Oxidative stress is a central pathogenic process in the earliest stages of Alzheimer’s disease (AD), promoting non-enzymatic protein modifications that accumulate in cerebrospinal fluid (CSF) before measurable neurodegeneration. These alterations impair proteostasis and disrupt sleep-regulating neural circuits, producing characteristic changes in sleep electroencephalographic patterns. Because CSF sampling is invasive, quantitative electroencephalography (qEEG) has emerged as a promising non-invasive proxy for early oxidative processes. Here, we investigated whether nonlinear and time-domain sleep qEEG features can estimate CSF oxidative stress biomarkers in early AD using machine learning (ML) models. Forty-two mild-to-moderate AD patients underwent overnight polysomnography, from which sleep qEEG features were extracted. CSF protein oxidation biomarkers—glutamic semialdehyde, aminoadipic semialdehyde, N-carboxyethyl-lysine, N-carboxymethyl-lysine, and N-malondialdehyde-lysine—were quantified by gas chromatography/mass spectrometry, and ML models were trained to predict CSF biomarker levels from qEEG features. The best-performing model was a random forest trained on the first principal component, achieving an R^2 of 0.625 and a mean absolute error (MAE) of 467.1 pg/mL. Features derived from frontal and central electrodes during slow-wave sleep and rapid eye movement sleep contributed most strongly to predictive performance. Predictions for healthy controls displayed distributions distinct from those of AD patients, supporting the biological specificity of the qEEG-based estimates. These exploratory analyses suggest that sleep qEEG combined with ML can noninvasively capture silent oxidative processes involved early in AD pathological cascades, with potential for risk stratification, disease monitoring, and non-invasive upstream biomarkers development.

BACKGROUND:Severe respiratory failure is the leading cause of intensive care unit (ICU) admission and mortality in critically ill COVID-19 patients. However, whether active viral replication persists in the lower respiratory tract of these patients and contributes to lung injury remains unclear. METHODS:We conducted a prospective cohort study of 159 critically ill COVID-19 patients requiring invasive mechanical ventilation (IMV). A bronchoalveolar lavage (BAL) sample was collected within 24 h of intubation. SARS-CoV-2 RNA load (N1, N2, E, and subgenomic E) and the expression of 18 host immune-related genes were assessed. A replication-competent virus was detected using a Vero cell culture assay by inoculating cells with BAL samples and monitoring cytopathic effects. SARS-CoV-2 replication was confirmed by RT-qPCR. Association of virological and immunological factors with time from symptom onset to IMV initiation was evaluated using multivariable linear regression. RESULTS:SARS-CoV-2 RNA was detected in 84.3% of BAL samples, and 71.7% were positive for subgenomic E RNA. Replication-competent virus was confirmed in 60% of the samples. High RNA levels and SARS-CoV-2 culture positivity were independently associated with shorter time from symptom onset to IMV initiation, with culture positivity showing the strongest association. Gene expression profiling revealed a marked suppression of innate immune effectors, despite robust expression of type I and type III interferons. CXCL10 and PDL1 were the only genes independently associated with shorter time from symptom onset to IMV initiation. CONCLUSIONS:At the time of IMV initiation, patients with early respiratory failure showed high levels of SARS-CoV-2 RNA and evidence of active viral replication in the lower respiratory tract. This group represents a distinct virological phenotype that could benefit from therapeutic interventions targeting pulmonary viral replication. REGISTRATION:Sub-study of the CIBERESUCICOVID project (NCT04457505).

BackgroundObstructive sleep apnea (OSA) is common in type 2 diabetes (T2D) and may contribute to its chronic complications. Whether STOP-Bang-defined OSA risk is associated with diabetic foot ulcer (DFU) severity and outcome remains unclear. We compared STOP-Bang score between T2D patients with and without DFU and explored the association between OSA risk and DFU severity and healing.MethodsWe conducted an observational study with a cross-sectional matched case-control comparison including 73 T2D patients with DFU and 73 T2D controls without DFU, matched by age, HbA1c, BMI and smoking. At the study visit, STOP-Bang-defined OSA risk was assessed as a continuous score and categorized as low versus moderate/high risk. In the DFU group, ulcer severity was graded at the same visit with the WIfI classification, and time to healing and amputation was recorded during clinical follow-up. Multivariable logistic regression identified predictors of moderate-to-high amputation risk.ResultsIn unadjusted analyses, DFU patients had higher STOP-Bang score than controls (4.3 ± 2.0 vs. 3.2 ± 2.2, p=0.004) and more often intermediate/high OSA risk (83.6% vs. 60.3%, p=0.002), although these differences were attenuated after accounting for sex imbalance. Among DFU patients, higher ulcer severity was associated with moderate/high STOP-Bang-defined OSA risk (97.1 vs. 71.8%; p=0.004). Median healing time was longer in those with moderate/high versus low STOP-Bang-defined OSA risk (120.0 vs. 65.0 days, p=0.032). In multivariable analysis, WIfI ulcer severity was associated with male sex, higher STOP-Bang category and poorer metabolic control.ConclusionSTOP-Bang-defined OSA risk was associated with greater DFU severity and delayed wound healing. Incorporating OSA risk stratification into routine assessment of patients with DFU may help identify individuals at higher risk of poor outcomes.

INTRODUCTION:Nocturnal hypertension (NH) is a high-risk, underdiagnosed blood pressure (BP) phenotype strongly associated with cardiovascular morbidity. Obstructive sleep apnea (OSA), which is common in patients with NH, promotes vascular injury through sympathetic activation, inflammation, and endothelial dysfunction; however, the molecular mechanisms underlying this association in patients with NH remain poorly defined. This study explored these mechanisms using targeted proteomics and endothelial cell models. METHODS:Adults undergoing polysomnography (PSG) with NH, defined as nighttime BP ≥120/70mmHg at the time of 24-hour ambulatory BP monitoring, were included. Fasting blood samples were collected after PSG. Participants were classified as controls, defined as an apnea-hypopnea index (AHI) <15eventsh-1, or severe OSA, defined as AHI ≥30eventsh-1; patients with moderate OSA, defined as AHI between 15 and 30eventsh-1, were excluded to maximize contrast between groups. Participants were matched for age, sex, BMI, and nocturnal mean arterial pressure. The Olink® platform was used to quantify proteins. Differential abundance was assessed using linear models, and sparse partial least squares discriminant analysis was used to identify OSA-associated protein signatures. Endothelial integrity was assessed in cells exposed to extracellular vesicles derived from a subset of participants (n=8 controls; n=8 severe OSA). RESULTS:A total of 58 matched participants were included, with 29 participants per group. Overall, 70.7% were men, the median age was 48 years, and the median BMI was 29.5kg/m2. Twenty-one proteins were differentially abundant and were enriched in pathways related to cell adhesion maintenance and extracellular vesicle composition. A 13-protein signature associated with OSA showed interconnectivity and enrichment for endothelial regulatory pathways. Extracellular vesicles from patients with OSA showed a trend toward increased endothelial barrier disruption compared with controls. CONCLUSIONS:In patients with NH, severe OSA appears to be associated with molecular alterations indicative of endothelial dysfunction, providing preliminary mechanistic insight into elevated cardiovascular risk that may help refine risk stratification.

OBJECTIVES:To prospectively evaluate the relationship between 4-year changes in lung function and the progression of subclinical atherosclerosis among 1623 middle-aged adults with at least one cardiovascular risk factor participating in ILERVAS, and to determine whether individuals who develop airflow obstruction (AO) are especially susceptible to accelerated atherosclerosis progression. METHODS:This prospective cohort study included 1623 middle-aged adults from the ILERVAS cohort, recruited in primary care centers in the province of Lleida (Catalonia, Spain), with baseline assessments conducted between 2015 and 2018 and follow-up visits between 2019 and 2021 (mean follow-up, 3.99 [SD, 0.22] years). Pulmonary function was assessed by spirometry at baseline and at 4-year follow-up. Subclinical atherosclerosis was evaluated using vascular ultrasound of 12 carotid and femoral territories at baseline and at follow-up, with total plaque area quantified. Associations were analyzed using multivariable linear regression models, adjusting for clinical variables and baseline plaque burden. Analyses were stratified by smoking status. RESULTS:Median annual declines were -95mL (-2.04%) for FVC and -78mL (-2.00%) for FEV1. Categorization of annual pulmonary function decline by tertiles showed no significant association with plaque progression. In contrast, incident AO was associated with greater annual FEV1 decline (-146.73 vs -74.90mL; P<.001) and with greater plaque burden, reflected by an increase in affected vascular territories (0.26 [IQR, 0.00-0.75]; P<.001). Multivariable models confirmed larger annual increases in total (4.40mm2; P<.001), carotid (2.33mm2; P<.001), and femoral (1.99mm2; P=.031) plaque areas among participants with incident AO, with consistent results across smoking strata. Sensitivity analyses using a lower limit of normal-based definition of AO showed similar findings, with effect estimates consistent with the primary fixed-ratio analyses. CONCLUSIONS:In this two-time-point analysis, lung function decline was not independently associated with subclinical atherosclerosis progression. In contrast, incident AO was consistently associated with greater plaque progression across smoking strata. These findings support incident AO as a spirometric marker associated with vascular risk.

Age is a well-known risk factor to develop severe viral respiratory infections, including severe COVID-19. This study aimed to identify the biological alterations linked to severe disease in elderly patients with COVID-19. For this purpose, we employed a derivation cohort with 450 SARS-CoV-2 infected and unvaccinated patients admitted to hospital wards and a validation cohort with 244 SARS-CoV-2 infected and unvaccinated patients admitted to hospital Intensive Care Unit (ICU). Twenty-one biomarkers were measured in plasma samples from patients upon admission, including SARS-CoV-2 RNA, IgG antibodies, and protein biomarkers. Patient cohorts were divided into two groups based on age: adult (≤ 70 years old) and elderly (> 70 years old) patients. In the derivation cohort, 90-day mortality rate observed in the adult group was 6.0

A substantial proportion of critical illness survivors experience circadian disruptions following intensive care unit (ICU) discharge. However, the long-term circadian function in these patients remains poorly understood. This study aimed to characterize the circadian health of ICU survivors over a 24 month follow-up. Patients admitted to the ICU due to SARS-CoV-2 infection were recruited, and rest–activity rhythms (7-day actigraphy), mental health (Hospital Anxiety and Depression Scale), quality of life (12-item Short Form Survey), and respiratory function (spirometry) were assessed at short-term follow-up and at 24 months. The main analysis included 52 patients (65.4% male) with a mean (SD) age of 59.2 (8.27) years. The cohort showed a mean (95% CI) increase in circadian function index (CFI) of 0.06 (0.03–0.09). Participants were categorized into two groups: those without and those with a clinically meaningful improvement, defined as a ≥ 10% increase in CFI. Improvements in CFI correlated with changes in DLCO (rrm = 0.31; 0.04–0.54) and FEV1 (0.43; 0.17–0.63). Longer duration of invasive mechanical ventilation was associated with lower CFI at 24 months (effect size = –0.338; –0.637 to –0.038). These findings indicate that while some survivors show circadian recovery over 24 months, others exhibit persistent alterations, supporting circadian-focused strategies in post-ICU rehabilitation.

Long COVID represents a significant health challenge, with 10–20

BACKGROUND:Obstructive Sleep Apnea (OSA) is a common chronic disease that affects more than 20% of the adult population. One of the most frequent and characteristic symptoms of OSA is excessive daytime sleepiness (EDS). This symptom is typically treated in patients with OSA with the application of continuous positive airway pressure (CPAP), the gold-standard treatment for this disease. In some patients who are adequately treated with CPAP, residual excessive daytime sleepiness (REDS) persists. The prevalence, associations, and outcomes associated with REDS remain poorly understood. METHODS:Multicenter, prospective, observational cohort study including 1000 patients. Participants will undergo a sleep study for the diagnosis of obstructive sleep apnea (OSA), 24-h ambulatory blood pressure monitoring, clinical assessment, quality-of-life questionnaires, Epworth Sleepiness Scale, and collection of biochemical variables and biological samples. Patients with OSA will receive standard care, and those prescribed continuous positive airway pressure (CPAP) will be monitored for treatment adherence. OSA patients will be assessed at baseline and at 6, 12, and 24 months. DISSCUSION:We aim to establish a prospective observational cohort of patients with obstructive sleep apnea (OSA) treated with CPAP, with and without REDS. The HYPNOSA project will create the largest available registry of patients with OSA and REDS using real-world data, providing accurate prevalence estimates and long-term outcomes. Biological samples will be analyzed to assess the role of specific biomarkers. TRIAL REGISTRATION:Registered at ClinicalTrials.gov. Identifer: NCT06514482.

RATIONALE:Obesity hypoventilation syndrome (OHS) is treated with noninvasive ventilation (NIV) that is titrated during polysomnography. Auto-adjusted NIV could obviate the need for polysomnographic titration, thereby reducing costs and delays in care. However, non-inferiority long-term clinical trials comparing auto-adjusted NIV with manually-adjusted NIV are lacking. OBJECTIVES:To determine the comparative effectiveness of automatic vs manual NIV modality in OHS. METHODS:In this multicenter, blinded, parallel group, non-inferiority and cost-effectiveness trial, we randomly assigned treatment-naïve ambulatory patients with OHS to auto-adjusted NIV (volume-targeted pressure support with auto-expiratory positive airway pressure) or manually-adjusted NIV (bilevel Positive Airway Pressure Spontaneous Timed mode (PAP ST). MEASUREMENTS:The primary outcome was change in daytime PaCO2 at 12 months, with the non-inferiority premise set at -2 mm Hg. Secondary outcomes included symptoms, quality of life, and healthcare resource utilization. Intention-to-treat and per-protocol analyses were performed. MAIN RESULTS:205 ambulatory patients with OHS were randomized, 107 to auto-adjusted NIV and 89 to manually-adjusted NIV. The mean [95% CI] improvement in PaCO2 was -9.2 [-9.7; -8.7] mm Hg in the auto-adjusted group and -8.7 [-9.1; -8.3] mm Hg in the manually-adjusted group, with mean adjusted difference of 0.15 mm Hg between groups ([low confidence limit -1.4]; non-inferiority P = .01). Cost-effectiveness was favorable to auto-adjusted group with a saving of 1528 € (95% CI, -2 370; -6 854) per patient. There were no significant differences in other secondary outcomes. CONCLUSIONS:In ambulatory patients with OHS, auto-adjusted NIV had a non-inferior long-term effectiveness compared to manually-adjusted NIV while being more cost-effective. Auto-adjusted NIV may be preferred in clinical practice given its lower complexity and cost. CLINICALTRIAL.GOV IDENTIFIER:NCT04327336.

Early detection and biological characterization of Alzheimer’s disease (AD) remain challenging, as current diagnostic approaches rely on invasive cerebrospinal fluid (CSF) sampling or costly neuroimaging, limiting scalability. Sleep quantitative electroencephalography (qEEG) provides a non-invasive measure of brain function and may capture early AD-related neural alterations; however, the high dimensionality and complexity of these features limit interpretation with conventional approaches, requiring multivariate methods. The objective of this study is to assess whether sleep qEEG features are associated with biologically meaningful stratification of AD in accordance with the NIA–AA 2024 framework. Forty-two patients with mild-to-moderate AD underwent overnight polysomnography and CSF biomarker assessment, while 58 cognitively unimpaired controls provided sleep EEG recording. EEG signals from four channels were preprocessed, segmented by sleep stage, and characterized using linear, spectral, and non-linear features. Dimensionality reduction was performed using principal component analysis (PCA), guided by random forest-based relevance to CSF biomarkers (A β 42, p-tau181, t-tau, and neurofilament light chain (NfL). Gaussian mixture models (GMMs) were applied to patient-level representations, including derived hybrid ratios (p-tau181/A β 42), to identify biologically coherent subgroups. A reduced 30-component qEEG representation explaining 92.4 β 42 and NfL. Sleep qEEG features show structured associations with CSF biomarker profiles and capture variability across the AD continuum. These findings suggest that higher-level qEEG-based machine learning approaches may complement established biomarker-based methods for biological characterization of AD within a geroscience framework.

BACKGROUND:Coronary artery vasospasm (CAV) is a major cause of myocardial ischemia in patients without obstructive coronary disease. Its detection remains challenging due to the lack of biomarkers. We investigated circulating microRNAs (miRNAs) as potential biomarkers for CAV. METHODS:The ANFIBIO study is a prospective, multicenter cohort study that enrolled consecutive patients presenting with chest pain of presumed coronary origin (ClinicalTrials.gov identifier: NCT05374694). Patients were referred for invasive physiological evaluation. For this substudy, only those who underwent a coronary vasospasm test were included (n=70). Circulating miRNA profiling was performed using RT-qPCR. RESULTS:The mean age of participants was 66.5 years and 40.0% were women. The prevalence of hypertension, dyslipidemia, and diabetes mellitus was 72.9%, 61.4% and 20.0%, respectively. Patients with CAV showed a higher use of oral nitrates. Notably, most individuals with undetectable plasma levels of miR-502-5p exhibited CAV (60%). Accordingly, detectability was used as the primary representation of miR-502-5p in further analyses. Adding miR-502-5p to a clinical model (age, sex, smoking status, nitrate use and transferrin concentration) was associated with a numerically higher AUC (0.74-0.81) and improved reclassification metrics (NRI=0.533; IDI=0.079). CONCLUSIONS:In this cohort, plasma miR-502-5p was associated with CAV and showed exploratory incremental value when added to a clinical model. These findings should be considered hypothesis-generating and require further validation in larger and independent cohorts.

BACKGROUND:Some evidence suggests that OSA may attenuate myocardial injury and reduce infarct severity during acute coronary syndromes (ACSs), potentially through stimulation of coronary collateral circulation (CCC). However, the relationship between OSA and collateral development, and their combined impact on ACS event severity, remains unclear. RESEARCH QUESTION:What is the relationship between OSA and coronary collateral development and what is their combined impact on ACS severity? STUDY DESIGN AND METHODS:Post hoc analysis of the Impact of Sleep Apnea in the Evolution of Acute Coronary Syndrome: Effect on Intervention With CPAP (ISAACC) trial, including patients with first-time ACS with CCC assessment using the Cohen-Rentrop scale (CRS), where a score of ≥ 2 (CRS grade 2 or 3) indicated well-developed collaterals. OSA was diagnosed via respiratory polygraphy performed within 24 to 72 hours of hospitalization. Associations between OSA and CRS grade 2 or 3 were evaluated using adjusted logistic regression. Peak creatine kinase (CK), peak cardiac troponin I (cTnI), and left ventricular ejection fraction (LVEF) were analyzed as ACS severity markers. RESULTS:Of 185 participants included, 79.5% had OSA. Participants were mainly middle-aged male individuals and demonstrated a high comorbidity burden. OSA was associated with greater odds of well-developed collaterals with an adjusted OR of 2.84 (95% CI, 1.24-7.19; P = .019), with a dose-response increase across OSA severity categories. Among patients with OSA, the presence of robust collaterals was associated with significantly lower peak CK and cTnI levels during the ACS episode, but not with improved LVEF. INTERPRETATION:Our research shows that in patients with first-time ACS, OSA was associated with a higher prevalence of well-developed coronary collaterals. Among patients with OSA, robust collateralization was associated with less myocardial injury during ACS, supporting the hypothesis that OSA may promote adaptive vascular remodeling, which warrants further mechanistic investigation. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT01335087; URL: www. CLINICALTRIALS:gov.

BACKGROUND AND OBJECTIVES:Sleep-wake dysregulation and elevated CSF orexin have been implicated in Alzheimer disease (AD). Sleep spindles (SPs) and slow oscillations (SOs) are linked to cognition and neurodegeneration; however, their relationship with CSF orexin concentrations in symptomatic AD has not been characterized. We investigated whether nonrapid eye movement (NREM) SP-SO activity is associated with CSF orexin and whether these oscillatory features moderate associations between orexin, cognition, neuropsychiatric symptom severity, and AD biomarkers. METHODS:This prospective observational cohort study was conducted at a tertiary memory clinic in Lleida, Spain. Individuals aged ≥60 years with biomarker-confirmed mild-to-moderate AD (National Institute on Aging-Alzheimer's Association criteria) underwent overnight polysomnography and morning CSF sampling. SP and SO were detected using validated automated algorithms with independent verification and visual quality control. CSF was assayed for orexin-A, amyloid-β42 (Aβ42), phosphorylated tau181 (pTau181), total tau, and YKL-40. Cognitive performance Alzheimer's Disease Assessment Scale-Cognitive Subscale ([ADAS-Cog], Mini-Mental State Examination (MMSE), California verbal learning test, ROCF) and neuropsychiatric symptoms (NPI) were assessed longitudinally over 36 months. Associations were examined using generalized linear models with robust estimators adjusted for age, sex, Aβ42, and apnea-hypopnea index. Multiple comparisons were controlled using false discovery rate correction. Interaction terms assessed moderation effects. RESULTS:Sixty participants (30 women; mean age 74.7 years) were included. Longer SO duration and higher SP density and power were associated with lower CSF orexin concentrations (SP density: β = -187.37 pg/mL, 95% CI -344.93 to -29.80). Orexin was not associated with global sleep continuity metrics. Higher CSF orexin concentrations were associated with worse global cognition (ADAS-Cog: β = 0.014, 95% CI 0.003-0.024; MMSE: β = -0.01, 95% CI -0.011 to -0.004) and greater neuropsychiatric symptom severity (NPI at: β = 0.03, 95% CI 0.011-0.041). Higher orexin was also associated with higher pTau181 (β = 0.11, 95% CI 0.04-0.19), total tau, and YKL-40 (β = 0.37, 95% CI 0.17-0.57). Significant orexin × SP-SO interactions were observed, such that greater oscillatory activity attenuated the adverse associations between orexin and cognitive outcomes, independent of Aβ42 and tau. DISCUSSION:In biomarker-confirmed AD, NREM SP and SO activity are associated with CSF orexin concentrations and moderate associations between orexin and longitudinal cognitive and neuropsychiatric outcomes. Limitations include the observational design and absence of a comparator group, precluding causal inference and limiting contextualization relative to normal aging. NREM oscillatory metrics and orexin concentrations may represent complementary physiologic markers for disease monitoring and therapeutic targeting. TRIAL REGISTRATION INFORMATION:Role of Hypoxia and Sleep Fragmentation in AD; ClinicalTrials.gov Identifier: NCT02814045.

Elderly patients with coronavirus disease 2019 (COVID-19) exhibit high mortality rates. We assessed whether microRNA (miRNA) profiling provides prognostic information in this population. This multicenter study included hospitalized COVID-19 patients aged ≥65 years (n = 763). Clinical subphenotypes were identified using clinical data through k-prototypes algorithm. Plasma miRNome was profiled using qPCR. Clinical and miRNA-based models predicting 90-day mortality were developed using Variable Selection Using Random Forests (VSURF). Median age was 79 years, 44.0% were female, and 90-day mortality was 26.7%. Although 13 candidate miRNAs were identified during screening (n = 39), none were associated with mortality in the full derivation cohort (n = 340), leading to a subphenotype-stratified analysis. Three subphenotypes (elderly COVID-1 [eCOVID-1], -2, and -3) with distinct clinical features and mortality risks were identified. In eCOVID-2, miR-106b-3p was the strongest predictor of 90-day mortality and improved model discrimination beyond clinical variables alone area under the curve (AUC: 0.75 vs. 0.66). Plasma miRNAs provide complementary prognostic information when integrated with clinical variables in elderly COVID-19 subphenotypes.