Significant Intra-individual Variation Research Articles

Diet and landscape use at Faraoskop from C, N and Sr isotopes in multiple skeletal tissues

The isotopic composition of body tissues can provide information about diet and patterns of movement or migration during life. Here, we report δ13C, δ15N and 87Sr/86Sr analyses for a small sample of fauna and for the 12 humans buried at Faraoskop, and make inferences about how these people ranged across the landscape as they hunted and foraged. δ13C and δ15N values for collagen from cortical and cancellous bone and (for two individuals) desiccated muscle tissue are similar, reflecting consumption of isotopically similar, mostly terrestrial foods throughout life. Not all individuals had teeth preserved but for five we were able to measure 87Sr/86Sr in tooth enamel in an earlier- and a later-forming tooth. Where possible, teeth were analysed near the occlusal surface, half-way up the height of the crown and near the dentine/enamel junction, to assess variation during the period of crown formation. Only one of the five (UCT 394) showed significant intra-individual variation in 87Sr/86Sr, between 0.6 and 3.5 years of age. Two individuals yielded enamel 87Sr/86Sr like the geologically recent sediments of the coastal plain to the west of Faraoskop, while three individuals had values intermediate between the coastal plain and the more ancient shales and sandstones of the Table Mountain Group to the east. As young children, people buried at Faraoskop ranged over different areas of the local landscape, probably as part of different social groups.

The association of metformin dose up-titration and treatment duration with adiposity, lipid profile indicators, and serum leptin levels in T2DM Iraqi patients

Introduction: Numerous factors, including age, gender, physical inactivity, insufficient dose, noncompliance, and drug-drug interactions, may contribute to significant intraindividual variation in metformin (MET) response. This study aims to determine the effect of Met dose and treatment duration on adiposity markers and serum leptin levels in Iraqi patients with type 2 diabetes. Methods: Between October 2021 and March 2022, a cross-sectional study at the Diabetes and Endocrinology Center in Baghdad included 150 type 2 diabetes mellitus (T2DM) patients with a disease duration of more than 1 year. Clinical and physical examinations were conducted before enrollment. We measured anthropometric variables such as body mass index, waist-to-hip ratio, and visceral adiposity index. We evaluated glycated hemoglobin, leptin, C-reactive protein, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TGs) in the serum. Results: Only the TC/HDL-c and TG/HDL-c ratios were significantly different after the data were arranged according to glycemic control level. Arrangement for MET doses and treatment duration, none of the evaluated parameters were significantly different (p > 0.05) between groups receiving different doses of MET for different durations, except visceral adiposity index (VAI), which shows a very slight decrease (p = 0.046) after more than 10 years of treatment. Pearson’s correlation analysis revealed a weak and significant association between waist circumference (WC) and hip circumference and MET doses, and a weak and significant association between WC, VAI, and TG levels and treatment duration. The other markers lacked a significant relationship with MET doses or duration of treatment. Conclusion: MET dose and duration of treatment were not significantly correlated with adiposity and lipid profiles in Iraqi patients with T2DM.

Blood RNA signature RISK4LEP predicts leprosy years before clinical onset.

BackgroundLeprosy, a chronic infectious disease caused by Mycobacterium leprae, is often late- or misdiagnosed leading to irreversible disabilities. Blood transcriptomic biomarkers that prospectively predict those who progress to leprosy (progressors) would allow early diagnosis, better treatment outcomes and facilitate interventions aimed at stopping bacterial transmission. To identify potential risk signatures of leprosy, we collected whole blood of household contacts (HC, n=5,352) of leprosy patients, including individuals who were diagnosed with leprosy 4-61 months after sample collection.MethodsWe investigated differential gene expression (DGE) by RNA-Seq between progressors before presence of symptoms (n=40) and HC (n=40), as well as longitudinal DGE within each progressor. A prospective leprosy signature was identified using a machine learning approach (Random Forest) and validated using reverse transcription quantitative PCR (RT-qPCR).FindingsAlthough no significant intra-individual longitudinal variation within leprosy progressors was identified, 1,613 genes were differentially expressed in progressors before diagnosis compared to HC. We identified a 13-gene prospective risk signature with an Area Under the Curve (AUC) of 95.2%. Validation of this RNA-Seq signature in an additional set of progressors (n=43) and HC (n=43) by RT-qPCR, resulted in a final 4-gene signature, designated RISK4LEP (MT-ND2, REX1BD, TPGS1, UBC) (AUC=86.4%).InterpretationThis study identifies for the first time a prospective transcriptional risk signature in blood predicting development of leprosy 4 to 61 months before clinical diagnosis. Assessment of this signature in contacts of leprosy patients can function as an adjunct diagnostic tool to target implementation of interventions to restrain leprosy development.FundingThis study was supported by R2STOP Research grant, the Order of Malta-Grants-for-Leprosy-Research, the Q.M. Gastmann-Wichers Foundation and the Leprosy Research Initiative (LRI) together with the Turing Foundation (ILEP# 702.02.73 and # 703.15.07).

Intra‐individual differences in the effect of endurance versus resistance training on vascular function: A cross‐over study

We used a within‐subject, cross‐over design study to compare the impact of 4‐weeks' resistance (RT) versus endurance (END) training on vascular function. We subsequently explored the association of intra‐individual effects of RT versus END on vascular function with a single nucleotide polymorphism (SNP) of the NOS3 gene. Thirty‐five healthy males (21 ± 2 years old) were genotyped for the NOS3 rs2070744 SNP and completed both training modalities. Participants completed 12 sessions over a 4‐week period, either RT (leg‐extension) or END (cycling) training in a randomized, balanced cross‐over design with a 3‐week washout period. Participants performed peak oxygen uptake (peak VO2) and leg‐extension single‐repetition maximum (1‐RM) testing, and vascular function assessment using flow‐mediated dilation (FMD) on 3 separated days pre/post‐training. Peak VO2 increased after END (p < 0.001), while 1‐RM increased after RT (p < 0.001). FMD improved after 4‐weeks’ training (time effect: p = 0.006), with no difference between exercise modalities (interaction effect: p = 0.92). No relation was found between individual changes (delta, pre‐post) in FMD to both types of training (R2 = 0.06, p = 0.14). Intra‐individual changes in FMD following END and RT were associated with the NOS3 SNP, with TT homozygotes significantly favoring only END (p = 0.016) and TC/CC tending to favor RT only (p = 0.056). Although both training modes improved vascular function, significant intra‐individual variation in the adaptation of FMD was found. The association with NOS3 genotype suggests a genetic predisposition to FMD adapting to a specific mode of chronic exercise. This study therefore provides novel evidence for personalized exercise training to optimize vascular health.

High-Resolution Longitudinal Dynamics of the Cystic Fibrosis Sputum Microbiome and Metabolome through Antibiotic Therapy.

Microbial diversity in the cystic fibrosis (CF) lung decreases over decades as pathogenic bacteria such as Pseudomonas aeruginosa take over. The dynamics of the CF microbiome and metabolome over shorter time frames, however, remain poorly studied. Here, we analyze paired microbiome and metabolome data from 594 sputum samples collected over 401 days from six adult CF subjects (subject mean = 179 days) through periods of clinical stability and 11 CF pulmonary exacerbations (CFPE). While microbiome profiles were personalized (permutational multivariate analysis of variance [PERMANOVA] r 2 = 0.79, P < 0.001), we observed significant intraindividual temporal variation that was highest during clinical stability (linear mixed-effects [LME] model, P = 0.002). This included periods where the microbiomes of different subjects became highly similar (UniFrac distance, <0.05). There was a linear increase in the microbiome alpha-diversity and in the log ratio of anaerobes to pathogens with time (n = 14 days) during the development of a CFPE (LME P = 0.0045 and P = 0.029, respectively). Collectively, comparing samples across disease states showed there was a reduction of these two measures during antibiotic treatment (LME P = 0.0096 and P = 0.014, respectively), but the stability data and CFPE data were not significantly different from each other. Metabolome alpha-diversity was higher during CFPE than during stability (LME P = 0.0085), but no consistent metabolite signatures of CFPE across subjects were identified. Virulence-associated metabolites from P. aeruginosa were temporally dynamic but were not associated with any disease state. One subject died during the collection period, enabling a detailed look at changes in the 194 days prior to death. This subject had over 90% Pseudomonas in the microbiome at the beginning of sampling, and that level gradually increased to over 99% prior to death. This study revealed that the CF microbiome and metabolome of some subjects are dynamic through time. Future work is needed to understand what drives these temporal dynamics and if reduction of anaerobes correlate to clinical response to CFPE therapy.IMPORTANCE Subjects with cystic fibrosis battle polymicrobial lung infections throughout their lifetime. Although antibiotic therapy is a principal treatment for CF lung disease, we have little understanding of how antibiotics affect the CF lung microbiome and metabolome and how much the community changes on daily timescales. By analyzing 594 longitudinal CF sputum samples from six adult subjects, we show that the sputum microbiome and metabolome are dynamic. Significant changes occur during times of stability and also through pulmonary exacerbations (CFPEs). Microbiome alpha-diversity increased as a CFPE developed and then decreased during treatment in a manner corresponding to the reduction in the log ratio of anaerobic bacteria to classic pathogens. Levels of metabolites from the pathogen P. aeruginosa were also highly variable through time and were negatively associated with anaerobes. The microbial dynamics observed in this study may have a significant impact on the outcome of antibiotic therapy for CFPEs and overall subject health.

Plasma oxalate levels in primary hyperoxaluria type I show significant intra-individual variation and do not correlate with kidney function.

Primary hyperoxalurias are rare diseases with endogenous overproduction of oxalate, thus leading to hyperoxaluria, hyperoxalemia, urolithiasis, and/or nephrocalcinosis and eventually early kidney failure. Plasma oxalate (POx) is an important diagnostic parameter in clinical studies on primary hyperoxaluria (PH). This is especially the case in kidney failure, where urinary parameters are no longer suitable. We aimed to evaluate whether POx would be an adequate endpoint for clinical studies in PH patients with stable kidney function. In addition, the correlation of POx to serum creatinine (SCr) and calculated glomerular filtration rate (eGFR) was examined. We retrospectively analyzed follow-up of individual POx values over time, as well as POx correlation to SCr, eGFR, and vitamin B6 (VB6), a common therapeutic in PH1. Results from 187 blood samples taken between 2009 and 2017, during routine laboratory evaluations from 41 patients with PH1 who had neither undergone dialysis nor transplantation, were evaluated. Negligibly low correlation coefficients (CCs) between POx vs. SCr (CC = -0.0950), POx vs. eGFR (CC = -0.1237), and POx vs. VB6 (CC = 0.1879) were found, with the exception of CKD stage 3a patients, who showed a positive correlation (CC of - 0.7329, POx vs eGFR).The intra-individual analysis of POx over time showed a high fluctuation of POx values. We conclude that POx has a limited validity as a primary endpoint for clinical studies in PH1 patients with stable kidney function. In addition, it does not correlate to SCr and eGFR in this group of patients.

Sexual conflict in action: An antagonistic relationship between maternal and paternal sex allocation in the tammar wallaby, Notamacropus eugenii.

Sex ratio biases are often inconsistent, both among and within species and populations. While some of these inconsistencies may be due to experimental design, much of the variation remains inexplicable. Recent research suggests that an exclusive focus on mothers may account for some of the inconsistency, with an increasing number of studies showing variation in sperm sex ratios and seminal fluids. Using fluorescent in‐situ hybridization, we show a significant population‐level Y‐chromosome bias in the spermatozoa of wild tammar wallabies, but with significant intraindividual variation between males. We also show a population‐level birth sex ratio trend in the same direction toward male offspring, but a weaning sex ratio that is significantly female‐biased, indicating that males are disproportionately lost during lactation. We hypothesize that sexual conflict between parents may cause mothers to adjust offspring sex ratios after birth, through abandonment of male pouch young and reactivation of diapaused embryos. Further research is required in a captive, controlled setting to understand what is driving and mechanistically controlling sperm sex ratio and offspring sex ratio biases and to understand the sexually antagonistic relationship between mothers and fathers over offspring sex. These results extend beyond sex allocation, as they question studies of population processes that assume equal input of sex chromosomes from fathers, and will also assist with future reproduction studies for management and conservation of marsupials.

Determination of the renal concentration capacity following intravenous administration of dDAVP in healthy humans

The synthetic AVP analogue 1-desamino-8-d-arginine-vasopressin (dDAVP) is used for treatment of polyuric disorders. Lack of commercially available assays limits the usefulness of dDAVP as a diagnostic tool in the assessment of renal concentrating capacity. We aimed to develop a specific radioimmunoassay (RIA) for determination of plasma dDAVP (pdDAVP) in order to investigate the relationship between pdDAVP levels and urine osmolality (Uosm). Further, we aimed to determine the onset, duration, and maximum concentrating capacity following intravenous (i.v.) bolus dDAVP injection. The dDAVP assay was based on a well-established RIA for measurements of AVP. Fourteen healthy subjects (aged 15–18 years) participated. Blood and urine samples were collected prior to and after i.v. bolus of 0.03 µg/kg dDAVP. Diuresis and Uosm was measured for nine hours following dDAVP administration. PdDAVP and Uosm were analyzed.We established a specific RIA for the measurement of pdDAVP. All subjects reached maximal pdDAVP concentration (Cmax) 30 minutes following infusion, and a rise in Uosm after 60 minutes. Maximal Uosm varied between subjects, with no direct correlation to the achieved pdDAVP levels. We found no significant intra-individual variation between two dDAVP infusions and the effect was reproducible in terms of Cmax and maximal Uosm. We characterized the relationship between pdDAVP and Uosm after dDAVP bolus injection in healthy adolescents using our dDAVP assay. Maximal Uosm achieved correlated with the baseline Uosm levels and seemed unrelated to achieved pdDAVP levels. The urine concentrating response was maintained at least eight hours.

The transition from foraging to farming (7000–500 cal BC) in the SE Baltic: A re-evaluation of chronological and palaeodietary evidence from human remains

Our knowledge of the timing and completeness of the transition from foraging, fishing and hunting to food production in boreal northeastern Europe is far from clear. Here, we present new bone collagen AMS 14C dates, and δ13C and δ15N isotope values for 20 humans and 17 animals from a 6500-year period dating from the Late Mesolithic to the Bronze Age in Lithuania. AMS 14C dates revealed large discrepancies in comparison to previously obtained radiocarbon dates, thus highlighting the need to re-date all prehistoric human remains where chronology was based on 14C dating of bone collagen. Stable isotope data indicate that inland Mesolithic-Subneolithic hunter-gatherers (7000–3000calBC) relied on a balance of freshwater food and game animals with regard to protein intake. The coastal Subneolithic groups (ca. 3000calBC) relied heavily on lagoon fishing, while seals and forest game were of lesser importance. Animal husbandry, most likely of sheep or goats, was a main source of protein for Neolithic Corded Ware Culture people (2900–2400calBC), although a significant contribution of freshwater food is also evident. Significant intra-individual variation in stable isotope values may demonstrate that a highly flexible subsistence strategy was adopted by the CWC people. Unusually high δ13C values indicate that millet had been already introduced into the farming economy of the Late Bronze Age around 1000calBC.

Single or double semen samples: the dilemma in epidemiological studies on semen quality.

Is it necessary to collect more than one semen sample from each individual in epidemiological studies? Single semen samples can be used in model construction as long as the model adjusts for major relevant covariates. If a series of semen samples are taken from one individual at different times, significant intra-individual variation may exist. A population-based cross-sectional study was conducted from 1 December 2000 to 20 November 2002. A total of 1010 volunteers, aged between 20 and 60 years old, were recruited. A total of 998 subjects were included for statistical analysis. Of these, 332 men provided single semen samples (group 1) and 666 men provided two samples (group 2). Semen parameters, including semen volume, sperm concentration, total sperm number, progressive motility, vitality, and sperm morphology, were analyzed with standardized methods according to the World Health Organization (WHO) laboratory manual for the examination of human semen and sperm-cervical mucus interaction (3rd edition). Rapidly progressive motility of semen from group 1 was lower than that of group 2, but other parameters were not significantly different. The differences in mean values between the double samples were small on all semen parameters. The correlations between the two ejaculates were high, but the agreements were poor except for sperm vitality and normal morphology. Model selection and validation analysis supported the premise that the regression model from the first samples was applicable for the second samples. The large sample size with extensive quality control provides robust parameter estimation and promises good applicability for model selection and validation. The results are valid for healthy men in China, not for subfertile or infertile men. The overall semen quality of a given group of healthy men will not vary significantly in the short term. Single semen samples can be used in model building as long as major relevant covariates are considered. Utilizing multiple semen donations may actually cause the samples to be less representative. This research was supported by a grant from Shanghai Science and Technical Committee (02DJ14053) and a grant from Ministry of Science and Technology, China (9902). All authors have no competing interests.

Intraindividual cognitive variability before and after sports-related concussion.

Inconsistent performance is associated with cognitive dysfunction in a number of clinical populations. However, intraindividual cognitive variability in healthy individuals is poorly understood. Inconsistency poses a challenge to clinicians when interpreting change over time. This study examined intraindividual cognitive variability within a sample of college athletes tested at baseline and postconcussion. Athletes (n = 71) and control participants (n = 42) were tested with a comprehensive neuropsychological battery at baseline and postconcussion (athletes) or one month later (controls). A subset of indices with high internal consistency was used to calculate overall performance and performance variability. A k-means cluster analysis of baseline and postconcussion performance variability examined heterogeneity within the sample. In the athlete sample, performance variability was significantly greater than zero, and was negatively correlated with overall performance at both time points (p < .001). Wechsler Test of Adult Reading Full Scale IQ estimate was significantly correlated with overall performance (p < .01), but not with performance variability. Cluster analysis revealed low-variability (n = 46) and high-variability (n = 25) cluster groups. Whereas the low-variability cluster group exhibited a pattern of performance similar to that of control participants, membership in the high-variability cluster group was associated with postconcussion cognitive dysfunction. These findings suggest that normative cognitive performance in college athletes is characterized by significant intraindividual variation across tests. Cross-test intraindividual variability may impart clinically meaningful information, as higher levels of variability were related to poorer overall performance and postconcussion cognitive dysfunction.

Testosterone implants in women: Pharmacological dosing for a physiologic effect

ObjectivesThe objectives of this study were to determine therapeutic serum testosterone (T) levels/ranges and inter-individual variance in women treated with subcutaneous T implants. Study designIn study group 1, T levels were measured at two separate time intervals in pre- and post-menopausal women treated with subcutaneous T for symptoms of androgen deficiency: (i) four weeks after pellet insertion, and (ii) when symptoms of androgen deficiency returned.In a separate pharmacokinetic study (study group 2), 12 previously untreated postmenopausal women each received a 100mg T implant. Serum T levels were measured at baseline, 4 weeks and 16 weeks following T pellet implantation.In study ‘group’ 3, serial T levels were measured throughout a 26h period in a treated patient. ResultsIn study group 1, serum T levels measured at ‘week 4’ (299.36±107.34ng/dl, n=154), and when symptoms returned (171.43±73.01ng/dl, n=261), were several-fold higher compared to levels of endogenous T. There was significant inter-individual variance in T levels at ‘week 4’ (CV 35.9%) and when symptoms returned (CV 42.6%). Even with identical dosing (study group 2), there was significant inter-individual variance in T levels at ‘week 4’ (CV 41.9%) and ‘week 16’ (CV 41.6%). In addition, there was significant intra-individual circadian variation (CV 25%). ConclusionsPharmacologic dosing of subcutaneous T, as evidenced by serum levels on therapy, is needed to produce a physiologic effect in female patients. Safety, tolerability and clinical response should guide therapy rather than a single T measurement, which is extremely variable and inherently unreliable.

PTU-106 A prospective single centre evaluation of the intra-individual variability of faecal calprotectin in quiescent Crohn's disease patients

IntroductionFaecal calprotectin (FC) has become an established non-invasive, sensitive marker of intestinal inflammation in Crohn's disease (CD). A single measurement of FC is used in clinical practice to aid decision...

An examination of stable hydrogen isotope (δD) variation in adult and juvenile feathers from a migratory songbird

Stable hydrogen isotopes (δD) can help predict geographic origin of tissue growth but within-site variation of feather δD (δDf) exists. Multiple hypotheses explain δDf variation: moult timing, physiology, and spatio-temporal differences in source deuterium, but there have been few direct tests of these factors. We assessed δDf variation within a breeding population of Wood Thrush ( Hylocichla mustelina (Gmelin, 1789)), by sampling feathers from hatch-year birds, returning adults (after migration), and to eliminate confounding variables from newly grown adult primary feathers during moult. We evaluated potential mechanisms explaining δDf variation by examining intraindividual variation (different feather types), precipitation δD, prey δD, corticosterone (CORT), and breeding productivity. In addition, we directly compared δDf of newly grown primary feathers to δD blood hematocrit (δDb). We found significant differences in δDf between years and age classes and observed no significant intraindividual variation. δDf and δDb were not significantly correlated. CORT weakly contributed to δDf, but there are other factors influencing δDf. Ten percent of all feather samples had outlying δDf values, and were likely grown away from the breeding grounds. Our results document intrapopulation and intraindividual variation of δDf at a single location and indicated that age class and year-to-year differences contributed to high δDf variance.

Mo1690 A Prospective Single Centre Evaluation of the Intra-Individual Variability of Faecal Calprotectin in Quiescent Crohn's Disease Patients

Introduction Faecal calprotectin (FC) has become an established non-invasive, sensitive marker of intestinal inflammation in Crohn9s disease (CD). A single measurement of FC is used in clinical practice to aid decision making in the management of CD patients. Data on the day to day variation of FC levels in CD patients is sparse. If there was significant intra-individual variation of FC within CD patients, this could impact on the interpretation of single values in isolation. A prospective study to evaluate the degree of variability of FC in three consecutive days stool samples in CD patients in clinical remission was performed. Methods 143 patients with CD in remission (CDAI Results Of the 143 patients recruited 34 did not return any samples, 6 returned less than the required number of stool samples, 2 withdrew consent and 2 developed clinical evidence of a flare of disease during the collection period and were excluded from analysis. Therefore 98 complete sets of three stool samples were obtained and analysed. The intraclass correlation coefficient of the 3 FC values, log-transformed, was 0.842 with corresponding 95% CI 0.788 to 0.886 showing that consistency between the three log-transformed FC measurements is high. The reliability of a “normal” FC result of Conclusion The consistency of three faecal calprotectin samples over three consecutive days is high and the CI is narrow suggesting that in a larger population consistency would also be high. This indicates that there is little intra-individual variability of the test and a one off sample can indeed provide reliable information for use in clinical practice. Higher intrapatient variability of high FC values suggests that the log-transformed values are more reliable. Competing interests None declared.

Intra-individual variation in G2 chromosomal radiosensitivity

Intra-individual variation in G(2) chromosomal radiosensitivity was examined by repeatedly taking blood samples from two individuals. Two healthy female volunteers provided a total of 44 blood samples, Donor 1 gave 28 samples in four time periods between 2001 and 2006 and Donor 2 gave 16 samples in two of the same time periods. Lymphocytes were cultured for 72 h prior to irradiation with 0.5 Gy, 300 kV X-rays. Colcemid was added 30 min post-irradiation. Cultures were harvested 90 min post-irradiation and analysed for chromatid gaps and breaks. Donor 1 exhibited significant intra-individual variation in G(2) chromosomal radiosensitivity for two of the four time periods. Variation was not significant for Period 1 (13 samples, P = 0.111) and Period 2 (six samples, P = 0.311) but was significant for Period 3 (two samples, P = 0.030) and Period 4 (seven samples, P = 0.005). Significant intra-individual variation was observed for both time periods involving Donor 2, these being Period 2 (nine samples, P = 0.002) and Period 4 (seven samples, P < 0.001). The combined data from all time periods exhibited a significant intra-individual variation for Donor 1 (P < 0.001) and Donor 2 (P < 0.001). These findings led to the conclusion that too much reliance should not be placed on the result from a single sample when assessing individual radiosensitivity status.

Inter and Intra-Individual Variation of Factor VIII Half-Life In Severe Haemophilia A

AbstractAbstract 544 Introduction:Conventional dosing of FVIII prophylaxis in adults with hemophilia is based on 3 weekly or alternate day regimes of 20–40IU/kg, aiming for a trough level above 1IU/dL. However, pharmacokinetics of FVIII widely varies between individuals, thus the amount of factor concentrate required to maintain trough levels above 1IU/dL is also disparate. Mathematical modeling indicates that half-life has a significant influence over trough level. An individualized dose based on FVIII half-life may therefore allow for more appropriate dosing of prophylaxis in adults. For this approach to be effective, half-life results obtained from pharmacokinetic studies need to be consistent and representative of an individual's steady state. Although it is recognised that half-life increases from early childhood until adolescence, intra-individual variation of half-life in adults has not been examined. Hypotheses:We hypothesized that for patients >18years significant inter-individual variation, but minimal intra-individual variation, in half-life would be detected. Method:This single center study investigated inter- and intra-individual variation in FVIII half-life based on 140 pharmacokinetic studies conducted in 73 individuals with severe hemophilia A (FVIII:C < 1IU/dL). Data for all FVIII pharmacokinetic studies performed over a 5-year period were extracted from an in-house database. Patient demographics and laboratory results were verified against electronic patient records. All half-life studies were performed according to a set protocol and analyzed within the same clinical pathology accredited reference laboratory. Results were tested using the non-parametric Wilcoxin signed rank test. Data is presented as median and range and p-values < 0.001 were considered significant. Results:The median age of patients was 17.5 years (range 5.0– 54.0).The wide range in FVIII half-life data indicated substantial inter-individual variation within the complete population (median 9.9hrs, range 2.3–19hrs), replicated upon division of data into age specific categories (Fig. 1). [Display omitted] 36 patients had undergone multiple studies over the 5-year period. Of these, 21 had at least 3 data sets. FVIII half-life showed considerable intra-individual variation with 17 patients (81%) demonstrating a range of half-life greater than 2hrs.FVIII half-life data was normalized to nullify the effect of extensive inter-individual variation in half-life within the population. Figure 2 demonstrates mean difference in normalized FVIII half-life for all patients with multiple half-life results. Testing against a null hypothesis of no variation, we found significant intra-individual variation upon examination of the entire population (n= 36, p<0.0001). Following exclusion of data from children less than 6 years, significant intra-individual variation could still be detected for children 6–18 years (n=19, p< 0.0001), and adults (n= 16, p<0.0001). [Display omitted] Discussion:This study verifies expected inter-individual variation of pharmacokinetic profiles and appears to support the concept of individualized prophylaxis regimes in adults based on half-life data. However, considerable intra-individual variation in FVIII half-life in adult patients was registered. Mathematical models have indicated that even modest changes in half-life influence dosing requirements for FVIII prophylaxis. Intra-individual fluctuations in FVIII half-life will necessitate regular pharmacokinetic studies to ensure appropriate dosing. This will naturally affect the cost, utility and acceptability of treatment. Disclosures:No relevant conflicts of interest to declare.

Dimensions of the human sclera: Thickness measurement and regional changes with axial length

Scleral thickness, especially near the region of the optic nerve head (ONH), is a potential factor of interest in the development of glaucomatous optic neuropathy. Our goal was to characterize the scleral thickness distribution and other geometric features of human eyes. Eleven enucleated human globes (7 normal and 4 ostensibly glaucomatous) were imaged using high-field microMRI, providing 80 μm isotropic resolution over the whole eye. The MRI scans were segmented to produce 3-D corneoscleral shells. Each shell was divided into 15 slices along the anterior–posterior axis of the eye, and each slice was further subdivided into the anatomical quadrants. Average thickness was measured in each region, producing 60 thickness measurements per eye. Hierarchical clustering was used to identify trends in the thickness distribution, and scleral geometric features were correlated with globe axial length. Thickness over the whole sclera was 670 ± 80 μm (mean ± SD; range: 564 μm–832 μm) over the 11 eyes. Maximum thickness occurred at the posterior pole of the eye, with mean thickness of 996 ± 181 μm. Thickness decreased to a minimum at the equator, where a mean thickness of 491 ± 91 μm was measured. Eyes with a reported history of glaucoma were found to have longer axial length, smaller ONH canal dimensions and thinner posterior sclera. Several geometrical parameters of the eye, including posterior scleral thickness, axial length, and ONH canal diameter, appear linked. Significant intra-individual and inter-individual variation in scleral thickness was evident. This may be indicative of inter-individual differences in ocular biomechanics.

Single semen analysis as a predictor of semen quality: clinical and epidemiological implications

It is generally thought that a single ejaculate is a bad predictor of semen quality of a subject, because of significant intra-individual variation. Therefore, we investigated the degree to which the results of a first semen analysis differ from that of a second analysis among men from a general population in Norway. In addition, we analysed how the two different semen results mirrored the overall semen quality assessment. A total of 199 volunteers participated in the study and delivered two semen samples with an interval of 6 months. The semen parameters were determined according to the World Health Organization (WHO) 1999 guidelines, which were also used to determine whether semen quality was normal or abnormal. In addition, the DNA fragmentation index (DFI) was determined using the Sperm Chromatin Structure Assay. The two samples from each individual were very similar with regard to standard semen parameters and DFI (r(s:) 0.67-0.72), and there were no significant systematic differences between the two samples. The result of the first sample (normal/abnormal) was highly predictive of the overall conclusion based on the two samples (sperm concentration: in 93% of the cases (95% confidence interval [CI]: 89%-96%); sperm motility: in 85% of the cases (95% CI: 79%-89%); overall semen quality: in 85% of the cases (95% CI: 80%-90%). In epidemiological studies, one ejaculate is a sufficient indicator of semen quality in a group of subjects. In a clinical situation, when the question is whether the semen quality is normal or not, the first ejaculate will, in at least 85% of cases, give a correct overall conclusion.

Gastric Emptying

Gastric Emptying