Inter-individual Coefficients Of Variation Research Articles

Biological variation in thyroid function tests in older adults and clinical implications.

Interpreting thyroid function tests can be challenging due to inherent variation, and the need for tests rises with age. While age-related changes in thyrotropin (TSH) levels are known, the biological variation in older adults remains unclear. We recruited nineteen 65-99-year-old (older adults) without thyroid disease for monthly blood sampling for 1 year. Serum was stored at -20C°, and TSH, total thyroxine (TT4) and total triiodothyronine (TT3) were analysed in random order in a single batch for each participant. Results were compared to test results from 15 euthyroid men aged 24-53 years (younger adults) collected previously using a similar methodology. Interindividual coefficients of variation in older/younger adults were 46.7%/44.0% for TSH, 12.7%/19.5% for TT4 and 14.6%/22.4% for TT3. Intraindividual coefficients of variation (CVI ) were 19.0%/25.4% for TSH, 5.5%/10.8% for TT4 and 6.9%/13.2% for TT3. The index of individuality was below 0.6 for all hormones in all age groups. The number of samples required to determine the homoeostatic set-point at 10% precision in older adults was 14-21 for TSH and 2 for TT4 and TT3. TT4 in older adults was the only parameter in any group with comparable CVI between individuals (p = .22). CVI for TT4 and TT3 was halved in older compared to younger adults with two tests of TT4 needed to describe the individual set-point. Similar CVI between older adults caused TT4 to provide a reliable estimate of thyroid function, and the added value of measuring thyroxine could improve clinical practice.

Annual stability of the plasma Aß40/42 ratio and associated factors.

The plasma Aß40/42 ratio is a biomarker of brain amyloidosis. However, the threshold difference between amyloid positivity and negativity is only 10-20% and fluctuates with circadian rhythms, aging, and APOE-ε4 during the decades of evolution of Alzheimer's disease. Plasma Aß40 and Aß42 levels in 1472 participants aged between 19 and 93 years in the Iwaki Health Promotion Project for 4 years were statistically analyzed. The means and standard deviations of annual inter-individual coefficients of variation were 5.3 ± 3.2% for Aß40, 7.8 ± 4.6% for Aß42, and 6.4 ± 4.1% for the Aß40/42 ratio. No significant age-dependent changes were observed in inter-individual coefficients of variation. Age-dependent increases in Aβ42 levels were suppressed, whereas those in the Aβ40/42 ratio were enhanced in APOE-ε4 carriers. The change points of Aß42, Aß40, and the Aß40/42 ratio were 36.4, 38.2, and 43.5 years, respectively. In the presence of APOE-ε4, the Aß40/42 ratio increased in middle-aged and elderly subjects while Aβ42 levels decreased in elderly subjects. Individual values for Aß40, Aß42, and the Aß40/42 ratio did not fluctuate annually or in an age-dependent manner. If the plasma Aβ40/42 ratio changes by more than 14.7% (+2 standard deviations) relative to age- and APOE-ε4-adjusted normal annual fluctuations, other biomarkers also need to be examined.

Conventional methods to prescribe exercise intensity are ineffective for exhaustive interval training

PurposeTo compare methods of relative intensity prescription for their ability to normalise performance (i.e., time to exhaustion), physiological, and perceptual responses to high-intensity interval training (HIIT) between individuals.MethodsSixteen male and two female cyclists (age: 38 ± 11 years, height: 177 ± 7 cm, body mass: 71.6 ± 7.9 kg, maximal oxygen uptake ( dot{text{V}} O2max): 54.3 ± 8.9 ml·kg−1 min−1) initially undertook an incremental test to exhaustion, a 3 min all-out test, and a 20 min time-trial to determine prescription benchmarks. Then, four HIIT sessions (4 min on, 2 min off) were each performed to exhaustion at: the work rate associated with the gas exchange threshold ( dot{text{W}} GET) plus 70% of the difference between dot{text{W}} GET and the work rate associated with dot{text{V}} O2max; 85% of the maximal work rate of the incremental test (85% dot{text{W}} max); 120% of the mean work rate of the 20 min time-trial (120%TT); and the work rate predicted to expend, in 4 min, 80% of the work capacity above critical power. Acute HIIT responses were modelled with participant as a random effect to provide estimates of inter-individual variability.ResultsFor all dependent variables, the magnitude of inter-individual variability was high, and confidence intervals overlapped substantially, indicating that the relative intensity normalisation methods were similarly poor. Inter-individual coefficients of variation for time to exhaustion varied from 44.2% (85% dot{text{W}} max) to 59.1% (120%TT), making it difficult to predict acute HIIT responses for an individual.ConclusionThe present study suggests that the methods of intensity prescription investigated do not normalise acute responses to HIIT between individuals.

Variability and Seasonal Change of Urinary Selenium, Molybdenum, and Iodine Excretion in Healthy Young Japanese Adults.

Selenium (Se), molybdenum (Mo), and iodine (I) are essential trace elements or nutrients and their adequate intake is essential for human health. These elements in foods are easily absorbed from the digestive tract and excreted predominantly into the urine, and their nutritional status is reflected in urinary excretion; however, information on the variability of urinary excretion is limited. To characterize the urinary Se, Mo, and I concentrations and their intra- and inter-individual coefficients of variation (CV), correlation, and seasonal change, spot urine samples were collected from 24 healthy university students, 10 males and 14 females, with the mean age of 20.6years, for 10 consecutive days in each of the four seasons according to a defined schedule of an interval of 3months throughout 1year. The median Se, Mo, and I concentrations for all urine samples (n = 947) were 52.8, 127.0, and 223μg/L, respectively. The Se and Mo intakes were highest in summer and lowest in spring, while the I intake was highest in autumn and lowest in summer. In all three elements, the intra-individual CVs were smaller than their inter-individual CVs. The log-transformed intra- and inter-individual CVs were 10.5 and 14.7% for Se, 12.3 and 15.1% for Mo, and 15.5 and 18.1% for I. There was no gender difference in Se and I concentrations, while Mo and Mo/Cr values in males were higher than those in females. Our results suggest adequate nutritional status of Se, Mo, and I with a relatively smaller variability of dietary intake except for I in this population.

The defense repertoire of males of Leptodactylus vastus Lutz 1930 in a fragment of the Atlantic Forest in northeastern Brazil

Anurans present different defence mechanisms against predator attacks. There are more than 30 defence strategies that these animals can display in the different environments where they can be preyed upon. We analysed the defence repertoire of the species Leptodactylus vastus Lutz 1930, including the male distress call and its intra and interindividual coefficients of variation. We carried out this study in a fragment of Semideciduous Atlantic Forest at the Camocim Conservation Unit in the metropolitan region of Recife, Pernambuco, northeastern Brazil. The defensive displays of 30 males to different stimuli simulating a predator were analysed. We observed five types of strategies which were used by these animals separately or concomitantly: puffing up the body (100%), push movement (83.3%), distress call (33.3%), hiding (23.3%), cloacal discharge (16.6%) and spine aggression (6.6%). The analysis of intra and interindividual coefficient of variation showed that there was no acoustic variation in the distress call of this species. Understanding the defensive mechanisms of a species is important to identify the antipredatory strategies used by animals, especially in face of emerging threats, and to help to produce proposals for the conservation of neotropical species.

The biological variation, index of individuality, and reference change value for hematological and blood chemical analytes in ferrets (Mustela putorius furo)

BackgroundUnderstanding biological variation is important when establishing or using currently published reference intervals (RIs) to evaluate hematological and blood chemical analysis results. Population based RIs may not be sensitive enough to identify clinically significant changes in individuals when the intraindividual variation is lower than the interindividual variation. This is the first study with the aim to investigate the biological variation of hematological and biochemical analytes and then to calculate the reference change values (RCVs) in ferrets. MethodsThis retrospective study analyzed blood test results of 13 ferrets that have been tested every year for 7 years. Intraindividual and interindividual coefficients of variation for each analyte were calculated using restricted maximum likelihood that is suitable for unbalanced design since five ferrets died earlier, before determining the index of individuality (IoI) and RCV. ResultsNo analytes had IoI lower than 0.6. The IoI of mean corpuscular hemoglobin (MCH), calcium, blood urea nitrogen (BUN), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total protein, albumin, and globulin were between 0.6 and 1.4. The IoI of red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, MCH concentration (MCHC), white blood cell count, lymphocytes, monocytes, neutrophils, eosinophils, basophils, sodium, potassium, phosphate, glucose, creatinine and amylase were higher than 1.4. In this study, the RCVs varied from 6.87% (sodium) to 391.46% (basophils). Conclusions and clinical relevanceThe results of this study indicate that population based RIs are appropriate to evaluate most analytes in this study. Population based RIs should be used with caution to evaluate MCH, calcium, BUN, ALT, ALP, total protein, albumin, and globulin. The hematological and blood chemical RCVs calculated in this study can assist in diagnosing diseases, and monitoring and evaluating the performance of long-term treatments.

Bayesian pharmacokinetic-guided prophylaxis with recombinant factor VIII in severe or moderate haemophilia A

IntroductionPersonalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients. Materials and methodsOur prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT® in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate®) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t1/2) were calculated. ResultsA total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t1/2, and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t1/2 was found (P = 0.010), especially in patients with short t1/2. This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t1/2 and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring. ConclusionsPK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.

Reproducibility of gastric emptying assessed with scintigraphy in patients with upper GI symptoms.

The reproducibility of gastric emptying (GE) measured with scintigraphy in patients is poorly understood. Our aims were to assess the intra and inter-individual reproducibility of these parameters in patients with upper gastrointestinal symptoms. Sixty patients (21 diabetics, 39 non-diabetics) with upper gastrointestinal symptoms underwent scintigraphic-assessment of GE of a solid meal (296kcal, 30% fat) over 4hours on two occasions at an average interval of 15days. The concordance correlation coefficient (CCC), intra and inter-individual coefficients of variation (COV) of GE endpoints were analyzed. The GE t1/2 was 134±8minutes (mean±SEM) for the first and 128±6minutes for the second study. The mean (95% CI) CCC between the two studies was 0.79 (0.67, 0.87) for GE at 1hour, 0.83 (0.75, 0.9) for GE at 2hours, 0.54 (0.34, 0.7) for GE at 4hours, and 0.79 (0.68, 0.86) for GE t1/2 . However, in 18 of 60 patients (30%), the characterization of GE as normal, delayed, or rapid differed between the first and second studies. For gastric empting t1/2 , the inter-individual coefficients of variation was 40%; the intra-individual COV was 20%, comparable in diabetics and non-diabetics, and greater in patients with rapid (28%) than delayed (18%) or normal GE (12%). Among patients with upper gastrointestinal symptoms, GE measured with scintigraphy is relatively reproducible. In 30% of cases, the interpretation was different between the two assessments. Hence, a diagnosis of gastroparesis based on a single study may occasionally be inaccurate.

Multipulse transcranial electrical stimulation (TES): normative data for motor evoked potentials in healthy horses

BackgroundThere are indications that transcranial electrical stimulation (TES) assesses the motor function of the spinal cord in horses in a more sensitive and reproducible fashion than transcranial magnetic stimulation (TMS). However, no normative data of TES evoked motor potentials (MEP) is available.ResultsIn this prospective study normative data of TES induced MEP wave characteristics (motor latency times (MLT); amplitude and waveform) was obtained from the extensor carpi radialis (ECR) and tibial cranialis (TC) muscles in a group of healthy horses to create a reference frame for functional diagnostic purposes. For the 12 horses involved in the study 95% confidence intervals for MLTs were 16.1–22.6 ms and 31.9–41.1 ms for ECR and TC muscles respectively. Intra-individual coefficients of variation (CV) and mean of MLTs were: ECR: 2.2–8,2% and 4.5% and TC: 1.4–6.3% and 3.5% respectively. Inter-individual CVs for MLTs were higher, though below 10% on all occasions.The mean ± sd of MEP amplitudes was respectively 3.61 ± 2.55 mV (ECR muscle left) and 4.53 ± 3.1 mV (right) and 2.66 ± 2.22 mV (TC muscle left) and 2.55 ± 1.85 mV (right). MLTs showed no significant left versus right differences.All MLTs showed significant (p < 0.05) voltage dependent decreases with slope coefficients of linear regression for ECR: − 0.049; − 0.061 ms/V and TC: − 0.082; − 0.089 ms/V (left; right). There was a positive correlation found between height at withers and MLTs in all 4 muscle groups. Finally, reliable assessment of MEP characteristics was for all muscle groups restricted to a transcranial time window of approximately 15–19 ms.ConclusionsTES is a novel and sensitive technique to assess spinal motor function in horses. It is easy applicable and highly reproducible. This study provides normative data in healthy horses on TES induced MEPs in the extensor carpi radialis and tibialis cranialis muscles bilaterally. No significant differences between MLTs of the left and right side could be demonstrated. A significant effect of stimulation voltage on MLTs was found. No significant effect of height at the withers could be found based upon the results of the current study. A study in which both TMS and TES are applied on the same group of horses is needed.

Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin

Background The direct oral anticoagulants (DOACs) dabigatran and rivaroxaban are both substrates of the P-glycoprotein (P-gp) transporter, encoded by the ABCB1 gene. Rivaroxaban is metabolized by cytochrome P450 A4 (CYP3A4). Interindividual variability in DOAC exposure and frequent P-gp-associated drug-drug interactions have been described in patients. Objective To assess the influence of ABCB1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban, associated or not with clarithromycin, a P-gp and CYP3A4 inhibitor. Methods Sixty healthy male volunteers, selected according to ABCB1 genotype (20 homozygous mutated, 20 heterozygous mutated, and 20 wild-type for haplotype 2677-3435), were included in this randomized, two-center, crossover study. All received sequentially a single dose of dabigatran etexilate (300 mg) and rivaroxaban (40 mg) associated or not with clarithromycin. Peak plasma concentration and area under the curve (AUC) were compared across the three ABCB1 genotypes. The effect of clarithromycin on dabigatran or rivaroxaban pharmacokinetics was assessed. Results Interindividual coefficients of variation for AUC were 77% for dabigatran and 51% for rivaroxaban. ABCB1 genotype did not significantly affect drug pharmacokinetics: AUC ratios between mutant-allele carriers and wild-type volunteers were 1.27 (95% confidence interval [CI] 0.84-1.92) and 1.20 (95% CI 0.96-1.51) for dabigatran and rivaroxaban, respectively. Clarithromycin coadministration led to a two-fold increase in both drugs' AUC, irrespective of ABCB1 genotype: ratios of geometric means were 2.0 (95% CI 1.15-3.60) and 1.94 (95% CI 1.42-2.63) for dabigatran and rivaroxaban, respectively. Conclusions ABCB1 genotype is not a significant determinant of interindividual variability in dabigatran and rivaroxaban pharmacokinetics. The levels of one drug did not predict the levels of the other. Coadministration of a P-gp/CYP3A4 inhibitor with dabigatran or rivaroxaban may warrant caution in patients at risk of overexposure.

Individualized Prophylactic Treatment with Recombinant Factor VIII in Severe or Moderate Haemophilia a Patients. Association Between Pharmacokinetic Parameters and Clinical Variables

Background:Prophylaxis with recombinant factor VIII (rFVIII) is considered the optimal treatment for severe or moderate haemophilia A (HA). Bleeding into joints determines a proportional chronic joint damage to its frequency and severity. Knowledge of the individual's pharmacokinetics (PK) using Bayesian analysis helps to individualize prophylaxis therapy with recombinant factor VIII (rFVIII) in severe or moderate haemophilia A (HA) and minimize the risk of bleeding, extracting only 2-3 samples.MethodsRetrospective study in HA patients with rFVIII (Advate®) prophylaxis from January 2014 to May of 2016. Bayesian model (myPKFit®) was employed to perform an individual PK profile using the retrospective data of rFVIII levels. PK parameters analyzed were: clearance (Cl); steady state volume (Vss); plasma half-life (t1/2); and time to reach rFVIII levels <1% (T1%). Intraindividual and interindividual coefficients of variation (CV) of the t1/2 were calculated. Besides, Kruskal-Wallis test (R® version 3.1.2) was employed in comparisons between t1/2 and clinical variables: annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), Gilbert score (GS), Pettersson scale (PS) & lower extremity affected joints detected by NMR.ResultsNineteen patients were analyzed, with a mean age of 32 years (SD: 11.3; range 11-46) and 86 PK monitoring (4.5 per patient). Two patients with <15 years were excluded because t1/2 was lower than adult patients. The mean PK values in adult patients were: Cl 2.9 (0.40) mL/h/kg; Vss 50.0 (<0.001) ml/kg; t1/2 14.1 (2.1) h; and T1% 74.4 (14.4) h. The mean intraindividual CV in t1/2 was 3.6% (SD 0.02; range 0.3-6.6), whereas interindividual CV was 14.8%. We categorized t1/2 in short (<p25: 12.3 h), normal (p25-p75) and long (>p75 14.4 h), with average age of 19.5; 39.4 & 35.8 years, respectively.We detected significant differences between t1/2 and median values of joint state, but not in ABR and AJBR. The mean values of joint scores were: PS (5.5, 22.1; 17; p=0.028), GS (1, 25.9, 17.6; p= 0,008) and NMR (1.2, 2.6, 2.0; p=0.042) for short, normal and long t1/2, respectively.The limited number of patients only allows observe significant differences in patients with short t1/2, patients that also have significantly lower age (p=0.007). The younger age of these patients also justifies the lower joint damage observed. After excluding two patients <15 years significant differences in the scores of the joint state disappeared, showing that age could be a confounding variable.ConclusionPK monitoring showed a low intraindividual variability in t1/2, but significant interindividual CV. Age could modify PK parameters, so it should be assessed in an integrated manner with other clinical variables. Bayesian estimate with MyPKFit® allows know the PK profile of each patient and could be a useful tool to individualize prophylaxis adjusting by the physical activity and the bleeding pattern. We are performing a personalized one-year program to identify and treat the specific causes of poor bleeding control in prophylaxis therapy, and these are our preliminary results.Acknowledgments: This study will be supported by Baxalta grant "H15-29403". DisclosuresCid:Baxalta Innovations GmbH, now part of Shire: Other: Investigator Clinical Studies.

Sex difference in substrate oxidation during low-intensity isometric exercise in young adults

Low-intensity physical activity is increasingly promoted as an alternative to sedentary behavior. However, much research to date has focused on moderate- to vigorous-intensity physical activity, and in particular dynamic work, with the effect of low-intensity isometric exercise (<4 METs) on substrate utilization yet to be explored. Here we investigate the effects of such exercise on respiratory quotient (RQ) and determine the extent of intra- and inter-individual variability in response. Energy expenditure, RQ, and substrate oxidation were measured by ventilated-hood indirect calorimetry at rest and in response to standardized, intermittent, low-level isometric leg-press exercises at 5 loads (+5, +10, +15, +20, +25 kg) in 26 healthy, young adults. Nine participants repeated the experiment on 3 separate days to assess within-subject, between-day variability. There was no significant difference in energy cost and heart rate responses to low-intensity isometric exercise (<2 METs) between men and women. However, a sex difference was apparent in terms of substrate oxidation - with men increasing both fat and carbohydrate oxidation, and women only increasing fat oxidation while maintaining carbohydrate oxidation at baseline, resting levels. This sex difference was repeatable and persisted when substrate oxidation was adjusted for differences in body weight or body composition. Individual variability in RQ was relatively low, with both intra- and inter-individual coefficients of variation in the range of 3%-6% in both sexes. These results suggest that women preferentially increase fat oxidation during low-level isometric exercise. Whether such physical activity could be incorporated into treatment/prevention strategies aimed at optimizing fat oxidation in women warrants further investigation.

Reproducibility of Physical Performance during Small- and Large-sided Games in Elite Soccer in Short Period: Practical Applications and Limits

The aim of the present study was to examine the reproducibility of the physical activity during different sided games in elite soccer players during different training sessions. Twenty elite soccer players belonging to a French first league team (age: 24.3 ± 3.2 years; height: 178.1 ± 4.2 cm; body mass: 76.9 ± 4.3 kg) participated in different small and large-sided games (SSG: i.e. 5 vs. 5, 6 vs. 6, 7 vs. 7; and LSG: i.e. 8 vs. 8, 9 vs. 9 and 10 vs. 10 with and without goalkeepers) repeated at 2 different sessions within a competitive season. Peak speed reached (Vmax), heart rate (HR) responses and the total distance covered (TDC) at walking (0-6 km.h-1), very-light (>6-10 km.h-1), light (>10-16 km.h-1), moderate (>16-23 km.h-1), and high (>23 km.h-1) intensities were measured and analyzed using global positional system (GPS) during all SSG and LSG. No statistical significant differences of Vmax, HR response, TDC, and TDC at high and moderate intensities for all sided games played between 2 different sessions were found. Moreover, the inter-individual coefficients of variation of HR during all SSG were lower than 8.6% with no statistical significant differences when SSG and LSG were repeated at 2 different sessions. In conclusion, the physical performance and especially the high intensities activities of elite soccer players present good reproducibility when different types of SSG were applied in 2 different sessions in the same period, even if the rules and formats were being manipulated allowing coaches to use it with a target time-motion characteristic and an equivalent workload week after week.

The Post-Illumination Pupil Response (PIPR)

The post-illumination pupil response (PIPR) has been quantified using four metrics, but the spectral sensitivity of only one is known; here we determine the other three. To optimize the human PIPR measurement, we determine the protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation. The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer. Experiment 1: Spectral sensitivity of four PIPR metrics (plateau, 6 seconds, area under curve early and late recovery) was determined from a criterion PIPR to a 1-second pulse and fitted with vitamin A1 nomogram (λ(max) = 482 nm). Experiment 2: The PLR was measured as a function of three stimulus durations (1 second, 10 seconds, 30 seconds), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8-14.8 log quanta.cm(-2).s(-1)), and two wavelengths, one with high (465 nm) and one with low (637 nm) melanopsin excitation. Intra- and interindividual coefficients of variation (CV) were calculated. The melanopsin (opn4) photopigment nomogram adequately describes the spectral sensitivity of all four PIPR metrics. The PIPR amplitude was largest with 1-second short-wavelength pulses (≥ 12.8 log quanta.cm(-2).s(-1)). The plateau and 6-second PIPR showed the least intra- and interindividual CV (≤ 0.2). The maximum duration of the sustained PIPR was 83.0 ± 48.0 seconds (mean ± SD) for 1-second pulses and 180.1 ± 106.2 seconds for 30-second pulses (465 nm; 14.8 log quanta.cm(-2).s(-1)). All current PIPR metrics provide a direct measure of the intrinsic melanopsin photoresponse. To measure progressive changes in melanopsin function in disease, we recommend that the PIPR be measured using short-duration pulses (e.g., ≤ 1 second) with high melanopsin excitation and analyzed with plateau and/or 6-second metrics. Our PIPR duration data provide a baseline for the selection of interstimulus intervals between consecutive pupil testing sequences.

Individual differences in cardiac and vascular components of the pressor response to isometric handgrip exercise in humans

We tested the hypotheses that, in humans, changes in cardiac output (CO) and total peripheral vascular resistance (TPR) occurring in response to isometric handgrip exercise vary considerably among individuals and that those individual differences are related to differences in muscle metaboreflex and arterial baroreflex function. Thirty-nine healthy subjects performed a 1-min isometric handgrip exercise at 50% of maximal voluntary contraction. This was followed by a 4-min postexercise muscle ischemia (PEMI) period to selectively maintain activation of the muscle metaboreflex. All subjects showed increases in arterial pressure during exercise. Interindividual coefficients of variation (CVs) for the changes in CO and TPR between rest and exercise periods (CO: 95.1% and TPR: 87.8%) were more than twofold greater than CVs for changes in mean arterial pressure (39.7%). There was a negative correlation between CO and TPR responses during exercise (r = -0.751, P < 0.01), but these CO and TPR responses correlated positively with the corresponding responses during PEMI (r = 0.568 and 0.512, respectively, P < 0.01). The CO response during exercise did not correlate with PEMI-induced changes in an index of cardiac parasympathetic tone and cardiac baroreflex sensitivity. These findings demonstrate that the changes in CO and TPR that occur in response to isometric handgrip exercise vary considerably among individuals and that the two responses have an inverse relationship. They also suggest that individual differences in components of the pressor response are attributable in part to variations in muscle metaboreflex-mediated cardioaccelerator and vasoconstrictor responses.

Development of a new Sonovue™ contrast-enhanced ultrasound approach reveals temporal and age-related features of muscle microvascular responses to feeding

Compromised limb blood flow in aging may contribute to the development of sarcopenia, frailty, and the metabolic syndrome. We developed a novel contrast-enhanced ultrasound technique using Sonovue™ to characterize muscle microvasculature responses to an oral feeding stimulus (15 g essential amino acids) in young (∼20 years) and older (∼70 years) men. Intensity-time replenishment curves were made via an ultrasound probe “fixed” over the quadriceps, with intermittent high mechanical index destruction of microbubbles within muscle vasculature. This permitted real-time measures of microvascular blood volume (MBV), microvascular flow velocity (MFV) and their product, microvascular blood flow (MBF). Leg blood flow (LBF) was measured by Doppler and insulin by enzyme-linked immunosorbent assay. Steady-state contrast concentrations needed for comparison between different physiological states were achieved <150 sec from commencing Sonovue™ infusion, and MFV and MBV measurements were completed <120 sec thereafter. Interindividual coefficients of variation in MBV and MFV were 35–40%, (N = 36). Younger men (N = 6) exhibited biphasic vascular responses to feeding with early increases in MBV (+36%, P < 0.008 45 min post feed) reflecting capillary recruitment, and late increases in MFV (+77%, P < 0.008) and MBF (+130%, P < 0.007 195 min post feed) reflecting more proximal vessel dilatation. Early MBV responses were synchronized with peak insulin but not increased LBF, while later changes in MFV and MBF occurred with insulin at post absorptive values but alongside increased LBF. All circulatory responses were absent in old men (N = 7). Thus, impaired postprandial circulation could impact age-related declines in muscle glucose disposal, protein anabolism, and muscle mass.

Stress and muscle damage monitoring in high-level basketball players

Close complex monitoring during the entire training period is essential for professional athletes to assess the effect of the training programme and to determine the quality of recovery. Follow-up of biochemical and hormonal variables throughout the season can help realize the above-mentioned goals. Objectives: To determine baseline blood creatine kinase (CK) and cortisol (C) levels in professional basketball players before the beginning of regular training and to follow up the subsequent levels of blood C and CK over an entire season with analysis of dynamic changes in relation to individual coefficients of variation. Methods: Six professional basketball players were monitored from the first pre-season day to the end of a regular season. Blood samples were collected at six time points: before the pre-season, after the pre-season and four times during the in-season to determine blood C and CK concentrations. Results: Individual trends of the investigated variables were established and analysed with respect to the calculated intra- and inter-individual coefficients of variation for C and CK. Dynamic changes in C and CK levels coincided with changes in the content of the training process. Conclusion: In summary, the findings in the present study suggest that long-term intensive exercise in basketball has a significant influence on the blood cortisol profile. Muscle damage was associated with bodily collisions between the players but not with stress response in the current study.

Large inter-individual variation of the pharmacodynamic effect of anticoagulant drugs on thrombin generation

Anticoagulation by a standard dosage of an inhibitor of thrombin generation presupposes predictable pharmacokinetics and pharmacodynamics of the anticoagulant. We determined the inter-individual variation of the effect on thrombin generation of a fixed concentration of direct and antithrombin-mediated inhibitors of thrombin and factor Xa. Thrombin generation was determined by calibrated automated thrombinography in platelet-poor plasma from 44 apparently healthy subjects which was spiked with fixed concentrations of otamixaban, melagatran, unfractionated heparin, dermatan sulfate and pentasaccharide. The variability of the inhibitory effect of the different anticoagulants within the population was determined using the coefficient of variation, i.e. the standard deviation expressed as a percentage of the mean. The inter-individual coefficients of variation of the endogenous thrombin potential and peak height before inhibition were 18% and 16%, respectively and became 20%-24% and 24%-43% after inhibition. The average inhibition of endogenous thrombin potential and peak height (ETP, peak) brought about by the anticoagulants was respectively: otamixaban (27%, 83%), melagatran (56%, 63%), unfractionated heparin (43%, 58%), dermatan sulfate (68%, 57%) and pentasaccharide (25%, 67%). This study demonstrates that the addition of a fixed concentration of any type of anticoagulant tested causes an inhibition that is highly variable from one individual to another. In this respect there is no difference between direct inhibitors of thrombin and factor Xa and heparin(-like) inhibitors acting on the same factors.

Intra- and inter-individual variability in urinary nicotine excretion and plasma cotinine in adult cigarette smokers

Urinary nicotine equivalents (NE) and plasma cotinine are widely used as a biomarker for exposure to tobacco products, but there is limited information on intra- and inter-individual variability in the literature. Data were gathered from 13 randomized controlled clinical studies sponsored by Philip Morris USA, with study durations between 2 and 8days for the short term (ST) and 3–12months for the long term (LT) studies. Coefficients of variation (CV) were compared and a linear mixed model was used to partition the total study variability into inter- and intra-individual variability. In the ST and LT studies respectively, the root–mean–square (RMS) intra-individual CV was 19% and 29% for NE (mg/24h); 19% and 33% for NE (mg/cig) and 13% and 22% for plasma cotinine. The RSM inter-individual CV was 38% and 38% for NE (mg/24h), 25% and 32% for NE (mg/cig) and 38% and 37% for plasma cotinine, in ST and LT study, respectively. Intra-individual CV was smaller in ST studies than in LT studies, and was significantly less than inter-individual CV in ST studies. Daily cigarette consumption alone could not explain all the variability in NE and plasma cotinine. The variability estimates could be used for clinical study design of clinical and developing regulatory guidance.

Development and analytic validation of an immunoassay for the quantification of canine S100A12 in serum and fecal samples and its biological variability in serum from healthy dogs

S100A12 (calgranulin C) is a Ca 2+-binding protein that has been proposed to play a central role in both innate and acquired immune responses. In humans, S100A12 has been reported to be increased in serum and/or plasma in patients with various inflammatory disorders, and this protein has been suggested to be a sensitive and specific marker for inflammatory bowel disease (IBD). An immunoassay for S100A12 is currently available for use in humans, but antibodies against the human protein do not cross-react with canine S100A12 (cS100A12). Both sensitive and specific markers for canine patients with systemic or localized inflammatory diseases are currently lacking, thus the aim of this study was to develop and analytically validate a radioimmunoassay (RIA) for the quantification of cS100A12 in serum and fecal specimens and to determine the biological variation of cS100A12 in serum from healthy dogs. A competitive liquid-phase RIA was developed and analytically validated by determining assay working range, dilutional parallelism, spiking recovery, and intra- and inter-assay variability. Reference intervals for serum and fecal concentrations of cS100A12 were established from 124 and 65 healthy dogs, respectively, and components of variation for serum cS100A12 were determined from 11 dogs over 2.6 months. The working range of the assay was 0.6–432.7 μg/L. No cross-reactivity was observed with the cS100A8/A9 protein complex, the closest structural analogues available. Observed-to-expected ratios (O/E) for the serial dilution of serum and fecal extracts ranged from 97.2 to 146.8% and from 75.3 to 129.8%, respectively. O/E for spiking recovery for serum and fecal extracts ranged from 87.8 to 130.4% and from 84.8 to 143.8%, respectively. Coefficients of variation (CV) for intra- and inter-assay variability for sera were ≤8.1% and ≤7.8%, respectively, and were ≤7.8% and ≤8.7%, respectively, for fecal extracts. Reference intervals for serum and fecal cS100A12 were 33.2–225.1 μg/L and <24−745 ng/g, respectively. For biological variability testing, analytical, intra-individual, inter-individual, and total CV were 5.7, 29.2, 31.2, and 66.0%, respectively, yielding an index of individuality of 0.95 and a minimum critical difference ( p < 0.05) for sequential values of 84.9%. The RIA for cS100A12 measurement described here is analytically sensitive and specific, linear, accurate, precise, and reproducible, and will facilitate further research into the clinical utility of quantifying serum and fecal cS100A12 in canine patients with inflammatory diseases. Moderate changes in serum cS100A12 concentrations may be clinically relevant; however, the use of a population-based reference interval may require caution.