Biological variation of serum neopterin concentrations in apparently healthy individuals.

OBJECTIVES: The aims of this study were to determine the biological variation (BV), reference change value (RCV), index of individuality (II), and quality specifications for serum neopterin concentrations; a measurand provided by clinical laboratories as an indicator of cellular immunity. METHODS: The study delivered serum samples collected for 10 consecutive weeks from 12 apparently healthy individuals (3 male, 9 female). Serum neopterin concentrations were measured using high-performance liquid chromatography with fluorometric detection. The data analysis was performed using an online statistical tool and addressed published criteria for estimation of biological variation. RESULTS: The mean neopterin concentration was 5.26 nmol/L. The within-subject biological variation (CVI) with 95 % confidence interval (CI) of neopterin serum concentrations was 11.54 % (9.98-13.59), and the between-subject biological variation (CVG) with 95 % CI was 43.27 % (30.52-73.67). The neopterin asymmetrical RCV was -24.9 %/+33.1 %, and the II was 0.27. The desirable quality specifications for neopterin were <5.77 % for precision, <11.20 % for bias, and <20.72 % for total allowable error (TEa). When analytical variation was used instead of CVI to calculate TEa, the desirable TEa was <18.39. CONCLUSIONS: This study determined BV data for neopterin, an indicator of cell-mediated immune response. Asymmetric RCV values, of 24.9 % decrease or a 33.1 % increase between consecutive measurements indicate significant change. The II of 0.27 indicates a high degree of individuality, therefore that it is appropriate to consider the use of personal reference data and significance of change rather than the reference interval as points of reference for the evaluation of neopterin serum concentrations.

Within-subject variation of HbA1c: A systematic review and meta-analysis.

BACKGROUND: Glycosylated haemoglobin (HbA1c) measurement is used to diagnose and to guide treatment of diabetes mellitus. Within-subject variability in measured HbA1c affects its clinical utility and interpretation, but no comprehensive systematic review has described within-subject variability. METHODS: A systematic review and meta-analysis was performed of within-subject variability of HbA1c. Multiple databases were searched from inception to November 2022 for follow-up studies of any design in adults or children, with repeated measures of HbA1c or glycosylated haemoglobin. Title and abstract screening was performed in duplicate, full text screening and data extraction by one reviewer and verified by a second. Risk of bias of included papers was assessed using a modified consensus-based standards for the selection of health measurement Instruments (COSMIN) tool. Intraclass correlation coefficient (ICC) results were pooled with a meta-analysis and coefficient of variation (CV) results were described by median and range. RESULTS: Of 2675 studies identified, 111 met the inclusion criteria. Twenty-five studies reported variability data in healthy patients, 19 in patients with type 1 diabetes and 59 in patients with type 2 diabetes. Median within-subject coefficient of variation (CV) was 0.070 (IQR 0.034 to .09). For healthy subjects the median CV for HbA1c % was 0.017 (IQR 0.013 to 0.022), for patients with type 1 diabetes 0.084 (IQR 0.067 to 0.89) and for type 2 diabetes 0.083 (IQR 0.06 to 0.10). CV increased with mean population HbA1c. LIMITATIONS: Assessment of variability was not the main aim of many of the included studies and some relevant papers may have been missed. Many included papers had few participants or few repeated measurements. CONCLUSIONS: Within-subject variability of HbA1c is higher for patients with than without diabetes and increases with mean population HbA1c. This may confound observed relationships between HbA1c variability and health outcomes. Because of its importance in clinical decision-making there is a need for better estimates and understanding of factors associated with of HbA1c variability.

Between-Person and Daily Within-Person Variation Patterns in Measures of Views of Aging.

OBJECTIVES: Recent work suggests that views of aging (VOA; a meta-construct reflective of individuals' aging-related thoughts, beliefs, feelings, and experiences) fluctuate within persons in day-to-day life. This study characterized the extent of daily variability in VOA and explored differences in variability patterns based on measure to enhance understanding of the dynamic nature of VOA. METHODS: An online sample of 122 adults aged 26-78 years completed multiple measures of VOA (subjective age, age group identity, aging attitudes, implicit theories of aging, awareness of age-related losses or gains) on each of 7 consecutive days. We partitioned variance in responses to each measure at the person level and day level to assess between-person and within-person variability, respectively. RESULTS: Between-person variability accounted for most of the total observed variation in VOA, whereas within-person variability accounted for a smaller amount. Different measures exhibited different ratios of between-person to within-person variation, with the lowest ratios observed for subjective age. Exploration of potential differences between age groups also suggests lower ratios in younger compared to older adults. DISCUSSION: Analyses suggest relative stability in daily measures of VOA over a 1-week period. Further study of measures (and age groups) showing greater within-person variability (evidenced by lower ratios of between-person to within-person variation) can increase understanding about constructs with greater sensitivity to fluctuating contexts. It can also inform future work linking VOA to other phenomenon in daily life.

Linking individual variability in functional brain connectivity to polygenic risk in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a highly heterogeneous disease, which brings great difficulties to clinical diagnosis and therapy. Its mechanism is still unknown. Prior neuroimaging studies mainly focused on mean differences between patients and healthy controls (HC), largely ignoring individual differences between patients. METHODS: This study included 112 MDD patients and 93 HC subjects. Resting-state functional MRI data were obtained to examine the patterns of individual variability of brain functional connectivity (IVFC). The genetic risk of pathways including dopamine, 5-hydroxytryptamine (5-HT), norepinephrine (NE), hypothalamic-pituitary-adrenal (HPA) axis, and synaptic plasticity was assessed by multilocus genetic profile scores (MGPS), respectively. RESULTS: The IVFC pattern of the MDD group was similar but higher than that in HCs. The inter-network functional connectivity in the default mode network contributed to altered IVFC in MDD. 5-HT, NE, and HPA pathway genes affected IVFC in MDD patients. The age of onset, duration, severity, and treatment response, were correlated with IVFC. IVFC in the left ventromedial prefrontal cortex had a mediating effect between MGPS of the 5-HT pathway and baseline depression severity. LIMITATIONS: Environmental factors and differences in locations of functional areas across individuals were not taken into account. CONCLUSIONS: This study found MDD patients had significantly different inter-individual functional connectivity variations than healthy people, and genetic risk might affect clinical manifestations through brain function heterogeneity.

Decomposition of variation of mixed variables by a latent mixed Gaussian copula model.

Many biomedical studies collect data of mixed types of variables from multiple groups of subjects. Some of these studies aim to find the group-specific and the common variation among all these variables. Even though similar problems have been studied by some previous works, their methods mainly rely on the Pearson correlation, which cannot handle mixed data. To address this issue, we propose a latent mixed Gaussian copula (LMGC) model that can quantify the correlations among binary, ordinal, continuous, and truncated variables in a unified framework. We also provide a tool to decompose the variation into the group-specific and the common variation over multiple groups via solving a regularized M-estimation problem. We conduct extensive simulation studies to show the advantage of our proposed method over the Pearson correlation-based methods. We also demonstrate that by jointly solving the M-estimation problem over multiple groups, our method is better than decomposing the variation group by group. We also apply our method to a Chlamydia trachomatis genital tract infection study to demonstrate how it can be used to discover informative biomarkers that differentiate patients.

The perfect qMR machine: Measurement variance much less than biological variance.

Implementing quantitative MR (qMR) methodology can be a time-consuming task, sometimes seemingly without an end. The concept of the Perfect qMR Machine offers the possibility that the implementation is complete and that no further improvements are needed. This is achieved by making the measurement repeatability variance much less than the biological variance. Thus the proposal is: A Perfect Quantitative MR machine is one that, in making a measurement, contributes no significant extra variation to that which already exists from biological variation. A medal system (platinum, gold, silver and bronze) recognises different sources of biological variance, depending on the type of measurement being carried out (whether a serial study or a group comparison), and different kinds of measurement variance (single machine or multi-centre). A perfect machine can in principle be demonstrated for each quantitative measure (T1, ADC etc).

Exercise duration: Independent effects on acute physiologic responses and the need for an individualized prescription.

An individualization of exercise prescription is implemented mainly in terms of intensity but not for duration. To survey the need for an individualized exercise duration prescription, we investigated acute physiologic responses during constant-load exercise of maximal duration (tmax ) and determined so-called duration thresholds. Differences between absolute (min) and relative terms (% tmax ) of exercise duration were analyzed. Healthy young and trained male and female participants (n = 11) performed an incremental exercise test and one tmax constant-load exercise test at a target intensity of 10% of maximal power output below the second lactate turn point (LTP2 ). Blood lactate, heart rate, and spirometric data were measured during all tests. tmax was markedly different across subjects (69.6 ± 14.8 min; range: 40-90 min). However, distinct duration phases separated by duration thresholds (DTh) were found in most measured variables. These duration thresholds (except DTh1) were significantly related to tmax (DTh2: r2  = 0.90, p < 0.0001; DTh3: r2  = 0.98, p < 0.0001) and showed substantial interindividual differences if expressed in absolute terms (DTh2: 24.8 ± 6.0 min; DTh3: 47.4 ± 10.6 min) but not in relative terms (DTh2: 35.4 ± 2.7% tmax ; DTh3: 67.9 ± 2.4% tmax ). Our data showed that (1) maximal duration was individually different despite the same relative intensity, (2) duration thresholds that were related to tmax could be determined in most measured variables, and (3) duration thresholds were comparable between subjects if expressed in relative terms. We therefore conclude that duration needs to be concerned as an independent variable of exercise prescription.

Automating microsatellite screening and primer design from multi-individual libraries using Micro-Primers.

Analysis of intra- and inter-population diversity has become important for defining the genetic status and distribution patterns of a species and a powerful tool for conservation programs, as high levels of inbreeding could lead into whole population extinction in few generations. Microsatellites (SSR) are commonly used in population studies but discovering highly variable regions across species' genomes requires demanding computation and laboratorial optimization. In this work, we combine next generation sequencing (NGS) with automatic computing to develop a genomic-oriented tool for characterizing SSRs at the population level. Herein, we describe a new Python pipeline, named Micro-Primers, designed to identify, and design PCR primers for amplification of SSR loci from a multi-individual microsatellite library. By combining commonly used programs for data cleaning and microsatellite mining, this pipeline easily generates, from a fastq file produced by high-throughput sequencing, standard information about the selected microsatellite loci, including the number of alleles in the population subset, and the melting temperature and respective PCR product of each primer set. Additionally, potential polymorphic loci can be identified based on the allele ranges observed in the population, to easily guide the selection of optimal markers for the species. Experimental results show that Micro-Primers significantly reduces processing time in comparison to manual analysis while keeping the same quality of the results. The elapsed times at each step can be longer depending on the number of sequences to analyze and, if not assisted, the selection of polymorphic loci from multiple individuals can represent a major bottleneck in population studies.

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

The relational regulation of within-person variation in personality expression.

There is renewed interest in how people express different levels of personality across situations or times (within-person variation). However, within-person studies typically do not focus on the specific relationship partners that are linked to the expression of personality. To remedy this, we applied relational regulation theory (RRT) to the study of within-person variation. RRT states that specific relationship partners are important social contexts for understanding within-person variation and describes how people regulate their affect, action and thought through interacting with or thinking about specific partners. In three studies of students (Ns = 136, 349, 110), participants rated their levels of six- or five-factor personality dimensions when with or thinking about different relationship partners. Personality expression was strongly consistent across partners. Yet, in each study, there were also strong effects whereby more extraversion, agreeableness and openness were expressed when with some partners but not others. In each study, when a recipient saw a relationship as supportive, the recipient expressed more extraversion, agreeableness, and openness. Effects for emotionality and conscientiousness were less consistent. Theoretical implications for RRT and within-person variation in personality were discussed.

Within-Person variations in mindfulness mediate effects of daily stressors on psychological distress in adolescence.

OBJECTIVE: We tested two competing models linking daily stress, mindfulness, and psychological distress in adolescence: 1) whether daily mindfulness moderates the impact of daily stressors on psychological distress or 2) whether mindfulness mediates the relationship between greater daily stressors and psychological distress. METHODS: Every evening for a week, 138 adolescents completed ecological momentary assessments (EMAs). Daily diaries assessed negative events, work-school conflict, mindfulness, and perceived stress. Multilevel mediation and moderation were tested. RESULTS: Results indicated that there were meaningful variations in adolescent mindfulness from day-to-day, and supported mediation rather than moderation; the within-person association between stressors and psychological distress was mediated by mindfulness at the daily level. CONCLUSION: It may be too challenging for adolescents to remain in a mindful state during stress to effectively use mindfulness as a buffer. Instead, daily stressors may indirectly impact psychological distress through decreasing mindfulness.

Within-Person Associations of Self-Reports of Memory Impairment and Depressive Symptoms in Older Adults: Moderation of Relationships Over Time by Personality.

OBJECTIVES: The current study examined within-person associations of self-reports of impaired current memory functioning and perceived decline with depressive symptoms in older adults without cognitive impairment, and whether these associations were moderated by individuals' levels of neuroticism, conscientiousness, and extraversion. METHODS: Samples were drawn from the Einstein Aging Study, Rush Memory and Aging Project (MAP), Minority Aging Research Study (MARS), Health and Retirement Study (HRS), and National Health and Aging Trends Study (NHATS), with over 8,000 participants (65+ years) included across data sets. In a series of coordinated analyses, multilevel linear models tested within-person relationships over periods of up to 22 years. RESULTS: Across HRS and NHATS samples, self-reports of impaired current memory functioning covaried with depressive symptoms over time. This association was moderated by neuroticism, such that the association was stronger for individuals with higher levels of neuroticism. Across all samples, perceived memory decline covaried with depressive symptoms over time. This association was moderated by neuroticism in MAP/MARS, HRS, and NHATS, such that the association was stronger for individuals with higher levels of neuroticism. DISCUSSION: Self-reports of impaired current memory functioning and perceived memory decline are important determinants of older adults' psychological well-being. In our results, at times when older adults perceive poorer memory functioning or decline, they also tend to report more depressive symptoms. Further, results from two larger data sets suggest that individuals' level of neuroticism may determine the extent to which self-reports of memory impairment and depressive symptoms covary over time.

Age Trajectories of Perceptual Speed and Loneliness: Separating Between-Person and Within-Person Associations.

OBJECTIVES: We aimed at examining between-person and within-person associations across age trajectories of perceptual speed and loneliness in old age. METHOD: We applied multilevel models to 4 waves of data collected over 6 years from 1,491 participants of the Berlin Aging Study II (60-88 years at baseline, 50% women) to disentangle between-person and within-person associations across age trajectories of perceptual speed and both emotional and social loneliness. Sex and education were considered as relevant individual characteristics and included as covariates in the model. RESULTS: Analyses revealed that on average perceptual speed exhibited moderate within-person age-related declines, whereas facets of loneliness were rather stable. Perceptual speed did not predict age trajectories of emotional or social loneliness, at either the between- or within-person level. In contrast, loneliness discriminated individuals at the between-person level, such that those feeling emotionally or socially more lonely showed lower cognitive performance than those feeling emotionally or socially less lonely. Predictive effects of social loneliness were stronger for relatively young people (i.e., in their mid to late 60s) than for relatively older participants (i.e., in their 80s). In addition, predictive effects of social loneliness for perceptual speed at the within-person level were modest and deviated in direction and size from between-person social loneliness effects among those in their mid- to late 60s, whereas they did not among those in their 80s. DISCUSSION: We conclude that loneliness may serve as a precursor for basic cognitive functioning in old age and suggest routes for further inquiry.

Immunosenescence and Autoimmunity: Exploiting the T-Cell Receptor Repertoire to Investigate the Impact of Aging on Multiple Sclerosis.

T-cell receptor (TCR) repertoire diversity is a determining factor for the immune system capability in fighting infections and preventing autoimmunity. During life, the TCR repertoire diversity progressively declines as a physiological aging progress. The investigation of TCR repertoire dynamics over life represents a powerful tool unraveling the impact of immunosenescence in health and disease. Multiple Sclerosis (MS) is a demyelinating, inflammatory, T-cell mediated autoimmune disease of the Central Nervous System in which age is crucial: it is the most widespread neurological disease among young adults and, furthermore, patients age may impact on MS progression and treatments outcome. Crossing knowledge on the TCR repertoire dynamics over MS patients' life is fundamental to investigate disease mechanisms, and the advent of high- throughput sequencing (HTS) has significantly increased our knowledge on the topic. Here we report an overview of current literature about the impact of immunosenescence and age-related TCR dynamics variation in autoimmunity, including MS.

Intra-Individual Variability of Human Dental Pulp Stem Cell Features Isolated from the Same Donor.

It is primarily important to define the standard features and factors that affect dental pulp stem cells (DPSCs) for their broader use in tissue engineering. This study aimed to verify whether DPSCs isolated from various teeth extracted from the same donor exhibit intra-individual variability and what the consequences are for their differentiation potential. The heterogeneity determination was based on studying the proliferative capacity, viability, expression of phenotypic markers, and relative length of telomere chromosomes. The study included 14 teeth (6 molars and 8 premolars) from six different individuals ages 12 to 16. We did not observe any significant intra-individual variability in DPSC size, proliferation rate, viability, or relative telomere length change within lineages isolated from different teeth but the same donor. The minor non-significant variances in phenotype were probably mainly because DPSC cell lines comprised heterogeneous groups of undifferentiated cells independent of the donor. The other variances were seen in DPSC lineages isolated from the same donor, but the teeth were in different stages of root development. We also did not observe any changes in the ability of cells to differentiate into mature cell lines-chondrocytes, osteocytes, and adipocytes. This study is the first to analyze the heterogeneity of DPSC dependent on a donor.

Untangling Absorption Mechanisms and Variability in Bioequivalence Studies Using Population Analysis.

PURPOSE: Both inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of crossover studies. METHODS: Data from 18 bioequivalence studies were used to develop population pharmacokinetics (popPK) models to characterize the absorption and disposition processes of 14 drugs, to estimate IOV for each drug substance and to evaluate possible correlations with biopharmaceutical properties of drug substances, classified in accordance to the Biopharmaceutics Drug Disposition Classification System (BDDCS). RESULTS: Plasma-pharmacokinetics profiles for the 14 drugs analyzed were successfully described using popPK. The pharmacokinetic parameters that showed greater variability were first-order rate constant of absorption, duration of the zero-order absorption process, relative bioavailability and time of latency. ISCV% estimated for Cmax seems to correlate with the log-Dose-Number for Class 1, 2 and 3, despite no direct correlation was observed between popPK model residual variability (RUV) and ISCV%. Nevertheless, higher RUV estimates were observed for Class 2 drugs in comparison to Class 1 and 3. CONCLUSION: Pharmacokinetic parameters related to drug absorption showed greater variability. Ingestion of the IMP along with 240 mL of water showed to standardize gastric emptying. Given the dependency between Cmax variability and dose-solubility ratio, for classes 2 and 4, ad libitum water intake may increase Cmax and AUC ISCV%. A water ingestion standardization until the expected Tmax of the drug is suggested.

Intrapatient Variability in Tacrolimus Trough Levels Over 2 Years Affects Long-Term Allograft Outcomes of Kidney Transplantation.

This study aimed to determine the impact of tacrolimus (TAC) trough level (C0) intrapatient variability (IPV) over a period of 2 years after kidney transplantation (KT) on allograft outcomes. In total, 1,143 patients with low immunologic risk were enrolled. The time-weighted coefficient variability (TWCV) of TAC-C0 was calculated, and patients were divided into tertile groups (T1: < 24.6%, T2: 24.6%-33.7%, T3: ≥ 33.7%) according to TAC-C0-TWCV up to post-transplant 1st year. They were classified into the low/low, low/high, high/low, and high/high groups based on a TAC-C0-TWCV value of 33.7% during post-transplant 0-1st and 1st-2nd years. The allograft outcomes among the three tertile and four TAC-C0-TWCV groups were compared. The T3 group had the highest rate of death-censored allograft loss (DCGL), and T3 was considered an independent risk factor for DCGL. The low/low group had the lowest and the high/high group had the highest risk for DCGL. Moreover, patients with a mean TAC-C0 of ≥5 ng/ml in the high/high group were at the highest risk for DCGL. Thus, TAC-IPV can significantly affect allograft outcomes even with a high mean TAC-C0. Furthermore, to improve allograft outcomes, a low TAC-IPV should be maintained even after the first year of KT.

Brain-Based Biotypes of Psychiatric Vulnerability in the Acute Aftermath of Trauma.

OBJECTIVE: Major negative life events, such as trauma exposure, can play a key role in igniting or exacerbating psychopathology. However, few disorders are diagnosed with respect to precipitating events, and the role of these events in the unfolding of new psychopathology is not well understood. The authors conducted a multisite transdiagnostic longitudinal study of trauma exposure and related mental health outcomes to identify neurobiological predictors of risk, resilience, and different symptom presentations. METHODS: A total of 146 participants (discovery cohort: N=69; internal replication cohort: N=77) were recruited from emergency departments within 72 hours of a trauma and followed for the next 6 months with a survey, MRI, and physiological assessments. RESULTS: Task-based functional MRI 2 weeks after a motor vehicle collision identified four clusters of individuals based on profiles of neural activity reflecting threat reactivity, reward reactivity, and inhibitory engagement. Three clusters were replicated in an independent sample with a variety of trauma types. The clusters showed different longitudinal patterns of posttrauma symptoms. CONCLUSIONS: These findings provide a novel characterization of heterogeneous stress responses shortly after trauma exposure, identifying potential neuroimaging-based biotypes of trauma resilience and psychopathology.

Variations in human body water isotope composition across the United States.

Accurate human provenancing using stable isotopes depends directly on solid understandings of the geographic and individual factors affecting isotope variability and incorporation into human tissues. Transfer of isotopic, and therefore spatial, information between environmental water and biological tissues is mediated by the isotopic composition of body water. Thus, there is a need to study body water isotope ratios at a population level and over a large isotopic and geographic range. We evaluated oxygen (δ18Obw) and hydrogen (δ2Hbw) isotope values of body water from 72 volunteers in 10 different cities across the US, and over a 5-10-day period. We analyzed covariates (e.g., water intake, physical activity, biometrics, gender) that might explain individual stable isotope ratio variations and tested a predictive model that incorporates the δ-values of drinking water, food, and O2 as well as individual variables to predict the δ-values of body water. The individual variability in body water isotope values overtime (mean 0.3‰ for δ18Obw and 2.3‰ for δ2Hbw) was lower than the intra-city variability (mean 0.9‰ for δ18Obw and 6.9‰ for δ2Hbw). Body water isotope values differed among cities (ANOVA: δ18ObwF = 97.2, p < 0.001; δ2HbwF = 176.2, p < 0.001). However, significant overlap among some cities with different drinking water was discovered. We detected significant covariation of measured drinking water and human body water isotope values (both isotope systems R2 ≥ 0.89, p < 0.001) and small but significant effects of the average daily exercise and amount of fluid intake. The differences between measured and model-predicted body water values (mean 0.12 ± 1.2‰ for Δδ18O and -1.2 ± 8.2‰ for Δδ2H) were statistically indistinguishable from zero (Δδ18O t = -0.751, p = 0.45; Δδ2H t = 1.133, p = 0.26). Here we show that community level variation exists in the δ18Obw and δ2Hbw values and the primary drivers are the regional differences in drinking water isotopes. Consistency of the body water isotope composition over the study period suggests that tissues would incorporate a stable isotope signal over time. The amount of drinking water and physical activity influence body water values, while the variation in the isotopic values of food may contribute to regional level variability, but that still remains to be assessed further. The human body water model provides accurate estimates for measured values, capturing and reproducing the main features of the body water isotope variation across space.

Effects of Within-Person Variability in Spot Urinary Sodium Measurements on Associations With Blood Pressure and Cardiovascular Disease.

Randomized trials of salt restriction have consistently demonstrated that decreasing salt consumption lowers blood pressure, but results of observational studies of salt intake and cardiovascular disease have been conflicting. After excluding individuals with prevalent cardiovascular or kidney disease in the prospective UK Biobank study, we examined the within-person variability in spot urinary sodium excretion and its impact on associations with systolic blood pressure and risk of incident cardiovascular disease. Spearman correlation coefficients were used to assess within-person variability in spot urinary sodium, and associations between sodium and blood pressure were assessed using linear regression in participants with measurements at baseline (N=355 134) and after 9 years (N=33 915). Cox regression was used to assess associations with the risk of cardiovascular disease over the same follow-up period (N=5566 events). The within-person variability in urinary sodium was extreme, with a self-correlation coefficient of 0.35 over 4 years. Each 100 mmol/L higher usual urinary sodium was associated with 3.09 mm Hg higher systolic blood pressure (95% CI, 2.7­3.48) at baseline, but had no association at 9 years (0.97 [−0.44 to 2.37]). Likewise, there was no association between urinary sodium and risk of cardiovascular disease over the same follow-up period (hazard ratio, 1.05, [0.87­1.26]). While spot urinary sodium measurements were associated with immediate effects on blood pressure at baseline, the extreme within-person variability in urinary sodium precluded detection of associations with future blood pressure at resurvey or risk of cardiovascular disease. The limitations of observational studies, irrespective of study size, should be recognized when assessing public policy on salt restriction.