COPD: systemic proteomic profiles in frequent and infrequent exacerbators.

Background: Some patients with COPD suffer frequent exacerbations (FE). We hypothesised that their systemic proteomic profile would be different from that of non-frequent exacerbators (NFE). The objective of the present study was to contrast the systemic proteomic profile in FE versus NFE. As a reference, we also determined the systemic proteomic profile of healthy controls (HC) and COPD patients during an actual episode of exacerbation (AE). Methods: In the analysis we included 40 clinically stable COPD patients (20 FE and 20 NFE), and 20 HC and 10 AE patients. Their plasma samples were analysed by combining two complementary proteomic approaches: label-free liquid chromatography-tandem mass spectrometry and multiplex immunoassays. Gene Ontology annotation, pathway enrichment and network analyses were used to investigate molecular pathways associated with differentially abundant proteins/peptides (DAPs). Results: Compared with HC, we identified 40 DAPs in FE, 10 in NFE and 63 in AE. Also compared to HC, pathway functional and protein-protein network analyses revealed dysregulation of inflammatory responses involving innate and antibody-mediated immunity in COPD, particularly in the FE group, as well as during an AE episode. Besides, we only identified alterations in the complement and coagulation cascades in AE. Conclusion: There are specific plasma proteome profiles associated with FE, which are partially shared with findings observed during AE, albeit others are uniquely present during the actual episode of AE.

Update on metabolomic findings in COPD patients.

COPD is a heterogeneous disorder that shows diverse clinical presentations (phenotypes and "treatable traits") and biological mechanisms (endotypes). This heterogeneity implies that to carry out a more personalised clinical management, it is necessary to classify each patient accurately. With this objective, and in addition to clinical features, it would be very useful to have well-defined biological markers. The search for these markers may either be done through more conventional laboratory and hypothesis-driven techniques or relatively blind high-throughput methods, with the omics approaches being suitable for the latter. Metabolomics is the science that studies biological processes through their metabolites, using various techniques such as gas and liquid chromatography, mass spectrometry and nuclear magnetic resonance. The most relevant metabolomics studies carried out in COPD highlight the importance of metabolites involved in pathways directly related to proteins (peptides and amino acids), nucleic acids (nitrogenous bases and nucleosides), and lipids and their derivatives (especially fatty acids, phospholipids, ceramides and eicosanoids). These findings indicate the relevance of inflammatory-immune processes, oxidative stress, increased catabolism and alterations in the energy production. However, some specific findings have also been reported for different COPD phenotypes, demographic characteristics of the patients, disease progression profiles, exacerbations, systemic manifestations and even diverse treatments. Unfortunately, the studies carried out to date have some limitations and shortcomings and there is still a need to define clear metabolomic profiles with clinical utility for the management of COPD and its implicit heterogeneity.

Treatment of COVID-19 during the Acute Phase in Hospitalized Patients Decreases Post-Acute Sequelae of COVID-19.

BACKGROUND: The post-acute sequelae of SARS-CoV-2 (PASC) infection have caused a significant impact on our health system, but there is limited evidence of approved drugs focused on its prevention. Our objective was to identify risk factors that can determine the presence of PASC, with special attention to the treatment received in the acute phase, and to describe the profile of persistent symptoms in a multidisciplinary Post-Coronavirus Disease-19 (COVID-19) Unit. METHODS: This one-year prospective observational study included patients following an acute COVID-19 infection, irrespective of whether they required hospital admission. A standardized symptom questionnaire and blood sampling were performed at the first follow-up visit, and demographic and clinical electronic data were collected. We compared subjects with PASC with those who had fully recovered. Multivariate logistic regression was performed to identify factors associated with PASC in hospitalized patients, and Kaplan-Meier curves were used to assess duration of symptoms according to disease severity and treatments received in the acute phase. RESULTS: 1966 patients were evaluated; 1081 had mild disease, 542 moderate and 343 severe; around one third of the subjects had PASC, and were more frequently female, with obesity, asthma, and eosinophilia during acute COVID-19 disease. Patients who received treatment with dexamethasone and remdesivir during the course of the acute illness showed a lower median duration of symptoms, compared with those who received none of these treatments. CONCLUSION: Treatment with dexamethasone and/or remdesivir may be useful to reduce the impact of PASC secondary to SARS-CoV-2 infection. In addition, we identified female gender, obesity, asthma, and disease severity as risk factors for having PASC.

Differences in acoustic features of cough by pneumonia severity in patients with COVID-19: a cross-sectional study.

Background: Acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2) is characterised by heterogeneous levels of disease severity. It is not necessarily apparent whether a patient will develop severe disease or not. This cross-sectional study explores whether acoustic properties of the cough sound of patients with coronavirus disease 2019 (COVID-19), the illness caused by SARS-CoV-2, correlate with their disease and pneumonia severity, with the aim of identifying patients with severe disease. Methods: Voluntary cough sounds were recorded using a smartphone in 70 COVID-19 patients within the first 24 h of their hospital arrival, between April 2020 and May 2021. Based on gas exchange abnormalities, patients were classified as mild, moderate or severe. Time- and frequency-based variables were obtained from each cough effort and analysed using a linear mixed-effects modelling approach. Results: Records from 62 patients (37% female) were eligible for inclusion in the analysis, with mild, moderate and severe groups consisting of 31, 14 and 17 patients respectively. Five of the parameters examined were found to be significantly different in the cough of patients at different disease levels of severity, with a further two parameters found to be affected differently by the disease severity in men and women. Conclusions: We suggest that all these differences reflect the progressive pathophysiological alterations occurring in the respiratory system of COVID-19 patients, and potentially would provide an easy and cost-effective way to initially stratify patients, identifying those with more severe disease, and thereby most effectively allocate healthcare resources.

Validity of prognostic models of critical COVID-19 is variable. A systematic review with external validation.

OBJECTIVES: To identify prognostic models which estimate the risk of critical COVID-19 in hospitalized patients and to assess their validation properties. STUDY DESIGN AND SETTING: We conducted a systematic review in Medline (up to January 2021) of studies developing or updating a model that estimated the risk of critical COVID-19, defined as death, admission to intensive care unit, and/or use of mechanical ventilation during admission. Models were validated in two datasets with different backgrounds (HM [private Spanish hospital network], n = 1,753, and ICS [public Catalan health system], n = 1,104), by assessing discrimination (area under the curve [AUC]) and calibration (plots). RESULTS: We validated 18 prognostic models. Discrimination was good in nine of them (AUCs ≥ 80%) and higher in those predicting mortality (AUCs 65%-87%) than those predicting intensive care unit admission or a composite outcome (AUCs 53%-78%). Calibration was poor in all models providing outcome's probabilities and good in four models providing a point-based score. These four models used mortality as outcome and included age, oxygen saturation, and C-reactive protein among their predictors. CONCLUSION: The validity of models predicting critical COVID-19 by using only routinely collected predictors is variable. Four models showed good discrimination and calibration when externally validated and are recommended for their use.

Metabolomics in COPD.

The clinical presentation of chronic obstructive pulmonary disease (COPD) is highly heterogeneous. Attempts have been made to define subpopulations of patients who share clinical characteristics (phenotypes and treatable traits) and/or biological characteristics (endotypes), in order to offer more personalized care. Assigning a patient to any of these groups requires the identification of both clinical and biological markers. Ideally, biological markers should be easily obtained from blood or urine, but these may lack specificity. Biomarkers can be identified initially using conventional or more sophisticated techniques. However, the more sophisticated techniques should be simplified in the future if they are to have clinical utility. The -omics approach offers a methodology that can assist in the investigation and identification of useful markers in both targeted and blind searches. Specifically, metabolomics is the science that studies biological processes involving metabolites, which can be intermediate or final products. The metabolites associated with COPD and their specific phenotypic and endotypic features have been studied using various techniques. Several compounds of particular interest have emerged, namely, several types of lipids and derivatives (mainly phospholipids, but also ceramides, fatty acids and eicosanoids), amino acids, coagulation factors, and nucleic acid components, likely to be involved in their function, protein catabolism, energy production, oxidative stress, immune-inflammatory response and coagulation disorders. However, clear metabolomic profiles of the disease and its various manifestations that may already be applicable in clinical practice still need to be defined.

Bacterial Patterns and Empiric Antibiotic Use in COPD Patients With Community-Acquired Pneumonia.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP. METHODS: We performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population. RESULTS: We enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.7-35.2]), hospitalization in the past 12 months (OR 3.7 [1.5-9.2]), and bronchiectasis (OR 3.2 [1.4-7.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%. CONCLUSIONS: COPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy.

Influence of COPD systemic environment on the myogenic function of muscle precursor cells in vitro.

BACKGROUND: Loss of muscle mass and function are well-recognized systemic manifestations of chronic obstructive pulmonary disease (COPD). Acute exacerbations, in turn, significantly contribute to upgrade these systemic comorbidities. Involvement of myogenic precursors in muscle mass maintenance and recovery is poorly understood. The aim of the present study was to investigate the effects of the vascular systemic environment from stable and exacerbated COPD patients on the myogenic behavior of human muscle precursor cells (MPC) in vitro. METHODS: Serum from healthy controls and from stable and exacerbated COPD patients (before and after Methylprednisolone treatment) was used to stimulate human MPC cultures. Proliferation analysis was assessed through BrdU incorporation assays. MPC differentiation was examined through real-time RT-PCR, western blot and immunofluorescence analysis. RESULTS: Stimulation of MPCs with serum obtained from stable COPD patients did not affect myogenic precursor cell function. The vascular systemic environment during an acute exacerbation exerted a mitotic effect on MPCs without altering myogenic differentiation outcome. After Methylprednisolone treatment of acute exacerbated COPD patients, however, the mitotic effect was further amplified, but it was followed by a deficient differentiation capacity. Moreover, these effects were prevented when cells were co-treated with the glucocorticoid receptor antagonist Mifepristone. CONCLUSION: Our findings suggest that MPC capacity is inherently preserved in COPD patients, but is compromised after systemic administration of MP. This finding strengthens the concept that glucocorticoid treatment over the long term can negatively impact myogenic stem cell fate decisions and interfere with muscle mass recovery.

Predictors and changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. METHODS: PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. RESULTS: Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI ≥ 25 kg/m2 and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. CONCLUSION: Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis.

Intravenous Iron Replacement Improves Exercise Tolerance in COPD: A Single-Blind Randomized Trial.

INTRODUCTION: Iron deficiency affects exercise capacity because of the critical role iron plays in the optimal functioning of skeletal muscle metabolism. We hypothesized that intravenous iron may improve exercise tolerance, quality of life (QoL), and daily physical activity (DPA) in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a placebo-controlled, single-blind, parallel-group, randomized clinical trial. Iron deficiency was defined as a ferritin level<100ng/mL or a ferritin level between 100 and 299ng/mL with a transferrin saturation<20%, with or without mild anaemia. Patients were randomized at a 2:1 ratio to receive intravenous ferric carboxymaltose or placebo. The primary objective was to investigate whether intravenous iron replacement improved endurance time from baseline by at least 33%. The secondary objectives were to evaluate impact on QoL using the COPD Assessment Test (CAT) and on DPA by accelerometry. RESULTS: We included 66 patients, 44 (66.7%) in the intervention group and 22 (33.3%) in the placebo group. Among patients receiving ferric carboxymaltose, 23 (52.3%) achieved the primary endpoint compared to 4 (18.2%) in the placebo group [p=0.009; relative risk 3.12, (95% CI, 1.19-8.12)]. CAT score decreased -3 (-6.0-1.3) points from baseline in the intervention group (p=0.007), in contrast to placebo group [-1 (-4.0-2.3) points, p=0.236] with no differences in DPA and adverse events in both groups. CONCLUSIONS: Iron replacement improved exercise capacity and QoL in stable COPD patients with iron deficiency. The treatment was well tolerated. CLINICAL TRIAL REGISTRATION: EudraCT 2016-001238-89.

Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD.

Accelerated ageing is implicated in the pathogenesis of respiratory diseases as chronic obstructive pulmonary disease (COPD), but recent evidence indicates that the COPD can have roots early in life. Here we hypothesise that the accelerated ageing markers might have a role in the pathobiology of young COPD. The objective of this study was to compare two hallmarks of ageing, telomere length (TL), and mitochondrial DNA copy number (mtDNA-CN, as a surrogate marker of mitochondrial dysfunction) in young (≤ 50 years) and old (>50 years) smokers, with and without COPD. Both, TL and mtDNA-CN were measured in whole blood DNA by quantitative PCR [qPCR] in: (1) young ever smokers with (n = 81) or without (n = 166) COPD; and (2) old ever smokers with (n = 159) or without (n = 29) COPD. A multivariable linear regression was used to assess the association of TL and mtDNA-CN with lung function. We observed that in the entire study population, TL and mtDNA-CN decreased with age, and the former but not the latter related to FEV1/FVC (%), FEV1 (% ref.), and DLCO (% ref.). The short telomeres were found both in the young and old patients with severe COPD (FEV1 <50% ref.). In addition, we found that TL and mtDNA-CN were significantly correlated, but their relationship was positive in younger while negative in the older patients with COPD, suggesting a mitochondrial dysfunction. We conclude that TL, but not mtDNA-CN, is associated with the lung function impairment. Both young and old patients with severe COPD have evidence of accelerated ageing (shorter TL) but differ in the direction of the correlation between TL and mtDNA-CN in relation to age.

Absence of relevant clinical effects of SARS-COV-2 on the affinity of hemoglobin for O2 in patients with COVID-19.

Pulmonary involvement in COVID-19 is frequently associated with alterations in oxygenation. The arterial partial pressure of oxygen (PaO2) is the most clinically used variable to assess such oxygenation, since it decisively influences the oxygen transported by hemoglobin (expressed by its percentage of saturation, SaO2). However, two recent studies conducted respectively in silico and using omic techniques in red blood cells of COVID-19 patients have suggested that SARS-CoV-2 could decrease the affinity of oxygen for the hemoglobin (which would imply that PaO2 would overestimate SaO2), and also reduce the amount of this carrier molecule. OBJECTIVE: To evaluate this hypothesis in blood samples from COVID-19 patients. METHODS: Blood gases of all COVID-19 patients performed in our laboratory in two months were included, as well as those from two control groups: synchronous patients with negative PCR for SARS-CoV-2 (SCG) and a historical group (HCG). Both SaO2 and venous saturations (SvO2) measured by cooximetry (COX) were compared separately with those calculated using the Kelman (K), Severinghaus (SV) and Siggaard-Andersen (SA) equations in each group. RESULTS: Measured and calculated SaO2 and SvO2 were practically equivalent in all groups. Intraclass correlation coefficients (ICC) for SaO2 in COVID-19 were 0.993 for COX-K and 0.992 for both COX-SV and COX-SA; being 0.995 for SvO2 for either COX-K, COX-SV or COX-SA. Hemoglobin and ferritin were slightly higher in COVID-19 compared to SCG and HCG (hemoglobin, p < 0.001 for both; ferritin, p < 0.05 for SCG and p < 0.001 for HCG). CONCLUSION: Under clinical conditions SARS-CoV-2 does not have an appreciable influence on the affinity of oxygen for the hemoglobin, nor on the levels of this carrier molecule. Therefore, PaO2 is a good marker of blood oxygenation also in COVID-19.

La afectación pulmonar por COVID-19 se asocia frecuentemente con alteraciones en la oxigenación. La presión parcial arterial de oxígeno (PaO2) es la variable más utilizada clínicamente para valorar dicha oxigenación, ya que influye decisivamente en el oxígeno transportado por la hemoglobina (expresado por porcentaje de saturación, SaO2). Sin embargo, dos estudios recientes realizados respectivamente in silico y mediante técnicas ómicas en hematíes de pacientes han sugerido que SARS-CoV-2 podría disminuir la afinidad del oxígeno por la hemoglobina (lo que implicaría que la PaO2 sobrevaloraría la SaO2 real), e incluso reduciría la cantidad de esta molécula transportadora. OBJETIVO: Evaluar dicha hipótesis en muestras gasométricas de pacientes con COVID-19. MÉTODOS: Se incluyeron las gasometrías de todos los pacientes con COVID-19 realizadas en nuestro laboratorio, así como las de dos grupos control: pacientes sincrónicos con PCR negativa (GCS) y grupo histórico (GCH). Se compararon por separado las SaO2 y saturaciones venosas (SvO2), medidas por cooximetría (COX) con las calculadas mediante las ecuaciones de Kelman (K), Severinghaus (SV) y Siggaard-Andersen (SA) en cada grupo. RESULTADOS: Las cifras de SaO2 y SvO2 medidas y calculadas fueron prácticamente superponibles en todos los grupos. Así, los coeficientes de correlación intraclase (CCI) en COVID-19 para SaO2 fueron 0,993 en COX-K y 0,992 en COX-SV y COX-SA; siendo 0,995 para SvO2 tanto en COX-K como en COX-SV y COX-SA. La hemoglobina y la ferritina resultaron algo superiores en el grupo COVID-19 respecto de GCS y GCH (hemoglobina, p < 0,001 en ambos; ferritina, p < 0,05 para GCS y p < 0,001 para GCH). CONCLUSIONES: En condiciones clínicas, el SARS-CoV-2 no influye de forma apreciable en la afinidad del oxígeno por la hemoglobina, ni tampoco en los niveles de esta última. Por tanto, la PaO2 es un buen marcador de oxigenación sanguínea también en COVID-19.

Impact of high-flow oxygen therapy during exercise in idiopathic pulmonary fibrosis: a pilot crossover clinical trial.

BACKGROUND: Supplemental oxygen delivered with standard oxygen therapy (SOT) improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Although high-flow nasal cannula oxygen therapy (HFNC) improves oxygenation in other respiratory diseases, its impact on exercise performance has never been evaluated in IPF patients. We hypothesized that HFNC may improve exercise capacity in IPF subjects compared to SOT. METHODS: This was a prospective, crossover, pilot randomized trial that compared both oxygenation methods during a constant submaximal cardiopulmonary exercise test (CPET) in IPF patients with exertional oxygen saturation (SpO2) ≤ 85% in the 6-min walking test. The primary outcome was endurance time (Tlim). Secondary outcomes were muscle oxygen saturation (StO2) and respiratory and leg symptoms. RESULTS: Ten IPF patients [71.7 (6) years old, 90% males] were included. FVC and DLCO were 58 ± 11% and 31 ± 13% pred. respectively. Tlim during CPET was significantly greater using HFNC compared to SOT [494 ± 173 vs. 381 ± 137 s, p = 0.01]. HFNC also associated with a higher increase in inspiratory capacity (IC) [19.4 ± 14.2 vs. 7.1 ± 8.9%, respectively; p = 0.04], and a similar trend was observed in StO2 during exercise. No differences were found in respiratory or leg symptoms between the two oxygen devices. CONCLUSIONS: This is the first study demonstrating that HFNC oxygen therapy improves exercise tolerance better than SOT in IPF patients with exertional desaturation. This might be explained by changes in ventilatory mechanics and muscle oxygenation. Further and larger studies are needed to confirm the benefits of HFNC in IPF patients and its potential usefulness in rehabilitation programs.

Invention and Pilot Study of the Efficacy and Safety of the SUPRAtube Device in Continuous Supraglottic Aspiration for Intubated and Mechanically Ventilated Patients.

BACKGROUND: Bronchoaspiration of content that accumulates in the supraglottic area (eg, saliva, gastroesophageal reflux) is a risk factor for ventilator-associated pneumonia. A continuous supraglottic suction system may decrease the risk of bronchoaspiration in these patients. OBJECTIVE: (1) Constructing a conceptual model and functional prototype of a continuous supraglottic suction device for use in humans; (2) defining functional characteristics in ex vivo swine head models; and (3) evaluating its efficacy and safety in mechanically ventilated patients. METHODS: Study conducted in three phases. First phase: definition of distances and diameters of the triangle determined by dental arch, posterior oropharynx and vallecula, and diameter of the oropharynx in axial projection; and identification of the declining area of supraglottic suction. Second phase: design engineering and functional prototype evaluated in ex vivo models. Third phase: evaluation of device use in terms of safety and efficacy in ventilated patients. RESULTS: We obtained a final functional model of the SUPRAtube device injected into PVC for medical use. Device effectiveness in in vitro simulation showed a high and fast suction capacity of liquid and thick volumes. Study of swine heads allowed to validate the shape, size and functional fenestration of the device. Study in intubated and mechanically ventilated patients showed a high supraglottic suction capacity and the absence of local adverse events during 72 (7-240) hours of continuous operation. CONCLUSION: Our study describes the process of conceptualization, design and production of a practical, safe, low-cost continuous supraglottic suction device without representing antibiotic pressure, which appears to be a new complementary preventive strategy for the standard management of intubated and mechanically ventilated patients.

Beneficial Effects of Resveratrol in Mouse Gastrocnemius: A Hint to Muscle Phenotype and Proteolysis.

We hypothesized that the phenolic compound resveratrol mitigates muscle protein degradation and loss and improves muscle fiber cross-sectional area (CSA) in gastrocnemius of mice exposed to unloading (7dI). In gastrocnemius of mice (female C57BL/6J, 10 weeks) exposed to a seven-day period of hindlimb immobilization with/without resveratrol treatment, markers of muscle proteolysis (tyrosine release, systemic troponin-I), atrophy signaling pathways, and muscle phenotypic features and function were analyzed. In gastrocnemius of unloaded mice treated with resveratrol, body and muscle weight and function were attenuated, whereas muscle proteolysis (tyrosine release), proteolytic and apoptotic markers, atrophy signaling pathways, and myofiber CSA significantly improved. Resveratrol treatment of mice exposed to a seven-day period of unloading prevented body and muscle weight and limb strength loss, while an improvement in muscle proteolysis, proteolytic markers, atrophy signaling pathways, apoptosis, and muscle fiber CSA was observed in the gastrocnemius muscle. These findings may have potential therapeutic implications in the management of disuse muscle atrophy in clinical settings.

EGFR and KRAS Mutations in Lung Parenchyma of Subjects With EGFR/KRAS Wild-Type Lung Adenocarcinoma.

The acquisition of driver mutations in non-tumoral cells appears to be very important during the carcinogenesis of adenocarcinoma (ADC). Recent studies suggest that cancer-related mutations may not necessarily be present only in malignant cells, but also in histologically "healthy cells". Objective: to demonstrate the presence of EGFR or KRAS mutations in non-tumoral lung cells in subjects with ADC and negative mutational status. Results: mutations in EGFR or KRAS oncogenes were identified in the normal lung in 9.7% of the subjects. Exon 21 substitution L858R in EGFR was detected in two cases while the exon 19 deletion E746-A750 in the EGFR, the G12C and G12D substitutions in the KRAS were detected once. One patient presented three different mutations in the normal lung parenchyma (EGFR_L858R, KRAS_G12C and KRAS_G12D). The negative-mutation status of the tumor and the mutations detected in the "normal lung" were confirmed using highly sensitive and specific TaqMan PCR (CAST-PCR). No differences were found in terms of progression, progression-free survival or overall survival during the 18 months follow-up. Conclusions: These results confirm the presence of driver mutations in the histologically normal lung parenchyma cells in the absence of mutations coexisting with the primary tumor.

Absence of Relevant Clinical Effects of SARS-COV-2 on the Affinity of Hemoglobin for O2 in Patients with COVID-19. / Ausencia de efectos clínicos destacables del SARS-CoV-2 sobre la afinidad de la hemoglobina por el O2 en pacientes con COVID-19.

Pulmonary involvement in COVID-19 is frequently associated with alterations in oxygenation. The arterial partial pressure of oxygen (PaO2) is the most clinically used variable to assess such oxygenation, since it decisively influences the oxygen transported by hemoglobin (expressed by its percentage of saturation, SaO2). However, two recent studies conducted respectively in silico and using omic techniques in red blood cells of COVID-19 patients have suggested that SARS-CoV-2 could decrease the affinity of oxygen for the hemoglobin (which would imply that PaO2 would overestimate SaO2), and also reduce the amount of this carrier molecule. OBJECTIVE: To evaluate this hypothesis in blood samples from COVID-19 patients. METHODS: Blood gases of all COVID-19 patients performed in our laboratory in two months were included, as well as those from two control groups: synchronous patients with negative PCR for SARS-CoV-2 (SCG) and a historical group (HCG). Both SaO2 and venous saturations (SvO2) measured by cooximetry (COX) were compared separately with those calculated using the Kelman (K), Severinghaus (SV) and Siggaard-Andersen (SA) equations in each group. RESULTS: Measured and calculated SaO2 and SvO2 were practically equivalent in all groups. Intraclass correlation coefficients (ICC) for SaO2 in COVID-19 were 0.993 for COX-K and 0.992 for both COX-SV and COX-SA; being 0.995 for SvO2 for either COX-K, COX-SV or COX-SA. Hemoglobin and ferritin were slightly higher in COVID-19 compared to SCG and HCG (hemoglobin, p < 0.001 for both; ferritin, p < 0.05 for SCG and p < 0.001 for HCG). CONCLUSION: Under clinical conditions SARS-CoV-2 does not have an appreciable influence on the affinity of oxygen for the hemoglobin, nor on the levels of this carrier molecule. Therefore, PaO2 is a good marker of blood oxygenation also in COVID-19.

Incidence of pulmonary embolism in patients with non-invasive respiratory support during COVID-19 outbreak.

While the incidence of thrombotic complications in critically ill patients is very high, in patients under non-invasive respiratory support (NIS) is still unknown. The specific incidence of thrombotic events in each of the clinical scenarios within the broad spectrum of severity of COVID-19, is not clearly established, and this has not allowed the implementation of thromboprophylaxis or anticoagulation for routine care in COVID-19. Patients admitted in a semi-critical unit treated initially with NIS, especially Continuous-Positive Airway Pressure (CPAP), were included in the study. The cumulative incidence of pulmonary embolism was analyzed and compared between patients with good response to NIS and patients with clinical deterioration that required orotracheal intubation. 93 patients were included and 16% required mechanical ventilation (MV) after the NIS. The crude cumulative incidence of the PE was 14% (95%, CI 8-22) for all group. In patients that required orotracheal intubation and MV, the cumulative incidence was significantly higher [33% (95%, CI 16-58)] compared to patients that continued with non-invasive support [11% (CI 5-18)] (Log-Rank, p = 0.013). Patients that required mechanical ventilation were at higher risk of PE for a HR of 4.3 (95%CI 1.2-16). In conclusion, cumulative incidence of PE is remarkably higher in critically patients with a potential impact in COVID-19 evolution. In this context, patients under NIS are a very high-risk group for developing PE without a clear strategy regarding thromboprophylaxis.