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.

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.

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.

Cerebrospinal fluid lipidomic fingerprint of obstructive sleep apnoea in Alzheimer's disease.

BACKGROUND: Obstructive sleep apnoea (OSA) has a high prevalence in patients with Alzheimer's disease (AD). Both conditions have been shown to be associated with lipid dysregulation. However, the relationship between OSA severity and alterations in lipid metabolism in the brains of patients with AD has yet to be fully elucidated. In this context, we examined the cerebrospinal fluid (CSF) lipidome of patients with suspected OSA to identify potential diagnostic biomarkers and to provide insights into the pathophysiological mechanisms underlying the effect of OSA on AD. METHODS: The study included 91 consecutive AD patients who underwent overnight polysomnography (PSG) to diagnose severe OSA (apnoea-hypopnea index ≥ 30/h). The next morning, CSF samples were collected and analysed by liquid chromatography coupled to mass spectrometry in an LC-ESI-QTOF-MS/MS platform. RESULTS: The CSF levels of 11 lipid species were significantly different between AD patients with (N = 38) and without (N = 58) severe OSA. Five lipids (including oxidized triglyceride OxTG(57:2) and four unknown lipids) were significantly correlated with specific PSG measures of OSA severity related to sleep fragmentation and hypoxemia. Our analyses revealed a 4-lipid signature (including oxidized ceramide OxCer(40:6) and three unknown lipids) that provided an accuracy of 0.80 (95% CI: 0.71-0.89) in the detection of severe OSA. These lipids increased the discriminative power of the STOP-Bang questionnaire in terms of the area under the curve (AUC) from 0.61 (0.50-0.74) to 0.85 (0.71-0.93). CONCLUSIONS: Our results reveal a CSF lipidomic fingerprint that allows the identification of AD patients with severe OSA. Our findings suggest that an increase in central nervous system lipoxidation may be the principal mechanism underlying the association between OSA and AD.

Breathing cessation events that compose the apnea-hypopnea index are distinctively associated with the adverse outcomes in Alzheimer's disease.

BACKGROUND: Previous studies challenge the impact of obstructive sleep apnea (OSA) once patients are diagnosed with Alzheimer's disease (AD). Nevertheless, OSA recognizably disrupts sleep, and relevant associations between sleep, AD pathological markers, and cognition have been demonstrated. We aimed to further explore this, evaluating the associations between each breathing cessation event that compose the apnea-hypopnea index (AHI) and the sleep structure to finally investigate whether this was related to increased levels of AD markers and higher cognitive decline. METHODS: Observational, prospective study, including consecutive patients diagnosed with mild-moderate AD. The participants were submitted to overnight polysomnography followed by a cerebrospinal fluid collection for AD pathological markers levels determination. Neuropsychological assessment was performed at baseline and after 12 months of follow-up. RESULTS: The cohort was composed of 116 patients (55.2% females) with a median [p25;p75] age of 76.0 [72.0;80.0] years and an AHI of 25.9 [15.1;48.5], which was mainly defined by the presence of hypopneas and obstructive apneas. These were distinctively associated with the sleep structure, with obstructive apneas being related to arousals and sleep lightening and hypopneas being related to an increased number of arousals only. Despite having a lower frequency, mixed and central apneas also presented associations with the sleep structure, particularly increasing the time spent in the lighter sleep stages. In relation to AD pathological markers, obstructive and mixed apneas were related to an augment in neurofilament light levels while hypopneas were associated with a higher phosphorylated-tau/amyloid-beta protein ratio. Hypopneas were the most important event for an increased cognitive decline at the 12-month follow-up. CONCLUSIONS: Our findings highlight the importance of a patient-centered approach, with a comprehensive and detailed analysis of the AHI to effectively predict the different outcomes and tailor the appropriate therapeutic strategies.

Once bitten twice shy: Risk factors associated with bovine tuberculosis recurrence in Castilla y Leon, Spain.

Persistence of bovine tuberculosis (bTB) in cattle herd remains a major challenge in disease elimination due to the ineffectual removal of all infected animals in a bTB breakdown. Characterization of herds with a higher probability of experiencing further bTB breakdowns can help to implement specific risk-based policies for disease control and eradication. Here, our aim was to identify herd- and breakdown-level risk factors in bTB infected herds in Castilla y Leon, Spain, associated with a decreased time to recurrence and an increased risk of recurrence using a mixed effects Cox proportional hazards model and a multivariable logistic regression model, respectively. Results revealed that location (province), herd size and number of incoming animals/contacts were good predictors of a decreased time to bTB recurrence and an increased risk of becoming a recurrent herd. Additionally, the duration of the previous outbreak and the number of IFN-γ herd-tests applied in it were associated with increased odds of (an early) recurrence. Risk factors identified here can be used for early identification of herds in which bTB eradication may be more challenging and that should thus be subjected to increased control efforts. The characterization of high-risk herds may help to minimize the risk of reinfection and emphasize early detection and removal of bTB positive animals in the herd.

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.

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.

Blood-based lipidomic signature of severe obstructive sleep apnoea in Alzheimer's disease.

BACKGROUND: Obstructive sleep apnoea (OSA) is the most frequent form of sleep-disordered breathing in patients with Alzheimer's disease (AD). Available evidence demonstrates that both conditions are independently associated with alterations in lipid metabolism. However, it is unknown whether the expression of lipids is different between AD patients with and without severe OSA. In this context, we examined the plasma lipidome of patients with suspected OSA, aiming to identify potential diagnostic biomarkers and to provide insights into the pathophysiological mechanisms underlying the disease. METHODS: The study included 103 consecutive patients from the memory unit of our institution with a diagnosis of AD. The individuals were subjected to overnight polysomnography (PSG) to diagnose severe OSA (apnoea-hypopnea index ≥30/h), and blood was collected the following morning. Untargeted plasma lipidomic profiling was performed using liquid chromatography coupled with mass spectrometry. RESULTS: We identified a subset of 44 lipids (mainly phospholipids and glycerolipids) that were expressed differently between patients with AD and severe and nonsevere OSA. Among the lipids in this profile, 30 were significantly correlated with specific PSG measures of OSA severity related to sleep fragmentation and hypoxemia. Machine learning analyses revealed a 4-lipid signature (phosphatidylcholine PC(35:4), cis-8,11,14,17-eicosatetraenoic acid and two oxidized triglycerides (OxTG(58:5) and OxTG(62:12)) that provided an accuracy (95% CI) of 0.78 (0.69-0.86) in the detection of OSA. These same lipids improved the predictive power of the STOP-Bang questionnaire in terms of the area under the curve (AUC) from 0.61 (0.50-0.74) to 0.80 (0.70-0.90). CONCLUSION: Our results show a plasma lipidomic fingerprint that allows the identification of patients with AD and severe OSA, allowing the personalized management of these individuals. The findings suggest that oxidative stress and inflammation are potential prominent mechanisms underlying the association between OSA and AD.

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.

Respiratory Polygraphy Patterns and Risk of Recurrent Cardiovascular Events in Patients With Acute Coronary Syndrome.

Introduction: Obstructive sleep apnea (OSA) severity is based on the apnea-hypopnea index (AHI). The AHI is a simplistic measure that is inadequate for capturing disease severity and its consequences in cardiovascular diseases (CVDs). Deleterious effects of OSA have been suggested to influence the prognosis of specific endotypes of patients with acute coronary syndrome (ACS). We aim to identify respiratory polygraphy (RP) patterns that contribute to identifying the risk of recurrent cardiovascular events in patients with ACS. Methods: Post hoc analysis of the ISAACC study, including 723 patients admitted for a first ACS (NCT01335087) in which RP was performed. To identify specific RP patterns, a principal component analysis (PCA) was performed using six RP parameters: AHI, oxygen desaturation index, mean and minimum oxygen saturation (SaO2), average duration of events and percentage of time with SaO2 < 90%. An independent HypnoLaus population-based cohort was used to validate the RP components. Results: From the ISAACC study, PCA showed that two RP components accounted for 70% of the variance in the RP data. These components were validated in the HypnoLaus cohort, with two similar RP components that explained 71.3% of the variance in the RP data. The first component (component 1) was mainly characterized by low mean SaO2 and obstructive respiratory events with severe desaturation, and the second component (component 2) was characterized by high mean SaO2 and long-duration obstructive respiratory events without severe desaturation. In the ISAACC cohort, component 2 was associated with an increased risk of recurrent cardiovascular events in the third tertile with an adjusted hazard ratio (95% CI) of 2.44 (1.07 to 5.56; p-value = 0.03) compared to first tertile. For component 1, no significant association was found for the risk of recurrent cardiovascular events. Conclusion: A RP component, mainly characterized by intermittent hypoxemia, is associated with a high risk of recurrent cardiovascular events in patients without previous CVD who have suffered a first ACS.

Comparison of Commercial Enzyme-linked Immunosorbent Assays for Diagnosis of Contagious Agalactia Caused By Mycoplasma Agalactiae.

Introduction: Contagious agalactia (CA) is a disease affecting small ruminants with worldwide distribution and caused by several mycoplasmas, especially M. agalactiae. The main option for systematic diagnosis under monitoring control programmes is the enzyme-linked immunosorbent assay (ELISA) test. Material and Methods: This study was designed to appraise the performance of two commercial indirect ELISA tests using M. agalactiae p48 protein and one using total protein, for antibody detection in small ruminants after natural infection with different M. agalactiae strains. We carried out the test evaluation using sera of confirmed M. agalactiae-positive goats with clinical signs. In addition, test agreement was assessed by kappa between the three commercial ELISA tests. Results: All three ELISA tests showed high validity scores (Youden's J: 72.9-84%). The sensitivity values for the P48 protein-based tests were 76.9% and 84.6%, and was 79% for the total protein-based test. The specificity of all tests was 100%. In addition, between the total protein-based ELISA test and the other two ELISA tests based on the P48 protein, the agreement was substantial (kappa: 0.762-0.763) and the agreement between the latter two tests was almost perfect (kappa: 0.93). Conclusion: The validity parameters for all tests allowed their application for diagnostic purposes in lactating goats excreting M. agalactiae in milk and presenting clinical signs. The agreements show that any of these ELISA tests could be equally well used for diagnosis in programmes against CA.

Long-Term Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Treatment on Blood Pressure in Patients with Acute Coronary Syndrome: A Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is prevalent in patients with acute coronary syndrome (ACS) and is a cause of secondary hypertension. Objectives: To explore the long-term effects of OSA and continuous positive airway pressure (CPAP) treatment on blood pressure (BP) in patients with ACS. Methods: Post hoc analysis of the ISAACC study (Continuous Positive Airway Pressure in Patients with Acute Coronary Syndrome and Obstructive Sleep Apnea; NCT01335087) included 1,803 patients admitted for ACS. Patients with OSA (apnea-hypopnea index [AHI], ⩾15 events/h) were randomly assigned to receive either CPAP or usual care and were seen in follow-up for 1-5 years. Office BP was determined at each visit. Results: We included 596 patients without OSA, 978 patients in the usual care or poor CPAP adherence group, and 229 patients in the good CPAP adherence group. At baseline, 52% of the patients were diagnosed with hypertension. Median (25th to 75th percentile) age and body mass index were 59 (52.0 to 67.0) years and 28.2 (25.6 to 31.2) kg/m2, respectively. After a median (25th to 75th percentile) follow-up of 41.2 (18.3 to 59.6) months, BP changes were similar in the OSA and non-OSA groups. However, we observed an increase in BP in the third tertile of the AHI (AHI, >40 events/h), with a maximum difference in mean BP of +3.3 mm Hg at 30 months. Patients with OSA with good CPAP adherence (⩾4 h/night) reduced mean BP after 18 months compared with patients with usual care/poor CPAP adherence, with a maximum mean difference (95% confidence interval) of -4.7 (-6.7 to -2.7) mm Hg. In patients with severe OSA, we observed a maximum mean difference of -7.1 (-10.3 to -3.8) mm Hg. Conclusions: In patients with ACS, severe OSA is associated with a long-term increase in BP, which is reduced by good CPAP adherence. Clinical trial registered with www.clinicaltrials.gov (NCT01335087).

Sleep and Circadian Health of Critical COVID-19 Survivors 3 Months After Hospital Discharge.

OBJECTIVES: To evaluate the sleep and circadian rest-activity pattern of critical COVID-19 survivors 3 months after hospital discharge. DESIGN: Observational, prospective study. SETTING: Single-center study. PATIENTS: One hundred seventy-two consecutive COVID-19 survivors admitted to the ICU with acute respiratory distress syndrome. INTERVENTIONS: Seven days of actigraphy for sleep and circadian rest-activity pattern assessment; validated questionnaires; respiratory tests at the 3-month follow-up. MEASUREMENTS AND MAIN RESULTS: The cohort included 172 patients, mostly males (67.4%) with a median (25th-75th percentile) age of 61.0 years (52.8-67.0 yr). The median number of days at the ICU was 11.0 (6.00-24.0), and 51.7% of the patients received invasive mechanical ventilation (IMV). According to the Pittsburgh Sleep Quality Index (PSQI), 60.5% presented poor sleep quality 3 months after hospital discharge, which was further confirmed by actigraphy. Female sex was associated with an increased score in the PSQI (p < 0.05) and IMV during ICU stay was able to predict a higher fragmentation of the rest-activity rhythm at the 3-month follow-up (p < 0.001). Furthermore, compromised mental health measured by the Hospital Anxiety and Depression Scale was associated with poor sleep quality (p < 0.001). CONCLUSIONS: Our findings highlight the importance of considering sleep and circadian health after hospital discharge. Within this context, IMV during the ICU stay could aid in predicting an increased fragmentation of the rest-activity rhythm at the 3-month follow-up. Furthermore, compromised mental health could be a marker for sleep disruption at the post-COVID period.

Endogenous controls and microRNA profile in female patients with obstructive sleep apnea.

Recent studies have evaluated the potential of circulating microRNAs (miRNAs) as valuable biomarkers for characterizing obstructive sleep apnea (OSA) in males. The potential use of miRNAs as clinical indicators in females is unknown. The objective is to identify a set of miRNAs to be used as endogenous controls (ECs) in female patients with OSA. Then, to analyze differences in the miRNA expression profile between patients with and without OSA. This observational, longitudinal study included 85 females with suspected OSA who underwent a polysomnography. OSA was defined as an apnea hypopnea index ≥ 15 events/h. The study population was stratified into 50 OSA patients and 38 non-OSA patients. Exploratory expression profiling of 188 miRNAs consistent and reliable in plasma was performed in a discovery cohort of 21 patients by TaqMan-Low-Density-Array (TLDA). The best ECs were identified by mean centre + standard deviation normalization and concordance correlation restricted normalization. Differentially expressed candidate miRNAs were selected for RT-qPCR validation in a validation cohort of 64 patients. Three circulating miRNAs (miR-30a-5p, miR-93-3p and miR-532-5p) were identified as most stable for use as ECs. Twenty-seven miRNA candidates were identified as potential biomarkers for OSA screening (p value < 0.025) in the TLDA cohort. However, validation cohort showed no differences in the circulating miRNA profile in female patients with and without OSA. We identified a set of ECs in females with OSA that may contribute to result homogeneity in determining circulating miRNAs. Exploratory analysis did not identify a significantly miRNA profile between female patients with and without OSA.

Impact of time to intubation on mortality and pulmonary sequelae in critically ill patients with COVID-19: a prospective cohort study.

QUESTION: We evaluated whether the time between first respiratory support and intubation of patients receiving invasive mechanical ventilation (IMV) due to COVID-19 was associated with mortality or pulmonary sequelae. MATERIALS AND METHODS: Prospective cohort of critical COVID-19 patients on IMV. Patients were classified as early intubation if they were intubated within the first 48 h from the first respiratory support or delayed intubation if they were intubated later. Surviving patients were evaluated after hospital discharge. RESULTS: We included 205 patients (140 with early IMV and 65 with delayed IMV). The median [p25;p75] age was 63 [56.0; 70.0] years, and 74.1% were male. The survival analysis showed a significant increase in the risk of mortality in the delayed group with an adjusted hazard ratio (HR) of 2.45 (95% CI 1.29-4.65). The continuous predictor time to IMV showed a nonlinear association with the risk of in-hospital mortality. A multivariate mortality model showed that delay of IMV was a factor associated with mortality (HR of 2.40; 95% CI 1.42-4.1). During follow-up, patients in the delayed group showed a worse DLCO (mean difference of - 10.77 (95% CI - 18.40 to - 3.15), with a greater number of affected lobes (+ 1.51 [95% CI 0.89-2.13]) and a greater TSS (+ 4.35 [95% CI 2.41-6.27]) in the chest CT scan. CONCLUSIONS: Among critically ill patients with COVID-19 who required IMV, the delay in intubation from the first respiratory support was associated with an increase in hospital mortality and worse pulmonary sequelae during follow-up.

Plasma profiling reveals a blood-based metabolic fingerprint of obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) is a chronic, heterogeneous and multicomponent disorder with associated cardiovascular and metabolic alterations. Despite being the most common sleep-disordered breathing, it remains a significantly undiagnosed condition. OBJECTIVE: We examined the plasma metabolome and lipidome of patients with suspected OSA, aiming to identify potential diagnosis biomarkers and to provide insights into the pathophysiological mechanisms underlying the disease. Additionally, we evaluated the impact of continuous positive airway pressure (CPAP) treatment on the circulating metabolomic and lipidomic profile. MATERIAL AND METHODS: Observational-prospective-longitudinal study including 206 consecutive subjects referred to the sleep unit. OSA was defined as an apnea-hypopnoea index ≥ 15 events/h after polysomnography (PSG). Patients treated with CPAP were followed-up for 6 months. Untargeted plasma metabolomic and lipidomic profiling was performed using liquid chromatography coulpled to massspectrometry. RESULTS: A plasma profile composed of 33 metabolites (mainly glycerophospholipids and bile acids) was identified in OSA vs. non-OSA patients. This profile correlated with specific PSG measures of OSA severity related to sleep fragmentation and hypoxemia. Machine learning analyses disclosed a 4-metabolites-signature that provided an accuracy (95% CI) of 0.98 (0.95-0.99) for OSA detection. CPAP treatment was associated with changes in 5 plasma metabolites previously altered by OSA. CONCLUSIONS: This analysis of the circulating metabolome and lipidome reveals a molecular fingerprint of OSA, which was modulated after effective CPAP treatment. Our results suggest blood-based biomarker candidates with potential application in the personalized management of OSA and suggest the activation of adaptive mechanisms in response to OSA-derived hypoxia.