Transmission dynamics and baseline epidemiological parameter estimates of Coronavirus disease 2019 pre-vaccination: Davao City, Philippines.

The Coronavirus disease 2019 (COVID-19) has exposed many systemic vulnerabilities in many countries' health system, disaster preparedness, and adequate response capabilities. With the early lack of data and information about the virus and the many differing local-specific factors contributing to its transmission, managing its spread had been challenging. The current work presents a modified Susceptible-Exposed-Infectious-Recovered compartmental model incorporating intervention protocols during different community quarantine periods. The COVID-19 reported cases before the vaccine rollout in Davao City, Philippines, are utilized to obtain baseline values for key epidemiologic model parameters. The probable secondary infections (i.e., time-varying reproduction number) among other epidemiological indicators were computed. Results show that the cases in Davao City were driven by the transmission rates, positivity proportion, latency period, and the number of severely symptomatic patients. This paper provides qualitative insights into the transmission dynamics of COVID-19 along with the government's implemented intervention protocols. Furthermore, this modeling framework could be used for decision support, policy making, and system development for the current and future pandemics.

Toward an optimal contraception dosing strategy.

Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH, and ovarian hormones E2, P4, and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation.

Polytherapeutic strategies with oncolytic virus-bortezomib and adjuvant NK cells in cancer treatment.

Proteasome inhibition and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts the degradation of proteins in the cell leading to accumulation of unfolded proteins inducing apoptosis. On the other hand, oncolytic virotherapy uses genetically modified oncolytic viruses (OV) to infect cancer cells, induce cell lysis, and activate an antitumour response. In this work, optimal control theory is used to minimize the cancer cell population by identifying strategic infusion protocols of bortezomib, OV and natural killer (NK) cells. Three different therapeutic protocols are explored: (i) periodic bortezomib and single administrations of both OV and NK cells therapy; (ii) alternating sequential combination therapy; and (iii) NK cell depletion and infusion therapy. In the first treatment scheme, early OV administration followed by well-timed adjuvant NK cell infusion maximizes antitumour efficacy. The second strategy supports timely OV infusion. The last treatment scheme indicates that transient NK cell depletion followed by appropriate NK cell adjuvant therapy yields the maximal benefits. Relative doses and administrative costs of the three anticancer agents for each approach are qualitatively presented. This study provides potential polytherapeutic strategies in cancer treatment.

An Edge-Based Model of SEIR Epidemics on Static Random Networks.

Studies have been done using networks to represent the spread of infectious diseases in populations. For diseases with exposed individuals corresponding to a latent period, an SEIR model is formulated using an edge-based approach described by a probability generating function. The basic reproduction number is computed using the next generation matrix method and the final size of the epidemic is derived analytically. The SEIR model in this study is used to investigate the stochasticity of the SEIR dynamics. The stochastic simulations are performed applying continuous-time Gillespie's algorithm given Poisson and power law with exponential cut-off degree distributions. The resulting predictions of the SEIR model given the initial conditions match well with the stochastic simulations, validating the accuracy of the SEIR model. We varied the contribution of the disease parameters and the average degree of the network in order to investigate their effects on the spread of disease. We verified that the infection and the recovery rates show significant effects on the dynamics of the disease transmission. While the exposed rate delays the spread of the disease, increasing it towards infinity would lead to almost the same dynamics as that of an SIR case. A network with high average degree results to an early and higher peak of the epidemic compared to a network with low average degree. The results in this paper can be used as an alternative way of explaining the spread of disease and it provides implications on the control strategies applied to mitigate the disease transmission.

Country-specific intervention strategies for top three TB burden countries using mathematical model.

Tuberculosis (TB) is one of the top 10 causes of death globally and the leading cause of death by a single infectious pathogen. The World Health Organization (WHO) has declared the End TB Strategy, which targets a 90% reduction in the incidence rate by the year 2035 compared to the level in the year 2015. In this work, a TB model is considered to understand the transmission dynamics in the top three TB burden countries-India, China, and Indonesia. Country-specific epidemiological parameters were identified using data reported by the WHO. If India and Indonesia succeed in enhancing their treatment protocols and increase treatment and treatment success rate to that of China, the incidence rate could be reduced by 65.99% and 68.49%, respectively, by the end of 2035. Evidently, complementary interventions are essential to achieve the WHO target. Our analytical approach utilizes optimal control theory to obtain time-dependent nonpharmaceutical and latent case finding controls. The objective functional of the optimal control problem includes a payoff term reflecting the goal set by WHO. Appropriate combinations of control strategies are investigated. Based on the results, gradual enhancement and continuous implementation of intervention measures are recommended in each country.

Strategies in regulating glioblastoma signaling pathways and anti-invasion therapy.

Glioblastoma multiforme is one of the most invasive type of glial tumors, which rapidly grows and commonly spreads into nearby brain tissue. It is a devastating brain cancer that often results in death within approximately 12 to 15 months after diagnosis. In this work, optimal control theory was applied to regulate intracellular signaling pathways of miR-451-AMPK-mTOR-cell cycle dynamics via glucose and drug intravenous administration infusions. Glucose level is controlled to activate miR-451 in the up-stream pathway of the model. A potential drug blocking the inhibitory pathway of mTOR by AMPK complex is incorporated to explore regulation of the down-stream pathway to the cell cycle. Both miR-451 and mTOR levels are up-regulated inducing cell proliferation and reducing invasion in the neighboring tissues. Concomitant and alternating glucose and drug infusions are explored under various circumstances to predict best clinical outcomes with least administration costs.

Dengue in the Philippines: model and analysis of parameters affecting transmission.

Dengue is endemic in the Philippines and poses a substantial economic burden in the country. In this work, a compartmentalized model which includes healthcare-seeking class is developed. The reproduction number is determined to investigate critical parameters influencing transmission. Partial rank correlation coefficient (PRCC) technique is performed to address how the model output is affected by changes in a specific parameter disregarding the uncertainty over the rest of the parameters. Results show that mosquito biting rate, transmission probability from mosquito to human, respectively, from human to mosquito, and fraction of individuals who seek healthcare at the onset of the disease, posted high PRCC values. In order to obtain the values for the desired parameters, the reported dengue cases by morbidity week in the Philippines for the year 2014 and 2015 are used. The reliability of parameters is then verified via parametric bootstrap.

A physiologically based model of vascular refilling during ultrafiltration in hemodialysis.

An assessment of fluid status can be obtained by monitoring relative blood volume (RBV) during hemodialysis (HD) treatment. The dynamics of RBV is determined by fluid removal from the intravascular compartment by ultrafiltration (UF) and vascular refill from the interstitium. To characterize this dynamics, a two-compartment model describing the short-term dynamics of vascular refilling and UF is developed. Fluid movement between the compartments is governed by lymphatic and microvascular fluid shifts. Further, protein flux is described by convection, diffusion and the lymphatic protein flux. Patient specific parameters are identified based on hematocrit (Hct) measurements by the Crit-Line monitor (CLM). Different measurement frequencies and UF profiles are compared to determine data fidelity and influence on the quality of parameter estimates. This relevant information can be used to assess the (patho)physiological status of hemodialysis patients and could aid in individualizing therapy.

Optimal control strategies of eradicating invisible glioblastoma cells after conventional surgery.

Glioblastoma, the most aggressive type of brain cancer, has median survival time of 1 year after diagnosis. It is characterized by alternating modes of rapid proliferation and aggressive invasion in response to metabolic stress in the microenvironment. A particular microRNA, miR-451, and its downstream signalling molecules, AMPK complex, are known to be key determinants in switching cell fate. These components form a core control system determining a balance between cell growth and migration which is regulated by fluctuating glucose levels in the microenvironment. An important factor from the treatment point of view is that low levels of glucose affect metabolism and activate cell migration through the miR-451-AMPK control system, creating 'invisible' migratory cells and making them inaccessible by conventional surgery. In this work, we apply optimal control theory to deal with the problem of maintaining upregulated miR-451 levels that prevent cell infiltration to surrounding brain tissue and thus induce localization of these cancer cells at the surgical site. The model also considers the effect of a drug that blocks inhibitive pathways of miR-451 from AMPK complex. Glucose infusion control and drug infusion control are chosen to represent dose rates of glucose and drug intravenous administrations, respectively. The characteristics of optimal control lead us to investigate the structure of optimal intravenous infusion regimen under various circumstances and predict best clinical outcomes with minimum expense possible.