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Background Understanding the enduring respiratory consequences of severe COVID-19 is crucial for comprehensive patient care. This study aims to evaluate the impact of post-COVID conditions on respiratory sequelae of severe acute respiratory distress syndrome (ARDS). Methods We examined 88 survivors of COVID-19-associated severe ARDS six months post-intensive care unit (ICU) discharge. Assessments included clinical and functional evaluation as well as plasma biomarkers of endothelial dysfunction, inflammation, and viral response. Additionally, an in vitro model using human umbilical vein endothelial cells (HUVECs) explored the direct impact of post-COVID plasma on endothelial function. Results Post-COVID patients with impaired gas exchange demonstrated persistent endothelial inflammation marked by elevated ICAM-1, IL-8, CCL-2, and ET-1 plasma levels. Concurrently, systemic inflammation, evidenced by NLRP3 overexpression and elevated levels of IL-6, sCD40-L, and C-reactive protein, was associated with endothelial dysfunction biomarkers and increased in post-COVID patients with impaired gas exchange. T-cell activation, reflected in CD69 expression, and persistently elevated levels of interferon-β (IFN-β) further contributed to sustained inflammation. The in vitro model confirmed that patient plasma, with altered levels of sCD40-L and IFN-β proteins, has the capacity to alter endothelial function. Conclusions Six months post-ICU discharge, survivors of COVID-19-associated ARDS exhibited sustained elevation in endothelial dysfunction biomarkers, correlating with the severity of impaired gas exchange. NLRP3 inflammasome activity and persistent T-cell activation indicate on going inflammation contributing to persistent endothelial dysfunction, potentially intensified by sustained viral immune response.

Background Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. Methods In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. Results S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1β formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1β. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC. Conclusion S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. BJi2XdMkuptrjYtS_YhKHe Video Abstract

IntroductionAlthough higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy.MethodsThe expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using in vitro models. In addition, PSGL-1 impact on T-cells function was evaluated by ex vivo models.ResultsData showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia.DiscussionIn conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.

In post-COVID survivors, transforming growth factor-beta-1 (TGF-β1) might mediate fibroblast activation, resulting in persistent fibrosis. In this study, 82 survivors of COVID-19-associated ARDS were examined at 6- and 24-months post-ICU discharge. At 6-months, quantitative CT analysis of lung attenuation was performed and active TGF-β1 was measured in blood and exhaled breath condensate (EBC). At 6-months of ICU-discharge, patients with reduced DmCO/alveolar volume ratio exhibited higher plasma and EBC levels of active TGF-β1. Plasma TGF-β1 levels were elevated in dyspneic survivors and directly related to the high-attenuation lung volume. In vitro, plasma and EBC from survivors induced profibrotic changes in human primary fibroblasts in a TGF-β receptor-dependent manner. Finally, at 6-months, plasma and EBC active TGF-β1 levels discriminated patients who, 24-months post-ICU-discharge, developed gas exchange impairment. TGF-β1 pathway plays a pivotal role in the early-phase fibrotic abnormalities in COVID-19-induced ARDS survivors, with significant implications for long-term functional impairment.

Obstructive Sleep Apnea (OSA) is a prevalent syndrome characterized by intermittent hypoxemia and elevated risk of comorbidities, including cancer. In this context, the immune response may contribute to tumor evasion though immune checkpoints. Herein, we investigate the TIGIT immune checkpoint in OSA patients and its association with hypoxemia. We recruited 94 severe OSA patients without cancer evidence and 92 control subjects to study the TIGIT receptors and their ligands in T cells and monocytes, respectively. Furthermore, we examined the role of hypoxemia - particularly the involvement of HIF-1α (hypoxia inducible factor-1α) - using a combination of models. Moreover, we evaluated the effect of one year of standard therapy with CPAP (continuous positive airway pressure) in OSA patients. Our data suggests that the TIGIT expression increase on T cells from OSA patients and is associated with clinical indicators of hypoxemia. hypoxemia models confirm the role of HIF-1α in the upregulation of TIGIT expression. However, within the OSA cohort without evidence of cancer, we did not detect significant differences in TIGIT ligands, either in their membrane-bound or soluble forms. Importantly, one year of CPAP treatment reduce the TIGIT expression. Hypoxemia in OSA patients increases TIGIT expression, contributing to a T-cell exhaustion phenotype. CPAP treatment reduces TIGIT expression on T lymphocytes. Altogether, these findings highlight the impact of hypoxemia effect on immune response, which may help explain the high cancer incidence in OSA patients.

Background The objective of this review was to investigate trends in clinical trial design, specifically, the primary outcomes used, interpretation of results, and the magnitude of the benefits described in phase III controlled clinical trials in the first‐line treatment of patients with advanced non‐small cell lung cancer (NSCLC). Methods Seventy‐six trials published between 2000 and 2012 were selected from a total of 122 identified in a structured search. Results Overall survival (OS) was evaluated as the primary study endpoint in 50 (65.8%) trials, followed by progression‐free survival (PFS) in 15 (19.7%), and other variables, such as toxicity, quality of life (QoL), and response rate in 11 (14.5%). Ten (66.7%) out of 15 clinical trials using PFS as the primary endpoint were published between 2010 and 2012. Median overall survival (mOS) was 9.90 months (interquartile range: 3.5) with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in mOS was obtained in only 13 (18.8%) trials. A total of 41 (53.9%) studies concluded that the result was positive. Of these, only 16 (39.1%) showed a statistically significant benefit in OS. QoL was assessed in 46 trials (60.5%) and of these, 10 (21.7%) reported significant improvements. Conclusions These findings raise important questions about how clinical benefits are measured in clinical trials in advanced NSCLC. Appropriate clinically relevant outcome variables should be established and validated, and post‐marketing studies should be requested by regulatory authorities to ensure meaningful clinical benefits in OS and QoL.

The objective of this review was to analyze trends in outcomes and in the quality of phase III randomized controlled trials on advanced NSCLC published between 2000 and 2012, selecting 76 trials from a total of 122 retrieved in a structured search. Over the study period, the number of randomized patients per trial increased by 14 per year (P = 0.178). The sample size significantly increased between 2000 and 2012 in trials of targeted agents (460.1 vs. 740.8 patients, P = 0.009), trials of >1 drug (360.4 vs. 584.8, P = 0.014), and those including patients with good performance status (675.3 vs. 425.6; P = 0.003). Quality of life was assessed in 46 trials (60.5%), and significant improvements were reported in 10 of these (21.7%). Platinum‐based regimens were the most frequently investigated (86.8% of trials). Molecular‐targeted agents were studied in 25.0% of chemotherapy arms, and the percentage of trials including these agents increased each year. The median (interquartile range) overall survival (MOS) was 9.90 (3.5) months with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in MOS was obtained in only 13 (18.8%) trials. The median progression‐free survival was 4.9 (1.9) months, with a nonsignificant increase of 0.026 months per year (P > 0.05). There has been a continuous but modest improvement in the survival of patients with advanced NSCLC over the past 12 years. Nevertheless, the quality of clinical trials and the benefit in outcomes should be carefully considered before the incorporation of novel approaches into clinical practice. Constant but moderate improvement in efficacy outcomes in advanced NSCLC until 2012. Critical analysis of the published results of phase III clinical trials in NSCLC is required.

Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-β) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-β pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.

La investigación buscaba analizar las representaciones sociales que tienen los estudiantes universitarios sobre el plagio en la escritura académica. Se planteó un enfoque mixto de investigación, con un diseño descriptivo transversal. En los instrumentos de recolección de información se incluyó una encuesta en línea, aplicada a 414 estudiantes, y se llevaron a cabo dos grupos de discusión, con ocho participantes cada uno. Se usó la técnica de análisis de contenido con apoyo del software Atlas.Ti 8.0. Los resultados se agruparon en cuatro categorías: conocimientos sobre el plagio, actitudes hacia el plagio, interacción con el contexto académico y prácticas de uso de información. Sobre el conocimiento, se encontró que los estudiantes identifican el concepto de plagio y sus principales características. Respecto a las actitudes, los alumnos perciben el plagio como una práctica inadecuada y deshonesta que debe evitarse y que les genera temor y bloqueos en la escritura. En cuanto a la interacción, la universidad demanda una mayor rigurosidad en el uso de la información que la educación secundaria, pero ofrece pocas orientaciones. Para evitar el plagio, en sus prácticas de escritura, los estudiantes usan el parafraseo y atribuyen la autoría a partir de la indicación de los enlaces de las páginas web consultadas. Aunque los participantes reconocen el plagio como una acción incorrecta, afirman que, en general, no cuentan con las competencias necesarias para evitarlo en sus textos académicos.