Competitive evolution of H1N1 and H3N2 influenza viruses in the United States: A mathematical modeling study.

Seasonal influenza causes vast public health and economic impact globally. The prevention and control of the annual epidemics remain a challenge due to the antigenic evolution of the viruses. Here, we presented a novel modeling framework based on changes in amino acid sequences and relevant epidemiological data to retrospectively investigate the competitive evolution and transmission of H1N1 and H3N2 influenza viruses in the United States during October 2002 and April 2019. To do so, we estimated the time-varying disease transmission rate from the reported influenza cases and the time-varying antigenic change rate of the viruses from the changes in amino acid sequences. By incorporating the time-varying antigenic change rate into the transmission models, we found that the models could capture the evolutionary transmission dynamics of influenza viruses in the United States. Our modeling results also showed that the antigenic change of the virus plays an essential role in seasonal influenza dynamics.

A mathematical model for Zika virus transmission dynamics with a time-dependent mosquito biting rate.

BACKGROUND: Mathematical modeling has become a tool used to address many emerging diseases. One of the most basic and popular modeling frameworks is the compartmental model. Unfortunately, most of the available compartmental models developed for Zika virus (ZIKV) transmission were designed to describe and reconstruct only past, short-time ZIKV outbreaks in which the effects of seasonal change to entomological parameters can be ignored. To make an accurate long-term prediction of ZIKV transmission, the inclusion of seasonal effects into an epidemic model is unavoidable. METHODS: We developed a vector-borne compartmental model to analyze the spread of the ZIKV during the 2015-2016 outbreaks in Bahia, Brazil and to investigate the impact of two vector control strategies, namely, reducing mosquito biting rates and reducing mosquito population size. The model considered the influences of seasonal change on the ZIKV transmission dynamics via the time-varying mosquito biting rate. The model was also validated by comparing the model prediction with reported data that were not used to calibrate the model. RESULTS: We found that the model can give a very good fit between the simulation results and the reported Zika cases in Bahia (R-square = 0.9989). At the end of 2016, the total number of ZIKV infected people was predicted to be 1.2087 million. The model also predicted that there would not be a large outbreak from May 2016 to December 2016 due to the decrease of the susceptible pool. Implementing disease mitigation by reducing the mosquito biting rates was found to be more effective than reducing the mosquito population size. Finally, the correlation between the time series of estimated mosquito biting rates and the average temperature was also suggested. CONCLUSIONS: The proposed ZIKV transmission model together with the estimated weekly biting rates can reconstruct the past long-time multi-peak ZIKV outbreaks in Bahia.

Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum.

The emergence of drug resistance continuously threatens global control of infectious diseases, including malaria caused by the protozoan parasite Plasmodium falciparum A critical parasite determinant is the P. falciparum chloroquine resistance transporter (PfCRT), the primary mediator of chloroquine (CQ) resistance (CQR), and a pleiotropic modulator of susceptibility to several first-line artemisinin-based combination therapy partner drugs. Aside from the validated CQR molecular marker K76T, P. falciparum parasites have acquired at least three additional pfcrt mutations, whose contributions to resistance and fitness have been heretofore unclear. Focusing on the quadruple-mutant Ecuadorian PfCRT haplotype Ecu1110 (K76T/A220S/N326D/I356L), we genetically modified the pfcrt locus of isogenic, asexual blood stage P. falciparum parasites using zinc-finger nucleases, producing all possible combinations of intermediate pfcrt alleles. Our analysis included the related quintuple-mutant PfCRT haplotype 7G8 (Ecu1110 + C72S) that is widespread throughout South America and the Western Pacific. Drug susceptibilities and in vitro growth profiles of our combinatorial pfcrt-modified parasites were used to simulate the mutational trajectories accessible to parasites as they evolved CQR. Our results uncover unique contributions to parasite drug resistance and growth for mutations beyond K76T and predict critical roles for the CQ metabolite monodesethyl-CQ and the related quinoline-type drug amodiaquine in driving mutant pfcrt evolution. Modeling outputs further highlight the influence of parasite proliferation rates alongside gains in drug resistance in dictating successful trajectories. Our findings suggest that P. falciparum parasites have navigated constrained pfcrt adaptive landscapes by means of probabilistically rare mutational bursts that led to the infrequent emergence of pfcrt alleles in the field.

Origin of robustness in generating drug-resistant malaria parasites.

Biological robustness allows mutations to accumulate while maintaining functional phenotypes. Despite its crucial role in evolutionary processes, the mechanistic details of how robustness originates remain elusive. Using an evolutionary trajectory analysis approach, we demonstrate how robustness evolved in malaria parasites under selective pressure from an antimalarial drug inhibiting the folate synthesis pathway. A series of four nonsynonymous amino acid substitutions at the targeted enzyme, dihydrofolate reductase (DHFR), render the parasites highly resistant to the antifolate drug pyrimethamine. Nevertheless, the stepwise gain of these four dhfr mutations results in tradeoffs between pyrimethamine resistance and parasite fitness. Here, we report the epistatic interaction between dhfr mutations and amplification of the gene encoding the first upstream enzyme in the folate pathway, GTP cyclohydrolase I (GCH1). gch1 amplification confers low level pyrimethamine resistance and would thus be selected for by pyrimethamine treatment. Interestingly, the gch1 amplification can then be co-opted by the parasites because it reduces the cost of acquiring drug-resistant dhfr mutations downstream in the same metabolic pathway. The compensation of compromised fitness by extra GCH1 is an example of how robustness can evolve in a system and thus expand the accessibility of evolutionary trajectories leading toward highly resistant alleles. The evolution of robustness during the gain of drug-resistant mutations has broad implications for both the development of new drugs and molecular surveillance for resistance to existing drugs.

Kinetics of domain registration in multicomponent lipid bilayer membranes.

The kinetics of registration of lipid domains in the apposing leaflets of symmetric bilayer membranes is investigated via systematic dissipative particle dynamics simulations. The decay of the distance between the centres of mass of the domains in the apposing leaflets is almost linear during early stages, and then becomes exponential during late times. The time scales of both linear and exponential decays are found to increase with decreasing strength of interleaflet coupling. The ratio between the time scales of the exponential and linear regimes decreases with increasing domain size, implying that the decay of the distance between the domains' centres of mass is essentially linear for large domains. These numerical results are largely in agreement with the recent theoretical predictions of Han and Haataja [Soft Matter, 2013, 9, 2120-2124]. We also found that the domains become elongated during the registration process.

First pandemic A (H1N1) pdm09 outbreak in a private school, Bangkok, Thailand, June 2009.

OBJECTIVE: On June 9, 2009, the Thailand Ministry of Public Health received their first report of an outbreak of the pandemic A (HIN1) pdm09 that occurred in a school. The authors conducted a study to describe the epidemiological characteristics of the outbreak and its resurgence, estimate the basic reproduction number (R) and review recommendations for prevention and control. MATERIAL AND METHOD: Active case finding in the school and reviewing reports to the national surveillance system identified 184 students infected by the new virus. A survey described the illness in the students and the prevention and control measures taken by the school. The basic reproduction number was estimated from data in the early epidemic phase. The other survey was done to assess factors contributing to the resurgence of the outbreak. RESULTS: Students with the pandemic A (HINI) pdm09 had a mild illness resembling seasonal influenza. Overcrowding in the classroom and activities that mixed students from different classes contributed to transmission in the school. The basic reproduction number for this school-based setting is 3.58. The second outbreak occurred because of poor monitoring of absenteeism and management of ill students. CONCLUSION: This was the first outbreak ofthepandemic A (HIN1) pdm09 in Thailand. The source could not be identified. Effective control measures monitoring, screening, strict personal hygiene and proper management of ill students.

Vaccination strategies impact the probability of outbreak extinction: A case study of COVID-19 transmission.

Mass vaccination has proven to be an effective control measure for mitigating the transmission of infectious diseases. Throughout history, various vaccination strategies have been employed to control infections and terminate outbreaks. In this study, we utilized the transmission of COVID-19 as a case study and constructed a stochastic age-structured compartmental model to investigate the effectiveness of different vaccination strategies. Our analysis focused on estimating the outbreak extinction probability under different vaccination scenarios in both homogeneous and heterogeneous populations. Notably, we found that population heterogeneity can enhance the likelihood of outbreak extinction at varying levels of vaccine coverage. Prioritizing vaccinations for individuals with higher infection risk was found to maximize outbreak extinction probability and reduce overall infections, while allocating vaccines to those with higher mortality risk has been proven more effective in reducing deaths. Moreover, our study highlighted the significance of booster doses as the vaccine effectiveness wanes over time, showing that they can significantly enhance the extinction probability and mitigate disease transmission.

LSTM-Powered COVID-19 prediction in central Thailand incorporating meteorological and particulate matter data with a multi-feature selection approach.

The COVID-19 pandemic has significantly impacted public health and necessitated urgent actions to mitigate its spread. Monitoring and predicting the outbreak's progression have become vital to devise effective strategies and allocate resources efficiently. This study presents a novel approach utilizing Multivariate Long Short-Term Memory (LSTM) to analyze and predict COVID-19 trends in Central Thailand, particularly emphasizing the multi-feature selection process. To consider a comprehensive view of the pandemic's dynamics, our research dataset encompasses epidemiological, meteorological, and particulate matter features, which were gathered from reliable sources. We propose a multi-feature selection technique to identify the most relevant and influential features that significantly impact the spread of COVID-19 in the region to enhance the model's performance. Our results highlight that relative humidity is the key factor driving COVID-19 transmission in Central Thailand. The proposed multi-feature selection technique significantly improves the model's accuracy, ensuring that only the most informative variables contribute to the predictions, avoiding the potential noise or redundancy from less relevant features. The proposed LSTM model demonstrates its capability to forecast COVID-19 cases, facilitating informed decision-making for public health authorities and policymakers.

Exploring indoor and outdoor dust as a potential tool for detection and monitoring of COVID-19 transmission.

This study investigated the potential of using SARS-CoV-2 viral concentrations in dust as an additional surveillance tool for early detection and monitoring of COVID-19 transmission. Dust samples were collected from 8 public locations in 16 districts of Bangkok, Thailand, from June to August 2021. SARS-CoV-2 RNA concentrations in dust were quantified, and their correlation with community case incidence was assessed. Our findings revealed a positive correlation between viral concentrations detected in dust and the relative risk of COVID-19. The highest risk was observed with no delay (0-day lag), and this risk gradually decreased as the lag time increased. We observed an overall decline in viral concentrations in public places during lockdown, closely associated with reduced human mobility. The effective reproduction number for COVID-19 transmission remained above one throughout the study period, suggesting that transmission may persist in locations beyond public areas even after the lockdown measures were in place.

Finite element analysis and optimization of microneedle arrays for transdermal vaccine delivery: comparison of coated and dissolving microneedles.

Microneedle arrays have recently been proposed as an alternative device for delivering vaccines into the skin. In recent years, many types of microneedles, such as coated and dissolving microneedles, have been developed with a variety of array configurations. However, the study that alongside compares the vaccine delivery efficiency of different types of microneedles and optimizes their arrangements on an array has been lacking. This study aimed to evaluate the vaccine delivery efficiency of coated and dissolving microneedles as well as to optimize the microneedle arrangements by using a three-dimensional finite element modeling approach. The constructed models describe the antigen release via diffusion, the antigen-receptor binding, and the antigen internalization by antigen-presenting cells (APCs) in the skin layers. Our modeling result reveals that the coated microneedle provides higher efficiency in activating APCs than the dissolving microneedle. It also predicts that the square arrangement of microneedles is not the optimal arrangement. According to the magnitude of APC activation, the acute-angle arrangement of microneedles outperforms the square arrangement by activating more APCs in the dermis.

Modeling vaccination strategies with limited early COVID-19 vaccine access in low- and middle-income countries: A case study of Thailand.

Low- and middle-income countries faced significant challenges in accessing COVID-19 vaccines during the early stages of the pandemic. In this study, we utilized an age-structured modeling approach to examine the implications of various vaccination strategies, vaccine prioritization, and vaccine rollout speeds in Thailand, an upper-middle-income country experiencing vaccine shortages during the early stages of the pandemic. The model directly compares the effectiveness of several vaccination strategies, including the heterologous vaccination where CoronaVac (CV) vaccine was administered as the first dose, followed by ChAdOx1 nCoV-19 (AZ) vaccine as the second dose, under varying disease transmission dynamics. We found that the traditional AZ homologous vaccination was more effective than the CV homologous vaccination, regardless of disease transmission dynamics. However, combining CV and AZ vaccines via either parallel homologous or heterologous vaccinations was more effective than relying solely on AZ homologous vaccination. Additionally, prioritizing vaccination for the elderly aged 60 years and above was the most effective way to reduce mortality when community transmission is well-controlled. On the other hand, prioritizing workers aged 20-59 was most effective in lowering COVID-19 cases, irrespective of the transmission dynamics. Lastly, despite the vaccine prioritization strategy, rapid vaccine rollout speeds were crucial in reducing COVID-19 infections and deaths. These findings suggested that in low- and middle-income countries where early access to high-efficacy vaccines might be limited, obtaining any accessible vaccines as early as possible and using them in parallel with other higher-efficacy vaccines might be a better strategy than waiting for and relying solely on higher-efficacy vaccines.

Multiple traces of monkeypox detected in non-sewered wastewater with sparse sampling from a densely populated metropolitan area in Asia.

The monkeypox virus is excreted in the feces of infected individuals. Therefore, there is an interest in using viral load detection in wastewater for sentinel early surveillance at a community level and as a complementary approach to syndromic surveillance. We collected wastewater from 63 sewered and non-sewered locations in Bangkok city center between May and August 2022. Monkeypox viral DNA copy numbers were quantified using real-time polymerase chain reaction (PCR) and confirmed positive by Sanger sequencing. Monkeypox viral DNA was first detected in wastewater from the second week of June 2022, with a mean copy number of 16.4 copies/ml (n = 3). From the first week of July, the number of viral DNA copies increased to a mean copy number of 45.92 copies/ml. Positive samples were Sanger sequenced and confirmed the presence of the monkeypox virus. Our study is the first to detect monkeypox viral DNA in wastewater from various locations within Thailand. Results suggest that this could be a complementary source for detecting viral DNA and predicting upcoming outbreaks.

COVID-19 monitoring with sparse sampling of sewered and non-sewered wastewater in urban and rural communities.

Equitable SARS-CoV-2 surveillance in low-resource communities lacking centralized sewers is critical as wastewater-based epidemiology (WBE) progresses. However, large-scale studies on SARS-CoV-2 detection in wastewater from low-and middle-income countries is limited because of economic and technical reasons. In this study, wastewater samples were collected twice a month from 186 urban and rural subdistricts in nine provinces of Thailand mostly having decentralized and non-sewered sanitation infrastructure and analyzed for SARS-CoV-2 RNA variants using allele-specific RT-qPCR. Wastewater SARS-CoV-2 RNA concentration was used to estimate the real-time incidence and time-varying effective reproduction number (Re). Results showed an increase in SARS-CoV-2 RNA concentrations in wastewater from urban and rural areas 14-20 days earlier than infected individuals were officially reported. It also showed that community/food markets were "hot spots" for infected people. This approach offers an opportunity for early detection of transmission surges, allowing preparedness and potentially mitigating significant outbreaks at both spatial and temporal scales.

Tracing the transmission of mpox through wastewater surveillance in Southeast Asia.

High population density and tourism in Southeast Asia increase the risk of mpox due to frequent interpersonal contacts. Our wastewater surveillance in six Southeast Asian countries revealed positive signals for Monkeypox virus (MPXV) DNA, indicating local transmission. This alerts clinicians and helps allocate resources like testing, vaccines and therapeutics in resource-limited countries.

Estimation of Excess All-Cause Mortality Due to COVID-19 in Thailand.

Thailand has experienced the most prominent COVID-19 outbreak in 2021, resulting in a new record for COVID-19 cases and deaths. To assess the influence of the COVID-19 outbreak on mortality, we estimated excess all-cause and pneumonia mortality in Thailand during the COVID-19 outbreak from April to October 2021. We used mortality from the previous 5 years to estimate the baseline number of deaths using generalized linear mixed models. The models were adjusted for seasonality and demographics. We found that, during the outbreak in 2021, there was a significant rise in excess fatalities, especially in the older age groups. The estimated cumulative excess death was 14.3% (95% CI: 8.6-18.8%) higher than the baseline. The results also showed that the excess deaths in males were higher than in females by approximately 26.3%. The excess deaths directly caused by the COVID-19 infections accounted for approximately 75.0% of the all-cause excess deaths. Furthermore, excess pneumonia deaths were also found to be 26.2% (95% CI: 4.8-46.0%) above baseline.

Modelling of the transmission dynamics of carbapenem-resistant Klebsiella pneumoniae in hospitals and design of control strategies.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a major threat to global public health. Epidemiological and infection controls associated with CRKP are challenging because of several potential elements involved in a complicated cycle of transmission. Here, we proposed a comprehensive mathematical model to investigate the transmission dynamics of CRKP, determine factors affecting the prevalence, and evaluate the impact of interventions on transmission. The model includes the essential compartments, which are uncolonized, asymptomatic colonized, symptomatic colonized, and relapsed patients. Additionally, symptomatic colonized and relapsed patients were further classified into subpopulations according to their number of treatment failures or relapses. We found that the admission of colonized patients and use of antibiotics significantly impacted the endemic transmission in health care units. Thus, we introduced the treatment efficacy, defined by combining the treatment duration and probability of successful treatment, to characterize and describe the effects of antibiotic treatment on transmission. We showed that a high antibiotic treatment efficacy results in a significantly reduced likelihood of patient readmission in the health care unit. Additionally, our findings demonstrate that CRKP transmission with different epidemiological characteristics must be controlled using distinct interventions.

Reconstruction of the transmission dynamics of the first COVID-19 epidemic wave in Thailand.

Thailand was the first country reporting the first Coronavirus disease 2019 (COVID-19) infected individual outside mainland China. Here we delineated the course of the COVID-19 outbreak together with the timeline of the control measures and public health policies employed by the Thai government during the first wave of the COVID-19 outbreak in Thailand. Based on the comprehensive epidemiological data, we reconstructed the dynamics of COVID-19 transmission in Thailand using a stochastic modeling approach. Our stochastic model incorporated the effects of individual heterogeneity in infectiousness on disease transmission, which allows us to capture relevant features of superspreading events. We found that our model could accurately capture the transmission dynamics of the first COVID-19 epidemic wave in Thailand. The model predicted that at the end of the first wave, the number of cumulative confirmed cases was 3091 (95%CI: 2782-3400). We also estimated the time-varying reproduction number (Rt) during the first epidemic wave. We found that after implementing the nationwide interventions, the Rt in Thailand decreased from the peak value of 5.67 to a value below one in less than one month, indicating that the control measures employed by the Thai government during the first COVID-19 epidemic wave were effective. Finally, the effects of transmission heterogeneity and control measures on the likelihood of outbreak extinction were also investigated.

Individual-based modeling reveals that the COVID-19 isolation period can be shortened by community vaccination.

The isolation of infected individuals and quarantine of their contacts are usually employed to mitigate the transmission of SARS-CoV-2. Although 14-day isolation of infected individuals could effectively reduce the risk of subsequent transmission, it also substantially impacts the patient's psychological and emotional well-being. It is, therefore, vital to investigate how the isolation duration could be shortened when effective vaccines are available. Here, an individual-based modeling approach was employed to estimate the likelihood of secondary infections and the likelihood of an outbreak following the isolation of a primary case for a range of isolation periods. Our individual-based model integrated the viral loads and infectiousness profiles of vaccinated and unvaccinated infected individuals. The effects of waning vaccine-induced immunity against infection were also considered. By simulating the transmission of the SARS-CoV-2 Delta (B.1.617.2) variant in a community, we found that in the baseline scenario in which all individuals were unvaccinated and nonpharmaceutical interventions were not used, there was an approximately 3% chance that an unvaccinated individual would lead to at least one secondary infection after being isolated for 14 days, and a sustained chain of transmission could occur with a less than 1% chance. With the outbreak risk equivalent to that of the 14-day isolation in the baseline scenario, we found that the isolation duration could be shortened to 7.33 days (95% CI 6.68-7.98) if 75% of people in the community were fully vaccinated with the BNT162b2 vaccine within the last three months. In the best-case scenario in which all individuals in the community are fully vaccinated, isolation of Delta variant-infected individuals may no longer be necessary. However, to keep the outbreak risk lower than 1%, a booster vaccination may be necessary three months after full vaccination.

The effects of geographical distributions of buildings and roads on the spatiotemporal spread of canine rabies: An individual-based modeling study.

Rabies is a fatal disease that has been a serious health concern, especially in developing countries. Although rabies is preventable by vaccination, the spread still occurs sporadically in many countries, including Thailand. Geographical structures, habitats, and behaviors of host populations are essential factors that may result in an enormous impact on the mechanism of propagation and persistence of the disease. To investigate the role of geographical structures on the transmission dynamics of canine rabies, we developed a stochastic individual-based model that integrates the exact configuration of buildings and roads. In our model, the spatial distribution of dogs was estimated based on the distribution of buildings, with roads considered to facilitate dog movement. Two contrasting areas with high- and low-risk of rabies transmission in Thailand, namely, Hatyai and Tepha districts, were chosen as study sites. Our modeling results indicated that the distinct geographical structures of buildings and roads in Hatyai and Tepha could contribute to the difference in the rabies transmission dynamics in these two areas. The high density of buildings and roads in Hatyai could facilitate more rabies transmission. We also investigated the impacts of rabies intervention, including reducing the dog population, restricting owned dog movement, and dog vaccination on the spread of canine rabies in these two areas. We found that reducing the dog population alone might not be sufficient for preventing rabies transmission in the high-risk area. Owned dog confinement could reduce more the likelihood of rabies transmission. Finally, a higher vaccination coverage may be required for controlling rabies transmission in the high-risk area compared to the low-risk area.

Modelling the effectiveness of intervention strategies to control COVID-19 outbreaks and estimating healthcare demand in Germany.

OBJECTIVES: An outbreak of the novel coronavirus in December 2019 caused a worldwide pandemic. This disease also impacts European countries, including Germany. Without effective medicines or vaccines, non-pharmaceutical interventions are the best strategy to reduce the number of cases. STUDY DESIGN: A deterministic model was simulated to evaluate the number of infectious and healthcare demand. METHOD: Using an age-structured SEIR model for the COVID-19 transmission, we project the COVID-19-associated demand for hospital and ICU beds within Germany. We estimated the effectiveness of different control measures, including active case-finding and quarantining of asymptomatic persons, self-isolation of people who had contact with an infectious person, and physical distancing, as well as a combination of these control measures. RESULTS: We found that contact tracing could reduce the peak of ICU beds as well as mass testing. The time delay between diagnosis and self-isolation influences the control measures. Physical distancing to limit the contact rate would delay the peak of the outbreak, which results in the demand for ICU beds being below the capacity during the early outbreak. CONCLUSIONS: Our study analyzed several scenarios in order to provide policymakers that face the pandemic of COVID-19 with insights into the different measures available. We highlight that the individuals who have had contact with a virus-positive person must be quarantined as soon as possible to reduce contact with possible infectious cases and to reduce transmission. Keeping physical distance and having fewer contacts should be implemented to prevent overwhelming ICU demand.