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As participation in women's soccer continues to grow and the longevity of female athletes' careers continues to increase, prevention and care for mTBI in women's soccer has become a major concern for female athletes since the long-term risks associated with a history of mTBI are well documented. Among women's sports, soccer exhibits among the highest concussion rates, on par with those of men's football at the collegiate level. Head impact monitoring technology has revealed that "concussive hits" occurring directly before symptomatic injury are not predictive of mTBI, suggesting that the cumulative effect of repetitive head impacts experienced by collision sport athletes should be assessed. Neuroimaging biomarkers have proven to be valuable in detecting brain changes that occur before neurocognitive symptoms in collision sport athletes. Quantifying the relationship between changes in these biomarkers and head impacts experienced by female soccer athletes may prove valuable to developing preventative measures for mTBI. This study paired functional magnetic resonance imaging with head impact monitoring to track cerebrovascular reactivity changes throughout a season and to test whether the observed changes could be attributed to mechanical loading experienced by female athletes participating in high school soccer. Marked cerebrovascular reactivity changes were observed in female soccer athletes, relative both to non-collision sport control measures and pre-season measures and were localized to fronto-temporal aspects of the brain. These changes persisted 4-5 months after the season ended and recovered by 8 months after the season. Segregation of the total soccer cohort into cumulative loading groups revealed that population-level changes were driven by athletes experiencing high cumulative loads, although athletes experiencing lower cumulative loads still contributed to group changes. The results of this study imply a non-linear relationship between cumulative loading and cerebrovascular changes with a threshold, above which the risk, of injury likely increases significantly.

Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6-Mercaptopurine (6-MP) treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i) 6-MP metabolism, ii) red blood cell mean corpuscular volume (MCV) dynamics, a surrogate marker for treatment efficacy, and iii) leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi-mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC) and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects.

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A methodology is developed that determines age-specific transition rates between cell cycle phases during balanced growth by utilizing age-structured population balance equations. Age-distributed models are the simplest way to account for varied behavior of individual cells. However, this simplicity is offset by difficulties in making observations of age distributions, so age-distributed models are difficult to fit to experimental data. Herein, the proposed methodology is implemented to identify an age-structured model for human leukemia cells (Jurkat) based only on measurements of the total number density after the addition of bromodeoxyuridine partitions the total cell population into two subpopulations. Each of the subpopulations will temporarily undergo a period of unbalanced growth, which provides sufficient information to extract age-dependent transition rates, while the total cell population remains in balanced growth. The stipulation of initial balanced growth permits the derivation of age densities based on only age-dependent transition rates. In fitting the experimental data, a flexible transition rate representation, utilizing a series of cubic spline nodes, finds a bimodal G(0)/G(1) transition age probability distribution best fits the experimental data. This resolution may be unnecessary as convex combinations of more restricted transition rates derived from normalized Gaussian, lognormal, or skewed lognormal transition-age probability distributions corroborate the spline predictions, but require fewer parameters. The fit of data with a single log normal distribution is somewhat inferior suggesting the bimodal result as more likely. Regardless of the choice of basis functions, this methodology can identify age distributions, age-specific transition rates, and transition-age distributions during balanced growth conditions.

Vitamin B6 is critical to normal development; however, the requirement for adequate nutriture of the human infant is based on limited experimental data. In this study vitamin B6 intakes of breast-fed (BF) and formula-fed (FF), healthy, term infants were related to levels of pyridoxal phosphate (PLP) in their plasma at 1, 2, 4, and 6 mo of age. Mothers of BF infants were supplemented with either 2.5 or 15.0 mg pyridoxine . hydrochloride (PN . HCl)/d. Growth was similar for FF and BF infants and was within normal ranges over the 6 mo period. Plasma PLP in cord blood was similar in BF and FF infants; however, at 1-5 d of age and at each subsequent age studied, levels of plasma PLP were significantly higher in FF infants than in BF. Lowest PLP values were for BF infants of mothers who received 2.5 mg PN . HCl/d. Mean plasma PLP decreased with age and was not correlated to vitamin B6 intakes except at 1 mo of age. At this age, vitamin B6 intake of BF infants whose mothers received 2.5 mg PN . HCl/d was only 0.1 mg B6/d. The consequences of this are uncertain; however, plasma PLP levels of the infants were low and reflected their intakes of vitamin B6.

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