Sleep and circadian rhythm disruptions are common in patients with mood disorders. The intricate relationship between these disruptions and mood has been investigated, but their causal dynamics remain unknown. We analysed data from 139 patients (76 female, mean age = 23.5 ± 3.64 years) with mood disorders who participated in a prospective observational study in South Korea. The patients wore wearable devices to monitor sleep and engaged in smartphone-delivered ecological momentary assessment of mood symptoms. Using a mathematical model, we estimated their daily circadian phase based on sleep data. Subsequently, we obtained daily time series for sleep/circadian phase estimates and mood symptoms spanning >40,000 days. We analysed the causal relationship between the time series using transfer entropy, a non-linear causal inference method. The transfer entropy analysis suggested causality from circadian phase disturbance to mood symptoms in both patients with MDD (n = 45) and BD type I (n = 35), as 66.7% and 85.7% of the patients with a large dataset (>600 days) showed causality, but not in patients with BD type II (n = 59). Surprisingly, no causal relationship was suggested between sleep phase disturbances and mood symptoms. Our findings suggest that in patients with mood disorders, circadian phase disturbances directly precede mood symptoms. This underscores the potential of targeting circadian rhythms in digital medicine, such as sleep or light exposure interventions, to restore circadian phase and thereby manage mood disorders effectively. Institute for Basic Science, the Human Frontiers Science Program Organization, the National Research Foundation of Korea, and the Ministry of Health & Welfare of South Korea.

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.

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.

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.