Sleep and Circadian Health of Critical Survivors: A 12-Month Follow-Up Study.

OBJECTIVES: To investigate the sleep and circadian health of critical survivors 12 months after hospital discharge and to evaluate a possible effect of the severity of the disease within this context. DESIGN: Observational, prospective study. SETTING: Single-center study. PATIENTS: Two hundred sixty patients admitted to the ICU due to severe acute respiratory syndrome coronavirus 2 infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was composed of 260 patients (69.2% males), with a median (quartile 1-quartile 3) age of 61.5 years (52.0-67.0 yr). The median length of ICU stay was 11.0 days (6.00-21.8 d), where 56.2% of the patients required invasive mechanical ventilation (IMV). The Pittsburgh Sleep Quality Index (PSQI) revealed that 43.1% of the cohort presented poor sleep quality 12 months after hospital discharge. Actigraphy data indicated an influence of the disease severity on the fragmentation of the circadian rest-activity rhythm at the 3- and 6-month follow-ups, which was no longer significant in the long term. Still, the length of the ICU stay and the duration of IMV predicted a higher fragmentation of the rhythm at the 12-month follow-up with effect sizes (95% CI) of 0.248 (0.078-0.418) and 0.182 (0.005-0.359), respectively. Relevant associations between the PSQI and the Hospital Anxiety and Depression Scale (rho = 0.55, anxiety; rho = 0.5, depression) as well as between the fragmentation of the rhythm and the diffusing lung capacity for carbon monoxide (rho = -0.35) were observed at this time point. CONCLUSIONS: Our findings reveal a great prevalence of critical survivors presenting poor sleep quality 12 months after hospital discharge. Actigraphy data indicated the persistence of circadian alterations and a possible impact of the disease severity on the fragmentation of the circadian rest-activity rhythm, which was attenuated at the 12-month follow-up. This altogether highlights the relevance of considering the sleep and circadian health of critical survivors in the long term.

MicroRNA-guided drug discovery for mitigating persistent pulmonary complications in critical COVID-19 survivors: A longitudinal pilot study.

BACKGROUND AND PURPOSE: The post-acute sequelae of SARS-CoV-2 infection pose a significant global challenge, with nearly 50% of critical COVID-19 survivors manifesting persistent lung abnormalities. The lack of understanding about the molecular mechanisms and effective treatments hampers their management. Here, we employed microRNA (miRNA) profiling to decipher the systemic molecular underpinnings of the persistent pulmonary complications. EXPERIMENTAL APPROACH: We conducted a longitudinal investigation including 119 critical COVID-19 survivors. A comprehensive pulmonary evaluation was performed in the short-term (median = 94.0 days after hospital discharge) and long-term (median = 358 days after hospital discharge). Plasma miRNAs were quantified at the short-term evaluation using the gold-standard technique, RT-qPCR. The analyses combined machine learning feature selection techniques with bioinformatic investigations. Two additional datasets were incorporated for validation. KEY RESULTS: In the short-term, 84% of the survivors exhibited impaired lung diffusion (DLCO  < 80% of predicted). One year post-discharge, 54.4% of this patient subgroup still presented abnormal DLCO . Four feature selection methods identified two specific miRNAs, miR-9-5p and miR-486-5p, linked to persistent lung dysfunction. The downstream experimentally validated targetome included 1473 genes, with heterogeneous enriched pathways associated with inflammation, angiogenesis and cell senescence. Validation studies using RNA-sequencing and proteomic datasets emphasized the pivotal roles of cell migration and tissue repair in persistent lung dysfunction. The repositioning potential of the miRNA targets was limited. CONCLUSION AND IMPLICATIONS: Our study reveals early mechanistic pathways contributing to persistent lung dysfunction in critical COVID-19 survivors, offering a promising approach for the development of targeted disease-modifying agents.

Association between adherence to the mediterranean diet, physical activity, and sleep apnea-hypopnea syndrome (SAHS) in a middle-aged population with cardiovascular risk: Insights from the ILERVAS cohort.

INTRODUCTION: Sleep Apnea-Hypopnea Syndrome (SAHS) is a common sleep disorder influenced by factors like age, gender, and obesity. The Mediterranean Diet (MedDiet) and physical activity have shown health benefits in lung diseases, but their effects on SAHS remain underexplored. METHODS: In a cross-sectional analysis of 678 middle-aged individuals with low-to-moderate cardiovascular risk from the ILERVAS cohort, we assessed adherence to the MedDiet and physical activity levels using validated tools. Sleep parameters, SAHS severity, and excessive daytime sleepiness were evaluated through non-attended cardiorespiratory polygraphy and the Epworth Sleepiness Scale. Multinomial logistic regression models were employed to assess the relationship between MedDiet adherence, physical activity, and SAHS severity. RESULTS: The prevalence of severe, moderate, and mild SAHS was 15.5%, 23.2% and 36.1%, respectively. We found no significant associations between adherence to the MedDiet, physical activity levels, and the presence or severity of SAHS. However, we noted a significant interaction between MedDiet and physical activity with minimum SpO2 values (p = 0.049). Notably, consuming more than one serving of red meat per day was independently associated with a higher risk of moderate SAHS [OR = 2.65 (1.29-5.44), p = 0.008]. CONCLUSION: Individually, MedDiet adherence and physical activity did not show independent correlations with SAHS. However, when considered together, a minimal but significant effect on minimum SpO2 was observed. Additionally, red meat consumption was associated with a moderate risk of SAHS. Further research is necessary to comprehend the intricate connections between lifestyle factors and sleep-breathing disorders, with a focus on personalized approaches for high-risk populations.

Obstructive sleep apnea and cardiovascular risk. / Apnea obstructiva del sueño y riesgo cardiovascular.

Patients with obstructive sleep apnea (OSA) experience repetitive episodes of upper airway obstruction due to recurrent collapse during sleep. This leads to intermittent hypoxia episodes, which, through complex pathophysiological mechanisms, trigger sympathetic overactivation, endothelial dysfunction, hypercoagulation, and metabolic dysregulation. Consequently, other cardiovascular risk factors such as hypertension, metabolic syndrome, and diabetes are induced. Furthermore, this enhances target organ damage, affecting the heart, arteries, and kidneys, leading to an increased risk of cardiovascular morbidity and mortality. Among the various treatments for OSA, Continuous Positive Airway Pressure (CPAP) has been extensively studied. To date, this treatment has shown mild benefits in reducing blood pressure, particularly noticeable in patients with resistant hypertension. Furthermore, CPAP treatment appears to reduce cardiovascular events, both in primary and secondary prevention, though this benefit is limited to individuals with good compliance (CPAP use ≥4h/night). Future research perspectives in OSA seem to focus on identifying patients in whom the condition significantly influences cardiovascular risk, thus determining those who would benefit the most from treatment in the reduction of cardiovascular risk.

Metabolipidomic Analysis in Patients with Obstructive Sleep Apnea Discloses a Circulating Metabotype of Non-Dipping Blood Pressure.

A non-dipping blood pressure (BP) pattern, which is frequently present in patients with obstructive sleep apnea (OSA), confers high cardiovascular risk. The mechanisms connecting these two conditions remain unclear. In the present study we performed a comprehensive analysis of the blood metabolipidome that aims to provide new insights into the molecular link between OSA and the dysregulation of circadian BP rhythmicity. This was an observational prospective longitudinal study involving adults with suspected OSA who were subjected to full polysomnography (PSG). Patients with an apnea-hypopnea index ≥ 5 events/h were included. Fasting plasma samples were obtained the morning after PSG. Based on the dipping ratio (DR; ratio of night/day BP values) measured via 24 h ambulatory BP monitoring, two groups were established: dippers (DR ≤ 0.9) and non-dippers (DR > 0.9). Treatment recommendations for OSA followed the clinical guidelines. Untargeted metabolomic and lipidomic analyses were performed in plasma samples via liquid chromatography-tandem mass spectrometry. Non-dipper patients represented 53.7% of the cohort (88/164 patients). A set of 31 metabolic species and 13 lipidic species were differentially detected between OSA patients who present a physiologic nocturnal BP decrease and those with abnormal BP dipping. Among the 44 differentially abundant plasma compounds, 25 were putatively identified, notably glycerophospholipids, glycolipids, sterols, and fatty acid derivates. Multivariate analysis defined a specific metabotype of non-dipping BP, which showed a significant dose-response relationship with PSG parameters of OSA severity, and with BP dipping changes after 6 months of OSA treatment with continuous positive airway pressure (CPAP). Bioinformatic analyses revealed that the identified metabolipidomic profile was found to be implicated in multiple systemic biological pathways, with potential physiopathologic implications for the circadian control of BP among individuals with OSA.

Challenges in the Management of Perianal Hidradenitis Suppurativa in an African American Male: A Case Report.

Hidradenitis suppurativa (HS), more commonly known as acne inversa, occurs due to chronic inflammation of the body's apocrine glands, most commonly affecting areas of the body where there is prolonged skin-on-skin friction. HS affects approximately 4% of the United States population, most commonly women in their second or third decade of life, especially those of African American ethnicity. HS presents as tender subcutaneous nodules which often rupture, leading to the formation of painful dermal abscesses which undergo fibrosis and lead to the formation of extensive sinus tracts, a phenomenon known as "tunneling". HS is staged clinically using the Hurley staging system, where the stage determines what treatment modalities are used. These modalities can include medical management such as antibiotics, or biologics such as tumor necrosis factor (TNF)-alpha inhibitors like adalimumab, as well as surgical options including incision with or without drainage. Due to the similar presentation of HS with other conditions, this disease is commonly misdiagnosed, often leading to delayed treatment initiation and worse outcomes for patients. Presented is a case report of a 30-year-old African American male with perianal HS and the potential long-term complications and challenges of management of this disease.

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events: A Meta-Analysis.

Importance: The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. Objective: To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. Data Sources: PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. Study Selection: For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Data Extraction and Synthesis: Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). Main Outcomes and Measures: One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). Results: A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Conclusions and Relevance: Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial.

BACKGROUND: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP). METHODS: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h-1) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h-1). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level. RESULTS: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship. CONCLUSION: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis.

Low adherence to the Mediterranean diet is associated with increased prevalence and number of atherosclerotic plaques in the ILERVAS cohort.

BACKGROUND AND AIMS: Current research on the association between dietary patterns and subclinical atherosclerotic disease (SAD) is still limited, and published results are inconsistent and often consist of small population sizes. We aimed to evaluate the association between the Mediterranean diet (MDiet) and SAD in a large cohort of Mediterranean individuals. METHODS: This was a cross-sectional study that included 8116 subjects from the ILERVAS cohort. The presence of atherosclerotic plaques (AP) was assessed by ultrasound examination. Adherence to the MDiet was assessed using the 14-item Mediterranean Diet Adherence Score (MEDAS). Inclusion criteria were subjects with at least one cardiovascular risk factor. Exclusion criteria were a clinical history of diabetes, chronic kidney disease, or a prior cardiovascular event. Bivariable and multivariable models were performed. RESULTS: Compared with subjects without SAD, participants with SAD were older and had a higher frequency of smoking habit, hypertension, dyslipidemia, HbA1c and waist circumference. The adjusted multivariable analysis showed that a higher MEDAS was associated with a lower risk of AP (incidence rate ratios [IRR] 0.97, 95% CI [0.96-0.98]; p<0.001). Furthermore, moderate or high adherence to the MDiet was associated with a lower number of AP compared with a low MDiet adherence (IRR 0.90, 95% CI [0.87-0.94]; p<0.001). In both models, female sex was associated with a lower risk of AP. CONCLUSIONS: Our findings point to a potentially protective role of MDiet for SAD in a Mediterranean population with low-to-moderate cardiovascular risk. Further research is needed to establish a causal relationship between both variables.

GATEKEEPER's Strategy for the Multinational Large-Scale Piloting of an eHealth Platform: Tutorial on How to Identify Relevant Settings and Use Cases.

BACKGROUND: The World Health Organization's strategy toward healthy aging fosters person-centered integrated care sustained by eHealth systems. However, there is a need for standardized frameworks or platforms accommodating and interconnecting multiple of these systems while ensuring secure, relevant, fair, trust-based data sharing and use. The H2020 project GATEKEEPER aims to implement and test an open-source, European, standard-based, interoperable, and secure framework serving broad populations of aging citizens with heterogeneous health needs. OBJECTIVE: We aim to describe the rationale for the selection of an optimal group of settings for the multinational large-scale piloting of the GATEKEEPER platform. METHODS: The selection of implementation sites and reference use cases (RUCs) was based on the adoption of a double stratification pyramid reflecting the overall health of target populations and the intensity of proposed interventions; the identification of a principles guiding implementation site selection; and the elaboration of guidelines for RUC selection, ensuring clinical relevance and scientific excellence while covering the whole spectrum of citizen complexities and intervention intensities. RESULTS: Seven European countries were selected, covering Europe's geographical and socioeconomic heterogeneity: Cyprus, Germany, Greece, Italy, Poland, Spain, and the United Kingdom. These were complemented by the following 3 Asian pilots: Hong Kong, Singapore, and Taiwan. Implementation sites consisted of local ecosystems, including health care organizations and partners from industry, civil society, academia, and government, prioritizing the highly rated European Innovation Partnership on Active and Healthy Aging reference sites. RUCs covered the whole spectrum of chronic diseases, citizen complexities, and intervention intensities while privileging clinical relevance and scientific rigor. These included lifestyle-related early detection and interventions, using artificial intelligence-based digital coaches to promote healthy lifestyle and delay the onset or worsening of chronic diseases in healthy citizens; chronic obstructive pulmonary disease and heart failure decompensations management, proposing integrated care management based on advanced wearable monitoring and machine learning (ML) to predict decompensations; management of glycemic status in diabetes mellitus, based on beat to beat monitoring and short-term ML-based prediction of glycemic dynamics; treatment decision support systems for Parkinson disease, continuously monitoring motor and nonmotor complications to trigger enhanced treatment strategies; primary and secondary stroke prevention, using a coaching app and educational simulations with virtual and augmented reality; management of multimorbid older patients or patients with cancer, exploring novel chronic care models based on digital coaching, and advanced monitoring and ML; high blood pressure management, with ML-based predictions based on different intensities of monitoring through self-managed apps; and COVID-19 management, with integrated management tools limiting physical contact among actors. CONCLUSIONS: This paper provides a methodology for selecting adequate settings for the large-scale piloting of eHealth frameworks and exemplifies with the decisions taken in GATEKEEPER the current views of the WHO and European Commission while moving forward toward a European Data Space.

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study.

BACKGROUND: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. METHODS: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. RESULTS: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. CONCLUSIONS: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.

Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients

Introduction: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors. Methods: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit. Results: The median [p25–p75] time from discharge to follow-up was 3.57 [2.77–4.92] months. Median age was 60 [53–67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (DLCO) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having DLCO<80% and 24% having DLCO<60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with DLCO<60% were chronic lung disease (CLD) (OR: 1.86 (1.18–2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37–1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18–1.63)), urea (OR: 1.16 (0.97–1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73–1.06)). Bacterial pneumonia (1.62 (1.11–2.35)) and duration of ventilation (NIMV (1.23 (1.06–1.42), IMV (1.21 (1.01–1.45)) and prone positioning (1.17 (0.98–1.39)) were associated with fibrotic lesions. Conclusion: Age and CLD, reflecting patients’ baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired DLCO and CT abnormalities. (AU)

Polysomnographic characterization of circadian blood pressure patterns in patients with obstructive sleep apnea.

We characterized the polysomnography (PSG) parameters associated with alterations in the circadian blood pressure (BP) pattern aiming to identify the main contributors to explain the nondipper profile in obstructive sleep apnea (OSA). This is an observational prospective-multicenter study that included participants referred to the sleep unit for suspected OSA. Following a PSG study, subjects with an apnea-hypopnea index (AHI) ≥5 events/hr were included. Two groups were established based on the 24-hr ambulatory blood pressure monitoring dipping ratio (DR; night/day BP ratio): dippers (DR ≤ 0.9) and nondippers (DR > 0.9). The cohort consisted of 299 patients: 131 (43.8%) dippers and 168 (56.2%) nondippers. A significant increase in the risk of presenting a nondipper BP pattern was found along with AHI gain [odds ratio (OR) (95% CI) = 1.71 (1.28 to 2.28)]. The best AHI cutoff for predicting nondipper status was 25.2 events/hr, increasing the OR (95% CI) to 3.50 (2.02 to 6.07). The hypopnea index [OR (95% CI) = 1.70 (1.27 to 2.26)], TSat90 [OR (95% CI) = 1.41 (1.06 to 1.87)], and respiratory arousal index [OR (95% CI) = 1.74 (1.30 to 2.34)] were individually associated with the risk of a nondipping pattern. Multivariate variable selection processes identified the respiratory arousal index as the most relevant risk factor for the nondipper profile, beyond classical clinical risk factors and usual PSG metrics.

Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients.

INTRODUCTION: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors. METHODS: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit. RESULTS: The median [p25-p75] time from discharge to follow-up was 3.57 [2.77-4.92] months. Median age was 60 [53-67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (DLCO) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having DLCO<80% and 24% having DLCO<60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with DLCO<60% were chronic lung disease (CLD) (OR: 1.86 (1.18-2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37-1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18-1.63)), urea (OR: 1.16 (0.97-1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73-1.06)). Bacterial pneumonia (1.62 (1.11-2.35)) and duration of ventilation (NIMV (1.23 (1.06-1.42), IMV (1.21 (1.01-1.45)) and prone positioning (1.17 (0.98-1.39)) were associated with fibrotic lesions. CONCLUSION: Age and CLD, reflecting patients' baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired DLCO and CT abnormalities.

Proteomic profiling for prediction of recurrent cardiovascular event in patients with acute coronary syndrome and obstructive sleep apnea: A post-hoc analysis from the ISAACC study.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with a recurrent cardiovascular event (CVE) risk in patients with a first acute coronary syndrome (ACS). However, the pathological pathways by which OSA promotes this deleterious role are unknown. We aim to explore the proteomic profile associated with OSA that promote the recurrent CVE risk in severe OSA patients with ACS without previous cardiovascular diseases. METHODS: This post-hoc analysis from the ISAACC study (NCT01335087) included 86 patients admitted for ACS. Patients underwent respiratory polygraphy for the first 24-72 h to OSA diagnosis. We analyzed of 276 cardiovascular and inflammatory related proteins in baseline fasting plasma samples using proximity expression assay technology (Olink®, Sweden). Protein levels were compared between severe OSA patients with/without recurrent CVEs during follow-up. Random forest was conducted to select relevant proteins and generate a predictive model of recurrent CVE. RESULTS: We included 86 patients (median age: 61 years, median BMI: 29.4 kg/m2 and 86 % males) admitted for ACS with severe OSA (56 without recurrent CVE/30 with recurrent CVE). The plasma levels of 38 proteins were differentially expressed between groups. Additionally, 12 proteins had a significant association with respiratory polygraphy parameters. Three proteins discriminate with an AUC of 0.81 (95 % CI of 0.71-0.9) between severe OSA patients with and without recurrent CVE. These proteins were implicated in cell proliferation, communication and apoptosis, and regulation/response to the inflammatory and immune systems. CONCLUSION: In ACS patients with severe OSA, a proteomic profile was associated with recurrent CVEs. This proteomic profile was correlated with specific OSA parameters from respiratory polygraphy. Proteomic profiling may provide an new direction for patient risk stratification and clinical management.

Genome-wide transcriptional profiling of pulmonary functional sequelae in ARDS- secondary to SARS-CoV-2 infection.

BACKGROUND: Up to 80% of patients surviving acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 infection present persistent anomalies in pulmonary function after hospital discharge. There is a limited understanding of the mechanistic pathways linked to post-acute pulmonary sequelae. AIM: To identify the molecular underpinnings associated with severe lung diffusion involvement in survivors of SARS-CoV-2-induced ARDS. METHODS: Survivors attended to a complete pulmonary evaluation 3 months after hospital discharge. RNA sequencing (RNA-seq) was performed using Illumina technology in whole-blood samples from 50 patients with moderate to severe diffusion impairment (DLCO<60%) and age- and sex-matched individuals with mild-normal lung function (DLCO≥60%). A transcriptomic signature for optimal classification was constructed using random forest. Transcriptomic data were analyzed for biological pathway enrichment, cellular deconvolution, cell/tissue-specific gene expression and candidate drugs. RESULTS: RNA-seq identified 1357 differentially expressed transcripts. A model composed of 14 mRNAs allowed the optimal discrimination of survivors with severe diffusion impairment (AUC=0.979). Hallmarks of lung sequelae involved cell death signaling, cytoskeleton reorganization, cell growth and differentiation and the immune response. Resting natural killer (NK) cells were the most important immune cell subtype for the prediction of severe diffusion impairment. Components of the signature correlated with neutrophil, lymphocyte and monocyte counts. A variable expression profile of the transcripts was observed in lung cell subtypes and bodily tissues. One upregulated gene, TUBB4A, constitutes a target for FDA-approved drugs. CONCLUSIONS: This work defines the transcriptional programme associated with post-acute pulmonary sequelae and provides novel insights for targeted interventions and biomarker development.

One Year Overview and Follow-Up in a Post-COVID Consultation of Critically Ill Patients.

The long-term clinical management and evolution of a cohort of critical COVID-19 survivors have not been described in detail. We report a prospective observational study of COVID-19 patients admitted to the ICU between March and August 2020. The follow-up in a post-COVID consultation comprised symptoms, pulmonary function tests, the 6-minute walking test (6MWT), and chest computed tomography (CT). Additionally, questionnaires to evaluate the prevalence of post-COVID-19 syndrome were administered at 1 year. A total of 181 patients were admitted to the ICU during the study period. They were middle-aged (median [IQR] of 61 [52;67]) and male (66.9%), with a median ICU stay of 9 (5-24.2) days. 20% died in the hospital, and 39 were not able to be included. A cohort of 105 patients initiated the follow-up. At 1 year, 32.2% persisted with respiratory alterations and needed to continue the follow-up. Ten percent still had moderate/severe lung diffusion (DLCO) involvement (<60%), and 53.7% had a fibrotic pattern on CT. Moreover, patients had a mean (SD) number of symptoms of 5.7 ± 4.6, and 61.3% met the criteria for post-COVID syndrome at 1 year. During the follow-up, 46 patients were discharged, and 16 were transferred to other consultations. Other conditions, such as emphysema (21.6%), COPD (8.2%), severe neurocognitive disorders (4.1%), and lung cancer (1%) were identified. A high use of health care resources is observed in the first year. In conclusion, one-third of critically ill COVID-19 patients need to continue follow-up beyond 1 year, due to abnormalities on DLCO, chest CT, or persistent symptoms.

Development and Validation of a Personalized, Sex-Specific Prediction Algorithm of Severe Atheromatosis in Middle-Aged Asymptomatic Individuals: The ILERVAS Study.

Background: Although European guidelines recommend vascular ultrasound for the assessment of cardiovascular risk in low-to-moderate risk individuals, no algorithm properly identifies patients who could benefit from it. The aim of this study is to develop a sex-specific algorithm to identify those patients, especially women who are usually underdiagnosed. Methods: Clinical, anthropometrical, and biochemical data were combined with a 12-territory vascular ultrasound to predict severe atheromatosis (SA: ≥ 3 territories with plaque). A Personalized Algorithm for Severe Atheromatosis Prediction (PASAP-ILERVAS) was obtained by machine learning. Models were trained in the ILERVAS cohort (n = 8,330; 51% women) and validated in the control subpopulation of the NEFRONA cohort (n = 559; 47% women). Performance was compared to the Systematic COronary Risk Evaluation (SCORE) model. Results: The PASAP-ILERVAS is a sex-specific, easy-to-interpret predictive model that stratifies individuals according to their risk of SA in low, intermediate, or high risk. New clinical predictors beyond traditional factors were uncovered. In low- and high-risk (L&H-risk) men, the net reclassification index (NRI) was 0.044 (95% CI: 0.020-0.068), and the integrated discrimination index (IDI) was 0.038 (95% CI: 0.029-0.048) compared to the SCORE. In L&H-risk women, PASAP-ILERVAS showed a significant increase in the area under the curve (AUC, 0.074 (95% CI: 0.062-0.087), p-value: < 0.001), an NRI of 0.193 (95% CI: 0.162-0.224), and an IDI of 0.119 (95% CI: 0.109-0.129). Conclusion: The PASAP-ILERVAS improves SA prediction, especially in women. Thus, it could reduce the number of unnecessary complementary explorations selecting patients for a further imaging study within the intermediate risk group, increasing cost-effectiveness and optimizing health resources. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03228459].