Linking Endogenous Factor Xa Activity, a Biologically Relevant Pharmacodynamic Marker, to Edoxaban Plasma Concentrations and Clinical Outcomes in the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: We previously reported exogenous antifactor Xa (FXa) activity as a pharmacokinetic surrogate marker for edoxaban plasma concentrations. Inhibition of endogenous FXa activity is a more biologically relevant pharmacodynamic measure of edoxaban activity. Here we describe the value of endogenous FXa activity as a pharmacodynamic marker linking edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48). METHODS: In ENGAGE AF-TIMI 48, edoxaban was administered in higher dose (60/30 mg QD) and lower dose (30/15 mg QD) regimens. Both regimens incorporated a 50% dose reduction in patients with characteristics known to increase edoxaban concentration. Pharmacokinetic-pharmacodynamic modeling was performed in a subgroup of 3029 patients who had samples collected for endogenous FXa activity (measured using an assay after endogenous FX was activated with Russell viper venom). RESULTS: Endogenous FXa activity decreased with increasing edoxaban concentrations of ≤440 ng/mL, indicating that inhibition of endogenous FXa activity is saturated above this concentration threshold. Baseline endogenous FXa activity averaged 92.1±20.9% (relative to normal control samples) and was lower with older age, with lower body weight, and in male patients. Model-predicted 24-hour average percentages of inhibition of endogenous FXa activity were 35.8±5.18, 29.1±3.92, 21.9±3.80, and 16.4±2.70 for the higher dose edoxaban regimen 60 mg, dose-reduced higher dose edoxaban regimen 30 mg, lower dose edoxaban regimen 30 mg, and dose-reduced lower dose edoxaban regimen 15 mg groups, respectively. A greater average percentage of inhibition of endogenous FXa activity was associated with a lower incidence of ischemic stroke or systemic embolism and a higher risk of major bleeding ( P<0.001). In a typical subject, the predicted risks for the 10th and 90th percentiles of inhibition of endogenous FXa activity were 1.04% and 0.57% for incidence of ischemic stroke or systemic embolism and 1.35% and 2.33% for major bleeding, respectively. CONCLUSIONS: The extent of inhibition of endogenous FXa activity is influenced by edoxaban dosing and clinical characteristics, and it is associated with both antithrombotic benefit and risk of bleeding. This approach of linking endogenous FXa activity to clinical outcomes may be used to guide dose selection in future clinical trials, monitor patients in certain clinical scenarios, or refine the doses of oral FXa inhibitors in patients who require precise anticoagulation therapy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Healthy Lifestyle During Early Pregnancy and Risk of Gestational Diabetes Mellitus.

Previous studies have found associations between individual healthy behaviors and reduced risk of gestational diabetes mellitus (GDM); however, the association of composite healthy lifestyle during pregnancy with GDM has not been examined. Participants in the Omega Study (n = 3,005), a pregnancy cohort study conducted in Washington State (1996-2008), reported information on diet, physical activity, smoking, and stress during early pregnancy. Lifestyle components were dichotomized into healthy/unhealthy and then combined into a total lifestyle score (range, 0-4). Regression models were used to determine relative risk of GDM (n = 140 cases) in relation to healthy lifestyle. Twenty percent of participants had a healthy diet, 66% were physically active, 95% were nonsmokers, and 55% had low stress. Each 1-point increase in lifestyle score was associated with a 21% lower risk of GDM (95% confidence interval: 0.65, 0.96) after adjustment for age, race, and nulliparity. Adjustment for prepregnancy body mass index, prepregnancy physical activity, and prepregnancy smoking attenuated the associations slightly. Associations were similar in normal-weight and overweight/obese women. In this study, a composite measure of healthy lifestyle during early pregnancy was associated with substantially lower GDM risk. Public health messaging and interventions promoting multiple aspects of a healthy lifestyle during early pregnancy should be considered for GDM prevention.

Maternal Leisure Time Physical Activity and Infant Birth Size.

BACKGROUND: Associations of maternal leisure time physical activity with birth size are inconsistent. Roles of infant sex and maternal prepregnancy body mass index (BMI) in these associations have not been studied. METHODS: Participants (N = 3,310) in the Omega study, a cohort in Washington State (1996-2008), reported leisure time physical activity duration and energy expenditure in the year prepregnancy and in early pregnancy (mean 15 weeks gestation). Regression models estimated mean differences in infant head circumference, birthweight, and ponderal index (birthweight/length) across quartiles of pre- or early-pregnancy leisure time physical activity. We assessed effect modification by infant sex or prepregnancy overweight/obese status (BMI ≥ 25 kg/m). RESULTS: We observed positive associations between prepregnancy leisure time physical activity and head circumference overall and among male infants. Among males, each quartile increase in prepregnancy physical activity duration was associated with 0.14 cm (95% confidence interval = 0.046, 0.24; trend P = 0.004) greater head circumference. We did not observe associations between leisure time physical activity and birthweight or ponderal index overall. Each quartile increase in pre- or early-pregnancy physical activity duration was associated with 17-23 g lower birthweight among female infants and among women with normal prepregnancy BMI. CONCLUSIONS: We observed positive associations between prepregnancy leisure time physical activity and head circumference among male infants, and inverse associations of pre- and early-pregnancy physical activity with birthweight among female infants and women with normal prepregnancy BMI. Future studies should confirm results and elucidate mechanisms of observed associations.

Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism--the Hokusai-VTE phase 3 study.

AIMS: This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism in the Hokusai-VTE phase 3 study. The impact of the protocol-specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL(cr)) of 30 to 50 ml min(-1) or concomitant P-glycoprotein inhibitor on edoxaban exposure was assessed using simulations. METHODS: The sparse data from Hokusai-VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance. RESULTS: A linear two-compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non-renal and renal. The latter increased non-linearly with increasing CL(cr). Compared with healthy volunteers, inter-compartmental clearance and the CL(cr) covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co-administration of P-glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model-based simulations revealed lower exposure in dose-reduced compared with non-dose-reduced patients. CONCLUSIONS: The adopted dose-reduction strategy resulted in reduced exposure compared with non-dose-reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.

The association of maternal adult weight trajectory with preeclampsia and gestational diabetes mellitus.

BACKGROUND: Preeclampsia (PE) and gestational diabetes mellitus (GDM) adversely affect pregnancy outcomes and the subsequent health of both mother and infant. It is known that elevated pre-pregnancy body mass index (BMI) is associated with increased risk of these obstetrical complications. However, little is known about the role of adult weight patterns prior to pregnancy. METHODS: Self-reported weight at ages prior to the current pregnancy was recorded in a prospective cohort study of 3567 pregnant women, allowing assessment of longitudinal pre-pregnancy weight trajectories and their association with subsequent PE and GDM in the study pregnancy. RESULTS: Women who would subsequently experience PE or GDM in the study pregnancy experienced on average almost double the rate of adult weight gain than other women [PE: additional 0.30 kg/year, 95% confidence interval (CI) 0.09, 0.51 and GDM: additional 0.34 kg/year, 95% CI 0.21, 0.48]. Women with mean adult annual weight gain above the 90th percentile (1.4 kg/year) had elevated risk of subsequent PE and GDM independent of their BMI at age 18 and of their obesity status at the time of the study pregnancy. Finite mixture trajectory modelling identified four monotonely ordered, increasing mean weight trajectories. Relative to the second lowest (most common) weight trajectory, women in the highest trajectory were at greater risk of PE [odds ratio (OR) 5.0, 95% CI 2.9, 8.8] and GDM (OR 2.8, 95% CI 1.7, 4.5). CONCLUSIONS: These results indicate that higher adult weight gain trajectories prior to pregnancy may play a role in predisposing women to PE or GDM.

Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation.

PURPOSE: The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure-response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF). METHODS: Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phase III) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein (P-gp) inhibitors as well as renal impairment on edoxaban PK. The potential relationship between edoxaban PK exposure and incidence of bleeding events was explored based on data from 893 AF patients. RESULTS: Absolute bioavailability of edoxaban was estimated as 58.3 %. With oral dosing of edoxaban, co-administration of various P-gp inhibitors significantly increased edoxaban bioavailability and decreased volume of distribution (V 2), resulting in a predicted increase of 33-77 % in area under the curve (AUC) and 65-104 % in C max. A much smaller increase was seen in edoxaban concentration at 24 h post-dose (C 24, -24 to 38 %), due to decreased V 2 and shortened elimination half-life. With IV dosing of edoxaban, co-administration of the P-gp inhibitor quinidine decreased both edoxaban clearance (CL) and V 2, resulting in an increase of 32 % in AUC and 66 % in C 24. Creatinine clearance was a significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Model-predicted steady state C min was slightly higher, but AUC was comparable for patients who had severe renal impairment and received edoxaban 15 mg once daily (QD) versus patients who had normal renal function or mild renal impairment and received edoxaban 30 mg QD. Exposure-response analysis suggested that edoxaban C min and country/region are significantly associated with the incidence of bleeds. CONCLUSIONS: The model provided reasonable estimation with regard to the absolute bioavailability of edoxaban, the magnitude of change in edoxaban exposure upon co-administration of P-gp inhibitors, and the impact of renal impairment on edoxaban clearance. Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. Further confirmation will be sought by incorporating clinical safety and efficacy information from larger phase III trials.

The Caenorhabditis elegans T-box factor MLS-1 requires Groucho co-repressor interaction for uterine muscle specification.

T-box proteins are conserved transcription factors that play crucial roles in development of all metazoans; and, in humans, mutations affecting T-box genes are associated with a variety of congenital diseases and cancers. Despite the importance of this transcription factor family, very little is known regarding how T-box factors regulate gene expression. The Caenorhabditis elegans genome contains 21 T-box genes, and their characterized functions include cell fate specification in a variety of tissues. The C. elegans Tbx1 sub-family member MLS-1 functions during larval development to specify the fate of non-striated uterine muscles; and, in mls-1 mutants, uterine muscles are transformed to a vulval muscle fate. Here we demonstrate that MLS-1 function depends on binding to the Groucho-family co-repressor UNC-37. MLS-1 interacts with UNC-37 via a conserved eh1 motif, and the MLS-1 eh1 motif is necessary for MLS-1 to specify uterine muscle fate. Moreover, unc-37 loss-of-function produces uterine muscle to vulval muscle fate transformation similar to those observed in mls-1 mutants. Based on these results, we conclude that MLS-1 specifies uterine muscle fate by repressing target gene expression, and this function depends on interaction with UNC-37. Moreover, we suggest that MLS-1 shares a common mechanism for transcriptional repression with related T-box factors in other animal phyla.

Caenorhabditis briggsae recombinant inbred line genotypes reveal inter-strain incompatibility and the evolution of recombination.

The nematode Caenorhabditis briggsae is an emerging model organism that allows evolutionary comparisons with C. elegans and exploration of its own unique biological attributes. To produce a high-resolution C. briggsae recombination map, recombinant inbred lines were generated from reciprocal crosses between two strains and genotyped at over 1,000 loci. A second set of recombinant inbred lines involving a third strain was also genotyped at lower resolution. The resulting recombination maps exhibit discrete domains of high and low recombination, as in C. elegans, indicating these are a general feature of Caenorhabditis species. The proportion of a chromosome's physical size occupied by the central, low-recombination domain is highly correlated between species. However, the C. briggsae intra-species comparison reveals striking variation in the distribution of recombination between domains. Hybrid lines made with the more divergent pair of strains also exhibit pervasive marker transmission ratio distortion, evidence of selection acting on hybrid genotypes. The strongest effect, on chromosome III, is explained by a developmental delay phenotype exhibited by some hybrid F2 animals. In addition, on chromosomes IV and V, cross direction-specific biases towards one parental genotype suggest the existence of cytonuclear epistatic interactions. These interactions are discussed in relation to surprising mitochondrial genome polymorphism in C. briggsae, evidence that the two strains diverged in allopatry, the potential for local adaptation, and the evolution of Dobzhansky-Muller incompatibilities. The genetic and genomic resources resulting from this work will support future efforts to understand inter-strain divergence as well as facilitate studies of gene function, natural variation, and the evolution of recombination in Caenorhabditis nematodes.

Forensic odontology in disaster victim identification.

This paper reviews MFI's from a historical perspective commencing with DVI in the late 20th century. For this paper, this era, 1970-90s is designated as the early modern period. As DVI by DNA analysis is introduced into the process, in the beginning of the mid-1990s, or late modern period, a shift in ID modality usage is noted. A statistical analysis of the primary identification (ID) methods established that dental identification was the majority identifier, or gold standard, in the early modern era. Although primarily viewed from a United States (US) perspective, referenced international incidents parallel the incidents investigated by US authorities. The introduction of DNA demarcated the early from the late modern era. Through research, development, and application this highly discriminating ID method would effectively, surpass dental ID as the gold standard into the late modern era. DNA ID would eventually overcome early criticism regarding cost and time consumption. In the MFI's discussed, the discriminating accuracy of DNA, when referenced against the dental identifications, validated the reliability of dental ID. Errors will be significantly minimized through confirmatory reconciliation by more than one ID method. In conclusion despite increased usage of DNA, dental ID has not been eliminated and remains a major contributor to DVI. Dental ID continues to develop through increased application of advanced imaging technology. Despite DNA's rapid advancement and application to DVI, the multidisciplinary approach to scientific identification should remain in the near future. Therefore, comparative dental ID will remain an important and reliable contributor to DVI.

Maternal birthweight is associated with subsequent risk of vitamin D deficiency in early pregnancy.

BACKGROUND: Maternal low birthweight and vitamin D deficiency in pregnancy are associated with a similar spectrum of adverse pregnancy outcomes including pre-eclampsia and gestational diabetes. However, the relationship between maternal birthweight and subsequent vitamin D concentrations in early pregnancy is largely unknown. METHODS: We assessed whether self-reported maternal birthweight was associated with risk of early pregnancy vitamin D deficiency (≤20 ng/mL) among a pregnancy cohort (n = 658). Serum 25-hydroxyvitamin D [25(OH)D] was measured using liquid chromatography-tandem mass spectroscopy. RESULTS: Adjusting for maternal characteristics and month of blood draw, a 100-g higher maternal birthweight was associated with a 5.7% decreased risk of early pregnancy 25(OH)D deficiency [odds ratio (OR) = 0.94; 95% confidence interval (CI) 0.90, 0.99]. Low-birthweight (<2500 g) women were 3.7 times as likely to have early pregnancy 25(OH)D deficiency compared with normal-birthweight women [OR = 3.69; 95% CI 1.63, 8.34]. These relationships were not modified by either pre-pregnancy overweight status [body mass index (BMI) ≥25 kg/m(2)] or adulthood weight trajectory (BMI change ≥2 kg/m(2) from age 18 to pre-pregnancy). CONCLUSIONS: Further research on shared developmental mechanisms that determine birthweight and vitamin D homeostasis may help identify targets and related preventative measures for adverse pregnancy and birth outcomes.

Analysis of exposure-response of CI-945 in patients with epilepsy: application of novel mixed hidden Markov modeling methodology.

We propose to describe exposure-response relationship of an antiepileptic agent, using mixed hidden Markov modeling methodology, to reveal additional insights in the mode of the drug action which the novel approach offers. Daily seizure frequency data from six clinical studies including patients who received gabapentin were available for the analysis. In the model, seizure frequencies are governed by underlying unobserved disease activity states. Individual neighbouring states are dependent, like in reality and they exhibit their own dynamics with patients transitioning between low and high disease states, according to a set of transition probabilities. Our methodology enables estimation of unobserved disease dynamics and daily seizure frequencies in all disease states. Additional modes of drug action are achievable: gabapentin may influence both daily seizure frequencies and disease state dynamics. Gabapentin significantly reduced seizure frequencies in both disease activity states; however it did not significatively affect disease dynamics. Mixed hidden Markov modeling is able to mimic dynamics of seizure frequencies very well. It offers novel insights into understanding disease dynamics in epilepsy and gabapentin mode of action.

Trimester-specific blood pressure levels and hypertensive disorders among pregnant migraineurs.

OBJECTIVE: We evaluated the influence of physician-diagnosed migraine on blood pressure levels and the risk of hypertensive disorders of pregnancy in a clinic-based prospective cohort study of 3373 healthy pregnant women. BACKGROUND: The relationship between migraine and blood pressure is controversial with results from several studies suggesting positive associations, while others suggest null or inverse associations. To our knowledge, no previous study has investigated blood pressure profiles among pregnant migraineurs. METHODS: We abstracted blood pressure values and delivery information from medical records of women presenting to prenatal clinics in Washington State. Mean blood pressure differences for pregnant migraineurs and non-migraineurs were estimated in regression models, using generalized estimating equations. We calculated odds ratios and 95% confidence intervals (95% CIs) for gestational hypertension and preeclampsia in relation to migraine status. RESULTS: Mean first, second, and third trimester systolic blood pressures (SBP) were elevated among pregnant migraineurs as compared with non-migraineurs. Migraineurs had higher mean third trimester SBP (4.08 mmHg) than non-migraineurs. Trimester-specific diastolic blood pressure (DBP) values were variably related with migraine status. Mean first (0.82 mmHg) and third (2.39 mmHg) trimester DBP were higher, and second trimester DBP values were lower (-0.24) among migraineurs as compared with non-migraineurs. Migraineurs had a 1.53-fold increased odds of preeclampsia (95% CI 1.09 to 2.16). Additionally, migraineurs who were overweight or obese had a 6.10-fold increased odds of preeclampsia (95% CI 3.83 to 9.75) as compared with lean non-migraineurs. CONCLUSIONS: Pregnant migraineurs had elevated blood pressures, particularly SBP measured in the third trimester, and a higher risk of preeclampsia than pregnant women without migraine. Observed associations were more pronounced among overweight or obese migraineurs. Our findings add to the accumulating evidence of adverse pregnancy outcomes among migraineurs.

Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database.

BACKGROUND: A mathematical model was developed to describe the longitudinal response in Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) obtained from the Alzheimer's Disease Neuroimaging Initiative. METHODS: The model was fit to the longitudinal ADAS-cog scores from 817 patients. Risk factors (age, apolipoprotein ɛ4 [APOE ɛ4] genotype, gender, family history of AD, years of education) and baseline severity were tested as covariates. RESULTS: Rate of disease progression increased with baseline severity. Age, APOE ɛ4 genotype, and gender were identified as potential covariates influencing disease progression. The rate of disease progression in patients with mild to moderate AD was estimated as approximately 5.5 points/yr. CONCLUSIONS: A disease progression model adequately described the natural decline of ADAS-cog observed in Alzheimer's Disease Neuroimaging Initiative. Baseline severity is an important covariate to predict a curvilinear rate of disease progression in normal elderly, mild cognitive impairment, and AD patients. Age, APOE ɛ4 genotype, and gender also influence the rate of disease progression.

A verified genomic reference sample for assessing performance of cancer panels detecting small variants of low allele frequency.

BACKGROUND: Oncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance. RESULTS: In reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100× more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels. CONCLUSION: These new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.

A toolkit for rapid gene mapping in the nematode Caenorhabditis briggsae.

BACKGROUND: The nematode C. briggsae serves as a useful model organism for comparative analysis of developmental and behavioral processes. The amenability of C. briggsae to genetic manipulations and the availability of its genome sequence have prompted researchers to study evolutionary changes in gene function and signaling pathways. These studies rely on the availability of forward genetic tools such as mutants and mapping markers. RESULTS: We have computationally identified more than 30,000 polymorphisms (SNPs and indels) in C. briggsae strains AF16 and HK104. These include 1,363 SNPs that change restriction enzyme recognition sites (snip-SNPs) and 638 indels that range between 7 bp and 2 kb. We established bulk segregant and single animal-based PCR assay conditions and used these to test 107 polymorphisms. A total of 75 polymorphisms, consisting of 14 snip-SNPs and 61 indels, were experimentally confirmed with an overall success rate of 83%. The utility of polymorphisms in genetic studies was demonstrated by successful mapping of 12 mutations, including 5 that were localized to sub-chromosomal regions. Our mapping experiments have also revealed one case of a misassembled contig on chromosome 3. CONCLUSIONS: We report a comprehensive set of polymorphisms in C. briggsae wild-type strains and demonstrate their use in mapping mutations. We also show that molecular markers can be useful tools to improve the C. briggsae genome sequence assembly. Our polymorphism resource promises to accelerate genetic and functional studies of C. briggsae genes.

Associations of early pregnancy sleep duration with trimester-specific blood pressures and hypertensive disorders in pregnancy.

STUDY OBJECTIVES: We evaluated the influence of maternal self-reported habitual sleep duration during early pregnancy on blood pressure (BP) levels and risk of hypertensive disorders of pregnancy. DESIGN: Prospective cohort study. SETTING: Clinic-based study. PARTICIPANTS: A cohort of 1,272 healthy, pregnant women. MEASUREMENTS AND RESULTS: We abstracted maternal antenatal BP values from medical records and estimated mean BP differences across hours of sleep categories in regression models, using generalized estimating equations. Odds ratios (OR) and 95% confidence intervals (95% CIs) for pregnancy induced hypertension (PIH) and preeclampsia (PE) in relation to long and short sleep duration were estimated. Mean 1st and 2nd trimester systolic (S) and diastolic (D) BP values were similar among women reporting to be short sleepers (< or = 6 h) vs. women reporting to sleep 9 hours. However, both short and long sleep duration in early pregnancy were associated with increased mean 3rd trimester SBP and DBP. For example, mean 3rd trimester SBP was 3.72, and 2.43 mm Hg higher for women reporting < or = 6 h and 7-8 h sleep, respectively, compared with women reporting 9 h of sleep. Mean 3rd trimester SBP was 4.21 mm Hg higher for women reporting long sleep (> or = 10 h) vs. the reference group. Short and long sleep durations were associated with increased risks of PIH and PE. The ORs for very short (< 5 h) and long (> or = 10 h) sleepers were 9.52 (95% CI 1.83 to 49.40) and 2.45 (95% CI 0.74 to 8.15) for PE. CONCLUSIONS: Our findings are consistent with a larger literature that documents elevated blood pressure and increased risks of hypertension with short and long sleep duration.

Comparison of C. elegans and C. briggsae genome sequences reveals extensive conservation of chromosome organization and synteny.

To determine whether the distinctive features of Caenorhabditis elegans chromosomal organization are shared with the C. briggsae genome, we constructed a single nucleotide polymorphism-based genetic map to order and orient the whole genome shotgun assembly along the six C. briggsae chromosomes. Although these species are of the same genus, their most recent common ancestor existed 80-110 million years ago, and thus they are more evolutionarily distant than, for example, human and mouse. We found that, like C. elegans chromosomes, C. briggsae chromosomes exhibit high levels of recombination on the arms along with higher repeat density, a higher fraction of intronic sequence, and a lower fraction of exonic sequence compared with chromosome centers. Despite extensive intrachromosomal rearrangements, 1:1 orthologs tend to remain in the same region of the chromosome, and colinear blocks of orthologs tend to be longer in chromosome centers compared with arms. More strikingly, the two species show an almost complete conservation of synteny, with 1:1 orthologs present on a single chromosome in one species also found on a single chromosome in the other. The conservation of both chromosomal organization and synteny between these two distantly related species suggests roles for chromosome organization in the fitness of an organism that are only poorly understood presently.

Modelling the association of blood pressure during pregnancy with gestational age and body mass index.

Improved understanding of the determinants of blood pressure (BP) changes during pregnancy is essential for decreasing the morbidity and mortality borne by women and their families worldwide. While most epidemiological studies consider associations based on categorical risk factor classifications, using measurements on a continuous scale has been advocated as a means of gaining richer insights into biological processes. We modelled the relationship during pregnancy of continuous systolic (S) and diastolic (D) BP distributions with gestational age and pre-pregnancy body mass index (BMI) using fractional polynomials. We used information, including antenatal BP values abstracted from medical records, from a prospective cohort of 1733 women recruited before 20 weeks' gestation. The percentiles for SBP and DBP changed over pregnancy, with DBP percentiles decreasing initially, followed by an increase starting about mid-second trimester. Modelling the joint impact of BMI and gestational age on mean BP indicated an increase in mean BP with increasing BMI that was attenuated at higher BMI levels, later in pregnancy. This attenuation persisted in a variety of sub-analyses which explored the possibility that it was caused by confounding or by influential groupings of subjects. Estimated longitudinal percentiles that characterise the BP distribution across gestation may facilitate evaluation of BP during pregnancy. BP patterns observed over pregnancy and, in particular, the attenuation of BP increases at high BMI, late in pregnancy, can provide insights towards elucidating the mechanisms that drive BP changes during pregnancy.

Joint modeling of dizziness, drowsiness, and dropout associated with pregabalin and placebo treatment of generalized anxiety disorder.

Dizziness and drowsiness are cited as being predictors of dropout from clinical trials for the medicine pregabalin. These adverse events are typically recorded daily on a four point ordinal scale (0 = none, 1 = mild, 2 = moderate, 3 = severe), with most subjects never reporting either adverse event. We modeled the dizziness, drowsiness, and dropout associated with pregabalin use in generalized anxiety disorder using piecewise Weibull distributions for the time to first non-zero dizziness or drowsiness score, after which the dizziness or drowsiness was modeled with ordinal regression with a Markovian element. Dropout was modeled with a Weibull distribution. Platykurtosis was encountered in the estimated random effects distributions for the ordinal regression models and was addressed with dynamic John-Draper transformations. The only identified predictor for the time to first non-zero dizziness or drowsiness score was daily titrated dose. Predictors for dropout included creatinine clearance and maximum daily adverse event score. Tolerance to adverse events over time was modeled by including a non-stationary component for the dizziness ordinal Markov regression while the piecewise Weibull distributions allowed a change point in the median time to first non-zero dizziness or drowsiness score.

Modelling overdispersion and Markovian features in count data.

The number of counts (events) per unit of time is a discrete response variable that is generally analyzed with the Poisson distribution (PS) model. The PS model makes two assumptions: the mean number of counts (lambda) is assumed equal to the variance, and counts occurring in non-overlapping intervals are assumed independent. However, many counting outcomes show greater variability than predicted by the PS model, a phenomenon called overdispersion. The purpose of this study was to implement and explore, in the population context, different distribution models accounting for overdispersion and Markov patterns in the analysis of count data. Daily seizures count data obtained from 551 subjects during the 12-week screening phase of a double-blind, placebo-controlled, parallel-group multicenter study performed in epileptic patients with medically refractory partial seizures, were used in the current investigation. The following distribution models were fitted to the data: PS, Zero-Inflated PS (ZIP), Negative Binomial (NB), and Zero-Inflated Negative Binomial (ZINB) models. Markovian features were introduced estimating different lambdas and overdispersion parameters depending on whether the previous day was a seizure or a non-seizure day. All analyses were performed with NONMEM VI. All models were successfully implemented and all overdispersed models improved the fit with respect to the PS model. The NB model resulted in the best description of the data. The inclusion of Markovian features in lambda and in the overdispersion parameter improved the fit significantly (P < 0.001). The plot of the variance versus mean daily seizure count profiles, and the number of transitions, are suggested as model performance tools reflecting the capability to handle overdispersion and Markovian features, respectively.