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  1. Newborn screening (NBS) is a state-level initiative that detects life-threatening genetic disorders for which early treatment can substantially improve health outcomes. Cystic fibrosis (CF) is among the most prevalent disorders in NBS. CF can be caused by a large number of mutation variants to the CFTR gene. Most states use a multitest CF screening process that includes a genetic test (DNA). However, due to cost concerns, DNA is used only on a small subset of newborns (based on a low-cost biomarker test with low classification accuracy), and only for a small subset of CF-causing variants. To overcome the cost barriersmore »of expanded genetic testing, we explore a novel approach, of multipanel pooled DNA testing. This approach leads not only to a novel optimization problem (variant selection for screening, variant partition into multipanels, and pool size determination for each panel), but also to novel CF NBS processes. We establish key structural properties of optimal multipanel pooled DNA designs; develop a methodology that generates a family of optimal designs at different costs; and characterize the conditions under which a 1-panel versus a multipanel design is optimal. This methodology can assist decision-makers to design a screening process, considering the cost versus accuracy trade-off. Our case study, based on published CF NBS data from the state of New York, indicates that the multipanel and pooling aspects of genetic testing work synergistically, and the proposed NBS processes have the potential to substantially improve both the efficiency and accuracy of current practices. This paper was accepted by Stefan Scholtes, healthcare management.« less
    Free, publicly-accessible full text available March 14, 2023
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  4. Cystic fibrosis (CF) is a life-threatening genetic disorder. Early treatment of CF-positive newborns can extend life span, improve quality of life, and reduce healthcare expenditures. As a result, newborns are screened for CF throughout the United States. Genetic testing is costly; therefore, CF screening processes start with a relatively inexpensive but not highly accurate biomarker test. Newborns with elevated biomarker levels are further screened via genetic testing for a panel of variants (types of mutations), selected from among hundreds of CF-causing variants, and newborns with mutations detected are referred for diagnostic testing, which corrects any false-positive screening results. Conversely, amore »false negative represents a missed CF diagnosis and delayed treatment. Therefore, an important decision is which CF-causing variants to include in the genetic testing panel so as to reduce the probability of a false negative under a testing budget that limits the number of variants in the panel. We develop novel deterministic and robust optimization models and identify key structural properties of optimal genetic testing panels. These properties lead to efficient, exact algorithms and key insights. Our case study underscores the value of our optimization-based approaches for CF newborn screening compared with current practices. Our findings have important implications for public policy.« less
    Free, publicly-accessible full text available January 1, 2023
  5. A facile way to generate compatibilized blends of immiscible polymers is through reactive blending of end-functionalized homopolymers. The reaction may be reversible or irreversible depending on the end-groups and is affected by the immiscibility and transport of the reactant homopolymers and the compatibilizing copolymer product. Here we describe a phase-field framework to model the combined dynamics of reaction kinetics, diffusion, and multi-component thermodynamics on the evolution of the microstructure and reaction rate in reactive blending. A density functional with no fitting parameters, which is obtained by adapting a framework of Uneyama and Doi and qualitatively agrees with self-consistent field theory,more »is used in a diffusive dynamics model. For a symmetric mixture of equal-length reactive polymers mixed in equal proportions, we find that depending on the Flory χ parameter, the microstructure of an irreversibly reacting blend progresses through a rich evolution of morphologies, including from two-phase coexistence to a homogeneous mixture, or a two-phase to three-phase coexistence transitioning to a homogeneous blend or a lamellar copolymer. The emergence of a three-phase region at high χ leads to a previously unreported reaction rate scaling. For a reversible reaction, we find that the equilibrium composition is a function of both the equilibrium constant for the reaction and the χ parameter. We demonstrate that phase-field models are an effective way to understand the complex interplay of thermodynamic and kinetic effects in a reacting polymer blend.« less
    Free, publicly-accessible full text available January 26, 2023
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  8. Abstract The once-contiguous Ellesmere Ice Shelf, first reported in writing by European explorers in 1876, and now almost completely disintegrated, has rolling, wave-like surface topography, the origin of which we investigate using a viscous buckling instability analysis. We show that rolls can develop during a winter season (~ 100 d) if sea-ice pressure (depth-integrated horizontal stress applied to the seaward front of the Ellesmere Ice Shelf) is sufficiently large (1 MPa m) and ice thickness sufficiently low (1–10 m). Roll wavelength initially depends only on sea-ice pressure, but evolves over time depending on amplitude growth rate. This implies that amore »thinner ice shelf, with its faster amplitude growth rate, will have a shorter wavelength compared to a thicker ice shelf when sea-ice pressure is equal. A drawback of the viscous buckling mechanism is that roll amplitude decays once sea-ice pressure is removed. However, non-Newtonian ice rheology, where effective viscosity, and thus roll change rate, depends on total applied stress may constrain roll decay rate to be much slower than growth rate and allow roll persistence from year to year. Whether the viscous-buckling mechanism we explore here ultimately can be confirmed as the origin of the Ellesmere Ice Shelf rolls remains for future research.« less
    Free, publicly-accessible full text available January 17, 2023
  9. COoking with gas Low concentrations of carbon monoxide (CO) have shown therapeutic benefit in preclinical models, but safe delivery of appropriate dose has been challenging to achieve. Here, inspired by molecular gastronomy, Byrne et al . designed gas-entrapping materials (GEMs) using components generally recognized as safe, including xanthan gum, methylcellulose, maltodextrin, and corn syrup. Solid, hydrogel, and foam GEMs containing CO could deliver different concentrations of the gas to healthy rodents and pigs through noninhaled routes. In rodent models of colitis, acetaminophen overdose, and radiation-induced proctitis, rectally administered foam GEMs reduced tissue injury and inflammation. Foam GEMs could help achievemore »safe therapeutic CO delivery.« less
    Free, publicly-accessible full text available June 29, 2023
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