Interindividual Coefficient Of Variation Research Articles

Defecatory Function Studies Using the Fecobionics Device Are Repeatable.

Only limited data exist on repeatability of anorectal studies with the established physiological and clinical technologies for assessment of anorectal function. Fecobionics is a new multi-sensor simulated feces that provide data by integrating elements from current tests. To study repeatability of anorectal data obtained with the Fecobionics device. We assessed the database of Fecobionics studies to determine how many repeated studies were done.From a total of 260 Fecobionics studies, 19 subjects with repeated studies using approximately the same protocol and prototype were identified. Key pressure and bending parameters were assessed and the repeatability analyzed using Bland Altman plots. Furthermore, the inter- and intra-individual coefficient of variation (CV) were computed. Fifteen subjects (5F/10M) with repeated studies were normal subjects, three were patients with fecal incontinence and one subject suffered from chronic constipation. The main analysis was conducted on the cohort of normal subjects. The bias for 11 parameters were within the confidence interval, whereas two were slightly outside. The interindividual CV was lowest for the bend angle (10.1-10.7) and between 16.3 and 51.6 for the pressure parameters. The intra-individual CVs were approximately half of the inter-individual CVs, spanning from 9.7 to 27.6. All data from normal subjects were within previously defined normality. The Fecobionics data showed acceptable repeatability with bias within the confidence limits for almost all parameters. The intra-individual CV was much lower than the inter-individual CV. Dedicated large-scale studies are warranted to evaluate the influence of age, sex, and disease on repeatability as well as comparing between technologies.

Blood Plasma Proteome: A Meta-Analysis of the Results of Protein Quantification in Human Blood by Targeted Mass Spectrometry.

A meta-analysis of the results of targeted quantitative screening of human blood plasma was performed to generate a reference standard kit that can be used for health analytics. The panel included 53 of the 296 proteins that form a “stable” part of the proteome of a healthy individual; these proteins were found in at least 70% of samples and were characterized by an interindividual coefficient of variation <40%. The concentration range of the selected proteins was 10−10−10−3 M and enrichment analysis revealed their association with rare familial diseases. The concentration of ceruloplasmin was reduced by approximately three orders of magnitude in patients with neurological disorders compared to healthy volunteers, and those of gelsolin isoform 1 and complement factor H were abruptly reduced in patients with lung adenocarcinoma. Absolute quantitative data of the individual proteome of a healthy and diseased individual can be used as the basis for personalized medicine and health monitoring. Storage over time allows us to identify individual biomarkers in the molecular landscape and prevent pathological conditions.

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.

An Ex Vivo Analysis of Thrombin Generation and Thromboelastometry in Patients Undergoing Treatment with Rivaroxaban Demonstrates Sustained Anticoagulant Effect and High Inter-Individual Variability

Background : Rivaroxaban, 20 mg orally administered once daily, is widely used for secondary prevention of venous thromboembolism (VTE) without the need for routine laboratory monitoring. It is licensed for the prevention of VTE after major orthopedic surgery, for the treatment of acute symptomatic VTE, the secondary prevention of VTE and for prevention of stroke in patients with non-valvular atrial fibrillation. Rivaroxaban selectively and competitively inhibits free factor Xa (FXa) and prothrombinase/clot-associated FXa through reversible interactions thereby inhibiting thrombin generation and decreasing fibrin clot formation. The need of laboratory evaluation of rivaroxaban is actually questioned.Aim : In patients treated for secondary prevention of VTE, we evaluated ex vivo the anticoagulant potency of rivaroxaban treatment at different times after drug intake.Methods : 97 patients (39 males, 58 females; median age: 59 years) with idiopathic VTE were treated with rivaroxaban (20 mg/day) for a period longer than 6 months and compared to 30 controls age and sex-matched. Rivaroxaban concentrations (STA®-Liquid Anti-Xa), thrombin generation (PPP-reagent 5 pM TF; calibrated automated thrombogram, Stago France) and whole blood thromboelastometry (5 pM tissue factor; ROTEM® Werfen) were assessed. The interval between drug intake and blood sampling was registered.Results : Treatment with rivaroxaban significantly inhibited thrombin generation (TG) and prolonged clotting time (CT): 93% of patients had TG inferior to the lower normal limit and 77% had CT longer than the upper normal limit. This effect in both assays, was not correlated to its plasma concentrations, it was significant from the 1st hour after drug intake and persisted at similar levels during the daily therapeutic cycle even at low concentrations (30 ng/ml). Rivaroxaban had no effect on clot firmness. The inter-individual coefficient of variation of rivaroxaban concentrations and TG/ROTEM alterations after drug intake ranged from 50% to 100%.Conclusion : Once daily administration of rivaroxaban induces sustained daily anticoagulant effect, detected by TG and ROTEM assays, with no significant changes related to drug concentration reduction. This profile could explain the wide therapeutic window and the favorable benefit risk ratio of the treatment with rivaroxaban. Due to the high variability the identification of patients with extreme values of TG could be useful strategy for treatment optimization on individual basis. DisclosuresNo relevant conflicts of interest to declare.

Therapeutic Drug Monitoring of Isavuconazole: Serum Concentration Variability and Success Rates for Reaching Target in Comparison with Voriconazole.

: IntroductionIsavuconazole (ISZ) is used in the treatment of aspergillosis and mucormycosis. The purpose of this study was to evaluate the therapeutic drug monitoring (TDM) of ISZ samples from a clinical setting performed at Statens Serum Institut. Materials/methods: Isavuconazole serum concentrations were determined by fluorescent detection on a UHPLC. Serum-ISZ (s-ISZ) results were included and compared to those of serum-voriconazole (s-VRZ) in a 33 month period from March 2017. Clinical data were obtained for patients receiving ISZ. The therapeutic range was initially 2–10 mg/L, but was adjusted to 2–5 mg/L during the study period except for selected patients with Mucorales infections who received off-label doses of ISZ. Results: A total of 273 s-ISZ and 1242 s-VRZ measurements from 35 and 283 patients, respectively, were included. Seventeen patients had received both ISZ and VRZ with TDM within the study period. The median s-ISZ was 4.3 mg/L (0.5–15.4 mg/L) with 83% of measurements within the therapeutic index. The median s-VRZ was 2.6 mg/L (0.2–21.9 mg/L) with 67% of measurements within the therapeutic index. The median intra-/interindividual coefficient of variation (CV) was 43.4%/54.8% for ISZ compared to 53.2%/83.3% for VRZ. For patients receiving ISZ, the adverse events were mostly gastroenteric and few drug–drug interactions were observed. Furthermore, immediate change from ISZ to VRZ treatment seemed to lead to prolonged metabolism of ISZ with detection up to 35 days after discontinuation. Conclusions: The majority of patients achieved s-ISZ levels well within the therapeutic range with less intra/interindividual CV than patients receiving VRZ.

Development and Validation of Test for “Leaky Gut” Small Intestinal and Colonic Permeability Using Sugars in Healthy Adults

Oral monosaccharides and disaccharides are used to measure invivo human gut permeability through urinary excretion. The aims were as follows: (1) to obtain normative data on small intestinal and colonic permeability; (2) to assess variance on standard 16 g fiber diet performed twice; (3) to determine whether dietary fiber influences gut permeability measurements; and (4) to present pilot data using 2 selected probes in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Sixty healthy female and male adults, age 18-70 years, participated in 3 randomized studies (2 studies on 16.25 g and 1 study on 32.5 g fiber) in otherwise standardized diets. At each test, the following sugars were ingested: 12C-mannitol, 13C-mannitol, rhamnose (monosaccharides), sucralose, and lactulose (disaccharides). Standardized meals were administered from 24 hours before and during 24 hours post-sugars with 3 urine collections: 0-2, 2-8, and 8-24 hours. Sugars were measured using high-performance liquid chromatography-tandem mass spectrometry. Eighteen patients with IBS-D underwent 24-hour excretion studies after oral 13C-mannitol and lactulose. Baseline sugars (>3-fold above lower limits of quantitation) were identified in the 3 studies: 12C-mannitol in all participants; sucralose in 4-8, and rhamnose in 1-3. Median excretions/24 h (percentage of administered dose) for 13C-mannitol, rhamnose, lactulose, and sucralose were ∼30%, ∼15%, 0.32%, and 2.3%, respectively. 13C-mannitol and rhamnose reflected mainly small intestinal permeability. Intraindividual saccharide excretions were consistent, with minor differences with 16.25 g vs 32.5 g fiber diets. Median interindividual coefficient of variation was 76.5% (10-90 percentile: 34.6-111.0). There were no significant effects of sex, age, or body mass index on permeability measurements in health. 13C-mannitol measurements are feasible in IBS-D. Baseline 12C-mannitol excretion precludes its use; 13C-mannitol is the preferred probe for small intestinal permeability.

Monitoring Training Volume Through Maximal Number of Repetitions or Velocity-Based Approach.

This study aimed (1)to analyze the interindividual variability in the maximal number of repetitions (MNR) performed against a given relative load (percentage of 1-repetition maximum [%1RM]) and (2)to examine the relationship between the velocity loss (VL) magnitude and the percentage of completed repetitions with regard to the MNR (%Rep), when the %1RM is based on individual load-velocity relationships. Following an assessment of 1RM strength and individual load-velocity relationships, 14 resistance-trained men completed 5 MNR tests against loads of 50%, 60%, 70%, 80%, and 90% 1RM in the Smith machine bench-press exercise. The relative loads were determined from the individual load-velocity relationship. Individual relationships between load and velocity displayed coefficients of determination (R2) ranging from .986 to .998. The MNR showed an interindividual coefficient of variation ranging from 8.6% to 33.1%, increasing as the %1RM increased. The relationship between %Rep and the magnitude of VL showed a general R2 of .92 to .94 between 50% and 80% 1RM, which decreased to .80 for 90% 1RM. The mean individual R2 values were between .97 and .99 for all loading conditions. The %Rep when a given percentage of VL was reached showed interindividual coefficient of variation values ranging from 5% to 20%, decreasing as the %Rep increased in each load condition. Setting a number of repetitions had acceptable interindividual variability, with moderate relative loads being adjusted based on the individual load-velocity relationship. However, to provide a more homogeneous level of effort between athletes, the VL approach should be considered, mainly when using individual VL-%Rep relationships.

Biological variation of immunological blood biomarkers in healthy individuals and quality goals for biomarker tests

BackgroundCytokines, chemokines, adipocytokines, soluble cell receptors, and immune activation markers play an important role in immune responsiveness and can provide prognostic value since they reflect underlying conditions and disease states. This study was undertaken to investigate the components of biological variation for various laboratory tests of blood immunological biomarkers.ResultsEstimates of intra-individual coefficient of variation (CVI) and inter-individual coefficient of variation (CVG) were examined for blood immunological biomarkers. Biomarkers with CVI < 10% for both genders were CD3, CD4, and CD8 T-cells, serum levels of soluble cluster of differentiation 14 (sCD14), sCD163, and soluble glycoprotein 130 (sgp130). The CVI for serum levels of adiponectin, interleukin-1 receptor antagonist (IL-1Ra), macrophage inflammatory protein 1 beta (MIP-1β), soluble CD40 Ligand (sCD40L), soluble interleukin-2 receptor alpha (sIL-2Rα), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor II (sTNF-RII), and tumor necrosis factor alpha (TNF-α) were between 11 and 20%. Biomarkers with CVG < 20% were CD3 T-cell, and serum concentrations of sCD14, sCD40L, and sgp130. The biomarkers with CVG > 40% were adiponectin, IL-1ra, leptin, MIP-1β, sCD163, and sIL-2Rα.ConclusionThe biological variations of biomarkers have important monitoring value for longitudinal investigation and are essential for quality specification of tests that are performed in the laboratory. The CVI was relatively small while CVG was comparatively large and mean values of each biomarker vary between subjects. The individuality of biomarkers significantly influences reference interval values. A majority of the biomarkers in this study had strong individuality and the result of each biomarker should be cautiously interpreted if using established reference interval values. Comparison of a patient’s test result with previous ones may be more useful than the usage of conventional reference values.

Optimization of the alkaline comet assay for easy repair capacity quantification of oxidative DNA damage in PBMC from human volunteers using aphidicolin block

Assessment of DNA repair capacity (DRC) upon ex vivo challenge of peripheral blood mononuclear cells (PBMC) with oxidative damage inducing agents, as evaluated by the comet assay, is widely used as biomarker to assess the antioxidant status in human studies. Here, the alkaline comet assay was now optimized for easy and time saving detection of repair capacity upon oxidative stress-induced DNA damage using the DNA polymerase inhibitor aphidicolin (APC) to block repair of hydrogen peroxide (H2O2) induced DNA damage. Addition of a DMSO-containing DNA damage stop solution was found suitable to replace washing steps for H2O2 removal before APC block. Cell treatment with APC at 6 μM did not impact baseline DNA damage but could reliably block DNA repair after H2O2 challenge in both fresh and cryopreserved samples thus omitting the use of a starting time point control. Under the conditions used, frozen cells, with or without an additional 4 h rest, showed the same repair capacity as their fresh counterpart. The intra assay coefficient of variation (CV) was 3.3%. To provide proof of principle, the modified assay was applied to cryopreserved PBMC from 19 participants of a short-term Brassica diet intervention study investigating potential health promoting effects of the food intervention. Then, a 33% increase in DRC (p ≤ 0.01) could be shown in samples after intervention (mean ± SD: 5.82 ± 1) as compared to baseline (mean ± SD: 4.38 ± 1.21). Individual samples from baseline and intervention showed an inter-individual CV of 27.65% (baseline) and 17.26% (intervention). Taken together this modified comet assay protocol allows the facilitated detection of DNA repair in fresh or cryopreserved human PBMC samples with a good sensitivity and reliability and could be useful in human studies addressing the antioxidant status and repair capacity of PBMC.

Determination of Hepatitis B Immunoglobulin Infusion Interval Using Pharmacokinetic Half-life Simulation for Posttransplant Hepatitis B Prophylaxis.

BackgroundProphylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. This study established an individualized HBV prophylaxis protocol, through optimization of hepatitis B immunoglobulin (HBIG) administration, with application of simulative half-life (SHL).MethodsThis study involved five parts: Part 1 developed the SHL estimation method with 20 patients; Parts 2 and 3 assessed the SHL variability and developed a simulation model to apply SHL in 100 patients; Part 4 validated the simulation model in 114 patients, and Part 5 was a cross-sectional study on the current status of HBIG infusion intervals in 660 patients.ResultsIn Part 1, infusion of 10,000 IU HBIG induced add-on rise hepatitis B surface antibody (anti-HBs) titer of 5,252.5 ± 873.7 IU/L, which was 4.4% lower than actual measurement. Mean SHL of 20.0 ± 3.7 days was 2.2% longer than actual measurement. In Part 2, the medians of the intra- and inter-individual coefficient of variation in SHL were 13.5% and 18.5%, respectively. Pretransplant HBV DNA load and posttransplant antiviral therapy did not affect SHL. In Part 3, a simulation model was developed to determine the interval of HBIG infusion, by using SHL. In Part 4, all 114 patients were successfully managed with regular HBIG infusion intervals of ≥ 8 weeks, and the interval was prolonged to ≥ 12 weeks in 89.4%, with a target trough anti-HBs titer ≥ 200 IU/L. In Part 5, 47.4% of our patients received HBIG excessively, at a target trough titer of 500 IU/L.ConclusionSHL estimation using only clinically available parameters seems to be reliably accurate when compared with actual measurements. We believe that SHL estimation is helpful to establish a personalized HBV prophylaxis protocol for optimizing HBIG administration.

How stable is oxidative stress level? An observational study of intra- and inter-individual variability in urinary oxidative stress biomarkers of DNA, proteins, and lipids in healthy individuals

Oxidative stress in humans is affected by the health and nutritional status as well as exposure to external environmental factors. To evaluate the effects of external factors, an assessment of baseline levels as well as diurnal variations in oxidative stress status of healthy individuals is needed. In this study, we examined intra- and inter-individual variability of oxidative stress biomarkers (OSBs) of lipids (malondialdehyde [MDA] and four F2-isoprostane isomers, namely, 8-isoprostaglandinF2α [8-PGF2α], 11β-prostaglandinF2α [11-PGF2α], 15(R)-prostaglandinF2α [15-PGF2α], and 8-iso,15(R)-prostaglandinF2α [8,15-PGF2α]); proteins (o,o′-dityrosine [diY]); and DNA (8-hydroxy-2′-deoxyguanosine [8-OHdG]) in urine from healthy individuals. The significance of creatinine correction, which is typically used to account for urinary dilution, on OSB concentrations was evaluated. Analysis of 515 urine samples, collected longitudinally from 19 healthy individuals daily for over a month, showed inter-individual coefficient of variation (CV) in concentrations from 112% for MDA to 272% for 15-PGF2α. Intra-individual CV in concentrations ranged from 29% for 8-OHdG to 149% for 15-PGF2α. MDA was the most abundant OSB found in urine. The intra- and inter-individual variability in F2-isoprostane concentrations were higher than the values calculated for diY, 8-OHdG, and MDA. All seven OSB concentrations were significantly correlated with each other and with creatinine. Creatinine normalization of OSB concentrations improved predictability in OSB concentrations over time. Our results suggest that 8-OHdG, showing the highest ICC (0.96), yielded more reproducible measurements with a low CV, and is the most suitable biomarker of OSB in spot urine samples. The measured concentrations and diurnal variability in urinary OSB levels in healthy individuals reported in this study are useful as a benchmark for future toxicological and epidemiological studies.

Protein variability in cerebrospinal fluid and its possible implications for neurological protein biomarker research.

Cerebrospinal fluid is investigated in biomarker studies for various neurological disorders of the central nervous system due to its proximity to the brain. Currently, only a limited number of biomarkers have been validated in independent studies. The high variability in the protein composition and protein abundance of cerebrospinal fluid between as well as within individuals might be an important reason for this phenomenon. To evaluate this possibility, we investigated the inter- and intraindividual variability in the cerebrospinal fluid proteome globally, with a specific focus on disease biomarkers described in the literature. Cerebrospinal fluid from a longitudinal study group including 12 healthy control subjects was analyzed by label-free quantification (LFQ) via LC-MS/MS. Data were quantified via MaxQuant. Then, the intra- and interindividual variability and the reference change value were calculated for every protein. We identified and quantified 791 proteins, and 216 of these proteins were abundant in all samples and were selected for further analysis. For these proteins, we found an interindividual coefficient of variation of up to 101.5% and an intraindividual coefficient of variation of up to 29.3%. Remarkably, these values were comparably high for both proteins that were published as disease biomarkers and other proteins. Our results support the hypothesis that natural variability greatly impacts cerebrospinal fluid protein biomarkers because high variability can lead to unreliable results. Thus, we suggest controlling the variability of each protein to distinguish between good and bad biomarker candidates, e.g., by utilizing reference change values to improve the process of evaluating potential biomarkers in future studies.

A comprehensive profile and inter-individual variations analysis of the human normal amniotic fluid proteome

Amniotic fluid contains large amounts of proteins produced by amnion epithelial cells, fetal tissues, fetal excretions and placental tissues; thus, it is an important potential source of biomarkers for identifying fetal pathologies. In this study, a pooled AF sample from 7 healthy volunteers was used to provide a comprehensive profile of normal human AF proteome using immunoaffinity depletion of 14 high-abundance proteins. Each individual AF sample was used to analyze inter-individual variations with iTRAQ method. As a result, a total of 2881 non-redundant proteins were identified, and 1624 proteins were quantified based on the peak intensity-based semi-quantification (iBAQ) method. Gene Ontology (GO) analysis showed that the AF proteome was enriched in extracellular region and extracellular matrix. Further function annotation showed that the top canonical pathway was axonal guidance signaling. The inter-individual variation analysis of 7 individual AF samples showed that the median inter-individual CV (Coefficient of variation) was 0.22. iBAQ quantification analysis revealed that the inter-individual variations were not correlated with protein abundance. GO analysis indicated that intracellular proteins tended to have higher CVs, and extracellular proteins tended to have lower CVs. These data will contribute to a better understanding of amniotic fluid proteomic analysis and biomarker discovery. SignificanceAmniotic fluid is an important potential source of biomarkers for identifying fetal pathologies. This study provided a large database for the normal human amniotic fluid proteome and analysis of inter-individual variations in amniotic fluid proteomes, which will offer a baseline reference for further AF proteomic analysis and pregnancy-related disease biomarker discovery.

A Model for Predicting the Interindividual Variability of Drug-Drug Interactions.

Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96-1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc = 1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.

Dolutegravir plasma concentrations according to companion antiretroviral drug: unwanted drug interaction or desirable boosting effect?

Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy. Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection. All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664-2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929-4,070] versus 738 [552-1,048], 603 [432-1,373] or 1,045 [856-1,115] ng/ml; P<0.001 for all comparisons). By multivariate analyses, only companion antiretroviral drug resulted in significant association with dolutegravir plasma trough concentrations (P=0.012). Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings.

The differential diagnosis between pancreatic cancer with acute pancreatitis and without acute pancreatitis

Reports on biological variation of plasma biochemical indicators are limited. We evaluated biological variations of 13 plasma biochemical indicators.Plasma samples were collected from 40 healthy individuals over 5 days. Intra-individual coefficient of variation (CVI), inter-individual coefficient of variation (CVG), index of individuality (II), reference change value (RCV), and analytical goal parameters were calculated.Albumin (Alb) showed the lowest CVI (2.50%) and the lowest CVG (5.08%), while C-reactive protein (hsCRP) presented the highest CVI (26.87%) and CVG (61.73%). II values were all less than 1.0. Alb presented the lowest 95% RCV (7.67), while hsCRP showed the highest 95% RCV (74.61). Alb, urea, creatinine (Cr), creatine kinase (CK), and creatine kinase isoenzyme MB (CKMBmass) CVI differed with gender (P < 0.05). The CVG of the 13 indicators presented a significant gender difference (P < 0.0001). Alb showed the lowest desirable imprecision CV (1.3%), the lowest desirable bias (1.4%), and the lowest desirable total error (3.5%), while hsCRP presented the highest desirable imprecision (13.4%), the highest desirable bias (16.8%), and the highest desirable total error (39.0%).Our findings add to the database of biological variations of plasma indicators.

Biological variations of thirteen plasma biochemical indicators

BackgroundReports on biological variation of plasma biochemical indicators are limited. We evaluated biological variations of 13 plasma biochemical indicators. MethodsPlasma samples were collected from 40 healthy individuals over 5days. Intra-individual coefficient of variation (CVI), inter-individual coefficient of variation (CVG), index of individuality (II), reference change value (RCV), and analytical goal parameters were calculated. ResultsAlbumin (Alb) showed the lowest CVI (2.50%) and the lowest CVG (5.08%), while C-reactive protein (hsCRP) presented the highest CVI (26.87%) and CVG (61.73%). II values were all less than 1.0. Alb presented the lowest 95% RCV (7.67), while hsCRP showed the highest 95% RCV (74.61). Alb, urea, creatinine (Cr), creatine kinase (CK), and creatine kinase isoenzyme MB (CKMBmass) CVI differed with gender (P<0.05). The CVG of the 13 indicators presented a significant gender difference (P<0.0001). Alb showed the lowest desirable imprecision CV (1.3%), the lowest desirable bias (1.4%), and the lowest desirable total error (3.5%), while hsCRP presented the highest desirable imprecision (13.4%), the highest desirable bias (16.8%), and the highest desirable total error (39.0%). ConclusionOur findings add to the database of biological variations of plasma indicators.

β‐carotene (BC) bioconversion is similar in men and women

Gender differences in plasma retinol and provitamin A carotenoids have been previously reported, with retinol being higher in men and BC higher in women(1). Furthermore, lower conversion efficiency is correlated with BMI in women but not in men(2). We investigated BC conversion efficiency in 23 female and 19 male volunteers by co-administering 2 mg [13C10] BC and 1 mg [13C10]-retinyl acetate. Data on fraction of the administered doses in plasma vs. time for each subject were analyzed by model-based compartmental analysis using the Simulation, Analysis and Modeling software WinSAAM. Relative absorption of BC in the first 24 hours represented 11% of total ingested [13C10]BC, with an inter-individual coefficient of variation of 49%. Although significantly higher plasma concentrations of preformed [13C10]-retinol and bio-converted [13C5]-retinol were found in men compared to women, differences in retinoid concentrations were independent of [13C10]BC cleavage, in that model-calculated bioconversion was not significantly different between men and women (Figure 1). Fig 1: Effect of gender on provitamin A conversion efficiency. In summary, application of [13C10]-retinyl acetate with [13C10]BC confirms that there are no differences in BC conversion efficiency between men and women.

Intra-day and inter-day biological variations of peripheral blood lymphocytes

BackgroundThe proportion and absolute numbers of lymphocyte subsets are important indices that reflect the immunological status of the body. Few studies on biological variations of absolute lymphocyte subset counts and no study in Asian population are currently available. Furthermore, there have been few reports on the biological variation of these indices in the short term. MethodsAt 8:00AM, 12:00PM, and 4:00PM on days 1, 3, and 5, venous blood was collected from 20 healthy volunteers. All participants maintained their normal lifestyles. The percent and absolute lymphocyte subset counts were measured using single -platform method. ResultsIntraday and interday biological variations for the absolute and percent counts of lymphocyte subsets were relatively constant. The intra-individual coefficient of variation (CVI) and inter-individual coefficient of variation (CVG) were similar to those in previous studies. Biological variations in the percent and absolute counts for the CD3+CD4−CD8−, CD3+CD4+CD8+, and CD3+CD16+CD56+ subsets were relatively high. ConclusionsThese observations are clinically valuable. Investigation on the CVI and CVG may allow us to determine the utility of traditional population based reference ranges. Documentation of the reference change values may be used as objective delta-check values in quality management and decide whether the change that occur in an individual's serial results before the change is significant. The present study also enriched the database regarding the biological variations of lymphocyte subsets in Asian population.

Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results.

2599 Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.