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.

Estimating direct and spill-over impacts of political elections on COVID-19 transmission using synthetic control methods.

Mass gathering events have been identified as high-risk environments for community transmission of coronavirus disease 2019 (COVID-19). Empirical estimates of their direct and spill-over effects however remain challenging to identify. In this study, we propose the use of a novel synthetic control framework to obtain causal estimates for direct and spill-over impacts of these events. The Sabah state elections in Malaysia were used as an example for our proposed methodology and we investigate the event's spatial and temporal impacts on COVID-19 transmission. Results indicate an estimated (i) 70.0% of COVID-19 case counts within Sabah post-state election were attributable to the election's direct effect; (ii) 64.4% of COVID-19 cases in the rest of Malaysia post-state election were attributable to the election's spill-over effects. Sensitivity analysis was further conducted by examining epidemiological pre-trends, surveillance efforts, varying synthetic control matching characteristics and spill-over specifications. We demonstrate that our estimates are not due to pre-existing epidemiological trends, surveillance efforts, and/or preventive policies. These estimates highlight the potential of mass gatherings in one region to spill-over into an outbreak of national scale. Relaxations of mass gathering restrictions must therefore be carefully considered, even in the context of low community transmission and enforcement of safe distancing guidelines.

Efficacy of targeted education in reducing topical steroid phobia: A randomized clinical trial.

BACKGROUND: Fear of adverse effects of corticosteroids is common in dermatology and results in medication nonadherence. OBJECTIVE: To study the efficacy of targeted education in reducing topical steroid phobia. METHODS: In this double-blinded, randomized controlled trial, participants in the intervention arm were presented with an educational video and patient information leaflet targeting common misconceptions of topical corticosteroids. Steroid phobia was assessed with the topical corticosteroid phobia (TOPICOP) scale, medication adherence with the Elaboration d'un outil d'evaluation de l'observance des traitements medicamenteux (ECOB) score, and quality of life with the Dermatology Life Quality Index (DLQI). RESULTS: The study randomized 275 patients. The mean TOPICOP score in the intervention arm decreased (improved) from 41.9 (SD, 17.4) to 37.1 (SD, 20.0) and to 33.8 (SD, 19.0) at 1 month and 3 months, respectively, with the reduction arising from the knowledge domain but not the fears and behaviors domain. This remained statistically significant after adjusting for demographic confounding with an expected reduction of 4.22 points (P = .031). After accounting for demographic factors, there was no statistical difference in medication adherence and quality of life. Limitations include the exclusion of non-English-speaking patients. CONCLUSION: Targeted education at a single time point improved the TOPICOP score primarily in the knowledge domain but not in the fear domain.

Evaluating smoking control policies in the e-cigarette era: a modelling study.

BACKGROUND: In jurisdictions in which electronic cigarettes are currently prohibited, policy makers must weigh the potentially lower risk compared with conventional cigarettes against the risk of initiation of e-cigarettes among non-smokers. METHODS: We simulated a synthetic population over a 50-year time horizon with an open cohort model using data from Singapore, a country where e-cigarettes are currently prohibited, and data from the USA, the UK and Japan. Using the smoking prevalence and the quality-adjusted life year gained calculated, we compared tobacco control policies without e-cigarettes-namely, raising the minimum legal age (MLA), introducing a smoke-free generation (SFG) and tax rises on tobacco consumption-with policies legalising e-cigarettes, either taking a laissez-faire approach or under some form of restriction. We also evaluated combinations of these policies. RESULTS: Regardless of the country informing the transition probabilities to and from e-cigarette use in Singapore, a laissez-faire e-cigarette policy could reduce the smoking prevalence in the short term, but it is not as effective as other policies in the long term. The most effective single policies evaluated were SFG and aggressive tax rises; the most effective combination of policies considered was MLA plus moderate tax rises and e-cigarettes on prescription. CONCLUSION: Policy makers in jurisdictions in which e-cigarettes are not yet established may be advised not to prioritise e-cigarettes in their tobacco end-game strategy, unless their use can be restricted to current smokers seeking to quit.

Surface Accessibility and Dynamics of Macromolecular Assemblies Probed by Covalent Labeling Mass Spectrometry and Integrative Modeling.

Mass spectrometry (MS) has become an indispensable tool for investigating the architectures and dynamics of macromolecular assemblies. Here we show that covalent labeling of solvent accessible residues followed by their MS-based identification yields modeling restraints that allow mapping the location and orientation of subunits within protein assemblies. Together with complementary restraints derived from cross-linking and native MS, we built native-like models of four heterocomplexes with known subunit structures and compared them with available X-ray crystal structures. The results demonstrated that covalent labeling followed by MS markedly increased the predictive power of the integrative modeling strategy enabling more accurate protein assembly models. We applied this strategy to the F-type ATP synthase from spinach chloroplasts (cATPase) providing a structural basis for its function as a nanomotor. By subjecting the models generated by our restraint-based strategy to molecular dynamics (MD) simulations, we revealed the conformational states of the peripheral stalk and assigned flexible regions in the enzyme. Our strategy can readily incorporate complementary chemical labeling strategies and we anticipate that it will be applicable to many other systems providing new insights into the structure and function of protein complexes.

SPEctacle Correction for the TReatment of Amblyopia (SPECTRA): study protocol for a prospective non-randomised interventional trial in adults with anisometropic/mixed mechanism amblyopia.

INTRODUCTION: Amblyopia is a neurodevelopmental vision disorder typically affecting one eye, resulting in compromised binocular function. While evidence-based treatments exist for children, there are no widely accepted treatments for adults. This trial aims to assess the efficacy of appropriate optical treatment in improving vision and visual functions in adults with amblyopia. This is hypothesised to significantly improve visual acuity of the amblyopic eye and other visual functions. METHODS AND ANALYSIS: SPEctacle Correction for the TReatment of Amblyopia is a prospective non-randomised interventional trial. The following criteria for amblyopia will be used: best corrected visual acuity (BCVA) in the amblyopic eye of 0.3 to 1.0 (inclusive) logMAR VA and in the fellow eye, 0.1 logMAR or better, with an interocular VA difference of ≥2 logMAR lines. Eligible participants aged 18-39 will receive full/near-full optical treatment requiring wear for at least half their waking hours for the trial duration. A difference of ≥1.00D spherical equivalent between a participant's current refractive correction and the study prescription is required for eligibility. Primary outcome is the change in amblyopic eye BCVA from baseline to 24-week postenrolment. Secondary outcomes include distance and near VA of both eyes, stereoacuity, contrast sensitivity, interocular suppression, angle of strabismus and fixation stability measured at monthly intervals. Visual evoked potentials will also be measured at baseline, week 12 and week 24. Treatment compliance and quality of life for all participants will be monitored.Analyses comparing baseline and week 24 will utilise pairwise comparisons. Linear mixed models will be fitted to the data for measures taken monthly. This allows estimates and inferences to be drawn from the coefficients of the model, while handling missing data. ETHICS AND DISSEMINATION: Human ethics approval was obtained from the respective ethics board of the Hong Kong Polytechnic University (HSEARS20210915002) and the University of Waterloo (#44235). The study protocol will conform to the principles of the Declaration of Helsinki. Results will be disseminated through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: NCT05394987; clinicaltrials.org.

Modelling the Impact of Mass Testing to Transition from Pandemic Mitigation to Endemic COVID-19.

As countries transition from pandemic mitigation to endemic COVID-19, mass testing may blunt the impact on the healthcare system of the liminal wave. We used GeoDEMOS-R, an agent-based model of Singapore's population with demographic distributions and vaccination status. A 250-day COVID-19 Delta variant model was run at varying maximal rapid antigen test sensitivities and frequencies. Without testing, the number of infections reached 1,021,000 (899,400-1,147,000) at 250 days. When conducting fortnightly and weekly mass routine rapid antigen testing 30 days into the outbreak at a maximal test sensitivity of 0.6, this was reduced by 12.8% (11.3-14.5%) and 25.2% (22.5-28.5%). An increase in maximal test sensitivity of 0.2 results a corresponding reduction of 17.5% (15.5-20.2%) and 34.4% (30.5-39.1%). Within the maximal test sensitivity range of 0.6-0.8, test frequency has a greater impact than maximal test sensitivity with an average reduction of 2.2% in infections for each day removed between tests in comparison to a 0.43% average reduction per 1% increase in test frequency. Our findings highlight that mass testing using rapid diagnostic tests can be used as an effective intervention for countries transitioning from pandemic mitigation to endemic COVID-19.

Testing strategies to contain COVID-19 in migrant worker dormitories.

INTRODUCTION: COVID-19 transmission within overcrowded migrant worker dormitories is an ongoing global issue. Many countries have implemented extensive control measures to prevent the entire migrant worker population from becoming infected. Here, we explore case count outcomes when utilizing lockdown and testing under different testing measures and transmissibility settings. METHODS: We built a mathematical model which estimates transmission across 10 different blocks with 1000 individuals per block under different parameter combinations and testing conditions over the period of 1 month. We vary parameters including differences in block connectivity, underlying recovered proportions at the time of intervention, case importation rates and testing protocols using either PCR or rapid antigen testing. RESULTS: We estimate that a relatively transmissible environment with fortnightly PCR testing at a relatively low initial recovered proportion of 40%, low connectivity where 10% of contacts occurred outside of the infected individuals' block and a high importation rate of 1 100 000 per day, results in an average of 39 (95%Interval: 9-121) new COVID-19 cases after one month of observation. Similar results were observed for weekly rapid antigen testing at 33 (9-95) cases. INTERPRETATION: Our findings support the need for either fortnightly PCR testing or weekly rapid antigen testing in high population density environments such as migrant worker dormitories. Repeated mass testing is highly effective, preventing localized site outbreaks and reducing the need for site wide lockdowns or other extensive social distancing measures within and outside of dormitories.

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.

Importance of Geospatial Heterogeneity in Chronic Disease Burden for Policy Planning in an Urban Setting Using a Case Study of Singapore.

Chronic disease burdens continue to rise in highly dense urban environments where clustering of type II diabetes mellitus, acute myocardial infarction, stroke, or any combination of these three conditions is occurring. Many individuals suffering from these conditions will require longer-term care and access to clinics which specialize in managing their illness. With Singapore as a case study, we utilized census data in an agent-modeling approach at an individual level to estimate prevalence in 2020 and found high-risk clusters with >14,000 type II diabetes mellitus cases and 2000-2500 estimated stroke cases. For comorbidities, 10% of those with type II diabetes mellitus had a past acute myocardial infarction episode, while 6% had a past stroke. The western region of Singapore had the highest number of high-risk individuals at 173,000 with at least one chronic condition, followed by the east at 169,000 and the north with the least at 137,000. Such estimates can assist in healthcare resource planning, which requires these spatial distributions for evidence-based policymaking and to investigate why such heterogeneities exist. The methodologies presented can be utilized within any urban setting where census data exists.

Assessing the Impact of Salt Reduction Initiatives on the Chronic Disease Burden of Singapore.

Globally, many countries are facing an increasing burden of chronic disease due to ageing populations, of which cardiovascular disease forms a large proportion. Excess dietary sodium contributes to cardiovascular disease risk and requires intervention at a population level. This study aimed to quantify the impact of several salt reduction initiatives on population health over a 30-year horizon using GeoDEMOS, a population model from Singapore. Four interventions were modelled in four demographic groups in 2020 for a total of 16 intervention scenarios. The effect of 0.5, 2.0, and 4.0 g/day reductions in daily salt consumption, along with adherence to the World Health Organization guidelines of a maximum of 5.0 g of salt each day, was modelled in the entire population, including the overweight and obese, the elderly, and diabetics. In each scenario, the number of averted incident cases of acute myocardial infarction and stroke, along with the disability-adjusted life years up to 2050, was monitored. We found 4.0 g/day reductions in salt consumption were the most effective when implemented across the entire population, resulting in 24,000 averted incident cases of cardiovascular disease and 215,000 disability-adjusted life years over 30 years. This is a large figure when compared with the 29,200 projected annual incident cases of cardiovascular disease in 2050. When targeted at specific high-risk demographic groups, the largest effects were observed in the overweight and obese, with the same intervention yielding 10,500 averted incident cases of cardiovascular disease and 91,500 disability-adjusted life years. Quantifying the benefits of salt reduction initiatives revealed a significant impact when administered across the entire population or the overweight and obese. Health promotion efforts directed toward sustainably reducing salt consumption will help to lower the chronic disease burden on the healthcare system in years to come.

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.

Projected burden of type 2 diabetes mellitus-related complications in Singapore until 2050: a Bayesian evidence synthesis.

OBJECTIVE: We examined the effects of age, gender, and ethnicity on the risk of acute myocardial infarction, stroke, and end-stage renal disease according to type 2 diabetes mellitus status among adults aged 40-79 in Singapore. METHODS: A Bayesian inference framework was used to derive age-specific, gender-specific and ethnicity-specific prevalence of type 2 diabetes mellitus from the 2010 Singapore National Health Survey, and age-standardized gender and ethnicity-specific incidence rates of acute myocardial infarction, stroke and end-stage renal disease from the National Registry of Diseases Office. Population forecasts were used in tandem with incidence rates to project the future chronic disease burden until 2050. RESULTS: The highest relative risk of acute myocardial infarction was observed in the youngest age group (aged 40-44), with higher relative risk for women (men: 4.3 (2.7-6.4); women: 16.9 (9.3-28.3)). A similar trend was observed for stroke (men: 6.5 (4.2-9.7); women: 10.7 (6.0-17.4)). For end-stage renal disease, the highest relative risk was for men aged 45-50 (11.8 (8.0-16.9)) and women aged 55-60 (16.4 (10.7-24.0)). The annual incidence of acute myocardial infarction is projected to rise from 9300 (in 2019) to 16 400 (in 2050), the number of strokes from 7300 to 12 800, and the number of end-stage renal disease cases from 1700 to 2700. CONCLUSIONS: Type 2 diabetes mellitus was associated with an increased risk of complications and is modulated by age and gender. Prevention and early detection of type 2 diabetes mellitus can reduce the increasing burden of secondary complications.

Ethnicity, Neighborhood and Individual Socioeconomic Status, and Obesity: The Singapore Multiethnic Cohort.

OBJECTIVE: It remains unclear whether ethnicity has an impact on obesity independent of socioeconomic status (SES) and environmental factors. Singapore provides a unique opportunity to address this issue because three major Asian ethnic groups are represented, and government policies prevent ethnic segregation. Therefore this study examined associations between ethnicity, SES, and obesity within neighborhoods in Singapore. METHODS: Cross-sectional data from 29,819 participants of the Singapore Multiethnic Cohort who were aged 21 to 75 years and of Chinese, Malay, and Indian ethnicity were used. Obesity was defined using Asian criteria. Multilevel models used obesity as the dependent variable and age, marital status, ethnicity, education level, income, and neighborhood SES as independent variables. RESULTS: Education level was more strongly inversely associated with obesity than income level or neighborhood SES. The association between ethnicity and obesity was not substantially explained by measures of individual and neighborhood SES. In females, the fully adjusted odds ratio of obesity was 5.01 for Malay ethnicity and 4.81 for Indian ethnicity as compared with Chinese ethnicity. In males, these odds ratios were 2.61 and 2.07, respectively. CONCLUSIONS: Ethnicity was strongly associated with obesity independent of SES and neighborhood environment. More research on sociocultural factors contributing to ethnic differences in obesity is warranted.

Dynamic dengue haemorrhagic fever calculators as clinical decision support tools in adult dengue.

BACKGROUND: The objective of this study was to develop multiple prediction tools that calculate the risk of developing dengue haemorrhagic fever. METHODS: Training data consisted of 1771 individuals from 2006-2008 admitted with dengue fever whereby 304 developed dengue haemorrhagic fever during hospitalisation. Least absolute shrinkage and selection operator regression was used to construct three types of calculators, static admission calculators and dynamic calculators that predict the risk of developing dengue haemorrhagic fever for a subsequent day (DAily Risk Tomorrow [DART]) or for any future point after a specific day since fever onset (DAily Risk Ever [DARE]). RESULTS: From 119 admission covariates, 35 were in at least one of the calculators, which reported area under the curve (AUC) values of at least 0.72. Addition of person-time data for DART improved AUC to 0.76. DARE calculators displayed a large increase in AUC to 0.79 past day 7 with the inclusion of a strong predictor, maximum temperature on day 6 since onset, indicative of a saddleback fever. CONCLUSIONS: All calculators performed well when validated with 2005 data. Addition of daily variables further improved the accuracy. These calculators can be used in tandem to assess the risk of dengue haemorrhagic fever upon admission and updated daily to obtain more precise risk estimates.

Incidence of breast cancer attributable to breast density, modifiable and non-modifiable breast cancer risk factors in Singapore.

Incidence of breast cancer is rising rapidly in Asia. Some breast cancer risk factors are modifiable. We examined the impact of known breast cancer risk factors, including body mass index (BMI), reproductive and hormonal risk factors, and breast density on the incidence of breast cancer, in Singapore. The study population was a population-based prospective trial of screening mammography - Singapore Breast Cancer Screening Project. Population attributable risk and absolute risks of breast cancer due to various risk factors were calculated. Among 28,130 women, 474 women (1.7%) developed breast cancer. The population attributable risk was highest for ethnicity (49.4%) and lowest for family history of breast cancer (3.8%). The proportion of breast cancers that is attributable to modifiable risk factor BMI was 16.2%. The proportion of breast cancers that is attributable to reproductive risk factors were low; 9.2% for age at menarche and 4.2% for number of live births. Up to 45.9% of all breast cancers could be avoided if all women had breast density <12% and BMI <25 kg/m2. Notably, sixty percent of women with the lowest risk based on non-modifiable risk factors will never reach the risk level recommended for mammography screening. A combination of easily assessable breast cancer risk factors can help to identify women at high risk of developing breast cancer for targeted screening. A large number of high-risk women could benefit from risk-reduction and risk stratification strategies.