Update to: Assessing the efficacy of male Wolbachia-infected mosquito deployments to reduce dengue incidence in Singapore.

BACKGROUND: This trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial. METHODS: The key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics. DISCUSSION: The findings from this study will provide the first experimental evidence for the efficacy of releasing male-Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023.

An Integrated Patient-Centred Medical Home (PCMH) Care Model Reduces Prospective Healthcare Utilisation for Community-Dwelling Older Adults with Complex Needs: A Matched Observational Study in Singapore.

The global ageing population is associated with increased health service use. The PCMH care model integrates primary care and home-based care management to deliver comprehensive and personalised healthcare to community-dwelling older adults with bio-psycho-social needs. We examined if an integrated PCMH reduced healthcare utilisation burden of older persons in Singapore. We compared the healthcare utilisation between the intervention group and coarsened exact matched controls for a follow-up of 15 months. Baseline matching covariates included socio-demographics, health status, and past healthcare use. We accounted for COVID-19 social distancing effects on health-seeking behaviour. The intervention group consisted of 165 older adults with complex needs. We analysed national administrative healthcare utilisation data from 2017 to 2020. We applied multivariable zero-inflated regression modelling and presented findings stratified by high (CCI ≥ 5) and low disease burden (CCI < 5). Compared to controls, there were significant reductions in emergency department (ß = -0.85; 95%CI = -1.55 to -0.14) and primary care visits (ß = -1.70; 95%CI = -2.17 to -1.22) and a decrease in specialist outpatient visits (ß = -0.29; 95%CI = -0.64 to 0.07) in the 3-month period immediately after one-year enrolment. The number of acute hospitalisations remained stable. Compared to controls, the intervention group with high and low comorbidity burden had significant decreases in primary care use, while only those with lower comorbidity burden had significant reductions in utilisation of other service types. An integrated PCMH appears beneficial in reducing healthcare utilisation for older persons with complex needs after 1 year in the programme. Future research can explore longer-term utilisation and scalability of the care model.

Understanding the characteristics of high users of hospital services in Singapore and their associations with healthcare utilisation and mortality: A cluster analysis.

INTRODUCTION: High users of hospital services require targeted healthcare services planning for effective resource allocation due to their high costs. This study aims to segmentize the population in the "Ageing In Place-Community Care Team" (AIP-CCT), a programme for complex patients with high inpatient service use, and examine the association of segment membership and healthcare utilisation and mortality. METHODS: We analysed 1,012 patients enrolled between June 2016 and February 2017. To identify patient segments, a cluster analysis was performed based on medical complexity and psychosocial needs. Next, multivariable negative binomial regression was performed using patient segments as the predictor, with healthcare and programme utilisation over the 180-day follow-up as outcomes. Multivariate cox proportional hazard regression was applied to assess the time to first hospital admission and mortality between segments within the 180-day follow-up. All models were adjusted for age, gender, ethnicity, ward class, and baseline healthcare utilisation. RESULTS: Three distinct segments were identified (Segment 1 (n = 236), Segment 2 (n = 331), and Segment 3 (n = 445)). Medical, functional, and psychosocial needs of individuals were significantly different between segments (p-value<0.001). The rates of hospitalisation in Segments 1 (IRR = 1.63, 95%CI:1.3-2.1) and 2 (IRR = 2.11, 95%CI:1.7-2.6) were significantly higher than in Segment 3 on follow-up. Similarly, both Segments 1 (IRR = 1.76, 95%CI:1.6-2.0) and 2 (IRR = 1.25, 95%CI:1.1-1.4) had higher rates of programme utilisation compared to Segment 3. Patients in Segments 1 (HR = 2.48, 95%CI:1.5-4.1) and 2 (HR = 2.25, 95%CI:1.3-3.6) also had higher mortality on follow-up. CONCLUSIONS: This study provided a data-based approach to understanding healthcare needs among complex patients with high inpatient services utilisation. Resources and interventions can be tailored according to the differences in needs among segments, to facilitate better allocation.

Singapore's 5 decades of dengue prevention and control-Implications for global dengue control.

This paper summarises the lessons learnt in dengue epidemiology, risk factors, and prevention in Singapore over the last half a century, during which Singapore evolved from a city of 1.9 million people to a highly urban globalised city-state with a population of 5.6 million. Set in a tropical climate, urbanisation among green foliage has created ideal conditions for the proliferation of Aedes aegypti and Aedes albopictus, the mosquito vectors that transmit dengue. A vector control programme, largely for malaria, was initiated as early as 1921, but it was only in 1966 that the Vector Control Unit (VCU) was established to additionally tackle dengue haemorrhagic fever (DHF) that was first documented in the 1960s. Centred on source reduction and public education, and based on research into the bionomics and ecology of the vectors, the programme successfully reduced the Aedes House Index (HI) from 48% in 1966 to <5% in the 1970s. Further enhancement of the programme, including through legislation, suppressed the Aedes HI to around 1% from the 1990s. The current programme is characterised by 4 key features: (i) proactive inter-epidemic surveillance and control that is stepped up during outbreaks; (ii) risk-based prevention and intervention strategies based on advanced data analytics; (iii) coordinated inter-sectoral cooperation between the public, private, and people sectors; and (iv) evidence-based adoption of new tools and strategies. Dengue seroprevalence and force of infection (FOI) among residents have substantially and continuously declined over the 5 decades. This is consistent with the observation that dengue incidence has been delayed to adulthood, with severity highest among the elderly. Paradoxically, the number of reported dengue cases and outbreaks has increased since the 1990s with record-breaking epidemics. We propose that Singapore's increased vulnerability to outbreaks is due to low levels of immunity in the population, constant introduction of new viral variants, expanding urban centres, and increasing human density. The growing magnitude of reported outbreaks could also be attributed to improved diagnostics and surveillance, which at least partially explains the discord between rising trend in cases and the continuous reduction in dengue seroprevalence. Changing global and local landscapes, including climate change, increasing urbanisation and global physical connectivity are expected to make dengue control even more challenging. The adoption of new vector surveillance and control tools, such as the Gravitrap and Wolbachia technology, is important to impede the growing threat of dengue and other Aedes-borne diseases.

Assessing the efficacy of male Wolbachia-infected mosquito deployments to reduce dengue incidence in Singapore: study protocol for a cluster-randomized controlled trial.

BACKGROUND: Dengue is a severe environmental public health challenge in tropical and subtropical regions. In Singapore, decreasing seroprevalence and herd immunity due to successful vector control has paradoxically led to increased transmission potential of the dengue virus. We have previously demonstrated that incompatible insect technique coupled with sterile insect technique (IIT-SIT), which involves the release of X-ray-irradiated male Wolbachia-infected mosquitoes, reduced the Aedes aegypti population by 98% and dengue incidence by 88%. This novel vector control tool is expected to be able to complement current vector control to mitigate the increasing threat of dengue on a larger scale. We propose a multi-site protocol to study the efficacy of IIT-SIT at reducing dengue incidence. METHODS/DESIGN: The study is designed as a parallel, two-arm, non-blinded cluster-randomized (CR) controlled trial to be conducted in high-rise public housing estates in Singapore, an equatorial city-state. The aim is to determine whether large-scale deployment of male Wolbachia-infected Ae. aegypti mosquitoes can significantly reduce dengue incidence in intervention clusters. We will use the CR design, with the study area comprising 15 clusters with a total area of 10.9 km2, covering approximately 722,204 residents in 1713 apartment blocks. Eight clusters will be randomly selected to receive the intervention, while the other seven will serve as non-intervention clusters. Intervention efficacy will be estimated through two primary endpoints: (1) odds ratio of Wolbachia exposure distribution (i.e., probability of living in an intervention cluster) among laboratory-confirmed reported dengue cases compared to test-negative controls and (2) laboratory-confirmed reported dengue counts normalized by population size in intervention versus non-intervention clusters. DISCUSSION: This study will provide evidence from a multi-site, randomized controlled trial for the efficacy of IIT-SIT in reducing dengue incidence. The trial will provide valuable information to estimate intervention efficacy for this novel vector control approach and guide plans for integration into national vector control programs in dengue-endemic settings. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT05505682 . Registered on 16 August 2022. Retrospectively registered.

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.

Cost analysis of a Patient-Centred Medical Home for community-dwelling older adults with complex needs in Singapore.

INTRODUCTION: The Patient-Centred Medical Home (PCMH) demonstration in Singapore, launched in November 2016, aimed to deliver integrated and patient-centred care for patients with biopsychosocial needs. Implementation was based on principles of comprehensiveness, coordinated care and shared decision-making. METHOD: We conducted a prospective single-arm pre-post study design, which aimed to perform cost analysis of PCMH from the perspectives of patients, healthcare providers and society. We assessed short-to-intermediate-term health-related costs by analysing data on resource use and unit costs of resources. RESULTS: We analysed 165 participants enrolled in PCMH from November 2017 to April 2020, with mean age of 77 years. Compared to the 3-month period before enrolment, mean total direct and indirect participant costs and total health system costs increased, but these were not statistically significant. There was a significant decrease in mean cost for primary care (government primary care and private general practice) in the first 3-month and second 3-month periods after enrolment, accompanied by a significant decrease in service utilisation and mean costs for PCMH services in the second 3-month period post-enrolment. This suggested a shift in resource costs from primary care to community-based care provided by PCMH, which had added benefits of both clinic-based primary care and home-based care management. Findings were consistent with a lower longer-term cost trajectory for PCMH after the initial onboarding period. Indirect caregiving costs remained stable. CONCLUSION: The PCMH care model was associated with reduced costs to the health system and patients for usual primary care, and did not significantly change societal costs.

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.

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.

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.

Impact of a patient-centered medical home demonstration on quality of life and patient activation for older adults with complex needs in Singapore.

BACKGROUND: The first Patient-Centered Medical Home (PCMH) demonstration in Singapore was launched in November 2016, which aimed to deliver integrated and patient-centered care for patients with bio-psycho-social needs. Implementation was guided by principles of comprehensiveness, coordinated care, shared decision-making, accessible services, and quality and safety. We aimed to investigate the impact of implementing the PCMH in primary care on quality of life (QoL) and patient activation. METHODS: The study design was a prospective single-arm pre-post study. We applied the 5-level EuroQol 5-dimension (EQ-5D-5L) and Visual Analog Scale (EQ VAS) instruments to assess health-related QoL. The CASP-19 tool was utilised to examine the degree that needs satisfaction was fulfilled in the domains of Control, Autonomy, Self-realisation, and Pleasure. The 13-item Patient Activation Measure (PAM-13) was used to evaluate knowledge, skills and confidence in management of conditions and ability to self-care. Multivariable linear regression models with random intercepts were applied to examine the impact of the PCMH intervention on outcome measures at 3 months and 6 months post-enrolment, compared to baseline. RESULTS: We analysed 165 study participants enrolled into the PCMH from November 2017 to April 2020, with mean age 77 years (SD: 9.9). Within-group pre-post (6 months) EQ-5D-5L Index (ß= -0.01, p-value = 0.35) and EQ VAS score (ß=-0.03, p-value = 0.99) had no change. Compared to baseline, there were improvements in CASP-19 total score at 3 months (ß = 1.34, p-value = 0.05) and 6 months post-enrolment (ß = 1.15, p-value = 0.08) that were marginally out of statistical significance. There was also a significant impact of the PCMH on the CASP-19 Pleasure domain (ß = 0.62, p = 0.03) at 6 months post-enrolment, compared to baseline. We found improved patient activation from a 15.2 % reduction in the proportion of participants in lower PAM levels, and a 23.4 and 16.7 % rise in proportion for higher PAM levels 3 and 4, respectively, from 3 months to 6 months post-enrolment. CONCLUSIONS: Preliminary demonstration of the PCMH model shows evidence of improved needs satisfaction and patient activation, with potential to have a greater impact after a longer intervention duration.

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.

The development and validation of a prototype mobility tracker for assessing the life space mobility and activity participation of older adults.

BACKGROUND: There is increasing interest in examining the life space mobility and activity participation of older adults in the community using sensor technology. Objective data from these technologies may overcome the limitations of self-reported surveys especially in older adults with age-associated cognitive impairment. This paper describes the development and validation of a prototype hybrid mobility tracker for assessing life space mobility and out-of-home activities amongst 33 community-ambulant older adults in Singapore. METHODS: A hybrid mobility tracker was developed by combining a passive Global Positioning System logger, tri-axial accelerometer and radio-frequency identification. Objective measures of life space, derived from 1 week of tracking data using Geographic Information Systems, were the maximum Euclidean distance from home (Max Euclid) and the area of the minimum convex polygon surrounding all GPS waypoints (MCP area). Out-of-home activities were quantified by visually identifying the total number of activity nodes, or places where participants spent ≥5 min, from mobility tracks. Self-reported measure of life space in 4 weeks was obtained using the University of Alabama at Birmingham Study of Life Space Assessment (UAB-LSA) questionnaire. Self-reported out-of-home activities were recorded daily in a travel diary for 1 week. Bivariate correlations were used to examine convergent validity between objective and subjective measures of life space and out-of-home activities. RESULTS: The mean age of participants was 69.2 ± 7.1 years. The mean UAB-LSA total score was 79.1 ± 17.4. The median (range) Max Euclid was 2.44 km (0.26-7.50) per day, and the median (range) MCP area was 3.31 km2 (0.03-34.23) per day. The UAB-LSA total score had good correlation with Max Euclid (r = 0.51, p = 0.002), and moderate correlation with MCP area (r = 0.46, p = 0.007). The median (range) total number of activity nodes measured by tracker of 20 (8-47) per week had a good correlation with the total activity count recorded in the travel diaries of 15 (6-40) per week (r = 0.52, p = 0.002). CONCLUSIONS: The tracking system developed to understand out-of-home travel was feasible and reliable. Comparisons with the UAB-LSA and travel diaries showed that it provided reliable and valid spatiotemporal data to assess the life space mobility and activity participation of older adults.

A Bayesian Belief Network for Murray Valley encephalitis virus risk assessment in Western Australia.

BACKGROUND: Murray Valley encephalitis virus (MVEV) is a clinically important virus in Australia responsible for a number of epidemics over the past century. Since there is no vaccine for MVEV, other preventive health measures to curtail its spread must be considered, including the development of predictive risk models and maps to help direct public health interventions. This article aims to support these approaches by presenting a model for assessing MVEV risk in Western Australia (WA). METHODS: A Bayesian Belief Network (BBN) for assessing MVEV risk was developed and used to quantify and map disease risks in WA. The model combined various abiotic, biotic, and anthropogenic factors that might affect the risk of MVEV into a predictive framework, based on the ecology of the major mosquito vector and waterbird hosts of MVEV. It was further refined and tested using retrospective climate data from 4 years (2000, 2003, 2009, and 2011). RESULTS: Implementing the model across WA demonstrated that it could predict locations of human MVEV infection and sentinel animal seroconversion in the 4 years tested with some degree of accuracy. In general, risks are highest in the State's north and lower in the south. The model predicted that short-term climate change, based on the Intergovernmental Panel on Climate Change's A1B emissions scenario, would decrease MVEV risks in summer and autumn, largely due to higher temperatures decreasing vector survival. CONCLUSIONS: To our knowledge, this is the first model to use a BBN to quantify MVEV risks in WA. The models and maps developed here may assist public health agencies in preparing for and managing Murray Valley encephalitis in the future. In its current form, the model is knowledge-driven and based on the analysis of potential risk factors that affect the dynamics of MVEV using retrospective data. Further work and additional testing should be carried out to test its validity in future years.