Efficacy of a spatial repellent for control of Aedes-borne virus transmission: A cluster-randomized trial in Iquitos, Peru.

Over half the world's population is at risk for viruses transmitted by Aedes mosquitoes, such as dengue and Zika. The primary vector, Aedes aegypti, thrives in urban environments. Despite decades of effort, cases and geographic range of Aedes-borne viruses (ABVs) continue to expand. Rigorously proven vector control interventions that measure protective efficacy against ABV diseases are limited to Wolbachia in a single trial in Indonesia and do not include any chemical intervention. Spatial repellents, a new option for efficient deployment, are designed to decrease human exposure to ABVs by releasing active ingredients into the air that disrupt mosquito-human contact. A parallel, cluster-randomized controlled trial was conducted in Iquitos, Peru, to quantify the impact of a transfluthrin-based spatial repellent on human ABV infection. From 2,907 households across 26 clusters (13 per arm), 1,578 participants were assessed for seroconversion (primary endpoint) by survival analysis. Incidence of acute disease was calculated among 16,683 participants (secondary endpoint). Adult mosquito collections were conducted to compare Ae. aegypti abundance, blood-fed rate, and parity status through mixed-effect difference-in-difference analyses. The spatial repellent significantly reduced ABV infection by 34.1% (one-sided 95% CI lower limit, 6.9%; one-sided P value = 0.0236, z = 1.98). Aedes aegypti abundance and blood-fed rates were significantly reduced by 28.6 (95% CI 24.1%, ∞); z = -9.11) and 12.4% (95% CI 4.2%, ∞); z = -2.43), respectively. Our trial provides conclusive statistical evidence from an appropriately powered, preplanned cluster-randomized controlled clinical trial of the impact of a chemical intervention, in this case a spatial repellent, to reduce the risk of ABV transmission compared to a placebo.

Fusing an agent-based model of mosquito population dynamics with a statistical reconstruction of spatio-temporal abundance patterns.

The mosquito Aedes aegypti is the vector of a number of medically-important viruses, including dengue virus, yellow fever virus, chikungunya virus, and Zika virus, and as such vector control is a key approach to managing the diseases they cause. Understanding the impact of vector control on these diseases is aided by first understanding its impact on Ae. aegypti population dynamics. A number of detail-rich models have been developed to couple the dynamics of the immature and adult stages of Ae. aegypti. The numerous assumptions of these models enable them to realistically characterize impacts of mosquito control, but they also constrain the ability of such models to reproduce empirical patterns that do not conform to the models' behavior. In contrast, statistical models afford sufficient flexibility to extract nuanced signals from noisy data, yet they have limited ability to make predictions about impacts of mosquito control on disease caused by pathogens that the mosquitoes transmit without extensive data on mosquitoes and disease. Here, we demonstrate how the differing strengths of mechanistic realism and statistical flexibility can be fused into a single model. Our analysis utilizes data from 176,352 household-level Ae. aegypti aspirator collections conducted during 1999-2011 in Iquitos, Peru. The key step in our approach is to calibrate a single parameter of the model to spatio-temporal abundance patterns predicted by a generalized additive model (GAM). In effect, this calibrated parameter absorbs residual variation in the abundance time-series not captured by other features of the mechanistic model. We then used this calibrated parameter and the literature-derived parameters in the agent-based model to explore Ae. aegypti population dynamics and the impact of insecticide spraying to kill adult mosquitoes. The baseline abundance predicted by the agent-based model closely matched that predicted by the GAM. Following spraying, the agent-based model predicted that mosquito abundance rebounds within about two months, commensurate with recent experimental data from Iquitos. Our approach was able to accurately reproduce abundance patterns in Iquitos and produce a realistic response to adulticide spraying, while retaining sufficient flexibility to be applied across a range of settings.

Disease-driven reduction in human mobility influences human-mosquito contacts and dengue transmission dynamics.

Heterogeneous exposure to mosquitoes determines an individual's contribution to vector-borne pathogen transmission. Particularly for dengue virus (DENV), there is a major difficulty in quantifying human-vector contacts due to the unknown coupled effect of key heterogeneities. To test the hypothesis that the reduction of human out-of-home mobility due to dengue illness will significantly influence population-level dynamics and the structure of DENV transmission chains, we extended an existing modeling framework to include social structure, disease-driven mobility reductions, and heterogeneous transmissibility from different infectious groups. Compared to a baseline model, naïve to human pre-symptomatic infectiousness and disease-driven mobility changes, a model including both parameters predicted an increase of 37% in the probability of a DENV outbreak occurring; a model including mobility change alone predicted a 15.5% increase compared to the baseline model. At the individual level, models including mobility change led to a reduction of the importance of out-of-home onward transmission (R, the fraction of secondary cases predicted to be generated by an individual) by symptomatic individuals (up to -62%) at the expense of an increase in the relevance of their home (up to +40%). An individual's positive contribution to R could be predicted by a GAM including a non-linear interaction between an individual's biting suitability and the number of mosquitoes in their home (>10 mosquitoes and 0.6 individual attractiveness significantly increased R). We conclude that the complex fabric of social relationships and differential behavioral response to dengue illness cause the fraction of symptomatic DENV infections to concentrate transmission in specific locations, whereas asymptomatic carriers (including individuals in their pre-symptomatic period) move the virus throughout the landscape. Our findings point to the difficulty of focusing vector control interventions reactively on the home of symptomatic individuals, as this approach will fail to contain virus propagation by visitors to their house and asymptomatic carriers.

Use of mobile data collection systems within large-scale epidemiological field trials: findings and lessons-learned from a vector control trial in Iquitos, Peru.

Vector-borne diseases are among the most burdensome infectious diseases worldwide with high burden to health systems in developing regions in the tropics. For many of these diseases, vector control to reduce human biting rates or arthropod populations remains the primary strategy for prevention. New vector control interventions intended to be marketed through public health channels must be assessed by the World Health Organization for public health value using data generated from large-scale trials integrating epidemiological endpoints of human health impact. Such phase III trials typically follow large numbers of study subjects to meet necessary power requirements for detecting significant differences between treatment arms, thereby generating substantive and complex datasets. Data is often gathered directly in the field, in resource-poor settings, leading to challenges in efficient data reporting and/or quality assurance. With advancing technology, mobile data collection (MDC) systems have been implemented in many studies to overcome these challenges. Here we describe the development and implementation of a MDC system during a randomized-cluster, placebo-controlled clinical trial evaluating the protective efficacy of a spatial repellent intervention in reducing human infection with Aedes-borne viruses (ABV) in the urban setting of Iquitos, Peru, as well as the data management system that supported it. We discuss the benefits, remaining capacity gaps and the key lessons learned from using a MDC system in this context in detail.

A review of the pathophysiology of functional hypothalamic amenorrhoea in women subject to psychological stress, disordered eating, excessive exercise or a combination of these factors.

INTRODUCTION: Functional hypothalamic amenorrhoea (FHA) is a common form of secondary amenorrhoea without an identifiable structural cause. Suppression of gonadotrophin-releasing hormone (GnRH) pulsatility results in reduced luteinizing hormone (LH) levels, with subsequent reduction in oestradiol, anovulation and cessation of menstruation. GnRH pulsatility suppression is a recognized complication of psychological stress, disordered eating, low body weight, excessive exercise or a combination of these factors. PATHOPHYSIOLOGY OF FHA: Individuals with FHA demonstrate low energy availability (EA), body fat percentage and energy expenditure. Documented adipocytokine changes notably, raised adiponectin, ghrelin, PYY, and decreased leptin, are associated with GnRH suppression. Other endocrine responses seen in this low EA state include low insulin levels, low total T3, increased basal cortisol levels and a reduced response to corticotrophin-releasing hormone (CRH) administration. FHA is associated with raised growth hormone (GH) and low insulin-like growth factor (IGF-1), suggesting relative GH resistance. Kisspeptins are a group of polypeptides, recently discovered to play a major role in the regulation of the reproductive axis through influencing GnRH release. KNDy (kisspeptin/neurokinin B/dynorphin) act on GnRH neurons and a multitude of factors result in their release. IMPLICATIONS FOR FUTURE TREATMENT: Management of FHA is imperative to prevent adverse outcomes in bone density, cardiovascular risk profile, psychological well-being and fertility. Outwith modification of nutritional intake and exercise, limited therapeutic strategies are currently available for women with FHA. Advancements in the understanding of the pathophysiological basis of this under-recognized and under-treated clinical entity will aid management and may result in the development of novel therapeutic approaches.

Optimizing the deployment of ultra-low volume and targeted indoor residual spraying for dengue outbreak response.

Recent years have seen rising incidence of dengue and large outbreaks of Zika and chikungunya, which are all caused by viruses transmitted by Aedes aegypti mosquitoes. In most settings, the primary intervention against Aedes-transmitted viruses is vector control, such as indoor, ultra-low volume (ULV) spraying. Targeted indoor residual spraying (TIRS) has the potential to more effectively impact Aedes-borne diseases, but its implementation requires careful planning and evaluation. The optimal time to deploy these interventions and their relative epidemiological effects are, however, not well understood. We used an agent-based model of dengue virus transmission calibrated to data from Iquitos, Peru to assess the epidemiological effects of these interventions under differing strategies for deploying them. Specifically, we compared strategies where spray application was initiated when incidence rose above a threshold based on incidence in recent years to strategies where spraying occurred at the same time(s) each year. In the absence of spraying, the model predicted 361,000 infections [inter-quartile range (IQR): 347,000-383,000] in the period 2000-2010. The ULV strategy with the fewest median infections was spraying twice yearly, in March and October, which led to a median of 172,000 infections [IQR: 158,000-183,000], a 52% reduction from baseline. Compared to spraying once yearly in September, the best threshold-based strategy utilizing ULV had fewer median infections (254,000 vs. 261,000), but required more spraying (351 vs. 274 days). For TIRS, the best strategy was threshold-based, which led to the fewest infections of all strategies tested (9,900; [IQR: 8,720-11,400], a 94% reduction), and required fewer days spraying than the equivalent ULV strategy (280). Although spraying twice each year is likely to avert the most infections, our results indicate that a threshold-based strategy can become an alternative to better balance the translation of spraying effort into impact, particularly if used with a residual insecticide.

Risk of cancer incidence and mortality associated with diabetes: A systematic review with trend analysis of 203 cohorts.

AIM: Whether the relative risk of cancer incidence and mortality associated with diabetes has changed over time is unknown. DATA SYNTHESIS: On August 12th, 2020, we electronically searched for observational studies reporting on the association between diabetes and cancer. We estimated temporal trends in the relative risk of cancer incidence or mortality associated with diabetes and calculated the ratio of relative risk (RRR) comparing different periods. As many as 193 eligible articles, reporting data on 203 cohorts (56,852,381 participants; 3,735,564 incident cancer cases; 185,404 cancer deaths) and covering the period 1951-2013, were included. The relative risk of all-site cancer incidence increased between 1980 and 2000 [RRR 1990 vs.1980: (1.24; 95% CI: 1.16, 1.34); 2000 vs.1990: (1.23; 1.15, 1.31)] and stabilised thereafter at a relative risk of 1.2; the relative risk of all-site cancer mortality was constant at about 1.2 from 1980 to 2010. Both magnitudes and trends in relative risk varied across cancer sites: the relative risk of colorectal, female breast, and endometrial cancer incidence and pancreatic cancer mortality was constant during the observed years; it increased for bladder, stomach, kidney, and pancreatic cancer incidence until 2000; and decreased for liver while increased for prostate, colon and gallbladder cancer incidence after 2000. CONCLUSIONS: Alongside the increasing prevalence of diabetes, the temporal patterns of the relative risk of cancer associated with diabetes may have contributed to the current burden of cancer in people with diabetes.

Guaroa Virus and Plasmodium vivax Co-Infections, Peruvian Amazon.

During April-June 2014 in a malaria-endemic rural community close to the city of Iquitos in Peru, we detected evidence of Guaroa virus (GROV) infection in 14 febrile persons, of whom 6 also had evidence of Plasmodium vivax malaria. Cases were discovered through a long-term febrile illness surveillance network at local participating health facilities. GROV cases were identified by using a combination of seroconversion and virus isolation, and malaria was diagnosed by thick smear and PCR. GROV mono-infections manifested as nonspecific febrile illness and were clinically indistinguishable from GROV and P. vivax co-infections. This cluster of cases highlights the potential for GROV transmission in the rural Peruvian Amazon, particularly in areas where malaria is endemic. Further study of similar areas of the Amazon may provide insights into the extent of GROV transmission in the Amazon basin.

Heterogeneity of Dengue Illness in Community-Based Prospective Study, Iquitos, Peru.

Measuring heterogeneity of dengue illness is necessary to define suitable endpoints in dengue vaccine and therapeutic trials and will help clarify behavioral responses to illness. To quantify heterogeneity in dengue illness, including milder cases, we developed the Dengue Illness Perceptions Response (IPR) survey, which captured detailed symptom data, including intensity, duration, and character, and change in routine activities caused by illness. During 2016-2019, we collected IPR data daily during the acute phase of illness for 79 persons with a positive reverse transcription PCR result for dengue virus RNA. Most participants had mild ambulatory disease. However, we measured substantial heterogeneity in illness experience, symptom duration, and maximum reported intensity of individual symptoms. Symptom intensity was a more valuable predicter of major activity change during dengue illness than symptom presence or absence alone. These data suggest that the IPR measures clinically useful heterogeneity in dengue illness experience and its relation to altered human behavior.

Contributions from the silent majority dominate dengue virus transmission.

Despite estimates that, each year, as many as 300 million dengue virus (DENV) infections result in either no perceptible symptoms (asymptomatic) or symptoms that are sufficiently mild to go undetected by surveillance systems (inapparent), it has been assumed that these infections contribute little to onward transmission. However, recent blood-feeding experiments with Aedes aegypti mosquitoes showed that people with asymptomatic and pre-symptomatic DENV infections are capable of infecting mosquitoes. To place those findings into context, we used models of within-host viral dynamics and human demographic projections to (1) quantify the net infectiousness of individuals across the spectrum of DENV infection severity and (2) estimate the fraction of transmission attributable to people with different severities of disease. Our results indicate that net infectiousness of people with asymptomatic infections is 80% (median) that of people with apparent or inapparent symptomatic infections (95% credible interval (CI): 0-146%). Due to their numerical prominence in the infectious reservoir, clinically inapparent infections in total could account for 84% (CI: 82-86%) of DENV transmission. Of infections that ultimately result in any level of symptoms, we estimate that 24% (95% CI: 0-79%) of onward transmission results from mosquitoes biting individuals during the pre-symptomatic phase of their infection. Only 1% (95% CI: 0.8-1.1%) of DENV transmission is attributable to people with clinically detected infections after they have developed symptoms. These findings emphasize the need to (1) reorient current practices for outbreak response to adoption of pre-emptive strategies that account for contributions of undetected infections and (2) apply methodologies that account for undetected infections in surveillance programs, when assessing intervention impact, and when modeling mosquito-borne virus transmission.

An agent-based model of dengue virus transmission shows how uncertainty about breakthrough infections influences vaccination impact projections.

Prophylactic vaccination is a powerful tool for reducing the burden of infectious diseases, due to a combination of direct protection of vaccinees and indirect protection of others via herd immunity. Computational models play an important role in devising strategies for vaccination by making projections of its impacts on public health. Such projections are subject to uncertainty about numerous factors, however. For example, many vaccine efficacy trials focus on measuring protection against disease rather than protection against infection, leaving the extent of breakthrough infections (i.e., disease ameliorated but infection unimpeded) among vaccinees unknown. Our goal in this study was to quantify the extent to which uncertainty about breakthrough infections results in uncertainty about vaccination impact, with a focus on vaccines for dengue. To realistically account for the many forms of heterogeneity in dengue virus (DENV) transmission, which could have implications for the dynamics of indirect protection, we used a stochastic, agent-based model for DENV transmission informed by more than a decade of empirical studies in the city of Iquitos, Peru. Following 20 years of routine vaccination of nine-year-old children at 80% coverage, projections of the proportion of disease episodes averted varied by a factor of 1.76 (95% CI: 1.54-2.06) across the range of uncertainty about breakthrough infections. This was equivalent to the range of vaccination impact projected across a range of uncertainty about vaccine efficacy of 0.268 (95% CI: 0.210-0.329). Until uncertainty about breakthrough infections can be addressed empirically, our results demonstrate the importance of accounting for it in models of vaccination impact.

Controlled Infection Immunization Using Delayed Death Drug Treatment Elicits Protective Immune Responses to Blood-Stage Malaria Parasites.

Naturally acquired immunity to malaria is robust and protective against all strains of the same species of Plasmodium This develops as a result of repeated natural infection, taking several years to develop. Evidence suggests that apoptosis of immune lymphocytes due to uncontrolled parasite growth contributes to the slow acquisition of immunity. To hasten and augment the development of natural immunity, we studied controlled infection immunization (CII) using low-dose exposure to different parasite species (Plasmodium chabaudi, P. yoelii, or P. falciparum) in two rodent systems (BALB/c and C57BL/6 mice) and in human volunteers, with drug therapy commencing at the time of initiation of infection. CIIs with infected erythrocytes and in conjunction with doxycycline or azithromycin, which are delayed death drugs targeting the parasite's apicoplast, allowed extended exposure to parasites at low levels. In turn, this induced strong protection against homologous challenge in all immunized mice. We show that P. chabaudi/P. yoelii infection initiated at the commencement of doxycycline therapy leads to cellular or antibody-mediated protective immune responses in mice, with a broad Th1 cytokine response providing the best correlate of protection against homologous and heterologous species of PlasmodiumP. falciparum CII with doxycycline was additionally tested in a pilot clinical study (n = 4) and was found to be well tolerated and immunogenic, with immunological studies primarily detecting increased cell-associated immune responses. Furthermore, we report that a single dose of the longer-acting drug, azithromycin, given to mice (n = 5) as a single subcutaneous treatment at the initiation of infection controlled P. yoelii infection and protected all mice against subsequent challenge.

Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: A meta-analysis with bias analysis.

BACKGROUND & AIMS: A causal association of non-alcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) and type 2 diabetes (T2DM) remains unproved. We aimed to quantify the likelihood of causality examining the sensitivity of observational associations to possible confounding. METHODS: Studies investigating longitudinal associations of NAFLD with CVD or T2DM were searched on 5 June 2018. Study-specific relative risks (RRs) were combined in random-effects meta-analyses and pooled estimates used in bias analyses. RESULTS: Associations of NAFLD with CVD and T2DM were reported in 13 (258 743/18 383 participants/events) and 20 (240 251/12 891) studies respectively. Comparing patients with NAFLD to those without, the pooled RR was 1.48 (95% CI: 0.96, 2.29) for CVD and 2.17 (1.77, 2.65) for T2DM. In bias analyses, for an unmeasured confounder associated to both NAFLD and CVD with a RR of 1.25, the proportion of studies with a true (causal) effect of NAFLD on CVD surpassing a RR of 1.10 (ie, 10% increased risk of CVD in participants with NAFLD) was 0.67 (95% CI: 0.42, 0.92) while for 75% increase, it was 0.36 (0.11, 0.62). Corresponding figures for T2DM were 0.97 (0.91, 1.00) for a 10% increased risk of T2DM in participants with NAFLD to 0.70 (0.49, 0.92) for a 75% increase. CONCLUSIONS: The results of this study are strongly suggestive for a causal relationship between NAFLD and T2DM, while the evidence for a causal link between NAFLD and CVD is less robust. Therapeutic strategies targeting NAFLD are likely to reduce the risk of developing T2DM.

Serologic Evidence of Scrub Typhus in the Peruvian Amazon.

Using a large, passive, febrile surveillance program in Iquitos, Peru, we retrospectively tested human blood specimens for scrub typhus group orientiae by ELISA, immunofluorescence assay, and PCR. Of 1,124 participants, 60 (5.3%) were seropositive, and 1 showed evidence of recent active infection. Our serologic data indicate that scrub typhus is present in the Peruvian Amazon.

When communities are really in control: ethical issues surrounding community mobilisation for dengue prevention in Mexico and Nicaragua.

We discuss two ethical issues raised by Camino Verde, a 2011-2012 cluster-randomised controlled trial in Mexico and Nicaragua, that reduced dengue risk though community mobilisation. The issues arise from the approach adopted by the intervention, one called Socialisation of Evidence for Participatory Action. Community volunteer teams informed householders of evidence about dengue, its costs and the life-cycle of Aedes aegypti mosquitoes, while showing them the mosquito larvae in their own water receptacles, without prescribing solutions. Each community responded in an informed manner but on its own terms. The approach involves partnerships with communities, presenting evidence in a way that brings conflicting views and interests to the surface and encourages communities themselves to deal with the resulting tensions.One such tension is that between individual and community rights. This tension can be resolved creatively in concrete day-to-day circumstances provided those seeking to persuade their neighbours to join in efforts to benefit community health do so in an atmosphere of dialogue and with respect for personal autonomy.A second tension arises between researchers' responsibilities for ethical conduct of research and community autonomy in the conduct of an intervention. An ethic of respect for individual and community autonomy must infuse community intervention research from its inception, because as researchers succeed in fostering community self-determination their direct influence in ethical matters diminishes. TRIAL REGISTRATION: ISRCTN 27581154.

Time-varying, serotype-specific force of infection of dengue virus.

Infectious disease models play a key role in public health planning. These models rely on accurate estimates of key transmission parameters such as the force of infection (FoI), which is the per-capita risk of a susceptible person being infected. The FoI captures the fundamental dynamics of transmission and is crucial for gauging control efforts, such as identifying vaccination targets. Dengue virus (DENV) is a mosquito-borne, multiserotype pathogen that currently infects ∼390 million people a year. Existing estimates of the DENV FoI are inaccurate because they rely on the unrealistic assumption that risk is constant over time. Dengue models are thus unreliable for designing vaccine deployment strategies. Here, we present to our knowledge the first time-varying (daily), serotype-specific estimates of DENV FoIs using a spline-based fitting procedure designed to examine a 12-y, longitudinal DENV serological dataset from Iquitos, Peru (11,703 individuals, 38,416 samples, and 22,301 serotype-specific DENV infections from 1999 to 2010). The yearly DENV FoI varied markedly across time and serotypes (0-0.33), as did daily basic reproductive numbers (0.49-4.72). During specific time periods, the FoI fluctuations correlated across serotypes, indicating that different DENV serotypes shared common transmission drivers. The marked variation in transmission intensity that we detected indicates that intervention targets based on one-time estimates of the FoI could underestimate the level of effort needed to prevent disease. Our description of dengue virus transmission dynamics is unprecedented in detail, providing a basis for understanding the persistence of this rapidly emerging pathogen and improving disease prevention programs.

Calling in sick: impacts of fever on intra-urban human mobility.

Pathogens inflict a wide variety of disease manifestations on their hosts, yet the impacts of disease on the behaviour of infected hosts are rarely studied empirically and are seldom accounted for in mathematical models of transmission dynamics. We explored the potential impacts of one of the most common disease manifestations, fever, on a key determinant of pathogen transmission, host mobility, in residents of the Amazonian city of Iquitos, Peru. We did so by comparing two groups of febrile individuals (dengue-positive and dengue-negative) with an afebrile control group. A retrospective, semi-structured interview allowed us to quantify multiple aspects of mobility during the two-week period preceding each interview. We fitted nested models of each aspect of mobility to data from interviews and compared models using likelihood ratio tests to determine whether there were statistically distinguishable differences in mobility attributable to fever or its aetiology. Compared with afebrile individuals, febrile study participants spent more time at home, visited fewer locations, and, in some cases, visited locations closer to home and spent less time at certain types of locations. These multifaceted impacts are consistent with the possibility that disease-mediated changes in host mobility generate dynamic and complex changes in host contact network structure.

Experiences with insecticide-treated curtains: a qualitative study in Iquitos, Peru.

BACKGROUND: Dengue is an arthropod-borne viral disease responsible for approximately 400 million infections annually; the only available method of prevention is vector control. It has been previously demonstrated that insecticide treated curtains (ITCs) can lower dengue vector infestations in and around houses. As part of a larger trial examining whether ITCs could reduce dengue transmission in Iquitos, Peru, the objective of this study was to characterize the participants' experience with the ITCs using qualitative methods. METHODS: Knowledge, attitudes, and practices (KAP) surveys (at baseline, and 9 and 27 months post-ITC distribution, with n = 593, 595 and 511, respectively), focus group discussions (at 6 and 12 months post-ITC distribution, with n = 18 and 33, respectively), and 11 one-on-one interviews (at 12 months post-distribution) were conducted with 605 participants who received ITCs as part of a cluster-randomized trial. RESULTS: Focus groups at 6 months post-ITC distribution revealed that individuals had observed their ITCs to function for approximately 3 months, after which they reported the ITCs were no longer working. Follow up revealed that the ITCs required re-treatment with insecticide at approximately 1 year post-distribution. Over half (55.3 %, n = 329) of participants at 9 months post-ITC distribution and over a third (34.8 %, n = 177) at 27 months post-ITC distribution reported perceiving a decrease in the number of mosquitoes in their home. The percentage of participants who would recommend ITCs to their family or friends in the future remained high throughout the study (94.3 %, n = 561 at 9 months and 94.6 %, n = 488 at 27 months post-distribution). When asked why, participants reported that ITCs were effective at reducing mosquitoes (81.6 and 37.8 %, at 9 and 27 months respectively), that they prevent dengue (5.7 and 51.2 %, at 9 and 27 months), that they are "beautiful" (5.9 and 3.1 %), as well as other reasons (6.9 and 2.5 %). CONCLUSION: ITCs have substantial potential for long term dengue vector control because they are liked by users, both for their perceived effectiveness and for aesthetic reasons, and because they require little proactive behavioral effort on the part of the users. Our results highlight the importance of gathering process (as opposed to outcome) data during vector control studies, without which researchers would not have become aware that the ITCs had lost effectiveness early in the trial.

House-to-house human movement drives dengue virus transmission.

Dengue is a mosquito-borne disease of growing global health importance. Prevention efforts focus on mosquito control, with limited success. New insights into the spatiotemporal drivers of dengue dynamics are needed to design improved disease-prevention strategies. Given the restricted range of movement of the primary mosquito vector, Aedes aegypti, local human movements may be an important driver of dengue virus (DENV) amplification and spread. Using contact-site cluster investigations in a case-control design, we demonstrate that, at an individual level, risk for human infection is defined by visits to places where contact with infected mosquitoes is likely, independent of distance from the home. Our data indicate that house-to-house human movements underlie spatial patterns of DENV incidence, causing marked heterogeneity in transmission rates. At a collective level, transmission appears to be shaped by social connections because routine movements among the same places, such as the homes of family and friends, are often similar for the infected individual and their contacts. Thus, routine, house-to-house human movements do play a key role in spread of this vector-borne pathogen at fine spatial scales. This finding has important implications for dengue prevention, challenging the appropriateness of current approaches to vector control. We argue that reexamination of existing paradigms regarding the spatiotemporal dynamics of DENV and other vector-borne pathogens, especially the importance of human movement, will lead to improvements in disease prevention.

Multicountry prospective clinical evaluation of two enzyme-linked immunosorbent assays and two rapid diagnostic tests for diagnosing dengue fever.

We evaluated four dengue diagnostic devices from Alere, including the SD Bioline Dengue Duo (nonstructural [NS] 1 Ag and IgG/IgM), the Panbio Dengue Duo Cassette (IgM/IgG) rapid diagnostic tests (RDTs), and the Panbio dengue IgM and IgG capture enzyme-linked immunosorbent assays (ELISAs) in a prospective, controlled, multicenter study in Peru, Venezuela, Cambodia, and the United States, using samples from 1,021 febrile individuals. Archived, well-characterized samples from an additional 135 febrile individuals from Thailand were also used. Reference testing was performed on all samples using an algorithm involving virus isolation, in-house IgM and IgG capture ELISAs, and plaque reduction neutralization tests (PRNT) to determine the infection status of the individual. The primary endpoints were the clinical sensitivities and specificities of these devices. The SD Bioline Dengue Duo had an overall sensitivity of 87.3% (95% confidence interval [CI], 84.1 to 90.2%) and specificity of 86.8% (95% CI, 83.9 to 89.3%) during the first 14 days post-symptom onset (p.s.o.). The Panbio Dengue Duo Cassette demonstrated a sensitivity of 92.1% (87.8 to 95.2%) and specificity of 62.2% (54.5 to 69.5%) during days 4 to 14 p.s.o. The Panbio IgM capture ELISA had a sensitivity of 87.6% (82.7 to 91.4%) and specificity of 88.1% (82.2 to 92.6%) during days 4 to 14 p.s.o. Finally, the Panbio IgG capture ELISA had a sensitivity of 69.6% (62.1 to 76.4%) and a specificity of 88.4% (82.6 to 92.8%) during days 4 to 14 p.s.o. for identification of secondary dengue infections. This multicountry prospective study resulted in reliable real-world performance data that will facilitate data-driven laboratory test choices for managing patient care during dengue outbreaks.