Fine-scale estimation of effective reproduction numbers for dengue surveillance.

The effective reproduction number Rt is an epidemiological quantity that provides an instantaneous measure of transmission potential of an infectious disease. While dengue is an increasingly important vector-borne disease, few have used Rt as a measure to inform public health operations and policy for dengue. This study demonstrates the utility of Rt for real time dengue surveillance. Using nationally representative, geo-located dengue case data from Singapore over 2010-2020, we estimated Rt by modifying methods from Bayesian (EpiEstim) and filtering (EpiFilter) approaches, at both the national and local levels. We conducted model assessment of Rt from each proposed method and determined exogenous temporal and spatial drivers for Rt in relation to a wide range of environmental and anthropogenic factors. At the national level, both methods achieved satisfactory model performance (R2EpiEstim = 0.95, R2EpiFilter = 0.97), but disparities in performance were large at finer spatial scales when case counts are low (MASE EpiEstim = 1.23, MASEEpiFilter = 0.59). Impervious surfaces and vegetation with structure dominated by human management (without tree canopy) were positively associated with increased transmission intensity. Vegetation with structure dominated by human management (with tree canopy), on the other hand, was associated with lower dengue transmission intensity. We showed that dengue outbreaks were preceded by sustained periods of high transmissibility, demonstrating the potential of Rt as a dengue surveillance tool for detecting large rises in dengue cases. Real time estimation of Rt at the fine scale can assist public health agencies in identifying high transmission risk areas and facilitating localised outbreak preparedness and response.

The influence of air quality and meteorological variations on influenza A and B virus infections in a paediatric population in Singapore.

INTRODUCTION: Influenza is an important cause of paediatric illness across the globe. However, information about the relationships between air pollution, meteorological variability and paediatric influenza A and B infections in tropical settings is limited. METHODS: We analysed all daily reports of influenza A and B infections in children <5 years old obtained from the largest specialist women and children's hospital in Singapore. In separate negative binomial regression models, we assessed the dependence of paediatric influenza A and B infections on air quality and meteorological variability, using multivariable fractional polynomial modelling and adjusting for time-varying confounders. RESULTS: Approximately 80% of 7329 laboratory-confirmed reports were caused by influenza A. We observed positive associations between sulphur dioxide (SO2) exposure and the subsequent risk of infection with both influenza types. We observed evidence of a harvesting effect of SO2 on Influenza A but not Influenza B. Ambient temperature was associated with a decline in influenza A reports (Relative Risk at lag 5 [RRlag5]: 0.949, 95% CI: 0.916-0.983). Rainfall was positively associated with a subsequent increase in influenza A reports (RRlag3: 1.044, 95% CI: 1.017-1.071). Nitrogen dioxide (NO2) concentration was positively associated with influenza B reports (RRlag5: 1.015, 95% CI: 1.005-1.025). There was a non-linear association between CO and influenza B reports. Absolute humidity increased the ensuing risk of influenza B (RRlag5: 4.799, 95% CI: 2.277-10.118). Influenza A and B infections displayed dissimilar but predictable within-year seasonal patterns. CONCLUSIONS: We observed different independent associations between air quality and meteorological variability with paediatric influenza A and B infections. Anticipated seasonal infection peaks and variations in air quality and meteorological parameters can inform the timing of community measures aimed at reducing influenza infection risk.

Effect of meteorological factors on Culex mosquitoes in Singapore: a time series analysis.

Culex mosquitoes transmit West Nile virus (WNV). We examined the weather dependence of adult Culex activity. Maximum temperature and absolute humidity were positively associated with adult Culex activity. Our findings support the use of weather data in timing WNV vector control measures.

Ambient temperature and hospital admissions for non-ST segment elevation myocardial infarction in the tropics.

BACKGROUND: Myocardial infarction is an important cause of cardiovascular mortality and can be precipitated by climatic factors. The temperature dependence of myocardial infarction risk has been well examined in temperate settings. Fewer studies have investigated this in the tropics where thermal amplitudes are narrower. This study investigated how ambient temperature influenced the risk of non-ST segment elevation myocardial infarction (NSTEMI), an increasingly common type of myocardial infarction, in the tropical city-state of Singapore. METHODS: All nationally reported NSTEMI cases from 2009 to 2018 were included and assessed for its short-term association with ambient temperature using conditional Poisson regression models that comprised a three-way interaction term with year, month and day of the week and adjusted for relative humidity. The Distributed Lag Non-Linear Modelling (DLNM) was used to account for the immediate and lagged effects of environmental exposures. Stratified analysis by sex and age groups was undertaken to assess potential effect modification. RESULTS: There were 60,643 reports of NSTEMI. Temperature decline (cool effect) was associated with a delayed cumulative, non-linear increase in NSTEMI risk over 10 days post exposure [Relative Risk (RRlag0-10, 10th percentile: 1.12, 95%CI: 1.02-1.24)]. Those aged 65 years and above were potentially more susceptible (RR lag0-10, 10th percentile: 1.19, 95 % CI: 1.06-1.33) to the cool effect compared to those below that age (RRlag0-10, 10th percentile: 1.00, 95 % CI: 0.85-1.18) (p-value for difference = 0.087). CONCLUSION: Short-term temperature fluctuations were independently associated with NSTEMI incidence in the tropics, with age as a potential effect modifier of this association. An increase in the frequency of climate change driven temperature events may trigger more instances of NSTEMI in tropical cosmopolitan cities.

Perfluoroalkyl substances and lipid concentrations in the blood: A systematic review of epidemiological studies.

BACKGROUND: Perfluoroalkyl substances (PFAS) are widely used synthetic aliphatic compounds. This systematic review aims to assess PFAS associations with low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), total cholesterol (TC) and total triglyceride (TG) concentrations in human populations. METHOD: We systematically searched four online databases, PubMed, Scopus, Embase, and Cochrane Library for relevant peer-reviewed English language articles published until July 2021. Additional relevant articles identified were also included in the search results. We categorised populations into adults (≥18 years old) and children. Primary findings were the associations between PFAS concentrations and LDL, HDL, TC, and TG concentrations in the serum, plasma, or whole blood; secondary findings were the associations between PFAS concentrations and the odds of lipid-related health outcomes. Quantitative synthesis was done by vote counting of the effect directions between concentrations of PFAS and lipids/health outcomes, repeated on articles with sample size >1000. Sign tests were performed to assess the statistical significance of the differences between positive and negative associations. Sensitivity analysis was performed by separating out articles with populations having high concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). Quality was assessed with the STROBE checklist and NHBLI Study Quality Assessment Tool. RESULTS: A total of 58 articles were included for review. There was evidence that PFAS exposure is associated with higher concentrations of LDL, HDL, and TC, particularly for PFOA-LDL, PFOA-TC, PFOS-TC, and PFNA-LDL. Associations between PFAS and TG tended to be negative, especially for perfluoroundecanoic acid (PFUnDA). Associations between PFAS concentration and the odds of secondary outcomes generally supported a positive association between PFAS and cholesterol concentrations. CONCLUSION: We found evidence of associations between the concentrations of some PFAS-lipid pairs in human populations. Future research should be conducted on the less well-studied PFAS to explore their effects on human health and in regions where such studies are currently lacking. (300 words).

Strategies to Mitigate Establishment under the Wolbachia Incompatible Insect Technique.

The Incompatible Insect Technique (IIT) strategy involves the release of male mosquitoes infected with the bacterium Wolbachia. Regular releases of male Wolbachia-infected mosquitoes can lead to the suppression of mosquito populations, thereby reducing the risk of transmission of vector-borne diseases such as dengue. However, due to imperfect sex-sorting under IIT, fertile Wolbachia-infected female mosquitoes may potentially be unintentionally released into the environment, which may result in replacement and failure to suppress the mosquito populations. As such, mitigating Wolbachia establishment requires a combination of IIT with other strategies. We introduced a simple compartmental model to simulate ex-ante mosquito population dynamics subjected to a Wolbachia-IIT programme. In silico, we explored the risk of replacement, and strategies that could mitigate the establishment of the released Wolbachia strain in the mosquito population. Our results suggest that mitigation may be achieved through the application of a sterile insect technique. Our simulations indicate that these interventions do not override the intended wild type suppression of the IIT approach. These findings will inform policy makers of possible ways to mitigate the potential establishment of Wolbachia using the IIT population control strategy.

Spatial Methods for Inferring Extremes in Dengue Outbreak Risk in Singapore.

Dengue is a major vector-borne disease worldwide. Here, we examined the spatial distribution of extreme weekly dengue outbreak risk in Singapore from 2007 to 2020. We divided Singapore into equal-sized hexagons with a circumradius of 165 m and obtained the weekly number of dengue cases and the surface characteristics of each hexagon. We accounted for spatial heterogeneity using max-stable processes. The 5-, 10-, 20-, and 30-year return levels, or the weekly dengue case counts expected to be exceeded once every 5, 10, 20, and 30 years, respectively, were determined for each hexagon conditional on their surface characteristics remaining constant over time. The return levels were higher in the country's east, with the maximum weekly dengue cases per hexagon expected to exceed 51 at least once in 30 years in many areas. The surface characteristics with the largest impact on outbreak risk were the age of public apartments and the percentage of impervious surfaces, where a 3-year and 10% increase in each characteristic resulted in a 3.8% and 3.3% increase in risk, respectively. Vector control efforts should be prioritized in older residential estates and places with large contiguous masses of built-up environments. Our findings indicate the likely scale of outbreaks in the long term.

The effects of maximum ambient temperature and heatwaves on dengue infections in the tropical city-state of Singapore - A time series analysis.

BACKGROUND: Global incidence of dengue has surged rapidly over the past decade. Each year, an estimated 390 million infections occur worldwide, with Asia-Pacific countries bearing about three-quarters of the global dengue disease burden. Global warming may influence the pattern of dengue transmission. While previous studies have shown that extremely high temperatures can impede the development of the Aedes mosquito, the effect of such extreme heat over a sustained period, also known as heatwaves, has not been investigated in a tropical climate setting. AIM: We examined the short-term relationships between maximum ambient temperature and heatwaves and reported dengue infections in Singapore, via ecological time series analysis, using data from 2009 to 2018. METHODS: We studied the effect of two measures of extreme heat - (i) heatwaves and (ii) maximum ambient temperature. We used a negative binomial regression, coupled with a distributed lag nonlinear model, to examine the immediate and lagged associations of extreme temperature on dengue infections, on a weekly timescale. We adjusted for long-term trend, seasonality, rainfall and absolute humidity, public holidays and autocorrelation. RESULTS: We observed an overall inhibitive effect of heatwaves on the risk of dengue infections, and a parabolic relationship between maximum temperature and dengue infections. A 1 °C increase in maximum temperature from 31 °C was associated with a 13.1% (Relative Risk (RR): 0.868, 95% CI: 0.798, 0.946) reduction in the cumulative risk of dengue infections over six weeks. Weeks with 3 heatwave days were associated with a 28.3% (RR: 0.717, 95% CI: 0.608, 0.845) overall reduction compared to weeks with no heatwave days. Adopting different heatwaves specifications did not substantially alter our estimates. CONCLUSION: Extreme heat was associated with decreased dengue incidence. Findings from this study highlight the importance of understanding the temperature dependency of vector-borne diseases in resource planning for an anticipated climate change scenario.

Hyperendemicity associated with increased dengue burden.

Over 105 million dengue infections are estimated to occur annually. Understanding the disease dynamics of dengue is often difficult due to multiple strains circulating within a population. Interactions between dengue serotype dynamics may result in complex cross-immunity dynamics at the population level and create difficulties in terms of formulating intervention strategies for the disease. In this study, a nationally representative 16-year time series with over 43 000 serotyped dengue infections was used to infer the long-run effects of between and within strain interactions and their impacts on past outbreaks. We used a novel identification strategy incorporating sign-identified Bayesian vector autoregressions, using structural impulse responses, historical decompositions and counterfactual analysis to conduct inference on dengue dynamics post-estimation. We found that on the population level: (i) across-serotype interactions on the population level were highly persistent, with a one time increase in any other serotype associated with long run decreases in the serotype of interest (range: 0.5-2.5 years) and (ii) over 38.7% of dengue cases of any serotype were associated with across-serotype interactions. The findings in this paper will substantially impact public health policy interventions with respect to dengue.

Economic impact of dengue in Singapore from 2010 to 2020 and the cost-effectiveness of Wolbachia interventions.

The release of Wolbachia-infected mosquitoes is a promising disease intervention strategy that aims to control dengue and other arboviral infections. While early field trials and modelling studies suggest promising epidemiological and entomological outcomes, the overall cost effectiveness of the technology is not well studied in a resource rich setting nor under the suppression approach that aims to suppress the wild-type mosquito population through the release of Wolbachia-infected males. We used economical and epidemiological data from 2010 to 2020 to first ascertain the economic and health costs of dengue in Singapore, a high income nation where dengue is hyper-endemic. The hypothetical cost effectiveness of a national Wolbachia suppression program was then evaluated historically from 2010 to 2020. We estimated that the average economic impact of dengue in Singapore from 2010 to 2020 in constant 2010US$ ranged from $1.014 to $2.265 Billion. Using empirically derived disability weights, we estimated a disease burden of 7,645-21,262 DALYs from 2010-2020. Under an assumed steady-state running cost of a national Wolbachia suppression program in Singapore, we conservatively estimate that Wolbachia would cost an estimated $50,453-$100,907 per DALYs averted and would lead to an estimated $329.40 Million saved in economic costs over 2010 to 2020 under 40% intervention efficacy. Wolbachia releases in Singapore are expected to be highly cost-effective and its rollout must be prioritised to reduce the onward spread of dengue.