Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.

A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline

Nonlinear Dynamical Friction in a Gaseous Medium

Using high-resolution, two-dimensional hydrodynamic simulations, we investigate nonlinear gravitational responses of gas to, and the resulting drag force on, a very massive perturber M_p moving at velocity V_p through a uniform gaseous medium of adiabatic sound speed a_0. We model the perturber as a Plummer potential with softening radius r_s, and run various models with differing A=GM_p/(a_0^2 r_s) and M=V_p/a_0 by imposing cylindrical symmetry with respect to the line of perturber motion. For supersonic cases, a massive perturber quickly develops nonlinear flows that produce a detached bow shock and a vortex ring, which is unlike in the linear cases where Mach cones are bounded by low-amplitude Mach waves. The flows behind the shock are initially non-steady, displaying quasi-periodic, overstable oscillations of the vortex ring and the shock. The vortex ring is eventually shed downstream and the flows evolve toward a quasi-steady state where the density wake near the perturber is in near hydrostatic equilibrium. We find that the detached shock distance $\delta$ and the nonlinear drag force F depend solely on \eta=A/(M^2-1) such that \delta/r_s=\eta and F/F_{lin}=(\eta/2)^{-0.45} for \eta>2, where F_{lin} is the linear drag force of Ostriker (1999). The reduction of F compared with F_{lin} is caused by front-back symmetry in the nonlinear density wakes. In subsonic cases, the flows without involving a shock do not readily reach a steady state. Nevertheless, the subsonic density wake near a perturber is close to being hydrostatic, resulting in the drag force similar to the linear case. Our results suggest that dynamical friction of a very massive object as in a merger of black holes near a galaxy center will take considerably longer than the linear prediction.Comment: 40 pages, 18 figures, accepted for publication in Astrophysical Journa

The effects of an unidentified pathogen, ‘Frill on Gill’, on body condition of Cape hake Merluccius capensis, on the south coast of South Africa

The unidentified pathogen, known as 'Frill on Gill’ (FOG), infects the shallow-water Cape hake Merluccius capensis off the south and west coast of South Africa. This pathogen, a parasitic castrator, occurs on the gill filaments of infected fish. This study investigates the effects of this pathogen on the body condition of M. capensis on the south coast of South Africa, through the use of two body condition measures, condition factor and hepatosomatic index (HSI). A total of 24275 M. capensis were sampled, of which 825 (3.4%) were infected with the FOG pathogen. The smallest M. capensis infected with FOG was 10 cm, and the largest was 84 cm. The smallest uninfected M. capensissampled was 6 cm and the largest was 106 cm. The presence of FOG had a significant impact on the condition factor and HSI of M. capensis (three-way analysis of variance (ANOVA): p-value = 0.002, and p-value = 5.13e-09 respectively), with the effect of the pathogen varying with length. For fish with a total length smaller than 26 cm, infected M. capensis were in poorer condition than uninfected fish at the same length, with lower condition factors and HSI values. However, for M. capensis with lengths between 30 and 34 cm, 42 and 46 cm, 54 and 62 cm, and 78 and 82 cm, the condition factors of FOG infected fish were higher than uninfected fish. The HSI values of M. capensis infected with FOG also steadily increase above those of uninfected fish, for lengths greater than 42 cm. The lower body condition measures of uninfected M. capensis could be linked to the large amounts of energy that these fish expend during reproduction and gonad maturation. In contrast, M. capensis infected with FOG do not partake in the energy intensive task of reproduction. Merluccius capensis infected with FOG don’t contribute to reproduction, but still compete with uninfected M. capensis for resources. The effect of FOG as a type of parasitic castrator on the regulation of M. capensis populations could become a concern for fishery managers, as they reduce reproductive output and impact fish body condition

The Resiliency of Highly Mobile Military Children: Implications for Military and Education Leadership

The life of a highly mobile child brings educational and social challenges. Highly mobile children who move at least four to five times during their PK-12 grade years generally experience greater difficulty in their social interactions and education than children with a more stable living experience. One specific group of highly mobile children, military children, face these challenges and more, due somewhat to the unique culture of the military. Military children are called upon to move across state lines and/or international borders and typically face multiple school absences and stress related to deployments of their active duty parent(s). There is a lack of research, generally, on the lives of highly mobile military children and, particularly, research that incorporates their own testimony. This qualitative study was conducted to gain a better understanding of the experiences of highly mobile military children and the strategies they claim to have developed to cope with the consequences of multiple moves. A total of 25 young adults who were highly mobile during their PK-12 grade years were interviewed to gain their perspective. Grounded theory was used to analyze the findings that emerged inductively from their interviews. The unit of analysis was the highly mobile military child; however, some parents were interviewed to provide contextual information about the experiences of their children. The participants’ ability to successfully navigate multiple moves showed that the interrelatedness of having a strong supportive family, being part of a military community that created a sense of belonging, having the benefit of culturally sensitive educators, and having a combination of formal and informal support structures helped these participants build resiliency and the human and social capital needed to navigate the multiple moves they experienced in their PK-12 grade years. This study responds to the gap in knowledge about the experiences of highly mobile military children by providing their perspective. This study better informs the community that works to support these children, including parents, school educators, and counselors, and it provides important knowledge to better support future generations of highly mobile military children

In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability

2017 zero8hundred\u27s Continuing the Promise of a New Day: Support for Service Members Transitioning to Civilian Life in San Diego

This report, prepared by the Caster Center, is a 2-year evaluation report about zero8hundred. Zero8hundred is a cross-sector community initiative whose mission is to proactively link transitioning service members and their families to resources and opportunities in the community, helping them successfully transition to civilian life.https://digital.sandiego.edu/npi-military/1000/thumbnail.jp

2016 The Promise of a New Day: Support for Service Members Transitioning to Civilian Life in San Diego

This report highlights the first year program evaluation of zero8hundred, a nonprofit organization whose mission is to proactively link transitioning military families to a broad range of resources, helping them successfully transition to civilian life in San Diego County.https://digital.sandiego.edu/npi-military/1002/thumbnail.jp