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SummaryImmune checkpoint blockade (ICB) has fundamentally improved the treatment landscape of advanced lung cancer. Improved tolerability and encouraging duration of response in selected patients are some of the advantages of ICB over conventional cytotoxic chemotherapies. However, immune-related adverse events (irAEs) possibly affecting multiple organs pose challenges in diagnosis and management. Checkpoint inhibitor pneumonitis (CIP) is a rare but clinically highly relevant irAE that can significantly impair quality of life and can be potentially life threatening. Since its heterogeneity in clinical and radiographic presentation, diagnosis can be challenging. Treatment usually consists of discontinuing or delaying the administration of ICB. If there is no sufficient recovery with this measure, steroid therapy is indicated. Although the majority of cases improves with this therapy, steroid-refractory CIP can be a therapeutic challenge as there is currently no evidence-based standard treatment. We herein present a short review of literature and a case report of relapsing CIP under steroid treatment.

The endeavors to understand the determinants of water permeation through membrane channels, the effect of the lipid or polymer membrane on channel function, the development of specific water flow inhibitors, the design of artificial water channels and aquaporins for the use in industrial water filtration applications all rely on accurate ways to quantify water permeabilities (Pf). A commonly used method is to reconstitute membrane channels into large unilamellar vesicles (LUVs) and to subject these vesicles to an osmotic gradient in a stopped-flow device. Fast recordings of either scattered light intensity or fluorescence self-quenching signals are taken as a readout for vesicle volume change, which in turn can be recalculated to accurate Pf values. By means of computational and experimental data, we discuss the pros and cons of using scattering versus self-quenching experiments or subjecting vesicles to hypo- or hyperosmotic conditions. In addition, we explicate for the first time the influence of the LUVs size distribution, channel distribution between vesicles and remaining detergent after protein reconstitution on Pf values. We point out that results such as the single channel water permeability (pf) depend on the membrane matrix or on the direction of the applied osmotic gradient may be direct results of the measurement and analysis procedure., Accurate pf values are of utmost importance to understand the structure–function relationship of water permeation through membrane channels, guiding the design of artificial or biological water channels for separation applications.

The water permeability of aquaporins (AQPs) varies by more than an order of magnitude even though the pore structure, geometry, as well as the channel lining residues are highly conserved. However, channel gating by pH, divalent ions or phosphorylation was only shown for a minority of AQPs. Structural and in silico indications of water flux modulation by flexible side chains of channel lining residues have not been experimentally confirmed yet. Hence, the aquaporin "open state" is still considered to be a continuously open pore with water molecules permeating in a single-file fashion. Using protein mutations outside the selectivity filter in the aqua(glycerol)facilitator GlpF of Escherichia coli we, to the best of our knowledge, for the first time, modulate the position of the highly conserved Arg in the selectivity filter. This in turn enhances or reduces the unitary water permeability of GlpF as shown in silico by molecular dynamics (MD) simulations and in vitro with purified and reconstituted GlpF. This finding suggests that AQP water permeability can indeed be regulated by lipid bilayer asymmetry and the transmembrane potential. Strikingly, our long-term MD simulations reveal that not only the conserved Arg in the selectivity filter, but the position and dynamics of multiple other pore lining residues modulate water passage through GlpF. This finding is expected to trigger a wealth of future investigations on permeability and regulation of AQPs among others with the aim to tune water permeability for biotechnological applications., Protein Science, 31 (10), ISSN:1469-896X, ISSN:0961-8368

Background COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients. Methods We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician's diagnosis of COPD and age ≥40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded. Results Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV1/FVC

Evolution turned aquaporins (AQPs) into the most efficient facilitators of passive water flow through cell membranes at no expense of solute discrimination. In spite of a plethora of solved AQP structures, many structural details remain hidden. Here, by combining extensive sequence- and structural-based analysis of a unique set of 20 non-redundant high-resolution structures and molecular dynamics simulations of four representatives, key aspects of AQP stability, gating, selectivity, pore geometry, and oligomerization, with a potential impact on channel functionality, are identified. The general view of AQPs possessing a continuous open water pore is challenged and it is depicted that AQPs’ selectivity is not exclusively shaped by pore-lining residues but also by the relative arrangement of transmembrane helices. Moreover, this analysis reveals that hydrophobic interactions constitute the main determinant of protein thermal stability. Finally, a numbering scheme of the conserved AQP scaffold is established, facilitating direct comparison of, for example, disease-causing mutations and prediction of potential structural consequences. Additionally, the results pave the way for the design of optimized AQP water channels to be utilized in biotechnological applications. Fonds zur Förderung der Wissenschaftlichen Forschung P31074 P35541 Deutsche Forschungsgemeinschaft (DE-588)2007744-0 390740016 Version of record

Lipid domains less than 200 nm in size may form a scaffold, enabling the concerted function of plasma membrane proteins. The size-regulating mechanism is under debate. We tested the hypotheses that large values of spontaneous monolayer curvature are incompatible with micrometer-sized domains. Here, we used the transition of photoswitchable lipids from their cylindrical conformation to a conical conformation to increase the negative curvature of a bilayer-forming lipid mixture. In contrast to the hypothesis, pre-existing micrometer-sized domains did not dissipate in our planar bilayers, as indicated by fluorescence images and domain mobility measurements. Elasticity theory supports the observation by predicting the zero free energy gain for splitting large domains into smaller ones. It also indicates an alternative size-determining mechanism: The cone-shaped photolipids reduce the line tension associated with lipid deformations at the phase boundary and thus slow down the kinetics of domain fusion. The competing influence of two approaching domains on the deformation of the intervening lipids is responsible for the kinetic fusion trap. Our experiments indicate that the resulting local energy barrier may restrict the domain size in a dynamic system.

Lipid domains less than 200 nm in size may form a scaffold, enabling the concerted function of plasma membrane proteins. The size-regulating mechanism is under debate. We tested the hypotheses that large values of spontaneous monolayer curvature are incompatible with micrometer-sized domains. Here, we used the transition of photoswitchable lipids from their cylindrical conformation to a conical conformation to increase the negative curvature of a bilayer-forming lipid mixture. In contrast to the hypothesis, pre-existing micrometer-sized domains did not dissipate in our planar bilayers, as indicated by fluorescence images and domain mobility measurements. Elasticity theory supports the observation by predicting the zero free energy gain for splitting large domains into smaller ones. It also indicates an alternative size-determining mechanism: The cone-shaped photolipids reduce the line tension associated with lipid deformations at the phase boundary and thus slow down the kinetics of domain fusion. The competing influence of two approaching domains on the deformation of the intervening lipids is responsible for the kinetic fusion trap. Our experiments indicate that the resulting local energy barrier may restrict the domain size in a dynamic system.

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.

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.

Simple Summary Retrospective analyses suggest that men treated with immune-checkpoint inhibitor (ICI) monotherapy for non-small cell lung cancer (NSCLC) have better outcomes than women. However, female patients have more favorable responses when chemotherapy (CHT) is given together with ICI. We aimed to explore the clinical impact of such sex differences in two cohorts, receiving ICI monotherapy or ICI-CHT combination, respectively. We found no significant difference in outcomes between men and women treated with either therapeutic regimen. However, known predictive factors for ICI response such as the expression of programmed-death ligand 1 (PD-L1) on tumor cells or patient performance status had significant implications for men rather than for women. Our results warrant increased research efforts to clarify sex-specific differences in anti-tumor immune response mechanisms and in the efficacy of ICI therapies, especially in women. Abstract 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.

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, metabolic tumor volume (MTV), total lesion glycolysis and bone marrow-/ 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. Multivariate selection for PFS/OS revealed MTV as most relevant PET/CT biomarker (p70mL (PFS: 10 months (M; 95% confidence interval 4-16) vs. 4M (3-5), p=0.001; OS: not reached vs. 10M (5-15), p=0.004). Disease control rate was 81% vs. 53% for MTV≤/>70mL (p=0.007). BLR ≤1.06 versus >1.06 was associated with better outcomes (PFS: 8M (4-13) vs. 4M (3-6), p=0.034; OS: 19M (12-/) vs. 6M (4-12), p=0.005). In patients with MTV>70mL, 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.

Background There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012. Methods A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC Results Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication. Conclusions False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.

Introdução: A profissão docente é considerada pela Organização Inter­nacional do Trabalho (OIT), uma das mais estressantes. Estudos envolvendo estresse no trabalho dos professores têm sido crescentes e essa tendência de pesquisas envolvendo o tema deve continuar, uma vez que o estresse ocupacional provoca um impacto negativo na saúde e consequentemente no funcionamento das instituições. Entre os fatores que geram doenças em decorrência do estresse ocupacional estão sobrecarga de trabalho, altos níveis de ansiedade e baixa qualidade de vida. Objetivo: avaliar o nível de estresse ocupacional, atividade física e características biossociais entre os professores de uma escola estadual de ensino fundamental e médio, do interior do Rio Grande do Sul. Métodos: estudo transversal, quantitativo-descritivo, utilizando três questionários de autopreenchimento: um biossocial, a escala de estresse no trabalho (EET) e para os níveis de atividade física o Questionário Internacional de Atividade Física - IPAQ versão curta, inicialmente proposto pela OMS no ano de 1998, e traduzido e validado no Brasil em 2001 por Matsudo et al.. Os dados foram analisados empregando estatística descritiva. Resultados: houve predomínio (72%) de professores do gênero feminino, média de idade de 45,44 anos, casados (50,94 %) que lecionava dois turnos na escola (39,62 %). Em relação escolaridade dois terços (66,04) possuiam um curso de pós-graduação e 33,96% só graduação. A maioria (75,47 %) ganhou peso, média foi de 6,80 Kg; porém a maioria (54,72 %) afirmou não ter sido o estresse o responsável. A maioria (60,38 %) trabalha na sua melhor disposição, 100% gostam de trabalhar nesta escola, mas 13,21% têm intenção de deixar a escola, e 15,09 % de deixar a profissão de professor. 54,72 % dos professores tiraram licenças saúde. Conclusão: a maioria dos professores participantes deste estudo apresentaram médio nível de estresse e o restante apresentou baixo nível.

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).

Background: Perception of global health status may differ between COPD patients and their physicians. Methods: We conducted a national, cross-sectional study among pulmonologists and general practitioners in Austria. The St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Furthermore, we asked, independent from each other, the patient as well as the treating physician to estimate the global health status of the patient (excellent, good, fair, poor, very poor). Inclusion criteria were a physician’s diagnosis of COPD and age ≥ 40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded. Results: Of 1,175 COPD patients, 248 did not fulfill the GOLD criteria for COPD (FEV1/FVC≥0.7) and 77 were excluded due to missing data. In 48.7% of study participants, patients and physicians disagreed on the global health status. In 29.7% it was estimated better by the physician than by the patient (overrated patients), and in 19.0% it was underrated. Multivariate regression analysis indicated that overrated patients had a statistically significant better lung function (FEV1), less exacerbations and a lower total SGRQ-C score compared to underrated patients. Conclusion: In stable COPD outpatients the global health status tends to be overestimated in patients with milder airway obstruction and less exacerbations and vice versa.

Background: Additional to high-resolution computed tomography (HRCT), peripheral blood (PBL) and broncho-alveolar lavage (BAL) could provide biomarkers to distinguish predominantly inflammatory from non-inflammatory/fibrotic interstitial lung disease (ILD) phenotypes. Methods:HRCT of 127 subsequent ILD-board patients were semi-quantitatively evaluated in a standardized way: Reticulation/honeycombing (RET), traction bronchiectasis (TBR) and emphysema (EMP) were classified as non-inflammatory/fibrotic; consolidations (CON), ground glass opacities (GGO), noduli (NDL) and mosaic attenuation (MOS) as active inflammatory findings. These HRCT findings were counted as present or absent in 6 distinct lung regions, resulting scores were graded as minimal (0-1 regions involved), medium (2-4) or extensive (5-6). Associations between routinely assessed PBL/BAL biomarkers with these radiological scores were evaluated using Spearman correlation coefficients; significance of the graded HRCT scores by applying Kruskal-Wallis tests.Results: Blood neutrophil, lymphocyte and eosinophil fraction, neutrophil-lymphocyte ratio (NLR) and BAL lymphocyte fraction consistently showed opposite correlations for 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). Conclusions: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 Nr. I-26-17).

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Percutaneouscomputedtomography(CT)guided transthoracic needle biopsy (PCNB) is a commondiagnosticprocedureandisespeciallyindispensable inthoracic oncology. Complications, suchas pulmonary hemorrhage and pneumothorax are frequent, but usually easy to manage. Systemic air embolism is a rare but relevant adverse event and its true incidence is probably underestimated, as not all cases may become clinically apparent. We present a case of systemic air embolism following a core-needle biopsy of a left upper lobe lesion, where immediately after the procedure CT scans documented air in the thoracic aorta and in the left ventricle. In this context, we review the current literature on technical aspects as wellas onfrequentand infrequentmajor complications of PCNB, together with risk factors, emergency treatment and prevention strategies. (VLID)4872025 Version of record

Water at interfaces governs many processes on the molecular scale from electrochemical and enzymatic reactions to protein folding. Here we focus on water transport through proteinaceous pores that are so narrow that the water molecules cannot overtake each other in the pore. After a short introduction into the single-file transport theory, we analyze experiments in which the unitary water permeability, p f, of water channel proteins (aquaporins, AQPs), potassium channels (KcsA), and antibiotics (gramicidin-A derivatives) has been obtained. A short outline of the underlying methods (scanning electrochemical microscopy, fluorescence correlation spectroscopy, measurements of vesicle light scattering) is also provided. We conclude that p f increases exponentially with a decreasing number N H of hydrogen bond donating or accepting residues in the channel wall. The variance in N H is responsible for a more than hundredfold change in p f. The dehydration penalty at the channel mouth has a smaller effect on p f. The intricate link between p f and the Gibbs activation energy barrier, ∆Gt‡ for water flow suggests that conformational transitions of water channels act as a third determinant of p f.

Background The burden of symptoms and risk of exacerbations are the main drivers of the overall assessment of the Chronic Obstructive Pulmonary Disease (COPD) and the adequate treatment approaches per current Global Initiative for Chronic Obstructive Lung Disease (GOLD). Physical activity has emerged as both functional outcome and non-pharmacological intervention in COPD patients, despite the lack of standardized measures or guidelines in clinical practice. This study aimed to explore in more depth the 24-h respiratory symptoms, the physical activity level (PAL) and the relationship between these two determinants in stable COPD patients. Methods This was a multinational, multicenter, observational, cross-sectional study conducted in ten European countries and Israel. Dedicated questionnaires for each part of the day (morning, daytime, night) were used to assess respiratory symptoms. PAL was evaluated with self- and interview-reported tools [EVS (exercise as vital sign) and YPAS (Yale Physical Activity Survey)], and physician’s judgement. Patients were stratified in ABCD groups by 2013 and 2017 GOLD editions using the questionnaires currently recommended: modified Medical Research Council dyspnea scale and COPD Assessment Test. Results The study enrolled 2190 patients (mean age: 66.9 years; male: 70.0%; mean % predicted FEV1: 52.6; GOLD groups II-III: 84.5%; any COPD treatment: 98.9%). Most patients (> 90%) reported symptoms in any part of the 24-h day, irrespective of COPD severity. PAL evaluations showed discordant results between patients and physicians: 32.9% of patients considered themselves completely inactive, while physicians judged 11.9% patients as inactive. By YPAS, the overall study population spent an average of 21.0 h/week performing physical activity, and 68.4% of patients were identified as sedentary. In any GOLD ABCD group, the percentage of inactive patients was high. Our study found negative, weak correlations between respiratory symptoms and self-reported PAL (p

Spontaneous solute and solvent permeation through membranes is of vital importance to human life, be it gas exchange in red blood cells, metabolite excretion, drug/toxin uptake, or water homeostasis. Knowledge of the underlying molecular mechanisms is the sine qua non of every functional assignment to membrane transporters. The basis of our current solubility diffusion model was laid by Meyer and Overton. It correlates the solubility of a substance in an organic phase with its membrane permeability. Since then, a wide range of studies challenging this rule have appeared. Commonly, the discrepancies have their origin in ill-used measurement approaches, as we demonstrate on the example of membrane CO2 transport. On the basis of the insight that scanning electrochemical microscopy offered into solute concentration distributions in immediate membrane vicinity of planar membranes, we analyzed the interplay between chemical reactions and diffusion for solvent transport, weak acid permeation, and enzymatic reactions adjacent to membranes. We conclude that buffer reactions must also be considered in spectroscopic investigations of weak acid transport in vesicular suspensions. The evaluation of energetic contributions to membrane translocation of charged species demonstrates the compatibility of the resulting membrane current with the solubility diffusion model. A local partition coefficient that depends on membrane penetration depth governs spontaneous membrane translocation of both charged and uncharged molecules. It is determined not only by the solubility in an organic phase but also by other factors like cholesterol concentration and intrinsic electric membrane potentials.

Background Evidence on PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy for advanced non-small-cell lung cancer (NSCLC) is mainly based on clinical trials in first- or second-line settings. Objective We aimed to investigate response and prognostic factors with special regard to third- or later-line therapy. Patients and Methods We retrospectively analyzed all patients who had received ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab for advanced NSCLC. Computed tomography evaluations were analyzed using response evaluation criteria in solid tumors (RECIST, version 1.1). KaplanMeier analyses were conducted to calculate progression-free (PFS) and overall (OS) survival; the impact of influencing variables was evaluated using uni- and multivariate Cox-regression analyses. Results Among 153 patients (59% men, mean age 66 years), median PFS was 4 months [mo; 95% confidence interval (95% CI) 35], OS was 13 mo (1017), and objective response rate (ORR) was 22%. Therapy line 3 was associated with significantly inferior PFS (p = 0.003) and OS (p = 0.001). In first-line therapy PFS, OS, and ORR were 7 mo (311), 17 mo [9not evaluable (n.e.)], and 36%; in second-line 4 mo (37), 18 mo (13n.e.) and 19%, and in third-line 2 mo (13), 9 mo (412), and 13%. PFS was significantly influenced by PD-L1 expression in first-line therapy (p = 0.006). In third-line patients, Eastern Cooperative Oncology Group (ECOG) performance status significantly affected PFS and OS (both p < 0.001). Conclusions Third- or later-line single-agent anti-PD-1/PD-L1 therapy is less efficacious as compared to first- and second-line treatment. In that setting, ECOG performance status predominates known predictors like PD-L1 expression or presence of an alteration in EGFR or ALK. Key Points Compared to first- or second-line of treatment, NSCLC patients who had received PD-1/PD-L1-directed immune checkpoint inhibitor monotherapy in line three had significantly inferior PFS and OS. In multivariate analyses among all patients, PFS was significantly influenced by PD-L1 expression and ECOG performance status, for OS only therapy line was shown to have a significant impact. In first-line treated patients, PFS was significantly influenced by PD-L1 expression, while there were no significant multivariate findings for first-line OS and second-line PFS/OS. In third-line patients, ECOG performance status significantly affected PFS and OS. (VLID)4641962

Measurements of the unitary hydraulic conductivity of membrane channels, pf , may be hampered by difficulties in producing sufficient quantities of purified and reconstituted proteins. Low yield expression, the purely empiric choice of detergents, as well as protein aggregation and misfolding during reconstitution may result in an average of less than one reconstituted channel per large unilamellar vesicle. This limits their applicability for pf measurements, independent of whether light scattering or fluorescence quenching of encapsulated dyes is monitored. Here the micropipette aspiration technique is adopted because its superb sensitivity allows resolving pf values for one order of magnitude smaller protein densities in sphingomyelin and cholesterol rich giant unilamellar vesicles (GUVs). Protein density is derived from intensity fluctuations that fluorescently labeled channels in the aspirated GUV induce by diffusing through the diffraction limited spot. A perfusion system minimizes unstirred layers in the immediate membrane vicinity as demonstrated by the distribution of both encapsulated and extravesicular aqueous dyes. pf amounted to 2.4 ± 0.1 × 10-13 cm³ s-1 for aquaporin-1 that served as a test case. The new assay paves the way for directly monitoring the effect that interaction of aquaporins with other proteins or inhibitors may have on pf on a single sample.

To evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy.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, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics.Among 84 patients (61% men, mean age 68 years), median PFS was significantly (p 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (2-fold: 6 M (3,8) N = 31; ≥2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p 0.001) median OS (not reached) than with STM increase (2-fold: 14 M (12,26); ≥2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p 0.001), presence of cerebral metastases (p = 0.036) and therapy line ≥3 (p = 0.001) were identified.Decreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.

Background COPD is a treatable disease with increasing prevalence worldwide. Treatment aims to stop disease progression, to improve quality of life, and to reduce exacerbations. We aimed to evaluate the association of the stage of COPD on adherence to inhaled therapy and the relationship between adherence and COPD exacerbations. Methods A retrospective analysis of patients hospitalized for acute exacerbation of COPD in a tertiary care hospital in Upper Austria and discharged with a guideline conform inhaled therapy was performed. Follow-up data on medical utilization was recorded for the subsequent 24 months. Adherence to inhaled therapy was defined according to the percentage of prescribed inhalers dispensed to the patient and classified as complete (> 80%), partial (50–80%) or low (

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Positively charged residues in the vicinity of the channel entrance or exit accelerate single-file water flow., Water molecules lose two of their four bulk neighbours when entering single-file channels. This process may be sensitive to the presence of positive and negative charges at the channel mouth, since the costs for dehydrating cations and anions differ by a large margin. However, it is not known whether entrance charges affect the single channel water permeability (pf). So far, pf is only known to be governed by H-bond formation between permeating water molecules and wall-lining residues. Here we compare the pf values of five different aquaporin species (AQP1, AQPZ, AQP4 wild type, and two phosphorylation mimicking AQP4 mutants) that offer the same number of hydrogen bond donating and receiving residues in their single-file region but display different entrance charges. The pf measurements were performed with reconstituted lipid vesicles. We assessed (i) the osmotically induced vesicle deflation from the light scattering intensity in a stopped-flow device and (ii) the aquaporin abundance by fluorescence correlation spectroscopy. Substitution of serine at positions 111 and 180 in AQP4 for aspartic acid showed only a marginal effect on pf, suggesting that negative entrance charges are of minor importance. In contrast, the total number of positively charged amino acid side chains at entrances and exits correlates with pf: a total of three, four and seven charges of AQP4, AQPZ, and AQP1 translate into pf values of 1.1, 1.8, and 3.2 × 10–13 cm3 s–1, respectively. Thus, positive interfacial charges boost the pf value of AQP1 to three times the value of AQP4. Nevertheless, the number of hydrogen bond donating and receiving residues in the single-file region remains the major determinant of pf. Their effect on pf may be a hundredfold larger than that of interfacial charges.

There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012.A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEVAmong 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication.False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.