-up. The high-dose and SoC group included 42/78 (53.8%) and 36/78 (46.2%) patients, respectively, which were matched according to baseline clinical variables. While the interval between the end of RT and the start of durvalumab was equal in both groups (p = 0.841), more courses were administered in the high-dose cohort (p = 0.031). Pulmonary toxicity was similar in both groups (p = 0.599), whereas intrathoracic disease control was better in the high-dose group (local control p = 0.081, regional control p = 0.184). Conclusion: The data of this hypothesis-generating study suggest that sequential high-dose chemoradiation followed by durvalumab might be similar to SoC in terms of pulmonary toxicity and potentially more effective with respect to intra-thoracic disease control. Larger trials with a prospective design are warranted to validate these results.

High Dose Thoracic Re-Irradiation and Chemo-Immunotherapy for Centrally Recurrent NSCLC.

INTRODUCTION: Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation. METHODS: A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients. RESULTS: Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3-25.1), median progression free survival (PFS) was nine months (range 4.5-16), and median loco-regional control (LRC) was 12.1 months (range 6.5-20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033). CONCLUSION: The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.

qSOFA score poorly predicts critical progression in COVID-19 patients.

BACKGROUND: In December 2019, the new virus infection coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged. Simple clinical risk scores may improve the management of COVID-19 patients. Therefore, the aim of this pilot study was to evaluate the quick Sequential Organ Failure Assessment (qSOFA) score, which is well established for other diseases, as an early risk assessment tool predicting a severe course of COVID-19. METHODS: We retrospectively analyzed data from adult COVID-19 patients hospitalized between March and July 2020. A critical disease progress was defined as admission to intensive care unit (ICU) or death. RESULTS: Of 64 COVID-19 patients, 33% (21/64) had a critical disease progression from which 13 patients had to be transferred to ICU. The COVID-19-associated mortality rate was 20%, increasing to 39% after ICU admission. All patients without a critical progress had a qSOFA score ≤ 1 at admission. Patients with a critical progress had in only 14% (3/21) and in 20% (3/15) of cases a qSOFA score ≥ 2 at admission (p = 0.023) or when measured directly before critical progression, respectively, while 95% (20/21) of patients with critical progress had an impairment oxygen saturation (SO2) at admission time requiring oxygen supplementation. CONCLUSION: A low qSOFA score cannot be used to assume short-term stable or noncritical disease status in COVID-19.

First-Line Pembrolizumab Mono- or Combination Therapy of Non-Small Cell Lung Cancer: Baseline Metabolic Biomarkers Predict Outcomes.

Quantitative biomarkers derived from positron-emission tomography/computed tomography (PET/CT) have been suggested as prognostic variables in immune-checkpoint inhibitor (ICI) treated non-small cell lung cancer (NSCLC). As such, data for first-line ICI therapy and especially for chemotherapy-ICI combinations are still scarce, we retrospectively evaluated baseline 18F-FDG-PET/CT of 85 consecutive patients receiving first-line pembrolizumab with chemotherapy (n = 70) or as monotherapy (n = 15). Maximum and mean standardized uptake value, total metabolic tumor volume (MTV), total lesion glycolysis, bone marrow-/and spleen to liver ratio (BLR/SLR) were calculated. Kaplan-Meier analyses and Cox regression models were used to assess progression-free/overall survival (PFS/OS) and their determinant variables. Median follow-up was 12 months (M; 95% confidence interval 10-14). Multivariate selection for PFS/OS revealed MTV as most relevant PET/CT biomarker (p < 0.001). Median PFS/OS were significantly longer in patients with MTV ≤ 70 mL vs. >70 mL (PFS: 10 M (4-16) vs. 4 M (3-5), p = 0.001; OS: not reached vs. 10 M (5-15), p = 0.004). Disease control rate was 81% vs. 53% for MTV ≤/> 70 mL (p = 0.007). BLR ≤ 1.06 vs. >1.06 was associated with better outcomes (PFS: 8 M (4-13) vs. 4 M (3-6), p = 0.034; OS: 19 M (12-/) vs. 6 M (4-12), p = 0.005). In patients with MTV > 70 mL, concomitant BLR ≤ 1.06 indicated a better prognosis. Higher MTV is associated with inferior PFS/OS in first-line ICI-treated NSCLC, with BLR allowing additional risk stratification.

18F-Choline PET/CT, MRI, and Software-Based Image Fusion Analysis in Patients With Primary Hyperparathyroidism.

PURPOSE: The aim of this study was to evaluate the diagnostic performance of 18F-choline PET and MRI in patients with primary hyperparathyroidism. Furthermore, the additional value of software-based PET/MRI scan fusion was analyzed. PATIENTS AND METHODS: This retrospective study includes 42 patients (38 women) with an age between 32.5 and 79.1 years. PET/CT scans were performed on a dedicated system after injection of 250 to 350 MBq 18F-choline. For the MRI examination, T1-weighted images of the cervical region were used. The image fusion was made by anatomical coregistration using an automated algorithm based on mutual information. RESULTS: A total of 46 lesions were discovered and histologically confirmed in 42 patients. Histopathological examination revealed 38 adenomas and 8 hyperplasias. This means that, in 4 of these 42 patients, 2 lesions per patient were discovered. PET/CT also detected 46 abnormal findings, but only 43 were correctly recognized, whereas the other 3 were false-positive (FP). Six lesions could not be detected correctly: 3 were FP and 3 false-negative, which resulted in a sensitivity of 93.5% and a specificity of 97.5%. The site-specific evaluation showed 18 true-positive enlarged parathyroid glands with MRI, but also produced 13 FP findings and failed to detect 28 lesions; the sensitivity and specificity are thus 39.1% and 89.3%, respectively. The difference in detection rate between 18F-choline PET/CT and MRI was statistically significant (P < 0.001). CONCLUSIONS: 18F-choline PET/CT is clearly superior to MRI for localization diagnostics in primary hyperparathyroidism. Image fusion of both modalities can be helpful for more precise anatomical assignment.

Computed Tomography Findings as Determinants of Local and Systemic Inflammation Biomarkers in Interstitial Lung Diseases: A Retrospective Registry-Based Descriptive Study.

PURPOSE: To evaluate the association of peripheral blood (PBL) and broncho-alveolar lavage (BAL) biomarkers with inflammatory versus fibrotic high-resolution computed tomography (HRCT) findings in interstitial lung disease (ILD) patients. METHODS: HRCT findings of 127 consecutive ILD-board patients were semi-quantitatively evaluated: reticulation/honeycombing (RET), traction bronchiectasis (TBR) and emphysema (EMP) were classified as non-inflammatory/fibrotic; consolidations (CON), ground glass opacities (GGO), parenchymal nodules (NDL) and mosaic attenuation (MOS) as active inflammatory. Each HRCT finding was assessed in six distinct lung regions, resulting scores were graded as minimal (0-1 regions involved), medium (2-4) or extensive (5-6). Associations of routinely assessed PBL/BAL biomarkers with these HRCT scores were evaluated using Spearman correlation coefficients and graphical presentation; significance was tested by applying Kruskal-Wallis tests. RESULTS: Blood neutrophil, lymphocyte and eosinophil fraction, neutrophil to lymphocyte ratio (NLR) and BAL lymphocyte fraction consistently showed opposite correlations with inflammatory versus non-inflammatory/fibrotic HRCT finding scores. Blood lymphocyte fraction significantly differed by graded GGO (p = 0.032) and CON (p = 0.027) extent, eosinophil fraction by TBR (p = 0.006) and NLR by CON (p = 0.009). C-reactive protein was significantly related to GGO (p = 0.023) and CON (p = 0.004), BAL lymphocyte fraction to GGO (p = 0.017) extent. CONCLUSION: Blood lymphocyte and eosinophil fraction, NLR, CRP and BAL lymphocyte fraction may aid to differentiate inflammatory from non-inflammatory/fibrotic ILD patterns. TRIAL REGISTRATION: This evaluation was based on data from the ILD registry of Kepler University Hospital Linz, as approved by the ethics committee of the Federal State of Upper-Austria (EK Number. I-26-17).

Sex-Based Clinical Outcome in Advanced NSCLC Patients Undergoing PD-1/PD-L1 Inhibitor Therapy-A Retrospective Bi-Centric Cohort Study.

Men with non-small cell lung cancer (NSCLC) have a more favorable response to immune-checkpoint inhibitor (ICI) monotherapy, while women especially benefit from ICI-chemotherapy (CHT) combinations. To elucidate such sex differences in clinical practice, we retrospectively analyzed two cohorts treated with either ICI monotherapy (n = 228) or ICI-CHT combination treatment (n = 80) for advanced NSCLC. Kaplan-Meier analyses were used to calculate progression-free (PFS) and overall survival (OS), influencing variables were evaluated using Cox-regression analyses. No significant sex differences for PFS/OS could be detected in either cohort. Men receiving ICI monotherapy had a statistically significant independent impact on PFS by Eastern Cooperative Oncology Group performance status (ECOG) ≥2 (hazard ratio (HR) 1.90, 95% confidence interval (CI): 1.10-3.29, p = 0.021), higher C-reactive protein (CRP; HR 1.06, 95%CI: 1.00-1.11, p = 0.037) and negative programmed death-ligand 1 (PD-L1) status (HR 2.04, 95%CI: 1.32-3.15, p = 0.001), and on OS by CRP (HR 1.09, 95%CI: 1.03-1.14, p = 0.002). In men on ICI-CHT combinations, multivariate analyses (MVA) revealed squamous histology (HR 4.00, 95%CI: 1.41-11.2, p = 0.009) significant for PFS; and ECOG ≥ 2 (HR 5.58, 95%CI: 1.88-16.5, p = 0.002) and CRP (HR 1.19, 95%CI: 1.06-1.32, p = 0.002) for OS. Among women undergoing ICI monotherapy, no variable proved significant for PFS, while ECOG ≥ 2 had a significant interaction with OS (HR 1.90, 95%CI 1.04-3.46, p = 0.037). Women treated with ICI-CHT had significant MVA findings for CRP with both PFS (HR 1.09, 95%CI: 1.02-1.16, p = 0.007) and OS (HR 1.11, 95%CI: 1.03-1.19, p = 0.004). Although men and women responded similarly to both ICI mono- and ICI-CHT treatment, predictors of response differed by sex.

Systemic Inflammation, Vascular Function, and Endothelial Progenitor Cells after an Exercise Training Intervention in COPD.

BACKGROUND: Exercise training is a cornerstone of the treatment of chronic obstructive pulmonary disease (COPD) in all disease stages. Data about the training effects with supplemental oxygen in nonhypoxemic patients remains inconclusive. In this study we set out to investigate the training and oxygen effects on inflammatory markers, vascular function, and endothelial progenitor cells in this population of increased cardiovascular risk. METHODS: In this prospective, randomized, double-blind, crossover study, 29 patients with nonhypoxemic COPD performed combined endurance and strength training 3 times a week while breathing medical air or supplemental oxygen for the first 6-week period, and were then reallocated to the opposite gas for the following 6 weeks. Exercise capacity, inflammatory biomarkers, endothelial function (peripheral arterial tone analysis), and endothelial progenitor cells were assessed. Data were also analyzed for a subgroup with endothelial dysfunction (reactive hyperemia index <1.67). RESULTS: Following 12 weeks of exercise training, patients demonstrated a significant improvement of peak work rate and an associated decrease of blood fibrinogen and leptin. Eosinophils were found significantly reduced after exercise training in patients with endothelial dysfunction. In this subgroup, peripheral arterial tone analysis revealed a significant improvement of reactive hyperemia index. Generally, late endothelial progenitor cells were found significantly reduced after the exercise training intervention. Supplemental oxygen during training positively influenced the effect on exercise capacity without impact on inflammation and endothelial function. CONCLUSIONS: This is the first randomized controlled trial in patients with COPD to show beneficial effects of exercise training not only on exercise capacity, but also on systemic/eosinophilic inflammation and endothelial dysfunction.

Impact of exercise training and supplemental oxygen on submaximal exercise performance in patients with COPD.

Functional impairment caused by chronic obstructive pulmonary disease (COPD) impacts on activities of daily living and quality of life. Indeed, patients' submaximal exercise capacity is of crucial importance. It was the aim of this study to investigate the effects of an exercise training intervention with and without supplemental oxygen on submaximal exercise performance. This is a secondary analysis of a randomized, controlled, double-blind, crossover trial. 29 COPD patients (63.5 ± 5.9 years; FEV1 46.4 ± 8.6%) completed two consecutive 6-week periods of high-intensity interval cycling and strength training, which was performed three times/week with either supplemental oxygen or medical air (10 L/min). Submaximal exercise capacity as well as the cardiocirculatory, ventilatory, and metabolic response were evaluated at isotime (point of termination in the shortest cardiopulmonary exercise test), at physical work capacity at 110 bpm of heart rate (PWC 110), at the anaerobic threshold (AT), and at the lactate-2 mmol/L threshold. After 12 weeks of exercise training, patients improved in exercise tolerance, shown by decreased cardiocirculatory (heart rate, blood pressure) and metabolic (respiratory exchange ratio, lactate) effort at isotime; ventilatory response was not affected. Submaximal exercise capacity was improved at PWC 110, AT and the lactate-2 mmol/L threshold, respectively. Although supplemental oxygen seems to affect patients' work rate at AT and the lactate-2 mmol/L threshold, no other significant effects were found. The improved submaximal exercise capacity and tolerance might counteract patients' functional impairment. Although cardiovascular and metabolic training adaptations were shown, ventilatory efficiency remained essentially unchanged. The impact of supplemental oxygen seems less important on submaximal training effects.

Serum Tumor Marker Dynamics as Predictive Biomarkers in NSCLC Chemo-Immunotherapy and Mono-Immunotherapy Maintenance: A Registry-Based Descriptive Study.

OBJECTIVE: To evaluate serum tumor markers (STM) as predictive biomarkers in advanced non-small cell lung cancer (NSCLC) treated with chemo-immunotherapy. METHODS: Patients having received platinum-based chemo-(CHT) and PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) combination therapy were retrospectively followed. Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis. The marker with the highest relative elevation was defined "leading STM", its change was assessed between CHT-ICI as well as mono-ICI maintenance initiation and the respective subsequent restaging. Corresponding computed tomography evaluations were analyzed using response evaluation criteria in solid tumors (RECIST). For CHT-ICI combination and subsequent mono-ICI-maintenance therapy, leading STM and RECIST response were evaluated regarding progression-free (PFS) and overall survival (OS) in Kaplan-Meier analyses. RESULTS: Among 80 CHT-ICI patients (41% women, mean age 63 years), median PFS was 5 months (M;4,9), median OS was 15M (10,/). PFS was significantly (p=0.042) longer, when the leading STM had decreased at first restaging under CHT-ICI combination therapy (9M (5,12; n=41) vs 5M (3,6; n=16)). In the 54 (67.5%) patients who received subsequent mono-ICI maintenance therapy, STM decrease was similarly associated with significantly (p<0.001) longer PFS (16M (7,/; n=16) vs 3.5M (2,6; n=22)). Patients with radiologically stable or progressive disease and concomitant leading STM decrease had similar PFS in the CHT-ICI combination phase (4M (3,7; n=16) vs 4.5M (2,6; n=14)), but longer PFS in the mono-ICI maintenance setting (13M (7,16; n=10) vs 3M (2,4; n=17)). Median OS was not reached in most subgroups. CONCLUSION: Leading STM dynamics provide predictive biomarker information additional to radiological response evaluation patients receiving CHT-ICI combination therapy, especially in the mono-ICI maintenance setting.

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2015 and GOLD 2019 staging: a pooled analysis of individual patient data.

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A-4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66-0.68) for GOLD 2015 and 0.65 (95% CI 0.63-0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system.

Computed tomography findings as determinants of pulmonary function tests in fibrotic interstitial lung diseases-Network-analyses and multivariate models.

The aim was to evaluate the impact of multiple high-resolution computed tomography (HRCT) features on pulmonary function test (PFT) biomarkers in fibrotic interstitial lung disease (FILD) patients. HRCT of subsequently ILD-board-discussed FILD patients were semi-quantitatively evaluated in a standardized approach: 18 distinct lung regions were scored for noduli, reticulation, honeycombing, consolidations, ground glass opacities (GGO), traction bronchiectasis (BRK) and emphysema. Total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC, diffusion capacity for carbon monoxide (DLCO) and transfer coefficient (KCO) were assessed. Interactions between each PFT biomarker and all HRCT scores were visualized by network analyses, modeled according to the Schwarz Bayesian Information Criterion and incorporated in uni- and multivariate stepwise regression analyses. Among 108 FILD patients (mean age 67 years, 77% male), BRK extent was a major significant uni- or multivariate determinant of all PFT analyzed. Besides that, diffusion-based variables DLCO and KCO showed a larger dependency on reticulation, emphysema and GGO, while forced expiratory volume-based measures FEV1, FVC and FEV1/FVC were more closely associated with consolidations. For TLC, the only significant multivariate determinant was reticulation. In conclusion, PFT biomarkers derived from spirometry, body plethysmography and diffusion capacity in FILD patients are differentially influenced by semi-quantified HRCT findings.

Acute Exposure to Environmental Tobacco Smoke: A Controlled Study in Adults with Asthma.

BACKGROUND: Short-term, indoor exposure to environmental tobacco smoke (ETS) is still highly prevalent; however, little is known about the acute lung response in adult asthma. OBJECTIVES: We investigated whether acute, experimental ETS exposure influences symptoms, lung function, and inflammatory parameters. METHODS: Human subjects with asthma (n = 23) were exposed for 180 min to either room air or ETS at 250, 450, or 850 µg/m3. Respiratory symptoms, lung function, and exhaled nitric oxide (FeNO) were measured. Additionally, blood samples were analyzed for pro- and anti-inflammatory cytokines. RESULTS: Humans with asthma demonstrate an increase in respiratory symptoms at all levels of ETS exposure, while the forced expiratory volume in 1 s (FEV1) and FeNO decrease with increasing ETS. The anti-inflammatory cytokine interleukin (IL)-10 increases at intermediate ETS concentrations, whereas tumor necrosis factor (TNF)-α and IL-8 increase only at the highest ETS concentration. CONCLUSION: Following 180 min of acute, experimental ETS exposure, we observed a significant increase in respiratory symptoms, a decrease in lung function, and an increase in inflammatory cytokines, indicating an acute lung response in asthma.