Association between obesity and statin use on mortality and hospital encounters in atrial fibrillation.

Background: Obesity increases risk of atrial fibrillation (AF) at least in part due to pro-inflammatory effects, but has been paradoxically associated with improved mortality. Although statins have pleiotropic anti-inflammatory properties, their interaction with obesity and clinical outcomes in AF is unknown. We explored the relationship between BMI, statin use, and all-cause mortality and AF/congestive heart failure (CHF)-related encounters, hypothesizing that statin exposure may be differentially associated with improved outcomes in overweight/obesity. Methods: This was a single center retrospective cohort study of adults with AF diagnosed between 2011-2018. Patients were grouped by body mass index (BMI) and statin use at time of AF diagnosis. Outcomes included all-cause mortality and ED or inpatient encounters for AF or CHF. Results and Conclusions: A total of 2503 subjects were included (median age 66 years, 43.4 % female, median BMI 29.8 kg/m2, 54.6 % on baseline statin therapy). Increasing BMI was associated with decreased mortality hazard but not associated with AF/CHF encounter risk. Adjusting for statin-BMI interaction, demographics, and cardiovascular comorbidities, overweight non-statin users experienced improved mortality (adjusted hazard ratio [aHR] 0.55, 95 % CI 0.35-0.84) compared to statin users (aHR 0.98, 95 % CI 0.69-1.40; interaction P-value = 0.013). Mortality hazard was consistently lower in obese non-statin users than in statin users, however interaction was insignificant. No significant BMI-statin interactions were observed in AF/CHF encounter risk. In summary, statin use was not differentially associated with improved mortality or hospitalization risk in overweight/obese groups. These findings do not support statins for secondary prevention of adverse outcomes based on overweight/obesity status alone.

Chemical Diversity of Aspergillus alliaceus Phenotypes: Discovery of brominated bianthrones with activity against triple-negative breast cancer cell lines.

Marine-derived fungi have emerged as a source for novel metabolites with a broad range of bioactivities. However, accessing the full potential of fungi under standard laboratory conditions remains challenging. LC-MS-based metabolomics in combination with varied culture conditions is a fast and powerful tool to detect new metabolites. Here, three developmental forms of the marine-derived fungus Aspergillus alliaceus were analyzed and 14 fungal metabolites, including new brominated polyketides (11-14) were isolated. Structure elucidation relied mainly on 1D and 2D NMR techniques and was supported by low- and high-resolution mass spectrometry and DFT-based computations. We sequenced the A. alliaceus genome, identified the bianthrone-producing biosynthetic gene cluster, and conducted expression analysis on genes involved in sexual development and biosynthesis. The NCI-60 cell line panel revealed selective in vitro activity against triple-negative breast cancer (TNBC) for the halogenated allianthrones and their full anti-proliferative and cytotoxic effects were evaluated in five TNBC cell lines.

Targeting the Substrate for Atrial Fibrillation: JACC Review Topic of the Week.

The identification of the pulmonary veins as a trigger source for atrial fibrillation (AF) has established pulmonary vein isolation (PVI) as a key target for AF ablation. However, PVI alone does not prevent recurrent AF in many patients, and numerous additional ablation strategies have failed to improve on PVI outcomes. This therapeutic limitation may be due, in part, to a failure to identify and intervene specifically on the pro-fibrillatory substrate within the atria and pulmonary veins. In this review paper, we highlight several emerging approaches with clinical potential that target atrial cardiomyopathy-the underlying anatomic, electrical, and/or autonomic disease affecting the atrium-in various stages of practice and investigation. In particular, we consider the evolving roles of risk factor modification, targeting of epicardial adipose tissue, tissue fibrosis, oxidative stress, and the inflammasome, along with aggressive early anti-AF therapy in AF management. Attention to combatting substrate development promises to improve outcomes in AF.

Biomathematical modeling of fatigue due to sleep inertia.

Biomathematical models of fatigue capture the physiology of sleep/wake regulation and circadian rhythmicity to predict changes in neurobehavioral functioning over time. We used a biomathematical model of fatigue linked to the adenosinergic neuromodulator/receptor system in the brain as a framework to predict sleep inertia, that is, the transient neurobehavioral impairment experienced immediately after awakening. Based on evidence of an adenosinergic basis for sleep inertia, we expanded the biomathematical model with novel differential equations to predict the propensity for sleep inertia during sleep and its manifestation after awakening. Using datasets from large laboratory studies of sleep loss and circadian misalignment, we calibrated the model by fitting just two new parameters and then validated the model's predictions against independent data. The expanded model was found to predict the magnitude and time course of sleep inertia with generally high accuracy. Analysis of the model's dynamics revealed a bifurcation in the predicted manifestation of sleep inertia in sustained sleep restriction paradigms, which reflects the observed escalation of the magnitude of sleep inertia in scenarios with sleep restriction to less than âˆ¼ 4 h per day. Another emergent property of the model involves a rapid increase in the predicted propensity for sleep inertia in the early part of sleep followed by a gradual decline in the later part of the sleep period, which matches what would be expected based on the adenosinergic regulation of non-rapid eye movement (NREM) sleep and its known influence on sleep inertia. These dynamic behaviors provide confidence in the validity of our approach and underscore the predictive potential of the model. The expanded model provides a useful tool for predicting sleep inertia and managing impairment in 24/7 settings where people may need to perform critical tasks immediately after awakening, such as on-demand operations in safety and security, emergency response, and health care.

Tachycardia and Atrial Fibrillation-Related Cardiomyopathies: Potential Mechanisms and Current Therapies.

Atrial fibrillation (AF) is associated with an increased risk of new-onset ventricular contractile dysfunction, termed arrhythmia-induced cardiomyopathy (AIC). Although cardioembolic stroke remains the most feared and widely studied complication of AF, AIC is also a clinically important consequence of AF that portends significant morbidity and mortality to patients with AF. Current treatments are aimed at restoring sinus rhythm through catheter ablation and rate and rhythm control, but these treatments do not target the underlying molecular mechanisms driving the progression from AF to AIC. Here, we describe the clinical features of the various AIC subtypes, discuss the pathophysiologic mechanisms driving the progression from AF to AIC, and review the evidence surrounding current treatment options. In this review, we aim to identify key knowledge gaps that will enable the development of more effective AIC therapies that target cellular and molecular mechanisms.

Myofilament dysfunction in diastolic heart failure.

Diastolic heart failure (DHF), in which impaired ventricular filling leads to typical heart failure symptoms, represents over 50% of all heart failure cases and is linked with risk factors, including metabolic syndrome, hypertension, diabetes, and aging. A substantial proportion of patients with this disorder maintain normal left ventricular systolic function, as assessed by ejection fraction. Despite the high prevalence of DHF, no effective therapeutic agents are available to treat this condition, partially because the molecular mechanisms of diastolic dysfunction remain poorly understood. As such, by focusing on the underlying molecular and cellular processes contributing to DHF can yield new insights that can represent an exciting new avenue and propose a novel therapeutic approach for DHF treatment. This review discusses new developments from basic and clinical/translational research to highlight current knowledge gaps, help define molecular determinants of diastolic dysfunction, and clarify new targets for treatment.

Multicellular species environmental DNA (eDNA) research constrained by overfocus on mitochondrial DNA.

Environmental DNA (eDNA) is becoming an established tool across the biological and medical sciences. Despite the evident successes and wide adoption of eDNA approaches, some fundamental questions remain. For instance, there is almost a dogma in the field around the superiority of mitochondrial DNA for use in eDNA studies, however robust comparison with nuclear eDNA is widely lacking. The dominance of mitochondrial-based eDNA for animal and plant studies appears to be largely settled, despite a widespread lack of rigorous nuclear eDNA testing. Outside of the source organism the protections conferred on eDNA by the cell, mitochondrial and nuclear membranes are poorly understood, including the contribution of each to eDNA persistence and degradation. Utilizing shotgun sequencing to unbiasedly assess the level of nuclear and mitochondrial eDNA across samples, we reveal stark differences in nuclear versus mitochondrial eDNA persistence and abundance. By focusing too heavily on mitochondrial DNA alone the field is underutilizing eDNA's full potential.

Long-term influence of sleep/wake history on the dynamic neurobehavioural response to sustained sleep restriction.

Chronic sleep restriction, common in today's 24/7 society, causes cumulative neurobehavioural impairment, but the dynamics of the build-up and dissipation of this impairment have not been fully elucidated. We addressed this knowledge gap in a laboratory study involving two, 5-day periods of sleep restriction to 4 hr per day, separated by a 1-day dose-response intervention sleep opportunity. We measured sleep physiological and waking neurobehavioural responses in 70 healthy adults, each randomized to one of seven dose-response intervention sleep doses ranging from 0 to 12 hr, or a non-sleep-restricted control group. As anticipated, sleep physiological markers showed homeostatic dynamics throughout the study, and waking neurobehavioural impairment accumulated across the two sleep restriction periods. Unexpectedly, there was only a slight and short-lived effect of the 1-day dose-response intervention sleep opportunity. Whether the dose-response intervention sleep opportunity involved extension, further restriction or total deprivation of sleep, neurobehavioural functioning during the subsequent second sleep restriction period was dominated by prior sleep-wake history. Our findings revealed a profound and enduring influence of long-term sleep-wake history as a fundamental aspect of the dynamic regulation of the neurobehavioural response to sleep loss.

PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility. METHODS: Right atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies. RESULTS: In human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (P=2.0×10-2; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (P=1.4×10-6; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10-2 and 6.7×10-3, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (P=5.0×10-6; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (P=1.8×10-2 and 4.1×10-2, respectively; n=6, 6, and 5). CONCLUSIONS: Patients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

Metabolomics-Guided Discovery, Isolation, Structure Elucidation, and Bioactivity of Myropeptins C-E from Myrothecium inundatum.

The saprotrophic filamentous fungus Myrothecium inundatum represents a chemically underexplored ascomycete with a high number of putative biosynthetic gene clusters in its genome. Here, we present new linear lipopeptides from nongenetic gene activation experiments using nutrient and salt variations. Metabolomics studies revealed four myropeptins, and structural analyses by NMR, HRMS, Marfey's analysis, and ECD assessment for their helical properties established their absolute configuration. A myropeptin biosynthetic gene cluster in the genome was identified. The myropeptins exhibit general nonspecific toxicity against all cancer cell lines in the NCI-60 panel, larval zebrafish with EC50 concentrations of 5-30 µM, and pathogenic bacteria and fungi (MICs of 4-32 µg/mL against multidrug-resistant S. aureus and C. auris). In vitro hemolysis, cell viability, and ionophore assays indicate that the myropeptins target mitochondrial and cellular membranes, inducing cell depolarization and cell death. The toxic activity is modulated by the length of the lipid side chain, which provides valuable insight into their structure-activity relationships.

Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.

Background: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility. Methods: Right atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation. In vitro studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies. Results: In human patients with AF, PPP1R12C expression was increased two-fold versus SR controls ( P =2.0×10 -2 , n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation ( P =1.4×10 -6 , n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF ( P =2.9×10 -2 and 6.7×10 -3 respectively, n=8,8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls ( P =5.0×10 -6 , n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls ( P =1.8×10 -2 and 4.1×10 -2 respectively, n= 6,6,5). Conclusions: AF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

Inadvertent human genomic bycatch and intentional capture raise beneficial applications and ethical concerns with environmental DNA.

The field of environmental DNA (eDNA) is advancing rapidly, yet human eDNA applications remain underutilized and underconsidered. Broader adoption of eDNA analysis will produce many well-recognized benefits for pathogen surveillance, biodiversity monitoring, endangered and invasive species detection, and population genetics. Here we show that deep-sequencing-based eDNA approaches capture genomic information from humans (Homo sapiens) just as readily as that from the intended target species. We term this phenomenon human genetic bycatch (HGB). Additionally, high-quality human eDNA could be intentionally recovered from environmental substrates (water, sand and air), holding promise for beneficial medical, forensic and environmental applications. However, this also raises ethical dilemmas, from consent, privacy and surveillance to data ownership, requiring further consideration and potentially novel regulation. We present evidence that human eDNA is readily detectable from 'wildlife' environmental samples as human genetic bycatch, demonstrate that identifiable human DNA can be intentionally recovered from human-focused environmental sampling and discuss the translational and ethical implications of such findings.

Left atrial echocardiographic parameters predict the onset of atrial fibrillation: the SMASH2 scoring system.

BACKGROUND: As AF-associated morbidity and mortality are increasing, there is an acute need for improved surveillance and prevention strategies to reduce the impact of AF and related strokes. Specific echocardiographic parameters that can best predict future onset of AF within 3 months are lacking. METHODS: Twenty patients with AF, as identified by presence of ICD-9 diagnosis code, were compared with a control group of twenty age- and sex-matched patients selected from the same clinic population but without a diagnosis of AF. Transthoracic echocardiograms (TTE) obtained within 90 days prior to first documented AF episode (study group) or obtained closest to first clinic visit (control) were selected for review. RESULTS: Baseline characteristics, including age, BMI, presence of hypertension, hyperlipidemia, diabetes, and heart failure were comparable. Increased left atrial (LA) size (end systolic major axis in 2-chamber view: AF 4.62±0.03 vs control 3.79±0.21, P =0.03), increased mitral inflow (E/A ratio: AF 1.35±0.15 vs control 1.06±0.07, P =0.04), and reduced LA global longitudinal strain (AF -2.69±0.26 vs control - 3.59±0.31, P =0.04) were most closely associated with AF compared with the control group. Multivariate logistic regression was used to develop predictive models for AF onset. A combination of imaging and traditional clinical risk factors was the best AF prediction model with AUC of 0.94, which greatly exceeds the current best predictors published. From these parameters, we developed the SMASH2 scoring system for 90- day AF risk estimation. CONCLUSIONS: Risk factors for AF and early features of atrial cardiomyopathy including male sex, hypertension, LA enlargement, reduced mitral inflow, and reduced LA strain are powerful predictors of AF onset within 90 days, and may be used to prognosticate future AF risk.

Heat Stress of Algal Partner Hinders Colonization Success and Alters the Algal Cell Surface Glycome in a Cnidarian-Algal Symbiosis.

Corals owe their ecological success to their symbiotic relationship with dinoflagellate algae (family Symbiodiniaceae). While the negative effects of heat stress on this symbiosis are well studied, how heat stress affects the onset of symbiosis and symbiont specificity is less explored. In this work, we used the model sea anemone, Exaiptasia diaphana (commonly referred to as Aiptasia), and its native symbiont, Breviolum minutum, to study the effects of heat stress on the colonization of Aiptasia by algae and the algal cell-surface glycome. Heat stress caused a decrease in the colonization of Aiptasia by algae that were not due to confounding variables such as algal motility or oxidative stress. With mass spectrometric analysis and lectin staining, a thermally induced enrichment of glycans previously found to be associated with free-living strains of algae (high-mannoside glycans) and a concomitant reduction in glycans putatively associated with symbiotic strains of algae (galactosylated glycans) were identified. Differential enrichment of specific sialic acid glycans was also identified, although their role in this symbiosis remains unclear. We also discuss the methods used to analyze the cell-surface glycome of algae, evaluate current limitations, and provide suggestions for future work in algal-coral glycobiology. Overall, this study provided insight into how stress may affect the symbiosis between cnidarians and their algal symbionts by altering the glycome of the symbiodinian partner. IMPORTANCE Coral reefs are under threat from global climate change. Their decline is mainly caused by the fragility of their symbiotic relationship with dinoflagellate algae which they rely upon for their ecological success. To better understand coral biology, researchers used the sea anemone, Aiptasia, a model system for the study of coral-algal symbiosis, and characterized how heat stress can alter the algae's ability to communicate to the coral host. This study found that heat stress caused a decline in algal colonization success and impacted the cell surface molecules of the algae such that it became more like that of nonsymbiotic species of algae. This work adds to our understanding of the molecular signals involved in coral-algal symbiosis and how it breaks down during heat stress.

Environment and Co-occurring Native Mussel Species, but Not Host Genetics, Impact the Microbiome of a Freshwater Invasive Species (Corbicula fluminea).

The Asian clam Corbicula fluminea (Family: Cyneridae) has aggressively invaded freshwater habitats worldwide, resulting in dramatic ecological changes and declines of native bivalves such as freshwater mussels (Family: Unionidae), one of the most imperiled faunal groups. Despite increases in our knowledge of invasive C. fluminea biology, little is known of how intrinsic and extrinsic factors, including co-occurring native species, influence its microbiome. We investigated the gut bacterial microbiome across genetically differentiated populations of C. fluminea in the Tennessee and Mobile River Basins in the Southeastern United States and compared them to those of six co-occurring species of native freshwater mussels. The gut microbiome of C. fluminea was diverse, differed with environmental conditions and varied spatially among rivers, but was unrelated to host genetic variation. Microbial source tracking suggested that the gut microbiome of C. fluminea may be influenced by the presence of co-occurring native mussels. Inferred functions from 16S rRNA gene data using PICRUST2 predicted a high prevalence and diversity of degradation functions in the C. fluminea microbiome, especially the degradation of carbohydrates and aromatic compounds. Such modularity and functional diversity of the microbiome of C. fluminea may be an asset, allowing to acclimate to an extensive range of nutritional sources in invaded habitats, which could play a vital role in its invasive success.

Ranking the biases: The choice of OTUs vs. ASVs in 16S rRNA amplicon data analysis has stronger effects on diversity measures than rarefaction and OTU identity threshold.

Advances in the analysis of amplicon sequence datasets have introduced a methodological shift in how research teams investigate microbial biodiversity, away from sequence identity-based clustering (producing Operational Taxonomic Units, OTUs) to denoising methods (producing amplicon sequence variants, ASVs). While denoising methods have several inherent properties that make them desirable compared to clustering-based methods, questions remain as to the influence that these pipelines have on the ecological patterns being assessed, especially when compared to other methodological choices made when processing data (e.g. rarefaction) and computing diversity indices. We compared the respective influences of two widely used methods, namely DADA2 (a denoising method) vs. Mothur (a clustering method) on 16S rRNA gene amplicon datasets (hypervariable region v4), and compared such effects to the rarefaction of the community table and OTU identity threshold (97% vs. 99%) on the ecological signals detected. We used a dataset comprising freshwater invertebrate (three Unionidae species) gut and environmental (sediment, seston) communities sampled in six rivers in the southeastern USA. We ranked the respective effects of each methodological choice on alpha and beta diversity, and taxonomic composition. The choice of the pipeline significantly influenced alpha and beta diversities and changed the ecological signal detected, especially on presence/absence indices such as the richness index and unweighted Unifrac. Interestingly, the discrepancy between OTU and ASV-based diversity metrics could be attenuated by the use of rarefaction. The identification of major classes and genera also revealed significant discrepancies across pipelines. Compared to the pipeline's effect, OTU threshold and rarefaction had a minimal impact on all measurements.

Virchow's Triad and the Role of Thrombosis in COVID-Related Stroke.

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as a virally transmitted disease. Three months later, SARS-CoV-2 became one of the largest pandemics in recent times, causing more than 235 million cases globally, and accounting for at least 4.8 million deaths to date. SARS-COV-2 infection was initially classified as a respiratory tract infection, but later was recognized as a multisystemic disease compromising gastrointestinal, hematological, cardiac, and neurological systems. With this Review, we aim to describe the epidemiology, risk factors, mechanisms, and management of cerebrovascular events in patients infected with COVID-19. Neurological manifestations related to thromboembolic cerebrovascular events in patients infected with COVID-19 have been frequent and associated with poor prognosis in the majority of cases. A better understanding of the mechanisms of thrombosis and etiologies of this new disease process are necessary to determine how to prevent and treat patients to reduce their length of stay, morbidity, and mortality.

Fatigue risk management based on self-reported fatigue: Expanding a biomathematical model of fatigue-related performance deficits to also predict subjective sleepiness.

Biomathematical models of fatigue can be used to predict neurobehavioral deficits during sleep/wake or work/rest schedules. Current models make predictions for objective performance deficits and/or subjective sleepiness, but known differences in the temporal dynamics of objective versus subjective outcomes have not been addressed. We expanded a biomathematical model of fatigue previously developed to predict objective performance deficits as measured on the Psychomotor Vigilance Test (PVT) to also predict subjective sleepiness as self-reported on the Karolinska Sleepiness Scale (KSS). Four model parameters were re-estimated to capture the distinct dynamics of the KSS and account for the scale difference between KSS and PVT. Two separate ensembles of datasets - drawn from laboratory studies of sleep deprivation, sleep restriction, simulated night work, napping, and recovery sleep - were used for calibration and subsequent validation of the model for subjective sleepiness. The expanded model was found to exhibit high prediction accuracy for subjective sleepiness, while retaining high prediction accuracy for objective performance deficits. Application of the validated model to an example scenario based on cargo aviation operations revealed divergence between predictions for objective and subjective outcomes, with subjective sleepiness substantially underestimating accumulating objective impairment, which has important real-world implications. In safety-sensitive operations such as commercial aviation, where self-ratings of sleepiness are used as part of fatigue risk management, the systematic differences in the temporal dynamics of objective versus subjective measures of functional impairment point to a potentially significant risk evaluation sensitivity gap. The expanded biomathematical model of fatigue presented here provides a useful quantitative tool to bridge this previously unrecognized gap.

Atrial Fibrillation and Longitudinal Change in Cognitive Function in CKD.

BACKGROUND: Studies in the general population suggest that atrial fibrillation (AF) is an independent risk factor for decline in cognitive function, but this relationship has not been examined in adults with chronic kidney disease (CKD). We investigated the association between incident AF and changes in cognitive function over time in this population. METHODS AND RESULTS: We studied a subgroup of 3254 adults participating in the Chronic Renal Insufficiency Cohort Study. Incident AF was ascertained by 12-lead electrocardiogram (ECG) obtained at a study visit and/or identification of a hospitalization with AF during follow-up. Cognitive function was assessed biennially using the Modified Mini-Mental State Exam. Linear mixed effects regression was used to evaluate the association between incident AF and longitudinal change in cognitive function. Compared with individuals without incident AF (n = 3158), those with incident AF (n = 96) were older, had a higher prevalence of cardiovascular disease and hypertension, and lower estimated glomerular filtration rate. After median follow-up of 6.8 years, we observed no significant multivariable association between incident AF and change in cognitive function test score. CONCLUSION: In this cohort of adults with CKD, incident AF was not associated with a decline in cognitive function.