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Intra- and inter-individual biological variability data bank.

Different results are usually observed when a quantity is measured in different specimens from the same individual obtained over a time span. For an individual, this variation is due to the imprecision of the measurement procedure, that is to say the metrological variability, as well as to the rhythmic and random fluctuations of the quantity value around a virtual homeostatic set point, that is to say the intra-individual biological variability. On the other hand, when studying the intra-individual biological variation of a quantity a mean value, the virtual homeostatic set point, is estimated for each individual participating in the study. The variation among these mean values is due to the inter-individual biological variability.

Chemistry, Clinical↗

Intravirion reverse transcripts in the peripheral blood plasma on human immunodeficiency virus type 1-infected individuals.

Variable levels of viral DNA have been demonstrated within human immunodeficiency virus type 1 (HIV-1) virions purified from cell cultures. In the present studies, it is demonstrated that DNase-resistant viral DNA is associated with HIV-1 virions purified from the peripheral blood plasma of both symptomatic and asymptomatic HIV-1-infected individuals. The differences in viral DNA copy numbers, detected by quantitative PCR in various regions of the HIV-1 genome, indicated that the intravirion HIV-1 DNA is frequently, but perhaps not totally, the result of partial reverse transcription. These in vivo data suggest that it may be valuable to further investigate the impact of virion-associated viral DNA upon the efficiency of intra- and interhost HIV-1 transmission modes.

Acquired Immunodeficiency Syndrome↗

Individual difference variables in close relationships: a contextual model of marriage as an integrative framework.

We examined and refined a contextual model of marriage (Bradbury & Fincham, 1987) in order to organize the associations between individual difference variables and satisfaction in close relationships. Seventy-eight spouses were administered instruments assessing marital satisfaction and individual differences in femininity, masculinity, dysfunctional relationship beliefs, and causal and responsibility attributions for marital difficulties. As predicted, higher levels of satisfaction were related to femininity and to partner's femininity, and lower levels of satisfaction were related to dysfunctional beliefs and less benign attributions. More important, two competing hypotheses relating to the contextual model were tested. A model in which the transitory, or proximal, context (e.g., responsibility attributions for specific relationship events) mediates the relation between the stable, or distal, context (e.g., general beliefs about relationships) and satisfaction was refuted. Support was obtained, however, for a model in which proximal and distal variables both account for unique variance in marital satisfaction. The usefulness of distinguishing between transitory and stable variables and the implications of the contextual model for organizing research on close relationships are discussed.

Adult↗

Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.

BACKGROUND: Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. METHODS AND FINDINGS: Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0-6h were observed. CONCLUSIONS: The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.

Administration, Rectal↗

Knee strength variability between individuals across ranges of motion and hip angles.

PURPOSE: Isokinetic strength is normally measured for a single range of motion and body position. This study quantified the variability, between individuals, in the relationships between a single peak knee extension moment and the isokinetic extension moments measured for different hip angles and ranges of knee motion. Effects of hip angle, and of the starting knee angle of the range of motion, on isokinetic knee extension strength were also determined. METHODS: The isokinetic knee extension strength of 10 subjects was measured at 30 degrees x s(-1) to a knee flexion angle of 10 degrees from starting knee angles of 90, 75, 60, 45, and 30 degrees, in both the seated and supine positions. Moments were normalized to the peak moment from a reference contraction. RESULTS: Peak moments and moments at larger knee flexion angles were greater in the seated than in the supine position. The starting knee angle affected the peak moment, the angle of peak moment, and the moments over the initial and final portions of the range of motion. Peak moments were highly correlated between all hip angle-starting knee angle combinations. However, the normalized peak moments, the angles of peak moment, and the normalized angle-specific moments all varied considerably between subjects. The pooled standard deviation and average coefficient of variation of the normalized angle-specific moments between subjects were 10.5% of the normalizing moment and 15.7%, respectively. Excluding the reference contraction, between-subject variability was unaffected by hip angle or starting knee angle. CONCLUSIONS: Influences of hip angle, starting knee angle, and individual differences on isokinetic knee extension strength must be considered to ensure that the moments obtained from isokinetic testing adequately reflect the general strength capabilities of an individual.

Adult↗

Reliability of the comet assay in cryopreserved human sperm.

BACKGROUND: Although the comet assay has potential value for measuring DNA damage in large epidemiological human sperm studies, it is impractical to perform the assay daily on fresh semen samples. Therefore, before its use in epidemiological studies, the reliability of the comet assay in measuring DNA damage in cryopreserved sperm should be compared with that in fresh human sperm. METHODS: Semen samples from 16 men were cryopreserved in liquid nitrogen (LN) using four methods: flash freezing with and without cryopreservative, and programmable freezing with and without cryopreservative. Neutral microgel electrophoresis was performed and comets were stained with YOYO-1. Comet length was measured using an eyepiece micrometer at x400 magnification. RESULTS: The highest correlation was between comet assay results obtained from fresh human semen compared with semen flash frozen without cryopreservative (R = 0.88). However, the method of cryopreservation, as compared with other sources of variability, accounted for only 6% of the variability. Inter-individual variability accounted for 20%, and individual sperm-to-sperm variability within an ejaculate accounted for 65%. CONCLUSIONS: Flash-freezing in LN without cryopreservative most closely reproduced the results obtained using fresh human semen samples, and thereby represents the most appropriate cryopreservation method for human semen in epidemiological studies utilizing the neutral comet assay.

Adult↗

[Estimate of the dialysis dose using ionic dialysance].

UNLABELLED: The Diascan equipment (Hospal) measures ionic dialysance from which it derives the Kt/V. It is automatic, does not need blood samples and displays the results in real time. The aim of the present study was to compare the Diascan Kt/V with the Kt/V obtained with four simple formulas: two based on a single pool model of urea kinetics (Lowrie 1983 and Daugirdas 1993) and the other based on the two pool model (Maduell formulation applied to Lowrie Kt/V and that proposed by Daugirdas 1995). We have analyzed the inter-method variability, the degree of relationship among the different procedures for Kt/V calculation and the intra-individual variability. The intermethod variability between Kt/V Diascan and Kt/V calculated by the four simple formulas were studied in one hemodialysis session in 19 patients. The Kt/V Diascan was statistically different from that calculated by the four formulas (1,021 +/- 0.140 Diascan vs 1,147 +/- 0.124 for Lowrie-83; vs 1,373 +/- 0.164 for Daugirdas-93; vs 0.963 +/- 0.105 for Maduell and vs 1,173 +/- 0.143 for Daugirdas-95, p < 0.01). The lowest inter-method variability was obtained with the Maduell's Kt/V (relative difference 9%) but even in this case 37% of patients had a variability above 10%. The correlation coefficient was not high enough to allow an estimation of the different Kt/V measurements from the Diascan Kt/V by a regression equation. To study the individual relationship between the Diascan Kt/V and the Kt/V calculated by the four formulations, we have determined the Kt/V every 30 minutes in one hemodialysis session in 30 patients. In all patients we observed a good relationship between the Diascan Kt/V and the other four (correlation coefficient of 0.9952 for Lowrie-83, 0.9976 for Daugirdas-93, 0.9961 for Maduell and 0.9971 for Daugirdas-95); with these correlation coefficientes it was possible to derive regression equations and to obtain an estimation of the four Kt/V's from the Diascan Kt/V. To study the individual variability of each procedure used in the Kt/V calculations we determined the coefficient of variation of the different methods in 5 consecutive hemodialysis sessions performed under identical conditions in 19 patients. The coefficient of variation was 3.7 +/- 1.8% for the Diascan Kt/V; 6.0 +/- 2.8 for the Lowrie-83 Kt/V; 5.8 +/- 2.4 for the Daugirdas-93 Kt/V; 6.5 +/- 2.6% for the Maduell Kt/V; and 5.7 +/- 2.2% for the Daugirdas-95 Kt/V (p < 0.01 between the Diascan Kt/V and the other four). CONCLUSIONS: Although the Diascan Kt/V was statistically different from the other four Kt/V's calculated by the usual formulas, the Diascan Kt/V has an excellent correlation with all of them and showed a lower intra-individual variability. It is possible to obtain an estimation of the calculated Kt/V for each patient by linear regression equation.

Electrophysiology↗

[Variability determination in chromatin condensation and seminal alpha glucosidase with relation with the spermiogram].

BACKGROUND: Sperm functional tests as an addition to semen analysis have been used to study the fertilization ability of spermatozoa. Besides the usual variability of the seminal analysis an individual variability in the results of functional tests has been recently found. AIM: To evaluate in a three months period, the individual variability of sperm parameters and sperm maturation using the chromatin condensation test and epidydime a-glucosidase (that allows to discriminate obstructive processes). MATERIAL AND METHOD: The evaluation was carried out in two donors (12 samples) apparently in good health. One of them presented evident semen analysis alterations (donor 1) and the other was considered normal under the WHO standards (donor 2). RESULTS: The averages for donor 1 were: Sperm count 24 x 106 sperm/ml (range 10-58 x 106 sperm/ml), morphology 31.8% (range 30-35%), total motility 33% (range 20-42%), sperm maturation 38% (range 28-78%), a-glucosidase 8.65 (U/ml (range 5-10 (U/ml). The averages for donor 2 were: Sperm count 96 x 106 sperm/ml (range 50-140 x 106 sperm/ml), morphology 32.2% (range 30-35%), total motility 69% (range 58-78%), sperm maturation 17% (range 7-30%), a-glucosidase 36.9 (U/ml (range 20-82 (U/ml). CONCLUSIONS: These results show that significant variations can be found in the sperm parameters and in seminal plasma a-glucosidase; however these variations are generally maintained at the normal or abnormal ranges for each individual, except the sperm morphology that was constant and with low variation in both donors. The determination of the chromatin condensation in the semen analysis gives an additional information about the grade of sperm maturation and would be of great value for differentiating between sperm samples that show similar morphology values.

Adult↗

Variability of the 13C-octanoic acid breath test for gastric emptying of solids in healthy children.

AIM: To assess the intra-individual variability of the 13C-octanoic acid breath test using non-dispersive infrared spectrometry for gastric emptying of solids in healthy children. METHODS: A 13C-octanoic acid breath test was performed at least two times in 19 healthy children (age 12.4 +/- 2.7 years) 2-7 days apart to measure gastric emptying of solids. Breath samples were taken before eating a 13C-octanoic acid-labelled pancake and at 15-min intervals for the following 240 min. Breath samples were analysed using non-dispersive infrared spectrometry; 13C-recovery was used to calculate values for gastric half-emptying time (t(1/2)), gastric lag phase (t(lag)) and gastric emptying coefficient. Intra-individual variability of the parameters t(1/2), t(lag) and gastric emptying coefficient were expressed as coefficient of intrasubject variation. RESULTS: The mean coefficient of intrasubject variation of t(1/2) was 13.3 +/- 7.9% (range 2.5-29.6%; interindividual range 99-204 min; intra-individual range 5-84 min for t(1/2)). The mean coefficient of intrasubject variation of t(lag) was 13.6 +/- 7.5% (range 0.8-27.8%) (interindividual range 65-146 min; intra-individual range 1-50 min for t(lag)). The mean coefficient of intrasubject variation of gastric emptying coefficient was 12.5 +/- 6.8% (range 3.4-30.2%; interindividual range 2.3-3.9; intra-individual range 0.17-1.4 for gastric emptying coefficient). The coefficient of intrasubject variations of t(1/2), t(lag) and gastric emptying coefficient were independent of the values of t(1/2), t(lag) and gastric emptying coefficient. CONCLUSIONS: Gastric emptying in healthy children is characterized by a large inter- and intra-individual variability and is concordant with the results obtained with other techniques.

Adolescent↗

Trends and variability in individual insurance products in California.

This paper examines recent trends in benefits and premiums for individual health insurance products purchased by Californians. There is much variability in the coverage available in the individual insurance market, with correspondingly wide variability in premiums. Despite concerns about increased consumer cost sharing, the average share of health spending covered by these products has remained constant between 1997 and 2002. Whether this trend can continue in the face of higher health costs is unclear.

California↗

Variability of pressure-flow analysis parameters in repeated cystometry in patients with benign prostatic hyperplasia.

Urodynamic investigation becomes increasingly important in the diagnosis of bladder outflow obstruction in patients with benign prostatic hyperplasia. To date, different methods for evaluation of the pressure-flow relationship and quantification of the grade of obstruction are available. Models for pressure-flow analysis are briefly explained. The variability of the parameters is investigated by evaluation of 75 patients in whom 2 sequential voidings during urodynamic investigation were analyzed. The results showed that in 87% of these patients individual maximum flow differences of first and second voidings were less than 2 ml. per second. Individual detrusor pressure at maximum flow differences were less than 15 cm. water in 80% of these patients, while in 80% the intra-individual variation of the pressure-flow results was less than 15 cm. water for the minimal voiding pressure parameters (minimal urethral opening detrusor pressure and urethral resistance factor). For the pressure-flow parameter that defines the theoretical urethral lumen during voiding, the variation was less than 1.5 mm.2 in 84% of the patients. Patients with larger intra-individual differences are discussed. We concluded that the observed, aforementioned differences can be regarded as an indication of normal intra-individual variability of voiding during urodynamic investigation. This intra-individual variability, however, seldom leads to a change in the clinical grade of bladder outflow obstruction. We conclude that investigators involved in therapeutic trials of benign prostatic hyperplasia must be aware of this intra-individual variability of micturition, since this variability is greater than the refined scale of the pressure-flow analysis models.

Humans↗

Prediction of mandibular growth rotation: assessment of the Skieller, Björk, and Linde-Hansen method.

The purpose of this investigation was to assess the method proposed by Skieller, Björk, and Linde-Hansen in 1984 to predict mandibular growth rotation. Our sample consisted of 40 randomly selected, untreated, adolescent subjects representative of the patient population generally encountered in orthodontic practice. The four independent variables identified in the Skieller study as having the highest predictive value (mandibular inclination, intermolar angle, shape of the lower border of the mandible, and inclination of the symphysis) were identified on initial lateral cephalograms. The proposed regression equations were applied and predicted mandibular rotations obtained. Final lateral cephalograms made 6 years after the initial profile radiographs were superimposed and actual mandibular rotation recorded. The observed and predicted rotations were compared and regression analyses performed to determine the amount of variability in observed values accounted for by the four variables individually and in combination. Only 5.6% of the variability in mandibular growth rotation could be accounted for using the four variables individually. Only 9% of the variability could be accounted for with a combination of the variables. In addition, we performed a Monte Carlo analysis, which mirrored the Skieller analysis but used random numbers instead of actual cephalometric data, to determine if the Skieller results may simply have capitalized on chance. Using the same forward stepwise selection procedure with a rejection level of P >.1, we found after 5000 simulations that a mean of 84% and a median of 94% of mandibular growth rotation variability could be accounted for using meaningless data in the Skieller analysis. This result was comparable to the Skieller value of 86%. In conclusion, information derived from pretreatment lateral cephalograms using the Skieller, Björk, and Linde-Hansen method does not permit clinically useful predictions to be made in a general population relative to the direction of future mandibular growth rotation.

Cephalometry↗

Introducing inter-individual growth variability in the assessment of a cephalopod population: application to the English Channel squid Loligo forbesi.

A new approach is presented here to better take into account inter-individual growth variability in age-structured models used for stock assessment. Cohort analysis requires knowledge of the age structure of the catch, generally derived from an age-length key and length-structure information. Age distribution at length is estimated by applying conditional quantile regression to a data set of lengths and ages estimated from calcareous parts. A "stochastic" age-length key that describes the probability of age-at-length is applied to the English Channel squid Loligo forbesi. Age distribution at length from quantile regression proved to be considerably less biased than that resulting from both polymodal decomposition (PD) and two separate slicing methods. Both catch-at-age and stock size were underestimated using classical methods. Estimations of fishing mortalities from classical methods were higher causing underestimation in yield simulations. Quantile regression offers a more complete statistical analysis of the stochastic relationships among random variables than mean regression and PD.

Age Factors↗

[Evaluation of the effect of environmental exposure to tobacco smoke on variability of peak expiratory flow rate in children].

A panel study was conducted in autumn (116 children) and repeated in spring (66 children) to test the hypothesis that the individual variability of peak expiratory flow rate (PEFR) depends on the environmental exposure to tobacco smoke (ETS). PEFR was measured twice a day (morning: PEFR-M; evening: PEFR-E), using individual meters at homes, in children exposed (ETS+) and not exposed (ETS-) to tobacco smoke at home. In examined groups the individual variability of PEFR-M was--on average--8.0% (ETS+; autumn), 8.1% (ETS+; spring), 10.5% (ETS-; autumn) and 7.7% (ETS-; spring). The individual variability of PEFR-E was 8.0% (ETS+; autumn), 7.9% (ETS+; spring), 9.5% (ETS-; autumn) and 7.4% (ETS-; spring). The results of multivariate analysis of within- and between-subject variability showed the presence of statistically significant within-subject variability only in ETS+ group (PEFR-M in autumn; PEFR-M and PEFR-E in spring). With all the limitations of a panel study design the findings suggest that environmental exposure to tobacco smoke in children affects the degree of within-subject variability of PEFR in children.

Child↗

Factors affecting the diffusion of online end user literature searching.

OBJECTIVES: The aim of this study was to identify factors that affect diffusion of usage of online end user literature searching. Fifteen factors clustered into three attribute sets (innovation attributes, organizational attributes, and marketing attributes) were measured to study their effect on the diffusion of online searching within institutions. METHODS: A random sample of sixty-seven academic health sciences centers was selected and then 1,335 library and informatics staff members at those institutions were surveyed by mail with electronic mail follow-up. Multiple regression analysis was performed. RESULTS: The survey yielded a 41% response rate with electronic mail follow-up being particularly effective. Two dependent variables, internal diffusion (spread of diffusion) and infusion (depth of diffusion), were measured. There was little correlation between them, indicating they measured different things. Fifteen independent variables clustered into three attribute sets were measured. The innovation attributes set was significant for both internal diffusion and infusion. Significant individual variables were visibility for internal diffusion and image enhancement effects (negative relation) as well as visibility for infusion (depth of diffusion). Organizational attributes were also significant predictors for both dependent variables. No individual variables were significant for internal diffusion. Communication, management support (negative relation), rewards, and existence of champions were significant for infusion. Marketing attributes were not significant predictors. CONCLUSIONS: Successful diffusion of online end user literature searching is dependent on the visibility of the systems, communication among, rewards to, and peers of possible users who promote use (champions). Personal image enhancement effects have a negative relation to infusion, possibly because the use of intermediaries is still seen as the more luxurious way to have searches done. Management support also has a negative relation to infusion, perhaps indicating that depth of diffusion can increase despite top-level management actions.

Diffusion of Innovation↗

Robustness of chlorzoxazone as an in vivo measure of cytochrome P450 2E1 activity.

AIMS: Chlorzoxazone is metabolized by cytochrome P450 2E1 (CYP2E1) to a single oxidized metabolite, 6-hydroxychlorzoxazone. The aim of the study was to test the robustness of chlorzoxazone as an in vivo probe of CYP2E1 activity in humans, with emphasis on investigating short-term and long-term intra-individual variabilities and effects of different doses of the drug. In addition, the influences of body build, drug metabolizing enzyme genotype, blood sampling time, and moderate recent ethanol intake were investigated. METHODS: The 6-hydroxychlorzoxazone:chlorzoxazone (metabolic) ratio in plasma was measured at 2 h in 28 male and nine female volunteers following a single oral dose of 500 mg chlorzoxazone. Similarly, the metabolic ratios at 4 h and 6 h were measured in 20 of the males. The metabolic ratio at 2 h was also determined 1.5 and 2.5 years later in 13 and seven males, respectively, and weekly for 3 weeks in seven males, after a dose of 500 mg, once at higher (750 mg) and lower (250 mg) doses, and once (500 mg) following moderate ethanol intake (0.5 g kg(-1) body weight) the preceding evening. Genotypes were determined for CYP2E1 as well as for N-acetyltransferase 2 and glutathione transferase M1. RESULTS: Excluding an outlier (ratio = 1.6) the metabolic ratio at 2 h ranged from 0.12 to 0.61 (n = 36). A positive correlation with body weight (r = 0.61, P < 0.001) suggested dose-dependent metabolism of chlorzoxazone. The metabolic ratio decreased with increasing chlorzoxazone dose (P = 0.01), again suggesting dose-dependent metabolism. Long-term (yearly intervals) and short-term (weekly intervals) intra- and interindividual variabilities in metabolic ratio were similar (30% and 63%vs 28% and 54%, respectively). Both inter- and intra-individual variabilities tended to decrease with increasing dose of chlorzoxazone. There was no significant influence of moderate ethanol intake the preceding evening, or of CYP2E1 genotype on the metabolic ratio. CONCLUSIONS: The relatively low intra-individual variability in the metabolism of chlorzoxazone suggests that a single-sample procedure may suffice to assess CYP2E1 activity in vivo. However, chlorzoxazone metabolism is dose-dependent at commonly used doses and it is therefore advisable to adjust the dose for body weight. Moderate intake of ethanol the preceding evening did not significantly affect the chlorzoxazone metabolic ratio.

Adult↗

Tapping and anticipation performance in attention deficit hyperactivity disorder.

The objective of this study was to examine the precise timing of a motor response in a sample of adolescents with ADHD and comparison participants. 46 participants with ADHD (M age=15.6, SD=1.4; 40 boys) and 44 control participants (M age=15.3, SD=1.4; 40 boys) were recruited through a metropolitan hospital. Participants were administered a tapping task and an anticipation task. Adolescents with ADHD displayed significantly more intra-individual variability on the visual 1000-msec. frequency interval of the tapping task and displayed lower accuracy on the cued and uncued trials of the anticipation task than comparison participants. Intra-individual variability on the tapping task was correlated with intra-individual variability on the anticipation task within both the ADHD and control groups. These findings suggest that adolescents with ADHD have impairments in both the cognitive representation and motor production of the precise timing of a motor response.

Acoustic Stimulation↗

Variability of cardiovascular and plasma noradrenaline responses to sustained isometric contraction in normal human subjects.

1. Eight healthy adult males underwent three sustained isometric contractions at 30% of maximal voluntary contraction for 3 min, within a 9 day period. 2. The study focuses on the inter-individual and day-to-day intra-individual variability of cardiovascular and plasma noradrenaline responses to sustained isometric contraction. 3. The results of this study indicate that inter-individual variability is generally greater than intra-individual variability. Diastolic blood pressure was the most sensitive as well as the least variable cardiovascular parameter measured. 4. The variability of plasma noradrenaline levels in both the basal and the stimulated state was high. The present study suggests that it is preferable to determine the 'true' noradrenaline peak after the release of handgrip, as this is associated with a lower variability than the plasma noradrenaline peak taken at the time of the release of handgrip.

Adult↗