Intraindividual Variability Research Articles

Personal Hypoxia Symptoms Vary Widely Within Individuals.

INTRODUCTION: Exposure to high ambient altitudes above 10,000 ft (3048 m) over sea level during aviation can present the risk of hypobaric hypoxia. Hypoxia can impair sensory and cognitive functions, degrading performance and leading to mishaps. Military aircrew undergo regular hypoxia familiarization training to recognize their symptoms and understand the consequences of hypoxia. However, over the years, aviators have come to believe that individuals have a "personal hypoxia signature." The idea is that intraindividual variability in symptom experience during repeated exposure is low. In other words, individuals will experience the same symptoms during hypoxia from day to day, year to year.METHODS: We critically reviewed the existing literature on this hypothesis. Most studies that claim to support the notion of a signature only examine group-level data, which do not inform individual-level consistency. Other studies use inappropriate statistical methods, while still others do not control for accuracy of recall over the period of years. To combat these shortcomings, we present a dataset of 91 individuals who completed nearly identical mask-off, normobaric hypoxia exposures days apart.RESULTS: We found that for every symptom on the Hypoxia Symptom Questionnaire, at least half of the subjects reported the symptom inconsistently across repeated exposure. This means that, at best, 50% of subjects did not report the same symptom across exposures.DISCUSSION: These data provide compelling evidence against the existence of hypoxia signatures. We urge that hypoxia familiarization training incorporate these findings and encourage individuals to expect a wide range of hypoxia symptoms upon repeated exposure.Cox BD, McHail DG, Blacker KJ. Personal hypoxia symptoms vary widely within individuals. Aerosp Med Hum Perform. 2024; 95(1):54-58.

Surrogate modelling of heartbeat events for improved J-peak detection in BCG using deep learning.

Sleep, or the lack thereof, has far-reaching consequences on many aspects of human physiology, cognitive performance, and emotional wellbeing. To ensure undisturbed sleep monitoring, unobtrusive measurements such as ballistocardiogram (BCG) are essential for sustained, real-world data acquisition. Current analysis of BCG data during sleep remains challenging, mainly due to low signal-to-noise ratio, physical movements, as well as high inter- and intra-individual variability. To overcome these challenges, this work proposes a novel approach to improve J-peak extraction from BCG measurements using a supervised deep learning setup. The proposed method consists of the modeling of the discrete reference heartbeat events with a symmetric and continuous kernel-function, referred to as surrogate signal. Deep learning models approximate this surrogate signal from which the target heartbeats are detected. The proposed method with various surrogate signals is compared and evaluated with state-of-the-art methods from both signal processing and machine learning approaches. The BCG dataset was collected over 17 nights using inertial measurement units (IMUs) embedded in a mattress, together with an ECG for reference heartbeats, for a total of 134h. Moreover, we apply for the first time an evaluation metric specialized for the comparison of event-based time series to assess the quality of heartbeat detection. The results show that the proposed approach demonstrates superior accuracy in heartbeat estimation compared to existing approaches, with an MAE (mean absolute error) of 1.1s in 64-s windows and 1.38s in 8-s windows. Furthermore, it is shown that our novel approach outperforms current methods in detecting the location of heartbeats across various evaluation metrics. To the best of our knowledge, this is the first approach to encode temporal events using kernels and the first systematic comparison of various event encodings for event detection using a regression-based sequence-to-sequence model.

Le rôle du mycobiome en santé

AbstractThe human mycobiome, which varies according to its location, remains a small entity compared with the other components of the microbiome. It appears to play an important role in health, notably as an activator of inflammation and immunity. The mycobiome is formed at birth and can vary according to delivery mode and the infant's diet. Throughout life, the mycobiome varies depending on a number of factors, including diet, age, sex and treatments. In the lung, as in the digestive tract, the mycobiome shows great intra-individual variability and changes according to the dietary or airborne exposome. The pulmonary or digestive "core mycobiome" is mainly composed of Candida-type yeasts (Saccharomycotina) and Malassezia spp. Fungal dysbiosis has been described in several pathologies, in particular chronic inflammatory diseases, but also cancers and non-fungal infectious diseases. Candida spp., which are involved in mycobiome, appear to play a pro-inflammatory role or even promote tumorigenesis. This review summarizes current knowledge of the mycobiome at different anatomical sites and its role in human health. Knowledge of the mycobiome in healthy subjects will eventually enable us to investigate fungal dysbiosis and its diagnostic or prognostic factors.

Pharmacokinetic Variability of Sulthiame: The Impact of Age, Drug-Drug Interactions, and Biochemical Markers of Toxicity in Patients with Epilepsy.

Sulthiame is an antiseizure medication increasingly used for epilepsy. The aim of this study was to investigate the pharmacokinetic variability of sulthiame in children and adults with epilepsy with respect to age, comedication, dose, serum concentration, and biochemical markers of toxicity in a clinical setting. Retrospective quantitative data from the therapeutic drug monitoring (TDM) database at the Section for Clinical Pharmacology, the National Center for Epilepsy, Norway (2015-2021), were used. TDM data from 326 patients (127 female/199 male) were included [mean age, 11.4 (range 2-44) years; mean weight, 41 (range 14-109) kg]. Interindividual pharmacokinetic variability in the concentration/(dose/body weight) (C/(D/kg)) ratio was 16-fold; intraindividual variability was up to 8-fold (coefficient of variation = 10%-78%). Young children (younger than 6 years) had a significantly lower C/(D/kg) ratio than older age groups ( P < 0.05). Various comedications did not significantly affect the C/(D/kg) ratio, possibly owing to the small sample size. However, CYP2C19-mediated inhibition by sulthiame was indicated because patients using clobazam and sulthiame (n = 28) had a 3.5-fold higher N-desmethylclobazam C/(D/kg) ratio than those using neutral comedication (n = 45; P < 0.001). Patients with pH values below the adjusted normal range (7.32-7.42; n = 15) had a 33% higher sulthiame concentration than those with normal pH values (n = 22; P < 0.05). Blood gas measurements, especially pH, may serve as markers of toxicity and can be used in combination with clinical data when toxicity is suspected. This study revealed the extensive intraindividual and interindividual pharmacokinetic variability of sulthiame, with age as a contributing factor. Sulthiame has clinically relevant interactions with clobazam. The use of TDM and pH as a biochemical marker may contribute to individualized and safe sulthiame treatment.

Model-Informed Precision Dosing to Reduce Vincristine-Induced Peripheral Neuropathy in Pediatric Patients: A Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis.

Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine, a drug often used in pediatric oncology. Previous studies demonstrated large inter- and intrapatient variability in vincristine pharmacokinetics (PK). Model-informed precision dosing (MIPD) can be applied to calculate patient exposure and individualize dosing using therapeutic drug monitoring (TDM) measurements. This study set out to investigate the PK/pharmacodynamic (PKPD) relationship of VIPN and determine the utility of MIPD to support clinical decisions regarding dose selection and individualization. Data from 35 pediatric patients were utilized to quantify the relationship between vincristine dose, exposure and the development of VIPN. Measurements of vincristine exposure and VIPN (Common Terminology Criteria for Adverse Events [CTCAE]) were available at baseline and for each subsequent dosing occasions (1-5). A PK and PKPD analysis was performed to assess the inter- and intraindividual variability in vincristine exposure and VIPN over time. In silico trials were performed to portray the utility of vincristine MIPD in pediatric subpopulations with a certain age, weight and cytochrome P450 (CYP)3A5 genotype distribution. A two-compartmental model with linear PK provided a good description of the vincristine exposure data. Clearance and distribution parameters were related to bodyweight through allometric scaling. A proportional odds model with Markovian elements described the incidence of Grades 0, 1 and ≥2 VIPN overdosing occasions. Vincristine area under the curve (AUC) was the most significant exposure metric related to the development of VIPN, where an AUC of 50 ng⋅h/mL was estimated to be related to an average VIPN probability of 40% over five dosing occasions. The incidence of Grade ≥2 VIPN reduced from 62.1 to 53.9% for MIPD-based dosing compared with body surface area (BSA)-based dosing in patients. Dose decreases occurred in 81.4% of patients with MIPD (vs. 86.4% for standard dosing) and dose increments were performed in 33.4% of patients (no dose increments allowed for standard dosing). The PK and PKPD analysis supports the use of MIPD to guide clinical dose decisions and reduce the incidence of VIPN. The current work can be used to support decisions with respect to dose selection and dose individualization in children receiving vincristine.

Cognitive and perceptual load have opposing effects on brain network efficiency and behavioral variability in ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder associated with suboptimal outcomes throughout the life-span. Extant work suggests that ADHD-related deficits in task performance may be magnified under high cognitive load and minimized under high perceptual load, but these effects have yet to be systematically examined, and the neural mechanisms that undergird these effects are as yet unknown. Herein, we report results from three experiments investigating how performance in ADHD is modulated by cognitive load and perceptual load during a naturalistic task. Results indicate that cognitive load and perceptual load influence task performance, reaction time variability (RTV), and brain network topology in an ADHD-specific fashion. Increasing cognitive load resulted in reduced performance, greater RTV, and reduced brain network efficiency in individuals with ADHD relative to those without. In contrast, increased perceptual load led to relatively greater performance, reduced RTV, and greater brain network efficiency in ADHD. These results provide converging evidence that brain network efficiency and intraindividual variability in ADHD are modulated by both cognitive and perceptual load during naturalistic task performance.

INTRAINDIVIDUAL VARIABILITY IN SLEEP DURATION IS ASSOCIATED WITH HIPPOCAMPAL VOLUME IN MID LIFE

Abstract Sleep is associated with global cognition, consolidation of memories, and structural &amp; functional integrity of areas of the brain that support healthy cognition. While there has been research on sleep in older adults that indicates associations between poor sleep, cognitive decline, memory performance, and changes in the brain, there has been comparatively little work assessing the impact of sleep on the structure of the brain during middle adulthood. Changes in the brain begin much earlier than older adulthood, with midlife seeing cortical thinning and a decrease in brain volume in areas that support healthy cognitive functioning and memory, such as the hippocampus. Understanding how sleep may contribute to hippocampal volume in midlife may help inform how changing poor sleep is important for supporting successful aging. The current study examines the associations between 7 days of actigraphy measured sleep and hippocampal volume (MRI) in 82 midlife adults (Mage = 49.13 years, SD = 11.74; 28-76 years old) who completed the Biomarker and Neuroscience projects in the Midlife in the United States Refresher study. Results indicated that bi-lateral hippocampal volume was negatively associated with high (vs low) intraindividual total sleep time variability (&amp;gt;= 60 min; mean average deviation), with a 280 and 252 mm3 (p’s = .006 &amp; .035) volume reduction for left and right hemispheres respectively. This relationship was not seen for other measures of sleep quality and the analysis additionally controlled for age, sex, BMI, race, depression status, education, and subjective physical &amp; mental/emotional health.

Sleep, Mental Health, and Cognition Across Diverse Adult Populations

Abstract Sleep is often impaired in late life, raising concerns about the effect of poor sleep on mental and cognitive health in aging individuals. This symposium brings together five rigorous studies that show how poor sleep may be an under-recognized risk factor for mental health and cognitive outcomes in the second half of life. Specifically, this symposium showcases data from a variety of study cohorts (including Midlife in the United Study, Einstein Aging Study, and Study of Muscle, Mobility, and Aging), using diverse indicators of subjective and objective sleep. Paper 1 focuses on healthcare workers (HCWs), a group critical for the delivery of quality patient care, and examines both individual and joint associations of poor sleep and pain with mental health in HCWs vs. non-HCWs. Paper 2 investigates the association between EEG-measured sleep and depressive symptoms in older adults. Paper 3 explores the relationship between intra-individual variability of sleep and mild cognitive impairment (MCI) and identifies gender differences in these associations. Paper 4 establishes the associations of actigraphy-measured sleep and circadian rest-activity rhythms with multiple domains of cognition in older adults. Paper 5 examines the effect of latent dose/duration patterns of common sleep medications on development of Alzheimer’s disease and related dementias. The discussant, Dr. Adam Spira, will integrate key findings from these studies, discuss their contributions to the literature, and consider opportunities for future research. This is a Sleep, Circadian Rhythms and Aging Interest Group Sponsored Symposium. This is a collaborative symposium between the Alzheimer’s Disease and Related Dementias, Geroscience, and Health Behavior Change Interest Groups.

GENDER DIFFERENCES IN ASSOCIATIONS OF SLEEP INTRAINDIVIDUAL VARIABILITY AND MILD COGNITIVE IMPAIRMENT

Abstract Previous studies suggest that cognitive function in older adults is related to sleep, with females more vulnerable to poor sleep. Little is known about the relationship between cognition and intraindividual variability of sleep (IIV). We examined the cross-sectional relationship between sleep IIV and mild cognitive impairment (MCI) by gender using data from the Einstein Aging Study. We hypothesize that individuals with MCI have a greater IIV in daily sleep characteristics, and these associations will be stronger for females. Eighty-nine men (age = 76.81±4.73, 61% White, 28% Black, 27% MCI) and 197 women (age = 76.60 ± 4.93, 40% White, 46% Black, 29% MCI) were included in the analysis. Individuals completed 2 weeks of actigraphy (mean ± SD = 15.7 ± 1.1 days), and the Montreal Cognitive Assessment, and MCI was based on the Jack/Bondi criteria. Sleep IIV was estimated as within person standard deviation of nighttime sleep duration, 24-hour sleep duration, wake after sleep onset, and nighttime sleep midpoint. Linear regression models evaluated associations between sleep IIV and MCI status separately by gender, controlling for BMI, age, ethnicity/race, nocturnal hypoxemia, Oxygen Desaturation Index ≥15. Among women, having MCI was associated with greater IIV in nighttime sleep midpoint (b=0.19, p=.002), and in 24-hour total sleep duration (b=13.10, p = .047) with a similar trend in nighttime sleep duration (p = .050). No significant associations were found among men. Findings suggest the importance to keep considering gender in work to understand how sleep variability relates to MCI status in older adults.

Localisation of nitrate-reducing and highly abundant microbial communities in the oral cavity.

The nitrate (NO3-) reducing bacteria resident in the oral cavity have been implicated as key mediators of nitric oxide (NO) homeostasis and human health. NO3--reducing oral bacteria reduce inorganic dietary NO3- to nitrite (NO2-) via the NO3--NO2--NO pathway. Studies of oral NO3--reducing bacteria have typically sampled from either the tongue surface or saliva. The aim of this study was to assess whether other areas in the mouth could contain a physiologically relevant abundance of NO3- reducing bacteria, which may be important for sampling in clinical studies. The bacterial composition of seven oral sample types from 300 individuals were compared using a meta-analysis of the Human Microbiome Project data. This analysis revealed significant differences in the proportions of 20 well-established oral bacteria and highly abundant NO3--reducing bacteria across each oral site. The genera included Actinomyces, Brevibacillus, Campylobacter, Capnocytophaga, Corynebacterium, Eikenella, Fusobacterium, Granulicatella, Haemophilus, Leptotrichia, Microbacterium, Neisseria, Porphyromonas, Prevotella, Propionibacterium, Rothia, Selenomonas, Staphylococcus, Streptococcus and Veillonella. The highest proportion of NO3--reducing bacteria was observed in saliva, where eight of the bacterial genera were found in higher proportion than on the tongue dorsum, whilst the lowest proportions were found in the hard oral surfaces. Saliva also demonstrated higher intra-individual variability and bacterial diversity. This study provides new information on where samples should be taken in the oral cavity to assess the abundance of NO3--reducing bacteria. Taking saliva samples may benefit physiological studies, as saliva contained the highest abundance of NO3- reducing bacteria and is less invasive than other sampling methods. These results inform future studies coupling oral NO3--reducing bacteria research with physiological outcomes affecting human health.

AGE DIFFERENCES IN AFFECT DYNAMICS: APPLYING A FORMALIZED THEORETICAL APPROACH

Abstract Emotional aging research is dominated by the idea of age-related improvements that result from shifts in motivation. Socioemotional selectivity theory (SST) proposes that as individuals age, they increasingly favor emotion-related goals and savor positive but avoid negative emotions. Previous age-comparative studies on everyday emotional experience typically were descriptive or studied the processes underlying emotional experience in isolation. We aimed at a more holistic approach to test hypotheses derived from SST regarding age-related differences in general emotional dispositions (i.e., anchoring), emotional reactivity, and emotion regulation by using a comprehensive computational approach. We applied our Model of Intraindividual Variability in Affect (MIVA) to data on everyday emotional experiences in an age-diverse sample (N = 378, age range 14 – 86 years). Parameter estimations were carried out within a Bayesian framework. Our results provide partial support for predictions derived from SST. Consistent with SST, affect elicited by pleasant events was down-regulated less by older adults and affect elicited by unpleasant events was down-regulated more by older compared to younger adults. Inconsistent with SST, anchoring showed a negative age-related trend, indicating a more positive general affect disposition in younger, not older adults. Reactions to pleasant events showed no age-related differences. Reactivity to unpleasant events was highest in midlife and lower for younger and older adults. We discuss the broader implications of our approach for understanding emotional development across the lifespan.

INTRAINDIVIDUAL VARIABILITY ACROSS ADULTHOOD: DIVERSITY, VARIETY, AND ADHERENCE AS KEY INDICATORS OF DAILY LIFE

Abstract Alongside long-term change, lifespan theories highlight the importance of examining intraindividual variability (the fluctuations that occur in daily and momentary life) as an indicator of dynamic characteristics, like plasticity or rigidity. The present symposium demonstrates five unique characterizations and implications of variability in daily life across the adult lifespan. Paper 1 demonstrates that greater social activity variety is linked to lower mortality risk over 11 years, and this effect is stronger for older adults. Paper 2 finds that consistent adherence to health behaviors in daily life is linked to better cognitive function in midlife adults. Paper 3 finds that middle-aged adults experience greater diversity in types of positive events in daily life (positive event diversity) compared to older adults, and positive event diversity is associated with higher positive affect. Paper 4 establishes that positive affect with high mean levels and high variability (fragile high positive affect) is associated with greater odds of depression 10 years later. Lastly, Paper 5 demonstrates that although the spread of stressor types experienced in daily life (stressor diversity) declines with age across both cohorts, the types of stressors experienced in modern life differ from those experienced 18 years prior. Together, findings demonstrate how variability in daily life changes across age and has implications for health and well-being of older adults. Dr. Susan Charles will critically discuss these contributions to our understanding of aging in the context of Strength and Vulnerability Integration Theory and provide considerations for understanding the complexity of daily life across the lifespan.

Intra- and inter-individual cognitive variability in schizophrenia and bipolar spectrum disorder: an investigation across multiple cognitive domains

There is substantial cognitive heterogeneity among patients with schizophrenia (SZ) and bipolar disorders (BD). More knowledge about the magnitude and clinical correlates of performance variability could improve our understanding of cognitive impairments. Using double generalized linear models (DGLMs) we investigated cognitive mean and variability differences between patients with SZ (n = 905) and BD spectrum disorders (n = 522), and healthy controls (HC, n = 1170) on twenty-two variables. The analysis revealed significant case-control differences on 90% of the variables. Compared to HC, patients showed larger intra-individual (within subject) variability across tests and larger inter-individual (between subject) variability in measures of fine-motor speed, mental processing speed, and inhibitory control (SZ and BD), and in verbal learning and memory and intellectual functioning (SZ). In SZ, we found that lager intra -and inter (on inhibitory control and speed functions) individual variability, was associated with lower functioning and more negative symptoms. Inter-individual variability on single measures of memory and intellectual function was additionally associated with disorganized and positive symptoms, and use of antidepressants. In BD, there were no within-subject associations with symptom severity. However, greater inter-individual variability (primarily on inhibitory control and speeded functions) was associated with lower functioning, more negative -and disorganized symptoms, earlier age at onset, longer duration of illness, and increased medication use. These results highlight larger individual differences in patients compared to controls on various cognitive domains. Further investigations of the causes and correlates of individual differences in cognitive function are warranted.

Igome Signatures in the IgM Repertoire Characterize Alzheimer's Disease and Differentiate it from Frontotemporal Dementia

The early diagnosis of Alzheimer's disease (AD) holds promise for timely therapeutic intervention and the search for appropriate biomarkers is ongoing. We propose the use of the global antibody reactivity profiling (igome) to discover serum biomarkers that can diagnose AD and differentiate it from other neurodegenerative diseases. Leveraging our optimized IgM mimotope library, we assessed the antibody repertoire of 16 patients with AD or frontotemporal dementia (FTD) and 8 healthy controls. This was performed using oriented, in situ synthesized peptide microarrays followed by recursive feature elimination for optimal diagnostic profile identification. We created reactivity graphs to map partial cross-reactivities between mimotopes, differentiating clusters significantly related to each disease. Unlike previous studies focused mainly on IgG repertoires and random peptides, our approach capitalizes on the natural biosensor properties of IgM and uses artificial intelligence-based biomarker mining to overcome limitations such as compositional bias and intra-individual variability. The identified mimotopes associated with AD or FTD offer potential as diagnostic probes for disease prediction and staging. Our study presents a proof of principle of exploiting the igome as a sensitive, low-cost tool for early AD diagnosis.

Age, sex and race distribution of accelerometer-derived sleep variability in US school-aged children and adults

Sleep variability (e.g. intra-individual variabilities in sleep duration or sleep timing, social jetlag, and catch-up sleep) is an important factor impacting health and mortality. However, limited information is available on the distribution of these sleep parameters across the human life span. We aimed to provide distribution of sleep variability related parameters across lifespan by sex and race in a national representative sample from the U.S. population. The study included 9981 participants 6 years and older from the National Health and Nutrition Examination Survey (NHANES) 2011–2014, who had 4–7 days of valid 24-h accelerometer recording with at least one day obtained during weekend (Friday or Saturday night). Of the study participants, 43% showed ≥ 60 min sleep duration standard deviation (SD), 51% experienced ≥ 60 min catch-up sleep, 20% showed ≥ 60 min sleep midpoint SD, and 43% experienced ≥ 60 min social jetlag. American youth and young adults averaged greater sleep variability compared to other age groups. Non-Hispanic Blacks showed greater sleep variability in all parameters compared to other racial groups. There was a main effect of sex on sleep midpoint SD and social jetlag with males averaging slightly more than females. Our study provides important observations on sleep variability parameters of residents of the United States by using objectively measured sleep patterns and will provide unique insights for personalized advice on sleep hygiene.

Pharmacology of Tyrosine Kinase Inhibitors: Implications for Patients with Kidney Diseases.

Tyrosine kinase inhibitors (TKI) have introduced a significant advancement in cancer management. These compounds are administered orally, and their absorption holds a pivotal role in determining their variable efficacy. They exhibit extensive distribution within the body, binding strongly to both plasma and tissue proteins. Often reliant on efflux and influx transporters, TKI undergo primary metabolism by intestinal and hepatic cytochrome P450 enzymes, with nonkidney clearance being predominant. Owing to their limited therapeutic window, many TKI display considerable intraindividual and interindividual variability. This review offers a comprehensive analysis of the clinical pharmacokinetics of TKI, detailing their interactions with drug transporters and metabolic enzymes, while discussing potential clinical implications. The prevalence of kidney conditions, such as AKI and CKD, among patients with cancer is explored in their effect on TKI pharmacokinetics. Finally, the potential nephrotoxicity associated with TKI is also examined.

Relationship between reaction time variability on go/no go tasks and neuropsychological functioning in younger and older adults

ABSTRACT Introduction Early detection of cognitive impairment in older adults is important for the prevention of dementia. Intra-individual variability in reaction time (IIV-RT) during go/no-go tasks can be used for the early detection of cognitive impairment in older adults living in the community. This study aimed to determine the relationship between IIV-RT and cognitive function during go/no-go tasks and the cutoff values for determining the risk of cognitive impairment in community-dwelling older adults. Methods This study included 31 older adults without cognitive impairment, 15 community-dwelling older adults with cognitive impairment, and 34 healthy young adults. All participants performed a go/no-go task to assess the IIV-RT. Additionally, older adults underwent neuropsychological testing. Based on the results of the Japanese version of the Montreal Test of Cognitive Abilities (MoCA-J), older adults were divided into those with normal cognition and those with cognitive impairment. Results There were significant differences in the IIV-RT among groups, including a higher IIV in the cognitively impaired group than in young adults and cognitively normal older adults. Moreover, the IIV-RT was correlated with the MoCA-J (r = −0.531, p < 0.001), Trail Making Test Part A (r = 0.571, p < 0.001), and Verbal Fluency Test scores (r = −0.442, p = 0.002). Receiver operating curve analysis showed that the area under the curve for IIV-RT was 0.935, and the cutoff value at which the IIV-RT identified cognitive impairment was 25.37%. Conclusions These findings indicate that the IIV-RT during go/no-go tasks is a useful early indicator of cognitive impairment in community-dwelling older adults.

Trajectories and associations of symptoms of mental health and well-being with insulin resistance and metabolic health in women with gestational diabetes

BackgroundGestational diabetes mellitus (GDM) is characterized by increased insulin resistance and carries perinatal and long-term risks for the mother and her offspring. There is a link between perinatal depression or anxiety and GDM. Mental health problems are associated with higher insulin resistance and could explain the underlying association between GDM and depression or anxiety symptoms. We investigated the trajectories and associations between symptoms of mental health and well-being with insulin resistance and metabolic health in women with GDM. MethodsThis study included the control group (n = 106) of a randomized controlled trial in women with GDM that were followed-up during pregnancy and up to 1-year postpartum. We measured symptoms of mental health (Edinburgh Postnatal Depression Scale (EPDS), Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A), well-being (The World Health Organization Well-Being Index (WHO-5)) and metabolic health, including insulin resistance variables (HOMA-insulin resistance (IR) and Matsuda Index of insulin sensitivity) as well as weight during pregnancy and in the postpartum. ResultsParticipants’ pre pregnancy weight and BMI were 69.7 kg ± 16.1 and 25.9 kg/m2 ± 5.5 respectively. HOMA-IR was higher during pregnancy compared to 6–8 weeks postpartum and increased between 6–8 weeks and 1-year postpartum (all p < 0.05). Matsuda index decreased between 6–8 weeks and 1-year postpartum (p < 0.001). EPDS scores decreased between pregnancy and both 6–8 weeks and 1-year postpartum (all p < 0.05). HADS-A scores did not change between pregnancy and the postpartum. WHO-5 scores improved significantly from pregnancy and both 6–8 weeks and 1-year postpartum (p < 0.001). Correlation coefficients within outcome at the three different time points were high for metabolic measures and ranged between 0.94 and 0.96 for weight, from 0.77 to 0.89 for HOMA-IR and 0.64 for the Matsuda index (all p < 0.001). Mental health and well-being variables were moderately correlated in all three time points including r = 0.36–0.55 for the EPDS (p < 0.001), r = 0.58 for HADS (p < 0.001), and r = 0.43–0.52 for the WHO-5 (p < 0.01). After adjustment for age and pre-pregnancy BMI, Matsuda index was negatively associated with EPDS scores and positively associated to WHO-5 scores at 6–8 weeks postpartum. No other association between insulin resistance and mental health or well-being outcomes were found. ConclusionWhile insulin resistance fluctuated with values being lowest in the early postpartum and increasing thereafter, both depression and well-being scores decreased between pregnancy and the postpartum and did not change in the postpartum period. Intraindividual variability was larger for mental health and well-being than for metabolic health outcomes at different time points, indicating a higher plasticity for mental health and well-being outcomes that could be acted upon. We found only few associations between mental health and well-being and metabolic health outcomes.

Translated article] Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy

ObjectiveThe objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. MethodsObservational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal–Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. ResultsTwenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7–48.8) and 10.1 (IQR 9.6–11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) μg/mL and 747.4 (standard deviation (SD) 444.3) μg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (P = .002) and decreased serum creatinine at both higher pre- and post-dose concentrations (P = .001 and P = .017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 μg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78–0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. ConclusionsThe present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Nutrimetric Validation of Solanidine as Dietary-Derived CYP2D6 Activity Marker InVivo.

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4-OH-solanidine and 3,4-secosolanidine-3,4-dioic acid (SSDA) were determined using a sensitive liquid chromatography-mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra-individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α-OH-metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day.