Sleep Advances

Study Objectives To develop and initially validate the Circadian Disruption Index (CDI), a self-report measure of circadian disruption, and obtain preliminary evidence of its responsiveness to circadian health education. Methods In Study 1, 244 participants completed a 22-item CDI version and external measures. The sample was randomly divided for exploratory and confirmatory factor analyses. Internal consistency, external associations, and discrimination of poor sleep quality were examined. In Study 2, 72 postgraduate students completed the CDI before and 1 week after a 16-hour circadian health education program in an uncontrolled pre-post design. Results Analyses yielded a 15-item, three-factor structure comprising rhythm stability and light exposure, behavioral habits and diet, and sleep quality and subjective complaints. Total-score internal consistency was acceptable (Cronbach's = 0.871). Confirmatory factor analysis showed a comparative fit index of 0.902 and a root mean square error of approximation of 0.072, although the Tucker-Lewis index was 0.882. CDI scores correlated with sleep quality, chronotype, corrected midsleep on free days, depression, and anxiety, but not social jetlag. The area under the curve for poor sleep quality was 0.807 (95% confidence interval, 0.753-0.862), with an exploratory cutoff of [≤] 23. In Study 2, CDI scores decreased from 22.26 to 19.88 (p = 0.002; Cohen's dz = 0.36). Conclusions The CDI demonstrated satisfactory internal consistency, a meaningful multidimensional structure, and responsiveness to short-term changes following circadian health education, supporting its potential utility for assessing circadian disruption and monitoring circadian-related behavioral changes.

Background: Automatic sleep staging algorithms are increasingly applied in clinical and home-based recordings. However, their performance may degrade when transferred to new montages and clinical populations. This is particularly relevant in reduced-channel portable PSG and in disorders such as REM sleep behaviour disorder (RBD), where altered sleep architecture may challenge pretrained models. Objective: To evaluate and compare multiple open-source sleep staging algorithms on a minimal portable PSG setup in controls and patients with and without RBD, and to assess the impact of fine-tuning on clinic-ascertained data. Methods: Six open-source models were applied to 76 subjects recruited from three clinical sleep medicine sites. Performance was assessed using accuracy, F1 scores, and Cohen's kappa, both overall and per sleep stage. Each model was evaluated out-of-the-box and after fine-tuning on clinical data. Results: Out-of-the-box performance varied substantially across models (Cohen's kappa 0.21-0.54). Fine-tuning consistently improved agreement, with the best-performing model (GSSC) reaching Cohen's kappa = 0.58 indicating moderate to good agreement. Performance was highest in controls and lower in patient groups. N3 was the most reliably classified stage across models, whereas N1 remained consistently challenging. REM classification improved after fine-tuning in several architectures but remained model, and subgroup-dependent, particularly in RBD subjects. Conclusion: Fine-tuning substantially mitigates domain shift, updating model parameters to align with new data distributions, when applying automatic sleep staging algorithms to portable clinical recordings. Model architecture influences robustness, with feature-learning approaches demonstrating greater adaptability than fixed-feature models. Despite moderate agreement after adaptation, performance, especially for REM and N1 remains insufficient for fully automated diagnostic use in clinical populations.

The slow oscillation (SO) of non-rapid eye movement (NREM) sleep has been implicated in the restorative properties of sleep. Slow oscillatory transcranial direct current stimulation (SO-tDCS), involving a positive oscillatory current applied to the scalp at a peak frequency of 0.75 Hz, has been used to enhance SO power during NREM sleep. We examined whether enhancing SO power with SO-tDCS during a restricted nighttime sleep opportunity would accelerate the restorative properties of sleep during an otherwise insufficient sleep period and help sustain performance during subsequent extended wakefulness. A total of twenty-six healthy young adults (ages 18-39, n=16 females) completed a 15-day study. After 7 baseline nights at home and 3 baseline nights in the laboratory, participants entered the laboratory for 5 consecutive days including a baseline day, a 2-hour nighttime sleep period with participants randomized to the SO-tDCS (n=11) or SHAM (n=15) condition, 46 hours of sleep deprivation, and two recovery nights. In the SO-tDCS condition, stimulation was administered for one hour starting exactly 60 minutes after sleep onset, with intervals of five minutes of continuous stimulation followed by one minute of no stimulation. Polysomnographic recordings were conducted during each sleep period. Performance was assessed using the Psychomotor Vigilance Test (PVT) approximately every 75 minutes across baseline, sleep deprivation, and recovery. Prior to the two-hour sleep opportunity, a Paired Words Associate Task was administered. Participants listened to 54-word pairs and were asked to recall 46 of the word pairs, with up to three attempts to successfully recall at least 60% of word pairs (T0). Recall was also assessed 20- (T20) and 120-minutes (T120) after awakening from the two-hour sleep period. Data were analyzed using mixed-effects ANOVA. PVT performance (defined as mean response time and number of response times greater than 1,000 ms) significantly declined across sleep deprivation with performance degradations peaking in the early morning hours. Participants in the STIM condition demonstrated significantly better performance during sleep deprivation relative to the SHAM condition. On the PWAT, participants in the SHAM condition recalled fewer word-pairs upon awakening relative to T0. In sharp contrast, performance of participants in the SO-tDCS condition did not deteriorate at T20 and was actually improved at T120 relative to T0. We conclude that SO-tDCS can robustly accelerate the restorative properties of sleep and can additionally enhance sleep related memory consolidation when sleep opportunity is restricted.

This study aimed to explore night-to-night variability of multiscale sleep patterns by analyzing subcutaneous electroencephalography (sqEEG) from 20 healthy participants over one year (205-388 nights per participant, 6,429 nights in total). We utilized the time series of aperiodic slopes, sigma and slow-wave power as a new whole-night unit of sleep macrostructure. Using dynamic time warping, we calculated the distances (differences) between those time series to assess night-to-night sleep macrostructure dissimilarity. We found that the overall sleep macrostructural patterns were relatively similar across nights (20% dissimilarity), while their temporal alignment was quite variable (time series warped by ~60% for the best alignment). Lower variation in macrostructure dissimilarity was associated with better subjective sleep quality (r=-0.25). Then, we qualitatively compared yearlong variation in macroscale, microscale (sleep stage proportions, mean spectral power) and mesoscale (sleep cycle duration) metrics. We found that intra-individual night-to-night variation was '"low (coefficients of variation < 20%) for spectral power, sleep duration, N2 and REM sleep; ''medium'' (20-40%) - for N3 and macrostructure dissimilarity; and "high" (>40%) - for sleep cycle duration, wake and N1. In summary, different sleep metrics showed differential night-to-night variability, which was more metric-specific than scale-dependent. This might reflect a distinction between more trait-like versus more dynamically varying features of sleep, although this assumption needs further clarification.

Study Objectives: To evaluate a framework using wearable data to personalize the definition of short sleep, comparing its temporal and functional characteristics against a fixed threshold. Methods: 462 healthy adults wore sleep trackers and provided daily ecological momentary assessments for a year. Short sleep was defined using either a fixed threshold of <6 h/night (fSS) or personalized thresholds anchored to individual sleep-duration distributions (pSS). Temporal patterns of consecutive short-sleep nights were characterized. Linear mixed-effects models examined associations between accumulating short-sleep nights and short- and long-term markers. Sleep patterns across six other countries were also evaluated. Results: pSS and fSS produced similar average thresholds and overall prevalence of short-sleep nights. However, pSS showed larger effect estimates for short-term outcomes, including alertness, sleep satisfaction, stress, sleep heart rate, HRV, and sedentariness. Effects increased with successive short-sleep nights. Proportion of pSS showed stronger association with blood pressure and arterial stiffness. Isolated short nights were common, whereas longer runs were uncommon and typically followed by incomplete recovery sleep. Personalized thresholds distinguished stable short sleepers with few pSS nights from individuals experiencing recurrent sleep shortfall and highlighted vulnerability among those achieving recommended sleep duration but with high variability. Despite marked cross-country differences in sleep habits, the distribution of short-sleep runs, and termination patterns were remarkably similar. Conclusion: Anchoring short sleep to individual habitual sleep distribution captures relative sleep shortfall beyond absolute duration, better characterizing the functional impact of short sleep. Preventive strategies may benefit from limiting pSS accumulation together with addressing sporadic inadequate sleep.

High-dimensional Mendelian randomization (MR) screens can prioritize candidate dietary and immune pathways for insomnia, but their interpretation is constrained by multiple testing, cross-dataset instability, and limited correspondence between genetic constructs and measured population variables. We conducted an exploratory cross-design analysis that combined MR screening of 231 dietary traits and 731 immune phenotypes, targeted cross-release genetic follow-up in FinnGen R12 and R13, and population-based analyses in NHANES and CHARLS. The targeted R13 follow-up prioritised an omelette-related dietary signal (OR 0.773, 95% CI 0.651-0.917; within-layer FDR q=0.00783), a mixed-fruit signal (OR 1.285, 95% CI 1.102-1.498; within-layer FDR q=0.00683), and CD33- and HLA-DR-related immune-cell traits. In NHANES, mapped omelet/scrambled-egg intake was associated with lower odds of sleep problems in 2017-March 2020 (OR 0.746, 95% CI 0.600-0.927; FDR=0.033) and doctor-reported sleep disorder in 2005-2006 (any intake: OR 0.313, 95% CI 0.157-0.624; FDR=0.008; per 50 g: OR 0.721, 95% CI 0.569-0.914; FDR=0.019). Mixed-fruit proxies were not directionally concordant. Higher C-reactive protein (CRP) was associated with sleep problems in NHANES (OR 1.192, 95% CI 1.085-1.309; FDR=0.001) and frequent restless sleep in CHARLS (OR 1.097, 95% CI 1.049-1.147; FDR<0.001). These findings provide exploratory genetic prioritization and population-based association evidence for selected dietary constructs and systemic inflammatory proxies. They do not establish a causal diet-immune-insomnia mechanism, confirm flow-cytometry immune-cell phenotypes, or support dietary intervention recommendations.

Study Objectives. To determine whether sleep-related respiratory disruption is associated with regionally specific alterations in sleep spindle topography and whether hypopnea-sensitive spindle features are associated with attentional performance in children. Methods. We recorded overnight high-density EEG in children across a wide range of respiratory disruption severity. Slow and fast spindle metrics were extracted per channel, and channel-wise regression models characterized topographic associations with hypopnea index (HI). Cluster-based permutation testing controlled for multiple comparisons. Hierarchically defined regions of interest were tested as predictors of attentional performance on the Test of Variables of Attention (TOVA). Results. Canonical slow-anterior and fast-posterior spindle organization was detectable across the cohort. Two HI-related topographic effects survived cluster-based permutation correction: higher HI was associated with shortened anterior fast spindle duration and with slower anterior slow spindle peak frequency. In cognitive models, anterior fast spindle duration was the strongest and most consistent predictor of attentional performance, associated with higher signal detection sensitivity, fewer omission errors, and fewer commission errors. By contrast, slow spindle peak frequency showed no attentional associations. Conclusions. Pediatric respiratory disruption is associated with regionally specific alterations in spindle morphology rather than global spindle reduction. Shortened anterior fast spindle duration showed convergent respiratory and attentional associations, suggesting that localized spindle integrity may provide a neurophysiological marker of cognitive vulnerability in pediatric sleep-disordered breathing beyond conventional clinical respiratory metrics.

Sleep is a ubiquitous, yet highly variable, behavior across species. The duration and timing of sleep are influenced by ecological demands and dietary context. In the mosquito Aedes aegypti, a blood-feeding insect with specialized nutritional requirements, the relationship between feeding and sleep remains poorly understood. Here, we investigated how blood-derived dietary protein influences sleep regulation. Using postural analysis, videography, and arousal-threshold assays, we established that immobility bouts of greater than 10 minutes reliably define sleep in Ae. aegypti. Mosquitoes lacking the circadian clock gene cycle still maintained daily sleep rhythms but exhibited reduced sleep duration and heightened overall activity. Infrared activity monitoring revealed that blood-fed females showed a marked increase in sleep beginning immediately after feeding and persisting for several days, accompanied by reduced locomotor activity. Notably, this sleep elevation lasted well beyond the cessation of previously reported host-seeking phases, raising the possibility of distinct phases of opportunistic versus targeted host pursuit. To determine the dietary basis of this effect, we tested mosquitoes fed a bovine serum albumin (BSA)-based diet. BSA feeding alone was sufficient to mimic the sleep-promoting and activity-reducing effects of blood, suggesting dietary protein is a major nutritional regulator. Moreover, RNAi-mediated knockdown of the leucokinin receptor (Lkr), which has previously been associated with fluid homeostasis and feeding behavior, resulted in enhanced sleep and reduced activity, implicating mosquito LK signaling in the modulation of postprandial sleep. Together, these findings demonstrate that blood-derived proteins drive sustained increases in sleep and reductions in locomotor activity in Ae. aegypti. This work positions Ae. aegypti as a model for dissecting nutrient-specific regulation of sleep and highlights potential adaptive functions of protein-induced quiescence, such as energy conservation and predator avoidance. More broadly, it provides insight into how specialized diets shape the neural and behavioral architecture of sleep.

Depression and dementia frequently co-occur, yet sex-specific population-level associations remain unclear. This ecological study examined cross-national relationships between sex-specific depressive disorder incidence and dementia incidence using Institute for Health Metrics and Evaluation data. Analyses included sex-stratified scatterplots, Pearson and Spearman correlations, principal component analysis, partial correlations adjusting for macro-structural factors, and sex-specific multiple linear regression. Visual analyses suggested positive associations in both sexes, but patterns were stronger and more structured among females. Female depressive disorder incidence correlated with dementia incidence in females and males, clustered with structural-development indicators, and remained associated after adjustment. Male depressive disorder incidence showed no significant associations. Overall, depressive disorder incidence was independently associated with dementia incidence among females but not males, supporting a sex-differentiated population level mental health dementia relationship with implications for global womens health and ageing. These findings inform sex-sensitive surveillance, prevention, and policy frameworks in rapidly ageing societies worldwide, particularly within resource-constrained transitional contexts.

Naturalistic social interaction provides an important context for examining how cognitive engagement is reflected in brain activity, yet electroencephalographic evidence from older adult caregiver interaction remains limited. This study examined alpha band EEG dynamics during museum-based storytelling interaction in older adult caregiver dyads. Thirty two dyads, comprising 32 older adults and 32 caregivers, completed cognitive and psychological screening and underwent EEG recording during eyes-closed resting, eyes open resting, storytelling, and listening conditions. Relative alpha power was analyzed using a predefined 10-electrode sensor-level set covering frontal, frontotemporal, temporal, central, and parietal midline regions. Task-related alpha modulation was examined relative to eyes-open resting. Associations between cognitive performance and Cz alpha power were tested using MoCA scores, and dyad level alpha band inter-brain similarity was examined using spatial alpha-power patterns with within site shuffled dyad surrogate comparisons. Alpha power was higher during eyes closed resting and lower during storytelling and listening relative to eyes-open resting, indicating robust task-related modulation of alpha activity during naturalistic narrative interaction. Associations between MoCA scores and Cz alpha power were weak, condition specific, and did not survive false discovery rate correction. During storytelling, dyad level alpha band inter brain similarity was modestly higher than within site shuffled dyad estimates, but this effect did not remain significant after correction across conditions. These findings suggest that alpha band EEG activity is sensitive to naturalistic storytelling and listening in older adult caregiver dyads. However, cognitive associations and dyad level inter brain similarity were modest and should be interpreted cautiously. The study demonstrates the feasibility of applying EEG to real world social cognitive interaction while highlighting the need for larger samples, behavioral coding, and time resolved dyadic EEG methods to clarify mechanisms of interpersonal neural coordination.

Digital technologies can support meaningful social interaction by providing personally relevant prompts for memory, communication, and shared reflection. In later life, mobile phone photography may offer an accessible medium through which older adults and caregivers construct stories, express meaning, and participate in relational engagement. However, limited psychophysiological evidence is available on how digital photo supported storytelling engages cognitive and social processes in older adult caregiver dyads. This study examined alpha band EEG dynamics during digital photo elicited storytelling in two museum settings. Thirty two older adult caregiver dyads completed cognitive and psychological screening and participated in a museum-based storytelling protocol. During the museum visit, participants used mobile-phone photography to capture personally meaningful objects, scenes, or exhibition spaces. Each participant then selected one photograph as a digital prompt for a structured but naturalistic storytelling interaction. EEG was recorded during eyes closed resting, eyes open resting, storytelling, and listening conditions. Relative alpha power was analyzed using a predefined 10 electrode sensor level set. Task related alpha modulation was examined relative to eyes open resting. Associations between Cz alpha power and MoCA scores were tested, and dyad level alpha band inter brain similarity was explored using spatial alpha power patterns with within site shuffled dyad surrogate comparisons. Alpha power was higher during eyes closed resting and lower during storytelling and listening relative to eyes-open resting, indicating task-related alpha modulation during digital photo supported narrative interaction. Associations between MoCA scores and Cz alpha power were weak, condition-specific, and did not survive false discovery rate correction. During storytelling, dyad level alpha-band inter brain similarity was modestly higher than within site shuffled dyad estimates, but this effect did not remain significant after correction across conditions. These findings suggest that digital photo elicited storytelling can provide a meaningful medium for studying cognitive and social engagement in older adult caregiver dyads. Alpha band EEG activity was sensitive to storytelling and listening, although cognition related and dyadic similarity effects were modest. The study contributes to research on technology supported human behavior by showing how digital image prompts can structure naturalistic social interaction while enabling psychophysiological measurement in real-world contexts.

Introduction: Mild Cognitive Impairment (MCI) is defined as a decline in one or more cognitive domains worse than expected for age and encompasses several subtypes depending on the cognitive(s) function(s) impaired. Older adults presenting amnestic MCI combined with one or several other impaired domains are the highest at risk of dementia. Yet, no consensual screening method for MCI in community-dwelling older adults has been established. The aim of this study was to identify cognitive aging profiles using multivariate analysis based on three neuropsychological assessments and to characterize profiles consistent with different probable MCI subtypes. Methods: A total of 161 community-dwelling older adults from the 13EVAL cluster-randomized controlled trial performed the Montreal Cognitive Assessment including the Memory Index Score, the Trail Making Test and the Victoria Stroop Test. Hierarchical clustering on principal components was conducted based on four cognitive domains (global cognition, memory, inhibition and cognitive flexibility) and age. Inter-groups comparisons were performed using one-way ANOVA. Individual performances were compared to normative standard for each assessment to characterize each group. Results: Three clusters were identified that differed significantly in age (F2,158=78.56, p<.001, 2p=.50), global cognition (F2,158=96.07, p<.001, 2p=.55), memory (F2,158=81.48, p<.001, 2p=.51), cognitive flexibility (F2,158=52.25, p<.001, 2p=.40) and inhibition (F2,158=12.14, p<.001, 2p=.13). Inter-groups comparisons and comparisons to normative values led to the characterization of Cluster 1 as normal cognition, Cluster 2 as probable executive MCI and Cluster 3 as probable amnestic and executive MCI. Conclusions: Individuals with cognitive profiles consistent with probable executive MCI were identified using simple assessments of global cognition, memory and executive functions in a community-dwelling older population. As participants were not clinically diagnosed, further prospective studies are needed to determine the screening performance of this approach.

Geroscience clinical trials need biomarker surrogate endpoints for healthspan. Leading candidates are omics-based composites developed from machine learning analysis of aging phenotypes including calendar age, survival, functional capacity, and Pace of Aging. Existing Pace of Aging biomarkers were developed in the Dunedin Longitudinal Study, limiting inference about strengths/weaknesses of the method as distinct from the Study, a unique single-year birth cohort followed through midlife with near-perfect retention and uniform measurement of multi-organ-system function across two decades of follow-up. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort, FraminghamPACE. Validation analyses across four independent cohorts and one clinical trial establish advantages for the Pace of Aging method in developing biomarkers that are both predictive of healthspan and responsive to geroprotective intervention.

Older adults in residential care are usually described as a group at high risk of undernutrition, yet data on the nutritional and cardiometabolic status of institutionalised older adults in Central Asia are scarce. We aimed to characterise the anthropometric, dietary and biochemical profile of older residents of a state social-care institution in Kazakhstan and to examine whether overnutrition, micronutrient inadequacy and cardiometabolic risk coexist. In this cross-sectional study, 62 adults aged 60 years and over from the "Sharapat" centre in Astana underwent anthropometry, bioelectrical impedance body-composition analysis, blood-pressure measurement, dietary assessment (specialized nutrition questionnaires, a 24-hour dietary recall and food diaries) with calculation of nutrient intakes, and venous blood and urine testing; serum 25-hydroxyvitamin D and trace elements were measured in 29 participants. Laboratory analyses and data processing were performed at the Research Institute of Preventive Medicine named after E.D. Dalenov, Astana Medical University. The sample (61.3% men; mean age 74.0 years) showed a high cardiometabolic burden, with arterial hypertension in 63%, total cholesterol of at least 5.0 mmol/L in 60%, LDL-cholesterol of at least 3.0 mmol/L in 71%, and overweight or obesity in 58%, whereas only 5% were underweight. Habitual diets were high in sodium (71% above 2000 mg/day) and low in potassium (92% below 3500 mg/day), calcium (85% below 1000 mg/day) and fibre (90% below 25 g/day). Among those tested, 79% had vitamin D deficiency, and overweight or obesity coexisted with vitamin D deficiency in 16 of 29 participants. None of 56 exploratory diet-risk correlations survived correction for multiple testing. Rather than the undernutrition typical of residential care, these residents displayed a double burden of malnutrition-excess adiposity and cardiometabolic risk alongside micronutrient-poor diets and widespread vitamin D deficiency-identifying concrete targets for institutional catering, supplementation and cardiometabolic screening.

BACKGROUND: Aging is associated with a progressive decline in cognitive performance and functional autonomy, both closely related to frailty. Understanding the interrelation between these domains is essential to identify modifiable factors influencing cognitive impairment in older adults. OBJECTIVES: To evaluate the relationship between physical frailty, cognitive performance, and functional dependence, and to identify sociodemographic and clinical variables associated with cognitive impairment in community-dwelling older adults. DESIGN: Cross-sectional study. SETTING: FREEDOM-LNA cohort, a population-based study conducted by the University Hospital of Limoges, France. PARTICIPANTS: A total of 753 community-dwelling older adults aged [&ge;]75 years, or [&ge;]65 years with at least two comorbidities, were included. MEASUREMENTS: Cognitive function was assessed using the Mini Mental State Examination (MMSE), 5-word test (5WT), clock drawing test (CDT), and verbal fluency tests. Frailty was defined according to Frieds physical criteria, and functional independence was evaluated using ADL and IADL scales. Sociodemographic, clinical, and lifestyle factors were analyzed using multivariate models to identify predictors of cognitive impairment. RESULTS: Of the participants, 34.4% had a pathologic MMSE, 46.0% failed the CDT, 68.0% the verbal fluency test, and 17.0% the 5WT. Cognitive performance was significantly lower among frail compared to prefrail and robust individuals. Older adults with pathologic cognition were more frequently dependent in activities of daily living. Independent predictors of poor cognitive performance included non-modifiable factors (age, sex, education) and modifiable ones (low BMI, hypertension, alcohol consumption, smoking, and polypharmacy). CONCLUSIONS: Cognitive impairment was highly prevalent among frail older adults and was strongly associated with loss of independence. Interventions targeting modifiable risk factors such as low BMI, hypertension, alcohol consumption, and smoking may help preserve cognitive and functional abilities in aging populations. Interventions to improve BMI and reduce alcohol consumption, smoking, and hypertension may preserve cognition in older adults.

Abstract Background: The influence of taurine on biological ageing remains unclear, particularly whether it acts as a causal driver or a functional biomarker. We aimed to disentangle the distinct roles of plasma taurine relative abundance, dietary taurine supply, and genetic metabolic capacity on all-cause mortality and unhealthy ageing. Methods: This prospective study used data from the Korean Genome and Epidemiology Study (2001~2022). A subcohort of 2,321 participants (mean age 56.5 years; 51.4% female) with complete metabolomic, dietary, and genomic data was analyzed. Three independent pathways were evaluated: (1) plasma taurine/total amino acid (AA) ratio, (2) dietary taurine to protein ratio, and (3) a weighted genetic risk score (GRS) from 21 SNPs in taurine biosynthesis and transport genes. Primary outcomes were all-cause mortality and unhealthy ageing (Physiological Healthy Ageing Index [PHAI] score [&le;] 25th percentile). Results: A higher plasma taurine/total AA ratio was consistently associated with improved ageing outcomes. Participants in the highest quartile showed 29% lower all-cause mortality (Hazard Ratio [HR], 0.71; 95% Confidence Interval [CI], 0.52-0.98; P for trend = .04) and lower risk of PHAI-based unhealthy ageing (HR, 0.77; 95% CI, 0.59-1.00; P for trend = .04) versus the lowest quartile. Dietary taurine-to-protein ratio was not associated with mortality (P for trend = .70), nor was the GRS (P for trend = .74). Conclusions: The protective association of taurine was linked to its relative abundance within the systemic amino acid pool, rather than dietary intake or genetic predisposition, supporting taurine as a functional biomarker of metabolic efficiency rather than a deterministic causal driver of ageing.

Spaceflight imposes unique physiological stresses on mammals, including microgravity and cosmic radiation, which drive complex molecular adaptations. However, the systemic and temporal dynamics of space-induced epigenetic regulation remain poorly understood. We constructed a comprehensive DNA methylome BodyMap across 12 organs or tissues from mice exposed to long-duration spaceflight across three time points using Reduced Representation Bisulfite Sequencing (RRBS). We also performed RNA-seq for five organs and integrated with DNA methylome. We mapped the methylome and transcriptome landscapes and found that spaceflight induces limited but highly tissue-specific differentially methylated CpGs (DMCs). Most spaceflight-induced methylation changes were reverted toward baseline within one to six months of post-flight. Functional enrichment analysis of DMCs highlighted metabolic and mitochondrial dysregulation commonly across organs, while developmental responses in immune, reproductive, and structural tissues were tissue-specific. Transcriptome data revealed that spaceflight suppressed immune and increased inflammatory responses at the multi-organ level, triggering a phenomenon resembling aging. Our study provides a comprehensive DNA methylome BodyMap across 12 organs/tissues in spaceflight mice, elucidating the tissue specificity of epigenetic changes. These insights are essential for developing biomarkers and countermeasures to safeguard astronaut health during extended missions.

Background: Elevated C-Reactive Protein (CRP), interleukin-6 (IL-6) and testosterone deficiency are associated with advanced age and chronic inflammatory diseases; while normal testosterone levels have been shown to decrease inflammation through several mechanisms. Cross-sectional studies have shown an inverse relationship between CRP, IL-6 and total testosterone (TT) levels, yet mixed findings have been reported when individual components of metabolic syndrome are considered. We evaluated the relationship between CRP, IL-6 and TT levels in men from 2004-2018 using the Baltimore Longitudinal Study of Aging to determine if low testosterone status is associated with a high inflammatory profile. Methods: Participants were selected from the Baltimore Longitudinal Study of Aging. Male participants with serum TT level measured during at least three visits were included in our cohort. Common measures of inflammatory disease such as CRP, High-Density Lipoprotein (HDL) and Triglyceride levels were collected via blood specimens. Comorbidity data were documented at each visit. Panel regression was used to analyze the relationship of a series of independent variables collected in pooled cross-sectional observations over time with a dependent variable for modeling. Results: A total of 347 patients were included in this study (median age = 70, IQR = 18, average follow up time = 6.7 +/- 3.2 years). Participants had a median CRP level of 1.0 mg/dL, median IL-6 level of 3.6, a median TT level of 446 ng/dL. On univariable analysis, increasing TT and HDL levels were associated with a decline in CRP, while high Body Mass Index (BMI), congestive heart failure (CHF), Diabetes, and increased serum triglycerides were associated with increased CRP. Age was not associated with CRP. On multivariable analysis, we found that increasing TT level was associated with a decline in CRP levels, independent of comorbidities (p = 0.018; Table 1). As expected, increased BMI was associated with a significant increase in CRP (p = 0.001, Table 1). Age, CHF, Diabetes, HDL, and Triglycerides were not significant predictors of CRP on multivariable analysis. Similarly, on multivariable analysis, increasing TT levels were independently associated with lower IL-6 levels. Higher HDL cholesterol levels were also associated with lower IL-6 levels, whereas increasing age was associated with higher IL-6 levels. BMI, CHF, diabetes, and triglycerides were not significant predictors of IL-6. Conclusions: Lower levels of serum total testosterone are associated with an increase in CRP in older men over time, independent of chronic inflammatory disease. Given the importance of CRP in pathogenesis of chronic disease, we highlight the potential benefits of using total testosterone as a biomarker of chronic inflammatory states.

Background: Clinical outcomes of switching versus continuing direct oral anticoagulant (DOAC) among atrial fibrillation (AF) patients who experienced an ischemic stroke despite receiving DOAC therapy are uncertain. Methods: We included patients with AF who were hospitalized for ischemic stroke (index stroke) between January 1, 2016, and June 30, 2022, while receiving DOAC therapy and who resumed DOAC within 90 days after discharge in the Merative MarketScan Commercial and Medicare databases. Patients were classified as DOAC-switched or DOAC-continued according to whether the DOAC agent changed or remained the same after the index stroke; secondary analyses considered individual DOACs. The primary outcome was recurrent ischemic stroke; secondary outcomes included major bleeding and a composite outcome (bleeding or ischemic stroke). Propensity score-based overlap weighting and weighted Cox models were used to estimate adjusted hazard ratios (aHRs). Results: A total of 1175 patients were eligible for the study, of whom 970 (82.6%) continued and 205 (17.4%) switched DOAC therapy. Comparing DOAC-switched to DOAC-continued was not significantly associated with recurrent ischemic stroke (aHR, 1.20; 95% CI, 0.63-2.30), major bleeding (aHR, 0.60; 95% CI, 0.21-1.72), or the composite outcome (aHR, 0.98; 95% CI, 0.56-1.70). However, among patients who received apixaban before stroke, switching to rivaroxaban was associated with a higher risk of recurrent ischemic stroke (aHR, 2.70; 95% CI, 1.05-6.95). Conclusions: Overall, switching DOAC therapy after ischemic stroke was not associated with improved clinical outcomes. Switching from apixaban to rivaroxaban, however, could increase risk of recurrent ischemic stroke.

Medical foundation models compress biomedical data into embeddings that support diverse downstream clinical tasks. However, successful model deployment is hampered by performance degradation on external data. It is recognized that embeddings capture acquisition signatures, such as hardware and technical differences, in addition to biology. Effective harmonization must remove the acquisition signature while preserving biological signals, a trade-off that current methods fail to balance adequately. Input-level normalization fails to eliminate acquisition signatures from embeddings, whereas embedding-level methods adjust features in an untargeted manner. We present FEATMAP, a harmonization approach that models acquisition signatures as geometric distortions between manifolds of similarly arranged embeddings. Using paired data that isolate the effect of acquisition signatures, FEATMAP fits a single global affine transformation per foundation model to correct acquisition signatures directly in the embedding space. This targeted, reusable correction aims to preserve biological and demographic variation while harmonizing across acquisition signatures. Across scanner and foundation-model harmonization in digital pathology and field-strength harmonization in brain MRI, FEATMAP improves cross-condition embedding similarity, reduces performance gaps without retraining, and suggests potential for the alignment of disparate embedding spaces.