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Asia remains vulnerable to new and emerging infectious diseases. Understanding how to improve next generation sequencing (NGS) use in pathogen surveillance is an urgent priority for regional health security. Here we developed a pathogen genomic surveillance assessment framework to assess capacity in low-resource settings in South and Southeast Asia. Data collected between June 2022 and March 2023 from 42 institutions in 13 countries showed pathogen genomics capacity exists, but use is limited and under-resourced. All countries had NGS capacity and seven countries had strategic plans integrating pathogen genomics into wider surveillance efforts. Several pathogens were prioritized for human surveillance, but NGS application to environmental and human-animal interface surveillance was limited. Barriers to NGS implementation include reliance on external funding, supply chain challenges, trained personnel shortages and limited quality assurance mechanisms. Coordinated efforts are required to support national planning, address capacity gaps, enhance quality assurance and facilitate data sharing for decision making., (© 2024. The Author(s).)

How do people resist in-the-moment temptation if they are poor at inhibiting their impulses? Theory on self-control suggests that people have a toolbox of strategies available to them that may be used preemptively to dampen temptations. Applying this to the goal of relationship maintenance, in two studies, we examined whether people motivated to maintain their romantic relationship but poor at inhibitory control would appraise an attractive alternative (AA) as less appealing prior to a face-to-face interaction. In Study 1 ( N = 190), those with high motivation and low inhibitory control (measured with the Stroop) rated the AA as less appealing as compared with singles and those high in motivation and inhibitory control. We replicated the motivation by inhibitory control interaction in Study 2 ( N = 219). The AAs paradigm and the Devaluation Effect provide a useful way to explore the toolbox approach to self-control strategies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The use of videoconferencing platforms has globally risen to facilitate face-to-face communication since the onset of COVID-19. But how do our first impressions of people we meet on Zoom compare to in-person interactions? Specifically, do we view others' personalities as accurately (in line with their unique personality) and normatively (in line with the average, desirable personality) as in-person? Across two Zoom first-impression round-robin studies (exploratory study: N = 567, Dyads = 3,053; preregistered replication: N = 371, Dyads = 1,961), which we compared to an in-person round-robin study ( N = 306; Dyads = 1,682), people viewed others' personalities as accurately and as normatively on Zoom as in-person. Moreover, people better liked interaction partners they viewed more accurately and normatively. However, in interactions of poorer audio-video quality, people viewed others less accurately, less normatively, and liked them less. Overall, through a screen, our impressions of others are as accurate and normative as face-to-face, but it depends on the quality of that screen., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Perceiving a partner's gratitude has several benefits for romantic relationships. We aimed to better understand these associations by decomposing perceptions into accuracy and bias. Specifically, we examined whether accuracy and bias in perceiving a partner's experience (Study 1: N dyads = 205) and expression (Study 2: N dyads = 309) of gratitude were associated with romantic relationship satisfaction. Using the Truth and Bias Model of Judgment, we found that perceivers generally underestimated their partner's gratitude, and lower perceptions of gratitude were related to lower perceiver satisfaction. Perceivers reported greater satisfaction when they assumed their partner's gratitude was similar to their own. Partners reported greater satisfaction when perceivers accurately gauged their partners' gratitude experience (but not expression) and lower satisfaction when perceivers underestimated their gratitude expression (but not experience). Overall, by decomposing gratitude perceptions into accuracy and bias, we provide insight into how these components differentially relate to relationship satisfaction., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

To what extent do individuals differ in understanding how others see them and who is particularly good at it? Answering these questions about the "good metaperceiver" is relevant given the beneficial outcomes of meta-accuracy. However, there likely is more than one type of the good metaperceiver: One who knows the specific impressions they make more than others do ( dyadic meta-accuracy ) and one who knows their reputation more than others do (generalized meta-accuracy ). To identify and understand these good metaperceivers, we introduce the social meta-accuracy model (SMAM) as a statistical and conceptual framework and apply the SMAM to four samples of first impression interactions. As part of our demonstration, we also investigated the routes to and the correlates of both types of good metaperceivers. Results from SMAM show that, overall, people were able to detect the unique and general first impressions they made, but there was little evidence for individual differences in dyadic meta-accuracy in a first impression. In contrast, there were substantial individual differences in generalized meta-accuracy, and this ability was largely explained by being transparent (i.e., good metaperceivers were seen as they saw themselves). We also observed some evidence that good generalized metaperceivers in a first impression tend to be extraverted and popular. This work demonstrated that the SMAM is a useful tool for identifying and understanding both types of good metaperceivers and paves the way for future work on individual differences in meta-accuracy in other contexts. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Many of us rely on online communication methods, such as videoconferencing, to connect with each other. However, less is known about how interpersonal processes unfold in this novel context. For example, do people believe others view them positively, displaying meta-positivity , and realize others' unique impression of them, displaying distinctive meta-accuracy , and do these processes have implications for liking in social interactions? And, do the same characteristics that predict lower meta-positivity and distinctive meta-accuracy in-person, such as being more socially anxious, predict similar difficulties in video interactions? We examined these questions in an online first impressions context using a videoconferencing platform, Zoom ( N = 555; N Dyads = 3,068), and compared them against an in-person sample ( N = 305; N Dyads = 1,683). People believed others saw them positively and understood others' unique impressions of them, displaying similar degrees of meta-positivity and distinctive meta-accuracy in video interactions as in in-person interactions. In both contexts, meta-positivity was related to liking others more, whereas distinctive meta-accuracy was related to being liked more by others. Further, social anxiety seemed to impair meta-positivity, which in turn contributed to why they liked others less in both contexts. In contrast to in-person interactions, social anxiety did not impair distinctive meta-accuracy in video interactions. Therefore, distinctive meta-accuracy did not account for the links between social anxiety and being liked in the video interaction context. Overall, metaperception processes generally operated very similarly online as in-person, though there were some noteworthy exceptions, in turn potentially bearing important implications for those with higher social anxiety. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Do people know how their romantic partner (i.e., the perceiver) views the self's (i.e., the metaperceiver's) emotions, displaying emotion meta-accuracy? Is it relevant to relationship quality? Using a sample of romantic couples ( N couples = 189), we found evidence for two types of emotion meta-accuracy across three different interactions: (a) normative emotion meta-accuracy , knowing perceivers' impressions of metaperceivers' emotions that are in line with how the average person may feel, and (b) distinctive emotion meta-accuracy , knowing perceivers' unique impression of metaperceivers' emotions. Furthermore, across interactions, normative emotion meta-accuracy was positively related to momentary relationship quality for metaperceivers and perceivers and this link was especially strong in the conflict interaction. Distinctive emotion meta-accuracy was negatively related to momentary relationship quality across interactions for perceivers and in the conflict interaction for metaperceivers. Overall, it may be adaptive for metaperceivers to accurately infer perceivers' normative impressions and to remain blissfully unaware of their unique impressions.

Background: Spatial repellents (SRs) have been widely used for prevention of mosquito bites, but their efficacy in reducing Aedes-borne viruses (ABV) has not been tested rigorously at large scale in Asia. To address this knowledge gap, a trial to evaluate the efficacy of Mosquito Shield™, a transfluthrin SR, was developed in Gampaha District of Sri Lanka across three Medical Officer of Health areas; i.e., Negombo, Wattala, and Kelaniya., Methods: This trial is a cluster-randomized, placebo-controlled, double-blinded clinical trial. A total of ~14,430 subjects aged ≥ 6 months in 30 clusters (15 intervention, 15 placebo) from ~3900 households (HH) will be randomly selected for enrolment into a "febrile surveillance cohort." A subset of the surveillance cohort, ~3570 subjects aged ≥4-16 years that test seronegative (naïve) or are serologically positive for a previous single dengue virus (DENV) infection (monotypic) at baseline sampling, will be enrolled into a "longitudinal cohort" for measuring DENV infection based on laboratory-confirmed seroconversion during the trial. Persons identified positive for antibodies against multiple DENV serotypes (multitypic) at baseline will be monitored for secondary analyses. Active ABV disease will be assessed using an enhanced passive surveillance system with case ascertainment performed in designated healthcare facilities. Serum samples will be taken from longitudinal cohort subjects within 1-2 weeks of when intervention is first deployed (T0) with additional samples taken ~12 (T1) and ~24 months (T2) from baseline sampling. DENV seroconversion and ABV active disease rates from baseline (pre-intervention) and follow-up (post-intervention) samples will be compared between intervention and placebo clusters. Participating houses will be monitored entomologically (indoor adult Aedes aegypti population densities and adult female blood fed status) within 3 months before intervention deployment and monthly during the intervention phase. Entomological surveys will monitor indoor adult Ae. aegypti population densities and blood fed status. Dengue incidence in each cohort will be estimated and compared to determine the public health benefit of using an SR. Entomological parameters will be measured to determine if there are entomological correlates of SR efficacy that may be useful for the evaluation of new SR products., Discussion: The trial will serve as an efficacy assessment of SR products in South Asia. Results will be submitted to the World Health Organization Vector Control Advisory Group for assessment of public health value towards an endorsement to recommend inclusion of SRs in ABV control programs., Trial Registration: Sri Lanka Clinical Trial Registry SLCTR /2022/018. Registered on July 1, 2022., Clinicaltrials: gov NCT05452447 . Registered on July 11, 2022. The Universal Trial Number is U1111-1275-3055., (© 2023. The Author(s).)

Introduction: Do people (i.e., metaperceivers) know their romantic partners' (i.e., perceivers') impressions, displaying meta-accuracy? Is it related to relationship well-being? We explored two components of meta-accuracy: (1) positive meta-accuracy (i.e., knowing the perceiver's positive impressions of the metaperceiver), and (2) distinctive meta-accuracy (i.e., knowing the perceiver's unique impressions of the metaperceiver). First, we compared baseline levels of each component across three domains (personality, emotions, values), and, second, examined and compared their links with relationship well-being., Method: A sample of 205 romantic couples were recruited. The Social Accuracy Model was adapted for analyses., Results: Metaperceivers displayed both positive and distinctive meta-accuracy across all domains, and displayed greater positive emotion meta-accuracy and distinctive personality meta-accuracy compared to the other domains. Positive meta-accuracy, in general, was related to metaperceivers' relationship well-being and distinctive meta-accuracy, in general, was related to relationship well-being for metaperceivers and perceivers. Further, positive personality meta-accuracy was associated with relationship well-being for metaperceivers, and positive emotion meta-accuracy was associated with relationship well-being for metaperceivers and perceivers., Conclusion: Overall, the present research broadens the meta-accuracy literature by expanding it to a novel domain (values) and highlighting the relative contributions of domains that has been previously explored in isolation (personality and emotions)., (© 2022 Wiley Periodicals LLC.)

Competing Interests: All authors disclose no financial and personal relationships with other people or organizations that could inappropriately influence their work.

Background: Dengue, transmitted by Aedes mosquitoes, is a major public health problem in Sri Lanka. Weather affects the abundance, feeding patterns, and longevity of Aedes vectors and hence the risk of dengue transmission. We aimed to quantify the effect of weather variability on dengue vector indices in ten Medical Officer of Health (MOH) divisions in Kalutara, Sri Lanka., Methods: Monthly weather variables (rainfall, temperature, and Oceanic Niño Index [ONI]) and Aedes larval indices in each division in Kalutara were obtained from 2010 to 2018. Using a distributed lag non-linear model and a two-stage hierarchical analysis, we estimated and compared division-level and overall relationships between weather and premise index, Breteau index, and container index., Findings: From Jan 1, 2010, to Dec 31, 2018, three El Niño events (2010, 2015-16, and 2018) occurred. Increasing monthly cumulative rainfall higher than 200 mm at a lag of 0 months, mean temperatures higher than 31·5°C at a lag of 1-2 months, and El Niño conditions (ie, ONI >0·5) at a lag of 6 months were associated with an increased relative risk of premise index and Breteau index. Container index was found to be less sensitive to temperature and ONI, and rainfall. The associations of rainfall and temperature were rather homogeneous across divisions., Interpretation: Both temperature and ONI have the potential to serve as predictors of vector activity at a lead time of 1-6 months, while the amount of rainfall could indicate the magnitude of vector prevalence in the same month. This information, along with knowledge of the distribution of breeding sites, is useful for spatial risk prediction and implementation of effective Aedes control interventions., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We performed a 2-year prospective cohort study to determine the incidence of dengue in Angoda, Colombo district, Sri Lanka (NCT02570152). The primary objective was to determine the incidence of acute febrile illness (AFI) because of laboratory confirmed dengue (LCD). Secondary objectives were to determine AFI incidence because of non-LCD, describe AFI symptoms, and estimate AFI incidence because of LCD by dengue virus (DENV)-type and age group. Participants from households with at least one minor and one adult (≤50 years) were enrolled and followed with scheduled weekly visits and, in case of AFI, unscheduled visits. Blood was collected for DENV detection at AFI visits, and symptoms recorded during the 7-day period following AFI onset. A total of 2,004 participants were enrolled (971 children, and 1,033 adults). A total of 55 LCD episodes were detected (overall incidence of 14.2 per 1,000 person-years). Incidence was the highest among children < 5 years (21.3 per 1,000 person-years) and 5-11 years (22.7 per 1,000 person-years), compared with adults ≥ 18 years (9.2 per 1,000 person-years). LCD was mostly (83.6%) caused by DENV-2 (n = 46), followed by DENV-1 (n = 6) and DENV-3 (n = 3). Common symptoms of LCD were headache, fatigue, myalgia, loss of appetite, and arthralgia. Incidence of AFI because of non-LCD was 47.3 per 1,000 person-years. In conclusion, this study reports the LCD incidence for a DENV-2 dominated epidemic that is comparable to the incidence of suspected dengue reported passively for 2017, one of the worst outbreaks in recent history.

A core component of social anxiety is the constant concern about what others think of the self. Could such metaperceptions-beliefs about how others view the self-play a role in relationship initiation attempts? In the present research, we examined whether metaperceptions may contribute to why people higher in social anxiety experience difficulties in initial interactions. In 2 first-impressions contexts, a platonic getting-acquainted context (Study 1: N = 544; 2,878 dyads) and a speed dating context (Study 2: N = 376; 4,797 dyads), we explored the roles of 2 components of metaperceptions: meta-positivity (i.e., believing interaction partners' perceptions of the self are in line with the socially desirable personality profile) and distinctive meta-accuracy (i.e., accurately recognizing interaction partners' unique perception of the self, controlling for meta-positivity). Results revealed that people higher in social anxiety were liked less by interaction partners across both contexts, a link that was partially accounted for by lower distinctive meta-accuracy displayed by those higher in social anxiety. Further, lower meta-positivity displayed by people higher in social anxiety also contributed to the links between greater social anxiety and being liked less in the platonic setting and liking others less in both contexts. In sum, metaperceptions may play an important role in shaping initial interactions, potentially helping to explain why people with greater social anxiety encounter difficulties forming new relationships. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Dengue infections are on the rise in Sri Lanka and are spreading to all areas in the country. Here, we discuss the changes in dengue epidemiology in Sri Lanka in relation to changes in age distribution, changes in seroprevalence rates over time, and possible reasons contributing to such changes., Methods and Findings: Although the incidence of dengue increased 20-fold from the year 2000 to 2012 and a further 3-fold from 2012 to 2019, this increase is not reflected in a similar increase in the age-stratified seropositivity rates for dengue. For instance, the annual seroconversion rates were 0.76% in 2013 and 0.91% in 2017. The annual seroconversion rates in the 6 to 17 age group were 1.5% per year in 2003, 3.9% in 2013, and 4.1% in 2017. In addition, although a 13-fold increase in dengue was seen in those who were <19 years of age, a 52.4-fold increase was seen in the 40- to 59-year age group. The case fatality rates (CFRs) have similarly changed, with 61.8% of deaths occurring in those <19 years of age in the year 2000, while in 2012 to 2018, the highest CFR were seen in those who were aged 20 to 39 years. Although there has been a marked increase in the number of cases, the vector densities did not change during a 4-year period. The proportion of adult individuals experiencing a secondary dengue infection has also remained between 65% and 75% between the years 2004 and 2018., Conclusions: A change in the ratio of symptomatic to asymptomatic infections can give rise to changes in the reported incidence of dengue. In order to take an appropriate policy decision in dengue control activities, it would be important to study the changes in virus serotypes, vector dispersion, and densities. Further, the contribution of the rise in metabolic diseases to an increase in the symptomatic as well as more severe infections due to dengue is explored., Competing Interests: The authors have declared that no competing interests exist.

Dengue, a mosquito-borne viral infection that affects millions around the world, poses a substantial economic burden in endemic countries. We conducted a prospective costing study in hospitalized pediatric dengue patients at the Lady Ridgeway Hospital for Children (LRHC), a public pediatric hospital in Colombo district, Sri Lanka, to assess household out-of-pocket and hospitalization costs of dengue in pediatric patients during peak dengue transmission season. Between August and October 2013, we recruited 216 hospitalized patients (aged 0-3 years, 27%; 4-7 years, 29%; 8-12 years, 42%) who were clinically or laboratory diagnosed with dengue. Using 2013 US dollars, household out-of-pocket spending, on average, was US$59 (SD 49) per episode and increased with disease severity (DF, US$52; DHF/DSS, US$78). Pediatric dengue patients received free-of-charge medical care during hospitalization at LRHC, and this places a high financial burden on hospitals. The direct medical cost of hospitalization was US$68 (SD 31.4) for DF episode, and US$122.7 (SD 65.2) for DHF/DSS episode. Yet a hospitalized dengue illness episode still accounted for 20% to 35% of household monthly income due to direct and indirect costs. Additionally, a majority of caregivers (70%) sought outpatient care before hospitalization, most of whom (81%) visited private health facilities. Our findings indicate that hospitalized pediatric dengue illness poses a nontrivial cost burden to households and healthcare systems, emphasizing the importance of preventing and controlling the transmission of dengue in endemic countries.

Objective: Major life transitions, such as the arrival of a new baby, can be stressful, and therefore, costly to one's health. Being in a satisfying romantic relationship has been previously linked with better health, perhaps because it provides access to a bank of psychosocial resources. The objective of the present research was two-fold. First, we examined whether prenatal relationship satisfaction benefitted mothers' postpartum health. Second, we examined whether this association was mediated by reduced postpartum stress. Design: Pregnant women ( N  = 431) were drawn from a larger prospective pregnancy and birth cohort study. Main Outcome Measures: Participants reported on their relationship satisfaction, perceived stress, and perceived health at two time points: 24-26 weeks of gestation and 6 months postpartum. Results: Greater prenatal romantic satisfaction predicted enhanced perceived postpartum health, and reduced perceived postpartum stress appeared to mediate this link. Conclusion: This research demonstrates that greater prenatal relationship satisfaction is associated with better postpartum health and provides evidence for one potential mechanism for this link: the reduction of perceived postpartum stress. Thus, assessments of women's prenatal relationship satisfaction may help identify those who are at higher risk of experiencing poor postpartum health. Implications for interventions are discussed.

Viewing other people with distinctive accuracy-the degree to which personality impressions correspond with targets' unique characteristics-often predicts positive interpersonal experiences, including liking and relationship satisfaction. Does this hold in the context of first dates, or might distinctive accuracy have negative links with romantic interest in such evaluative settings? We examined this question using two speed-dating samples (Sample 1: N = 172, N = 2,407 dyads; Sample 2: N = 397, N = 1,849 dyads). Not surprisingly, positive impressions of potential dating partners were strongly associated with greater romantic interest. In contrast, distinctively accurate impressions were associated with significantly less romantic interest. This association was even stronger for potential partners whose personalities were less romantically appealing, specifically, those lower in extraversion. In sum, on a first date, distinctive accuracy tends to be paired with lower romantic interest. The potential implications of distinctive accuracy for romantic interest and of romantic interest for distinctive accuracy are discussed.

Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. Mast cells (MCs), which line blood vessels and regulate vascular function, are able to detect DENV in vivo and promote vascular leakage. Here, we identified that a MC-derived protease, tryptase, is consequential for promoting vascular permeability during DENV infection, through inducing breakdown of endothelial cell tight junctions. Injected tryptase alone was sufficient to induce plasma loss from the circulation and hypovolemic shock in animals. A potent tryptase inhibitor, nafamostat mesylate, blocked DENV-induced vascular leakage in vivo. Importantly, in two independent human dengue cohorts, tryptase levels correlated with the grade of DHF severity. This study defines an immune mechanism by which DENV can induce vascular pathology and shock.

Background: Dengue has become a major public health problem in Sri Lanka with a considerable economic burden. As a response, in June, 2014, the Ministry of Health initiated a proactive vector control programme in partnership with military and police forces, known as the Civil-Military Cooperation (CIMIC) programme, that was targeted at high-risk Medical Officer of Health (MOH) divisions in the country. Evaluating the effectiveness and cost-effectiveness of population-level interventions is essential to guide public health planning and resource allocation decisions, particularly in resource-limited health-care settings., Methods: Using an interrupted time series design with a non-linear extension, we evaluated the impact of vector control interventions from June 22, 2014, to Dec 29, 2016, in Panadura, a high-risk MOH division in Western Province, Sri Lanka. We used dengue notification and larval survey data to estimate the reduction in Breteau index and dengue incidence before and after the intervention using two separate models, adjusting for time-varying confounding variables (ie, rainfall, temperature, and the Oceanic Niño Index). We also assessed the cost and cost-effectiveness of the CIMIC programme from the perspective of the National Dengue Control Unit under the scenarios of different levels of hospitalisation of dengue cases (low [25%], medium [50%], and high [75%]) in terms of cost per disability-adjusted life-year averted (DALY)., Findings: Vector control interventions had a significant impact on combined Breteau index (relative risk reduction 0·43, 95% CI 0·26 to 0·70) and on dengue incidence (0·43, 0·28 to 0·67), the latter becoming prominent 2 months after the intervention onset. The mean number of averted dengue cases was estimated at 2192 (95% CI 1741 to 2643), and the total cost of the CIMIC programme at 2016 US$271 615. Personnel costs accounted for about 89% of the total cost. In the base-case scenario of moderate level of hospitalisation, the CIMIC programme was cost-saving with a probability of 70% under both the lowest ($453) and highest ($1686) cost-effectiveness thresholds, resulting in a net saving of $20 247 (95% CI -57 266 to 97 790) and averting 176 DALYs (133 to 226), leading to a cost of -$98 (-497 to 395) per DALY averted. This was also the case for the scenario with high hospitalisation levels (cost per DALY averted -$512, 95% CI -872 to -115) but with a higher probability of 99%. In the scenario with low hospitalisation levels (cost per DALY averted $690, 143 to 1379), although the CIMIC programme was cost-ineffective at the lowest threshold with a probability of 77%, it was cost-effective at the highest threshold with a probability of 99%., Interpretation: This study suggests that communities affected by dengue can benefit from investments in vector control if interventions are implemented rigorously and coordinated well across sectors. By doing so, it is possible to reduce the disease and economic burden of dengue in endemic settings., Funding: None., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The frequency of epidemics caused by Dengue viruses 1-4, Zika virus and Chikungunya viruses have been on an upward trend in recent years driven primarily by uncontrolled urbanization, mobility of human populations and geographical spread of their shared vectors, Aedes aegypti and Aedes albopictus. Infections by these viruses present with similar clinical manifestations making them challenging to diagnose; this is especially difficult in regions of the world hyperendemic for these viruses. In this study, we present a targeted-enrichment methodology to simultaneously sequence the complete viral genomes for each of these viruses directly from clinical samples. Additionally, we have also developed a customized computational tool (BaitMaker) to design these enrichment baits. This methodology is robust in its ability to capture diverse sequences and is amenable to large-scale epidemiological studies. We have applied this methodology to two large cohorts: a febrile study based in Colombo, Sri Lanka taken during the 2009-2015 dengue epidemic (n = 170) and another taken during the 2016 outbreak of Zika virus in Singapore (n = 162). Results from these studies indicate that we were able to cover an average of 97.04% ± 0.67% of the full viral genome from samples in these cohorts. We also show detection of one DENV3/ZIKV co-infected patient where we recovered full genomes for both viruses., Competing Interests: The authors have declared that no competing interests exist.

Background: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification., Methods: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research., Results: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets., Conclusion: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials., Competing Interests: Beth-Ann G. Coller is an employee, shareholder and patent inventor of Merck & Co., Inc., Kenilworth, New Jersey, United States of America. Robert Edelman is a paid consultant to Takeda Pharmaceutical Company vaccine trials for service as Chairman of the Data and Safety Monitoring Board (DSMB) of Takeda's Tetravalent Dengue Vaccine Program. Alexander C. Schmidt is an employee and shareholder of the GlaxoSmithKline plc (GSK), Brentford, London, United Kingdom. Stephen J. Thomas has performed both paid and unpaid consultations and safety reviews for GSK Vaccines, Merck, Takeda, Sanofi Pasteur, Chugai Pharma, Themisbio, and Primevax. Derek Wallace is an employee of Takeda Pharmaceuticals International AG, Zurich, Switzerland. Bridget Wills is a paid consultant on the DSMB for the Takeda vaccine trials. No other authors have declared that a competing interest exists.

Dengue virus infections are a major cause of febrile illness that significantly affects individual and societal productivity and drives up health care costs principally in the developing world. Two dengue vaccine candidates are in advanced clinical efficacy trials in Latin America and Asia, and another has been licensed in more than fifteen countries but its uptake has been limited. Despite these advances, standardized metrics for comparability of protective efficacy between dengue vaccines remain poorly defined. The Dengue Illness Index (DII) is a tool that we developed thru refinement of previous similar iterations in an attempt to improve and standardize the measurement of vaccine and drug efficacy in reducing moderate dengue illness. The tool is designed to capture an individual's overall disease experience based on how the totality of their symptoms impacts their general wellness and daily functionality. We applied the DII to a diary card, the Dengue Illness Card (DIC), which was examined and further developed by a working group. The card was then refined with feedback garnered from a Delphi methodology-based query that addressed the adequacy and applicability of the tool in clinical dengue research. There was overall agreement that the tool would generate useful data and provide an alternative perspective to the assessment of drug or vaccine candidates, which in the case of vaccines, are assessed by their reduction in any virologically confirmed dengue of any severity with a focus on the more severe. The DIC needs to be evaluated in the field in the context of vaccine or drug trials, prospective cohort studies, or during experimental human infection studies. Here, we present the final DIC resulting from the Delphi process and offer its further development or use to the dengue research community., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: at the time of the submission, AS was an employee of GlaxoSmithKline Vaccines and holds shares related to this employment status.

Background: The 4 dengue virus serotypes (DENV1-4) and Zika virus (ZIKV) are related mosquito-borne flaviviruses of major importance globally. While monoclonal antibodies and plasma from DENV-immune donors can neutralize or enhance ZIKV in vitro and in small-animal models, and vice versa, the extent, duration, and significance of cross-reactivity in humans remains unknown, particularly in flavivirus-endemic regions., Methods: We studied neutralizing antibodies to ZIKV and DENV1-4 in longitudinal serologic specimens collected through 3 years after infection from people in Latin America and Asia with laboratory-confirmed DENV infections. We also evaluated neutralizing antibodies to ZIKV and DENV1-4 in patients with Zika through 6 months after infection., Results: In patients with Zika, the highest neutralizing antibody titers were to ZIKV, with low-level cross-reactivity to DENV1-4 that was greater in DENV-immune individuals. We found that, in primary and secondary DENV infections, neutralizing antibody titers to ZIKV were markedly lower than to the infecting DENV and heterologous DENV serotypes. Cross-neutralization was greatest in early convalescence, then ZIKV neutralization decreased, remaining at low levels over time., Conclusions: Patterns of antibody cross-neutralization suggest that ZIKV lies outside the DENV serocomplex. Neutralizing antibody titers can distinguish ZIKV from DENV infections when all viruses are analyzed simultaneously. These findings have implications for understanding natural immunity and vaccines.

Background: Dengue fever persists as a major global disease burden, and may increase as a consequence of climate change. Along with other measures, research actions to improve diagnosis, surveillance, prevention, and predictive models are highly relevant. The European Commission funded the DengueTools consortium to lead a major initiative in these areas, and this review synthesises the outputs and findings of this work conducted from 2011 to 2016. Research areas: DengueTools organised its work into three research areas, namely [1] Early warning and surveillance systems; [2] Strategies to prevent dengue in children; and [3] Predictive models for the global spread of dengue. Research area 1 focused on case-studies undertaken in Sri Lanka, including developing laboratory-based sentinel surveillance, evaluating economic impact, identifying drivers of transmission intensity, evaluating outbreak prediction capacity and developing diagnostic capacity. Research area 2 addressed preventing dengue transmission in school children, with case-studies undertaken in Thailand. Insecticide-treated school uniforms represented an intriguing potential approach, with some encouraging results, but which were overshadowed by a lack of persistence of insecticide on the uniforms with repeated washing. Research area 3 evaluated potential global spread of dengue, particularly into dengue-naïve areas such as Europe. The role of international travel, changing boundaries of vectors, developing models of vectorial capacity under different climate change scenarios and strategies for vector control in outbreaks was all evaluated., Concluding Remarks: DengueTools was able to make significant advances in methods for understanding and controlling dengue transmission in a range of settings. These will have implications for public health agendas to counteract dengue, including vaccination programmes., Outlook: Towards the end of the DengueTools project, Zika virus emerged as an unexpected epidemic in the central and southern America. Given the similarities between the dengue and Zika viruses, with vectors in common, some of the DengueTools thinking translated readily into the Zika situation.

Background: Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels., Methods: Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS., Results: An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF., Conclusions: These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Since December 2015, the first dengue vaccine has been licensed in several Asian and Latin American countries for protection against disease from all four dengue virus serotypes. While the vaccine demonstrated an overall good safety and efficacy profile in clinical trials, some key research questions remain which make risk-benefit-assessment for some populations difficult. As for any new vaccine, several questions, such as very rare adverse events following immunization, duration of vaccine-induced protection and effectiveness when used in public health programs, will be addressed by post-licensure studies and by data from national surveillance systems after the vaccine has been introduced. However, the complexity of dengue epidemiology, pathogenesis and population immunity, as well as some characteristics of the currently licensed vaccine, and potentially also future, live-attenuated dengue vaccines, poses a challenge for evaluation through existing monitoring systems, especially in low and middle-income countries. Most notable are the different efficacies of the currently licensed vaccine by dengue serostatus at time of first vaccination and by dengue virus serotype, as well as the increased risk of dengue hospitalization among young vaccinated children observed three years after the start of vaccination in one of the trials. Currently, it is unknown if the last phenomenon is restricted to younger ages or could affect also seronegative individuals aged 9years and older, who are included in the group for whom the vaccine has been licensed. In this paper, we summarize scientific and methodological considerations for public health surveillance and targeted post-licensure studies to address some key research questions related to live-attenuated dengue vaccines. Countries intending to introduce a dengue vaccine should assess their capacities to monitor and evaluate the vaccine's effectiveness and safety and, where appropriate and possible, enhance their surveillance systems accordingly. Targeted studies are needed, especially to better understand the effects of vaccinating seronegative individuals., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dengue is the major public health burden in Sri Lanka. Kalutara is one of the highly affected districts. Understanding the drivers of dengue is vital in controlling and preventing the disease spread. This study focuses on quantifying the influence of weather variability on dengue incidence over 10 Medical Officer of Health (MOH) divisions of Kalutara district. Weekly weather variables and data on dengue notifications, measured at 10 MOH divisions in Kalutara from 2009 to 2013, were retrieved and analysed. Distributed lag non-linear model and hierarchical-analysis was used to estimate division specific and overall relationships between weather and dengue. We incorporated lag times up to 12 weeks and evaluated models based on the Akaike Information Criterion. Consistent exposure-response patterns between different geographical locations were observed for rainfall, showing increasing relative risk of dengue with increasing rainfall from 50 mm per week. The strongest association with dengue risk centred around 6 to 10 weeks following rainfalls of more than 300 mm per week. With increasing temperature, the overall relative risk of dengue increased steadily starting from a lag of 4 weeks. We found similarly a strong link between the Oceanic Niño Index to weather patterns in the district in Sri Lanka and to dengue at a longer latency time confirming these relationships. Part of the influences of rainfall and temperature can be seen as mediator in the causal pathway of the Ocean Niño Index, which may allow a longer lead time for early warning signals. Our findings describe a strong association between weather, El Niño-Southern Oscillation and dengue in Sri Lanka., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Dengue is a leading public health problem in Sri Lanka. All 26 districts and all age groups are affected, with high disease transmission; the estimated average annual incidence is 175/100 000 population. Harnessing the World Health Organization Global strategy for dengue prevention and control, 2012-2020, Sri Lanka has pledged in its National Strategic Framework to achieve a mortality from dengue below 0.1% and to reduce morbidity by 50% (from the average of the last 5 years) by 2020. Turning points in the country's dengue-control programme have been the restructuring and restrategizing of the core functions; this has involved establishment of a separate dengue-control unit to coordinate integrated vector management, and creation of a presidential task force. There has been great progress in disease surveillance, clinical management and vector control. Enhanced real-time surveillance for early warning allows ample preparedness for an outbreak. National guidelines with enhanced diagnostics have significantly improved clinical management of dengue, reducing the case-fatality rate to 0.2%. Proactive integrated vector management, with multisector partnership, has created a positive vector-control environment; however, sustaining this momentum is a challenge. Robust surveillance, evidence-based clinical management, sustainable vector control and effective communication are key strategies that will be implemented to achieve set targets. Improved early detection and a standardized treatment protocol with enhanced diagnostics at all medical care institutions will lead to further reduction in mortality. Making the maximum effort to minimize outbreaks through sustainable vector control in the three dimensions of risk mapping, innovation and risk modification will enable a reduction in morbidity.

Introduction: Dengue has emerged as a significant public health problem in Sri Lanka. Historically surveillance was passive, with mandatory dengue notifications based on clinical diagnosis with only limited laboratory confirmation. To obtain more accurate data on the disease burden of dengue, we set up a laboratory-based enhanced sentinel surveillance system in Colombo District. Here we describe the study design and report our findings of enhanced surveillance in the years 2012-2014., Methods: Three outpatient clinics and three government hospitals in Colombo District that covered most of the Colombo metropolitan area were selected for the sentinel surveillance system. Up to 60 patients per week presenting with an undifferentiated fever were enrolled. Acute blood samples from each patient were tested by dengue specific PCR, NS1 ELISA and IgM ELISA. A sub-set of samples was sent to Duke-NUS Singapore for quality assurance, virus isolation and serotyping. Trained medical research assistants used a standardized case report form to record clinical and epidemiological data. Clinical diagnoses by the clinicians-in-charge were recorded for hospitalized cases., Results: Of 3,127 febrile cases, 43.6% were PCR and/or NS1 positive for dengue. A high proportion of lab confirmed dengue was observed from inpatients (IPD) (53.9%) compared to outpatient (clinics in hospitals and general practice) (7.6%). Dengue hemorrhagic fever (DHF) was diagnosed in 11% of patients at the time of first contact, and the median day of illness at time of presentation to the sentinel sites was 4. Dengue serotype 1 was responsible for 85% of the cases and serotype 4 for 15%. The sensitivity and specificity of the clinicians' presumptive diagnosis of dengue was 84% and 34%, respectively., Conclusion: DENV-1, and to a lesser degree DENV-4, infection were responsible for a high proportion of febrile illnesses in Colombo in the years 2012 to 2014. Clinicians' diagnoses were associated with high sensitivity, but laboratory confirmation is required to enhance specificity.

Background: Reported as a public health problem since the 1960s in Sri Lanka, dengue has become a high priority disease for public health authorities. The Ministry of Health is responsible for controlling dengue and other disease outbreaks and associated health care. The involvement of large numbers of public health staff in dengue control activities year-round and the provision of free medical care to dengue patients at secondary care hospitals place a formidable financial burden on the public health sector., Methods: We estimated the public sector costs of dengue control activities and the direct costs of hospitalizations in Colombo, the most heavily urbanized district in Sri Lanka, during the epidemic year of 2012 from the Ministry of Health's perspective. The financial costs borne by public health agencies and hospitals are collected using cost extraction tools designed specifically for the study and analysed retrospectively using a combination of activity-based and gross costing approaches., Results: The total cost of dengue control and reported hospitalizations was estimated at US$3.45 million (US$1.50 per capita) in Colombo district in 2012. Personnel costs accounted for the largest shares of the total costs of dengue control activities (79%) and hospitalizations (46%). The results indicated a per capita cost of US$0.42 for dengue control activities. The average costs per hospitalization ranged between US$216-609 for pediatric cases and between US$196-866 for adult cases according to disease severity and treatment setting., Conclusions: This analysis is a first attempt to assess the economic burden of dengue response in the public health sector in Sri Lanka. Country-specific evidence is needed for setting public health priorities and deciding about the deployment of existing or new technologies. Our results suggest that dengue poses a major economic burden on the public health sector in Sri Lanka.

Dengue viruses (DENVs) are mosquito-borne flaviviruses that infect humans. The clinical presentation of DENV infection ranges from inapparent infection to dengue hemorrhagic fever and dengue shock syndrome. We analyzed samples from a pediatric dengue cohort study in Sri Lanka to explore whether antibody responses differentiated clinically apparent infections from clinically inapparent infections. In DENV-naive individuals exposed to primary DENV infections, we observed no difference in the quantity or quality of acquired antibodies between inapparent and apparent infections. Children who experienced primary infections had broad, serotype-cross-neutralizing antibody responses that narrowed in breadth to a single serotype over a 12-month period after infection. In DENV immune children who were experiencing a repeat infection, we observed a strong association between preexisting neutralizing antibodies and clinical outcome. Notably, children with preexisting monospecific neutralizing antibody responses were more likely to develop fever than children with cross-neutralizing responses. Preexisting DENV neutralizing antibodies are correlated with protection from dengue disease., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Dengue is the most significant arthropod-borne viral infection of humans. Persons infected with dengue viruses (DENV) have subclinical or clinically apparent infections ranging from undifferentiated fever to dengue hemorrhagic fever/shock syndrome. Although recent studies estimated that the Indian subcontinent has the greatest burden of DENV infection and disease worldwide, we do not have reliable, population-based estimates of the incidence of infection and disease in this region. The goal of this study was to follow-up a cohort of 800 children living in a heavily urbanized area of Colombo, Sri Lanka to obtain accurate estimates of the incidence of DENV infection and disease. Annual blood samples were obtained from all children to estimate dengue seroprevalence at enrollment and to identify children exposed to new DENV infections during the study year. Blood was also obtained from any child in whom fever developed over the course of the study year to identify clinically apparent DENV infections. At enrollment, dengue seroprevalence was 53.07%, which indicated high transmission in this population. Over the study year, the incidence of DENV infection and disease were 8.39 (95% confidence interval = 6.56-10.53) and 3.38 (95% confidence interval = 2.24-4.88), respectively, per 100 children per year. The ratio of clinically inapparent to apparent infections was 1.48. These results will be useful for obtaining more accurate estimates of the burden of dengue in the region and for making decisions about testing and introduction of vaccines., (© The American Society of Tropical Medicine and Hygiene.)