Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors.

UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro-in vivo extrapolations in chemical risk assessment are discussed.

Prospective cohort study of daily alcoholic beverage intake as a potential trigger of headaches among adults with episodic migraine.

PURPOSE: To determine whether alcohol intake is associated with occurrence of headaches on the following day. METHODS: In this prospective cohort study, adults with episodic migraine completed electronic diaries every morning and evening for at least six weeks in March 2016-October 2017. Every day, participants reported alcohol intake, lifestyle factors, and details about each headache. We constructed within-person fixed-effect models adjusted for time-varying factors to calculate odds ratios for the association between 1,2,3,4, or 5+ servings of alcohol and headache the following day. We also calculated the adjusted risk of headache the following day for each level of intake. RESULTS: Among 98 participants who reported 825 headaches over 4,467 days, there was a statistically significant linear association (p-trend = 0.03) between alcohol and headache the following day. Compared to no alcohol, 1-2 servings were not associated with headaches, but 5+ servings were associated with a 2.08-fold (95% confidence interval [CI] 1.16-3.73) odds of headache. The adjusted absolute risk of headaches was 20% (95%CI 19%-22%) on days following no alcohol compared with 33% (95%CI 22%-44%) on days following 5+ servings. CONCLUSION: 1-2 servings of alcoholic beverages were not associated with higher risk of headaches the following day, but 5+ servings were associated with higher risk. KEY MESSAGES 1-2 servings of alcoholic beverages were not associated with a higher risk of headaches on the following day, but higher levels of intake may be associated with higher risk. Five or more servings were associated with 2.08 times (95% confidence interval 1.16-3.73 the odds of headache on the following day. The adjusted absolute risk of headaches was 20% (95%CI 19%-22%) on days following no alcohol consumption compared with 33% (95% CI 22%-44%) on days following 5+ servings.

Longitudinal Intra- and Inter-individual variation in T-cell subsets of HIV-infected and uninfected men participating in the LA Multi-Center AIDS Cohort Study.

To assess the intra-individual and inter-individuals biological variation and the effect of aging on lymphocyte T-cells subsets.We assessed lymphocyte phenotypes (CD3, CD4, and CD8 T-cells) in 89 HIV-1-infected and 88 uninfected white non-Hispanic men every 6 months, to examine the biological variation for those measurements, and the average change in lymphocyte phenotype over 34 years.The markers showed significant intra-individuality in HIV-infected and uninfected individuals with index of individuality of <1.4. No mean changes were seen over the 34 years, with the exception of percentage CD4T-cells in HIV-uninfected individuals.In the pre-HAART era, HIV-infected individuals experienced an increase in mean absolute CD3 T-cell numbers (11.21 cells/µL, P = 0.02) and absolute CD8 T-cell numbers (34.57 cell/µl, P < .001), and in the percentage of CD8 T-cells (1.45%, P < .001) per year and a significant decrease in mean absolute CD4 T-cell numbers (23.68 cells/µl, P < .001) and in the percentage of CD4 T-cells (1.49%, P < .001) per year.In the post-HAART era, no changes in mean levels were observed in absolute CD3 T-cell count (P = .15) or percentage (P = .99). Significant decreases were seen in mean count (8.56 cells/µl, P < .001) and percentage (0.59%, P < .001) of CD8 T-cells, and increases in mean absolute count (10.72 cells/µl, P < .001) and percentage (0.47%, P < .001) of CD4 T-cells.With the exception of CD4 (%), no average changes per year were seen in lymphocyte phenotype of HIV-uninfected men. The results of coefficients of variation of intra and inter-individuals of this study can be useful for HIV-1 infection monitoring and in addition the observation could be a useful guide for intra- and inter-individual coefficient variations, and establishing quality goal studies of different blood biomarkers in healthy and other diseases.

What is the difference in morphologic features of the lumbar vertebrae between Caucasian and Taiwanese subjects? A CT-based study: implications of pedicle screw placement via Roy-Camille or Weinstein method.

BACKGROUND: Safe placement of pedicle screws without jeopardizing neurovascular structures medially and anteriorly is important during spine surgery. Inferior breach of pedicle is also dangerous due to low margin of error. Lumbar morphology and identical pedicle orientation at L1 to L5 shown on CT scan of young Taiwanese patients (90 patients) were analyzed and compared with findings reported for Caucasian subjects. METHODS: Previously reported techniques were employed to quantitatively elucidate the parameters regarding lumbar morphology and identical pedicle orientation at each vertebra. The parameters for pedicle angle (PA), pedicle diameter (PD), pedicle axis distance (PAD), midline axis distance (MAD), transverse pedicle axis distance (TPAD) and transverse intertangential angle (TITA) were measured. RESULTS: Taiwanese subjects had different PA, PD, PAD, MAD at L1 to L5 and TITA at L3 to L5 compared with Caucasian subjects. L5 had the most convergent pedicle axis, the widest PD and the shortest antero-posterior axis morphology. CONCLUSIONS: This study provides detailed information for identifying pedicle orientation during pedicle screw placement and elucidate racial differences in lumbar morphology and pedicle orientation between Taiwanese and Caucasian populations.

Population pharmacokinetics of immediate- and prolonged-release tacrolimus formulations in liver, kidney and heart transplant recipients.

AIMS: Develop a population pharmacokinetics model of tacrolimus in organ transplant recipients receiving twice-daily, immediate-release (IR-T; Prograf) and/or once-daily, prolonged-release (PR-T; Advagraf or Astagraf XL) tacrolimus. METHODS: Tacrolimus concentration-time profiles were analysed from 8 Phase II studies in adult and paediatric liver, kidney and heart transplant patients receiving IR-T and/or PR-T. A tacrolimus population pharmacokinetic model, including identification of significant covariates, was developed using NONMEM. RESULTS: Overall, 23,176 tacrolimus concentration records were obtained from 408 patients. A 2-compartment model with first-order absorption and elimination described the concentration-time profiles. Tacrolimus absorption rate was 50% slower with PR-T vs IR-T. Tacrolimus apparent oral clearance was 44.3 L/h in Whites and 59% higher in Asians. Tacrolimus central volume of distribution was 108 L in males and 55% lower in females; trough concentrations were similar between formulations. Tacrolimus relative bioavailability was similar between formulations (geometric mean ratio PR-T:IR-T 95%, 90% confidence intervals: 89%, 101%). Asians had 83% and 51% higher relative bioavailability than Whites and Blacks, respectively, for IR-T and PR-T. Whites had 49% and 77% higher relative bioavailability than Blacks for PR-T and IR-T, respectively. Blacks had 52% lower relative bioavailability than Whites and Asians for IR-T and PR-T. Type of organ transplanted and patient population (adult/paediatric) did not have a significant effect on tacrolimus pharmacokinetics. CONCLUSIONS: This population pharmacokinetic model described data from transplant recipients who received IR-T and/or PR-T. Tacrolimus trough concentrations and relative bioavailability were similar between formulations, supporting 1 mg:1 mg conversion from Prograf to Advagraf/Astagraf XL in clinical practice.

Climatic adaptation in human inferior nasal turbinate morphology: Evidence from Arctic and equatorial populations.

OBJECTIVES: The nasal turbinates directly influence the overall size, shape, and surface area of the nasal passages, and thus contribute to intranasal heat and moisture exchange. However, unlike the encapsulating walls of the nasal cavity, ecogeographic variation in nasal turbinate morphology among humans has not yet been established. Here we investigate variation in inferior nasal turbinate morphology in two populations from climatically extreme environments. MATERIALS AND METHODS: Twenty-three linear measurements of the inferior turbinate, nasal cavity walls, and airway passages were collected from CT scans of indigenous modern human crania from Equatorial Africa (n = 35) and the Arctic Circle (n = 35). MANOVA and ANCOVA were employed to test for predicted regional and sex differences in morphology between the samples. RESULTS: Significant morphological differences were identified between the two regional samples, with no evidence of significant sexual dimorphism or region-sex interaction effect. Individuals from the Arctic Circle possessed superoinferiorly and mediolaterally larger inferior turbinates compared to Equatorial Africans. In conjunction with the surrounding nasal cavity walls, these differences in turbinate morphology produced airway dimensions that were both consistent with functional expectations and more regionally distinct than either skeletal component independently. CONCLUSION: This study documents the existence of ecogeographic variation in human nasal turbinate morphology reflecting climate-mediated evolutionary demands on intranasal heat and moisture exchange. Humans adapted to cold-dry environments exhibit turbinate morphologies that enhance contact between respired air and nasal mucosa to facilitate respiratory air conditioning. Conversely, humans adapted to hot-humid environments exhibit turbinate morphologies that minimize air-to-mucosa contact, likely to minimize airflow resistance and/or facilitate expiratory heat-shedding.

The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis.

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

Racial Experience as an Alternative Operationalization of Race.

The study of human variation is central to both social and biomedical sciences, but social and biomedical scientists diverge in how variation is theorized and operationalized. Race is especially problematic because it is a cultural concept that contains implicit and explicit understandings of how collective bodies differ. In this article, we propose an operationalization of race that addresses both racial experience and human biological diversity, placing them within the same ontological sphere. Furthermore, this approach can more effectively advance antiracist pedagogy and politics. We argue that human biological diversity does not have to be in opposition to constructivist notions of race. Rather, racial experience is emphasized as an embodied experience that is as real and as valid as biological variation. By focusing on both racial experience and biological diversity, it becomes more feasible to operationalize race to fruitfully inform the pedagogy and politics of antiracism. To do so, racial experience must be more broadly conceived and should not always equate to negative outcomes. With the recognition that racial experience has the potential to be something other than damaging, an antiracist anthropology can more effectively address issues pertaining to racial health disparities.