A finite element-guided mathematical surrogate modeling approach for assessing occupant injury trends across variations in simplified vehicular impact conditions.

A finite element (FE)-guided mathematical surrogate modeling methodology is presented for evaluating relative injury trends across varied vehicular impact conditions. The prevalence of crash-induced injuries necessitates the quantification of the human body's response to impacts. FE modeling is often used for crash analyses but requires time and computational cost. However, surrogate modeling can predict injury trends between the FE data, requiring fewer FE simulations to evaluate the complete testing range. To determine the viability of this methodology for injury assessment, crash-induced occupant head injury criterion (HIC15) trends were predicted from Kriging models across varied impact velocities (10-45 mph; 16.1-72.4 km/h), locations (near side, far side, front, and rear), and angles (-45 to 45°) and compared to previously published data. These response trends were analyzed to locate high-risk target regions. Impact velocity and location were the most influential factors, with HIC15 increasing alongside the velocity and proximity to the driver. The impact angle was dependent on the location and was minimally influential, often producing greater HIC15 under oblique angles. These model-based head injury trends were consistent with previously published data, demonstrating great promise for the proposed methodology, which provides effective and efficient quantification of human response across a wide variety of car crash scenarios, simultaneously. This study presents a finite element-guided mathematical surrogate modeling methodology to evaluate occupant injury response trends for a wide range of impact velocities (10-45 mph), locations, and angles (-45 to 45°). Head injury response trends were predicted and compared to previously published data to assess the efficacy of the methodology for assessing occupant response to variations in impact conditions. Velocity and location were the most influential factors on the head injury response, with the risk increasing alongside greater impact velocity and locational proximity to the driver. Additionally, the angle of impact variable was dependent on the location and, thus, had minimal independent influence on the head injury risk.

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies.

SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.

Ovulation detection methods for urinary hormones: precision, daily and intermittent sampling and a combined hierarchical method.

BACKGROUND: We evaluate the performance of ovulation detection methods and present new approaches, including evaluation of methods for precision, combining multiple markers into a hierarchical system and using ovulation markers in intermittent sampling designs. METHODS: With serum LH peak day as the 'gold standard' of ovulation, we estimated accuracy and precision of ovulation day algorithms using 30 ovulatory menstrual cycles with daily urinary and serum hormones and transvaginal ultrasound. Sensitivity and specificity for estimating the presence of ovulation were tested using visually assessed ovulatory (30) and anovulatory (22) cycles. RESULTS: Sensitivity and specificity ranged from 70 to 100% for estimating presence of ovulation with twice-per-cycle, weekly, twice weekly, every-other-day and daily specimens. A combined hierarchical method estimated ovulation day using daily specimens within +/-2 days of the gold standard in 93% of cases. Accuracy of estimating ovulation day within +/-2 days using intermittent sampling ranged from 40% (weekly sampling) to 97% (every-other-day). CONCLUSIONS: A combined hierarchical algorithm using precise and accurate markers allows maximal use of available data for efficient and objective identification of ovulation using daily specimens. In intermittent sampling designs, the presence and the timing of ovulation can be estimated with good sensitivity, specificity and accuracy.

Menstrual cycle variability and the perimenopause.

Menopause, the final cessation of menstrual cycling, occurs when the pool of ovarian follicles is depleted. The one to five years just prior to the menopause are usually marked by increasing variability in menstrual cycle length, frequency of ovulation, and levels of reproductive hormones. Little is known about the mechanisms that account for these characteristics of ovarian cycles as the menopause approaches. Some evidence suggests that the dwindling pool of follicles itself is responsible for cycle characteristics during the perimenopausal transition. Another hypothesis is that the increased variability reflects "slippage" of the hypothalamus, which loses the ability to regulate menstrual cycles at older reproductive ages. This paper examines the underlying cause of the increasing variability in menstrual cycle length prior to the menopause. A model of ovarian cycles is developed, based on the process of follicular growth and depletion. Under this model, the follicular phase of each menstrual cycle is preceded by an inactive phase, a period of time when no ovarian follicles have left the resting state and begun secreting steroids in response to gonadotropin stimulation. The model makes predictions about the variability in menstrual cycles across the reproductive life span based on the size of the surviving pool of ovarian follicles. We show that the model can explain several characteristics of the perimenopause in humans and macaques and illustrate how the model can be applied to research on the biological and cultural correlates of the timing of menopause.

St. Jude SPV versus Medtronic Freestyle: a single institution comparison of two stentless aortic valves.

BACKGROUND: Improved hemodynamics with the SPV and Freestyle bioprostheses compared to stented valves have been reported. It has been suggested that there is more aortic insufficiency (Al) with the Freestyle than with the SPV valve. This study was designed to assess the hemodynamic performance of these two valves implanted at a single institution with all echocardiograms reviewed by one echocardiographer. METHODS: From 1993 to 1997 112 patients underwent aortic valve replacement with stentless aortic valves (69 SPV, 43 Freestyle). There were no major preoperative differences in patient age, gender, NYHA class, or ejection fraction between groups. Echocardiographic assessment was obtained at discharge, 3 to 6 months following surgery, and yearly thereafter. RESULTS: Mean follow-up was 15.9 months for the SPV and 28.6 months for the Freestyle. Both valves have excellent valve areas and low transvalvar mean gradients. There is a trend for more Al in the SPV group. At 1 year, 1+ or greater Al was present in 11 of 42 SPV patients compared to 2 of 34 Freestyle patients (p = 0.030). Al has tended to remain stable over time, has not progressed, and is not clinically evident. DISCUSSION: Differences in the previously reported incidence of aortic insufficiency with these valves may have more to do with the method of reporting Al than its actual frequency. Within our institution, there has been slightly more mild Al with the SPV valve than with Freestyle. Long-term follow-up of these valves is needed to determine if the Al progresses or becomes clinically important. To date there is no such trend with either valve.

Declining fecundity and ovarian ageing in natural fertility populations.

Worldwide, human fertility declines with increasing maternal age, after contraceptive-use patterns and behavioral factors are taken into consideration. Here, we summarize some of our theoretical and empirical work examining the biological factors contributing to this age pattern of fertility. We undertook an 11 month prospective endocrinological study in a natural fertility (non-contracepting) population (rural Bangladesh) to estimate the contributions of fetal loss and fecundability (the probability of conception) to declining fecundity with age. Prospective interviews and urine samples for pregnancy tests were collected twice weekly from up to 700 women. These data were used to test mathematical models of the underlying biological processes contributing to changing fecundability and fetal loss risk with maternal age. The results indicate that much of the decline in fecundity can be attributed to an increasing risk of fetal loss with maternal age. Much of this fetal loss is due to chromosomal abnormalities--a result of ageing oocytes. Fecundability, on the other hand, does not begin to decline until the early 40s. We hypothesize that this is also a result of ageing at the ovarian level, namely follicular atresia, in the years just prior to menopause. The irregularity of menstrual cycles--longer cycles and increasingly variable hormonal patterns--at these ages may be a direct result of the small and rapidly dwindling remaining pool of follicles. We present a simple mathematical model of this process, and some preliminary laboratory results that support the model.

The evaluation of delayed-type hypersensitivity responsiveness and nutritional status as predictors of gastro-intestinal and acute respiratory infection: a prospective field study among traditional nomadic Kenyan children.

A 10-month prospective study of children from a nomadic pastoralist community in northwest Kenya was conducted to examine the relationship between nutritional status, cell-mediated immunity (CMI), and morbidity due to gastroenteritis and acute respiratory infection (ARI). In children ages 6 months to 10 years, nutritional status and cellular immunocompetence, determined by delayed-type hypersensitivity (DTH), were related to individual attack rates of diarrhoea and ARI over two 5-month observation periods, one each in the wet and dry season. While no association was found between premorbid nutritional status and gastroenteritis, DTH responsiveness was a significant predictor of diarrhoeal disease, with anergic children experiencing, on average, 20 per cent higher attack rates than immunocompetent children. When examined separately, both nutritional status and DTH responsiveness were significant predictors of individual attack rates of ARI in the wet season. However, when the effects of nutritional and immunological status were simultaneously tested, only DTH responsiveness was significant. Anergic children experienced 34 per cent excess ARI, compared to immunocompetent children. These results indicate that cellular immunocompetence is a sensitive predictor of gastrointestinal and respiratory infection, and that the effect of nutritional status on the occurrence of ARI may be mediated by cellular immune function.

Laboratory Scale Thermal Plasma Arc Vitrification Studies of Heavy Metal-Laden Waste.

Plasma processing has been identified as a useful tool for immobilizing heavy metal-contaminated wastes into safe, leach-resistant slag. Although much effort has gone into developing this technology on a pilot scale, not much information has been published on basic research topics. A laboratory-scale plasma arc furnace located at the University of Illinois was operated in cooperation with the U.S. Army Construction Engineering Research Laboratories in an effort to establish an understanding of the chemical and physical processes (such as metal volatilization and resultant gas evolution) that occur during thermal plasma treatment of metal-spiked samples. Experiments were conducted on nickel and chromium using a highly instrumented furnace equipped with a 75 kW transferred arc plasma torch. The volatility of nickel and chromium was examined as a function of varying oxygen partial pressures. Oxidizing conditions reduced the total dust gathered for both the nickel and chromium samples, although each dust sample was found to be metal-enriched. Plasma treating increased the leach-resistance of the slags by at least one order of magnitude when compared to unprocessed specimens. The leach- resistance of the nickel-containing slags increased in the presence of oxygen, whereas chromium samples remained relatively constant.

Automation of flow injection gas diffusion-ion chromatography for the nanomolar determination of methylamines and ammonia in seawater and atmospheric samples.

The automation and improved design and performance of Flow Injection Gas Diffusion-Ion Chromatography (FIGD-IC), a novel technique for the simultaneous analysis of trace ammonia (NH(3)) and methylamines (MAs) in aqueous media, is presented. Automated Flow Injection Gas Diffusion (FIGD) promotes the selective transmembrane diffusion of MAs and NH(3) from aqueous sample under strongly alkaline (pH > 12, NaOH), chelated (EDTA) conditions into a recycled acidic acceptor stream. The acceptor is then injected onto an ion chromatograph where NH(3) and the MAs are fully resolved as their cations and detected conductimetrically. A versatile PC interfaced control unit and data capture unit (DCU) are employed in series to direct the selonoid valve switching sequence, IC operation and collection of data. Automation, together with other modifications improved both linearily (R(2) > 0.99 MAs 0-100 nM, NH(3) 0-1000 nM) and precision (<8%) of FIGD-IC at nanomolar concentrations, compared with the manual procedure. The system was successfully applied to the determination of MAs and NH(3) in seawater and in trapped particulate and gaseous atmospheric samples during an oceanographic research cruise.

Women's reproductive cancers in evolutionary context.

Reproductive experiences for women in today's affluent Western nations differ from those of women in hunting and gathering societies, who continue the ancestral human pattern. These differences parallel commonly accepted reproductive risk factors for cancers of the breast, endometrium and ovary. Nutritional practices, exercise requirements, and body composition are nonreproductive influences that have been proposed as additional factors affecting the incidence of women's cancers. In each case, these would further increase risk for women in industrialized countries relative to forager women. Lifestyles and reproductive patterns new from an evolutionary perspective may promote women's cancers. Calculations based on a theoretical model suggest that, to age 60, modern Western women have a breast cancer risk as much as 100 times that of preagricultural women.

A multistate model of fecundability and sterility.

This paper develops a multistate hazards model for estimating fecundability and sterility from data on waiting times to conception. Important features of the model include separate sterile and nonsterile states, a distinction between preexisting sterility and sterility that begins after initiation of exposure, and log-normally distributed fecundability among nonsterile couples. Application of the model to data on first birth intervals from Taiwan, Sri Lanka, and the Amish shows that heterogeneity in fecundability is statistically significant at most ages, but that preexisting sterility and new sterility are unimportant before age 40. These results suggest that sterility may not be an important determinant of natural fertility until later reproductive ages.

Proportional hazards analysis of diarrhea due to enterotoxigenic Escherichia coli and breast feeding in a cohort of urban Mexican children.

Ninety-eight women-infant pairs were followed for up to 50 weeks in the northern part of Guadalajara, Mexico, from August 1986 to July 1987 as part of a community-based, prospective study of the relation between infant feeding patterns and enterotoxigenic Escherichia coli producing heat-labile toxin (LT-ETEC) diarrheal disease. Strictly formula-fed children had an incidence of diarrhea over three times that of strictly breast-fed infants and twice that of breast-fed and supplementally fed children. Strictly formula-fed infants colonized by LT-ETEC were symptomatic for diarrhea nearly three times as often as strictly breast-fed infants and twice as often as infants receiving a mixed diet. The fitting of parametric hazard models to durations until LT-ETEC colonization revealed that the hazard for the first colonization was time invariant. The hazard of diarrhea increased by 400-500% during the rainy season or among children 3 months of age or older who received avena, a barley drink. The best-fitting hazard models to durations until symptomatic expression of LT-ETEC infection all increased through time. This hazard was inversely impacted by the overall amount of LT-ETEC-specific, immunoglobulin A antibodies the infant received via the mother's breast milk and by the provision of traditional medicinal teas.

Hazards models for human population biology.

PIP: Population biologists often wish to examine the effects of continuous biological variables such as measures of growth, body size,nutritional status, and exposure to environmental risk factors on discrete vital events like birth, onset of disease, and death. Traditional statistical analyses are unable to accommodate some complexities which develop in studying such effects, including the censoring of observations and explanatory variables which change over time. Most traditional methods also provide only empirical rather than etiologic models of pertinent processes. Statistical techniques on hazards analysis deemed especially appropriate for studying biodemographic events and processes are reviewed. A general likelihood framework is also presented which allows the efficient estimation and testing of etiologic hazards models. Past attempts to model biological processes underlying age patterns of fertility and mortality are reviewed, while discussion is had on how the hazards framework may be adapted to study the quantitative genetics of vital events.^ieng

Birth spacing patterns in humans and apes.

Comparative studies of birth interval dynamics in wild primates suffer from several problems of analysis and interpretation: (1) the data are always right-censored, (2) sample sizes are usually small, (3) the distribution of birth intervals is expected to be non-normal, (4) early offspring mortality is a confounding variable, and (5) differences in life history (e.g., presence or absence of menopause) can complicate interpretation of the results. A survival analysis designed to minimize these problems is applied to published data on wild chimpanzees and gorillas from Gombe and Virunga Parks, respectively, and to new data on wild orangutans from Tanjung Puting National Park and on a human population, the Gainj of highland Papua New Guinea. According to this analysis, the estimated median birth interval (when the offspring whose birth opens the interval does not die within the interval) is 43.3 +/- 1.0 months for the Gainj, 45.5 +/- 1.2 months for gorillas, 66.6 +/- 1.3 months for chimpanzees, and 92.6 +/- 2.4 months for orangutans.

Female fecundity in highland Papua New Guinea.

Demographers often assume that interpopulation variation in birth spacing is attributable primarily to behavioral differences (e.g., in breastfeeding, coital frequency, or contraceptive practice), and that the contribution of physiological factors is negligible. This assumption may be correct, but it should be tested, especially in light of recent evidence that there may be more variation in ovarian function among human populations than was previously believed. In this paper, we apply a stochastic model of the determinants of fecundability (the monthly probability of conception) to endocrinological data collected among the Gainj, a tribal population in highland Papua New Guinea. Based on previous research, the Gainj are known to have age patterns of ovarian function that differ markedly from the Western norms. When account is taken of the late menarche, early menopause, and long ovarian cycles that appear to characterize Gainj women, mean apparent fecundability across the female reproductive span is reduced by about 27 per cent (from 0.316 to 0.235), and the mean waiting time to next apparent conception is increased by just over one month. Thus, despite the fact that Gainj women differ from Western women with respect to reproductive physiology by as much as or more than any other known population, the demographic impact of these differences appears to be slight.

Fertility in anthropological populations.

"In this review I draw upon statistical demography and, to a lesser extent, reproductive endocrinology to formulate a coherent strategy for investigating fertility and reproduction in anthropological populations. The object, it must be emphasized, is not to reduce anthropology to demography or endocrinology, but rather to acquaint anthropologists with a powerful set of tools with which they can address issues of anthropological interest." The author first discusses the concept of natural fertility. Next, he summarizes the most significant generalizations concerning variations in fertility among preindustrial societies using the concept of proximate determinants developed by John Bongaarts. Finally, he outlines an alternative approach that might be more suited to the analysis of such fertility variations.