Bimekizumab treatment in patients with active axial spondyloarthritis: 52-week efficacy and safety from the randomised parallel phase 3 BE MOBILE 1 and BE MOBILE 2 studies.

OBJECTIVES: Bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated superior efficacy versus placebo in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA) at Week 16. Here, the objective is to report the efficacy and safety of BKZ at Week 52. METHODS: BE MOBILE 1 (nr-axSpA; NCT03928704) and BE MOBILE 2 (r-axSpA; NCT03928743) comprised a 16-week, double-blind, placebo-controlled period, then a 36-week maintenance period. From Week 16, all patients received subcutaneous BKZ 160 mg every 4 weeks. RESULTS: Improvements versus placebo in Assessment of SpondyloArthritis International Society ≥40% response (primary endpoint), Ankylosing Spondylitis Disease Activity Score, high-sensitivity C-reactive protein levels and MRI inflammation of the sacroiliac joints/spine at Week 16 were sustained to Week 52 in BKZ-randomised patients. At Week 52, responses of patients switching from placebo to BKZ at Week 16 were comparable to BKZ-randomised patients. At Week 52, ≥1 treatment-emergent adverse events (TEAEs) were reported in 183 (75.0%) and 249 (75.5%) patients with nr-axSpA and r-axSpA, respectively. Serious TEAEs occurred in 9 (3.7%) patients with nr-axSpA and 20 (6.1%) patients with r-axSpA. Oral candidiasis was the most frequent fungal infection (nr-axSpA: 18 (7.4%); r-axSpA: 20 (6.1%)). Uveitis occurred in three (1.2%) and seven (2.1%) patients with nr-axSpA and r-axSpA, and inflammatory bowel disease in two (0.8%) and three (0.9%). CONCLUSIONS: At Week 52, dual inhibition of IL-17A and IL-17F with BKZ resulted in sustained efficacy across the axSpA spectrum; the safety profile was consistent with the known safety of BKZ. TRIAL REGISTRATION NUMBER: NCT03928704; NCT03928743.

Safe and Effective Subcutaneous Self-Injection of Bimekizumab with Safety Syringe and Auto-Injector Devices: Results from a Multicenter, Randomized, Open-Label Study in Patients with Psoriatic Arthritis.

Purpose: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, key drivers of chronic inflammation. Bimekizumab must be injected subcutaneously and so patients require self-injection options that meet their preferences. This study evaluated safe and effective self-injection of bimekizumab by patients with psoriatic arthritis using the 1 mL safety syringe (SSy) or the 1 mL auto-injector (AI). Patients and Methods: The DV0004 devices study (NCT04109976) was a sub-study of BE VITAL, a multicenter, open-label extension of BE OPTIMAL (NCT03895203) and BE COMPLETE (NCT03896581) in patients with active psoriatic arthritis. After receiving training, patients subcutaneously self-injected bimekizumab 160 mg at Baseline and Week 4. The primary and secondary endpoints were the proportion of patients self-injecting bimekizumab safely and effectively at Week 4 and Baseline, respectively. Patient self-injection experience was evaluated using the pain visual analog scale (VAS) and the Self-Injection Assessment Questionnaire (SIAQ). Results: Overall, 214 patients were randomized 1:1 at Baseline. All evaluable patients safely and effectively self-injected bimekizumab at Week 4 (SSy: n=105; AI: n=104) and Baseline (SSy: n=106; AI: n=106). Mean pain VAS scores were generally low at Week 4 (SSy: 11.0; AI: 11.4) and Baseline (SSy: 9.5; AI: 14.9). High mean pre- and post-injection SIAQ scores (≥6.7) were observed for both devices indicating a positive overall patient experience with self-injection. Self-injection was well tolerated with no reports of treatment-emergent adverse device effects (TEADEs), serious TEADEs or discontinuations due to TEADEs. Four non-device-related injection site reactions during the sub-study were reported in the parent study; all were mild, did not lead to discontinuation and resolved without treatment. All devices maintained their structural and functional integrity post-use. Conclusion: All patients self-injected subcutaneous bimekizumab safely and effectively using either device at Baseline and Week 4. Overall, patients reported a positive self-injection experience.

Efficacy and safety of bimekizumab in axial spondyloarthritis: results of two parallel phase 3 randomised controlled trials.

OBJECTIVES: Axial spondyloarthritis (axSpA) is a complex disease with diverse manifestations, for which new treatment options are warranted. BE MOBILE 1 (non-radiographic (nr)-axSpA) and BE MOBILE 2 (radiographic axSpA (r-axSpA)) are double-blind, phase 3 trials designed to evaluate efficacy and safety of bimekizumab, a novel dual interleukin (IL)-17A and IL-17F inhibitor, across the axSpA spectrum. METHODS: In parallel 52-week trials, patients with active disease were randomised 1:1 (nr-axSpA) or 2:1 (r-axSpA) to bimekizumab 160 mg every 4 weeks:placebo. From week 16, all patients received bimekizumab 160 mg every 4 weeks. Primary (Assessment of SpondyloArthritis international Society ≥40% improvement (ASAS40)) and secondary endpoints were assessed at week 16. Here, efficacy and treatment-emergent adverse events (TEAEs) are reported up to week 24. RESULTS: 254 patients with nr-axSpA and 332 with r-axSpA were randomised. At week 16, primary (ASAS40, nr-axSpA: 47.7% bimekizumab vs 21.4% placebo; r-axSpA: 44.8% vs 22.5%; p<0.001) and all ranked secondary endpoints were met in both trials. ASAS40 responses were similar across TNFi-naïve and TNFi-inadequate responder patients. Improvements were observed in Ankylosing Spondylitis Disease Activity Score (ASDAS) states and objective measures of inflammation, including high-sensitivity C-reactive protein (hs-CRP) and MRI of the sacroiliac joints and spine. Most frequent TEAEs with bimekizumab (>3%) included nasopharyngitis, upper respiratory tract infection, pharyngitis, diarrhoea, headache and oral candidiasis. More fungal infections (all localised) were observed with bimekizumab vs placebo; no major adverse cardiovascular events (MACE) or active tuberculosis were reported. Incidence of uveitis and adjudicated inflammatory bowel disease was low. CONCLUSIONS: Dual inhibition of IL-17A and IL-17F with bimekizumab resulted in significant and rapid improvements in efficacy outcomes vs placebo and was well tolerated in patients with nr-axSpA and r-axSpA.

Patient-reported distress as an early warning sign of unmet palliative care needs and increased healthcare utilization in patients with advanced cancer.

INTRODUCTION: Cancer patients' sources of distress are often unaddressed, and patient-reported distress data could be utilized to identify those with unmet and impending care needs. We explored the association between moderate/severe distress and healthcare utilization in a large sample of non-small cell lung cancer (NSCLC) and non-colorectal gastrointestinal cancer patients. METHODS AND MATERIALS: Adult patients treated between July 2013 and March 2019. Data from the NCCN Distress Thermometer (DT) and the accompanying "Problem List" were extracted from the EHR. A DT score of ≥ 4 indicates "actionable distress." Statistical analysis was performed using descriptive analysis for patient characteristics, clinical outcomes, and sources of distress. Generalized linear mixed models were fit to determine the relationship between distress and healthcare utilization (hospitalization, emergency department (ED) visit, or both). RESULTS: The ten most frequently reported problems were from the Physical and Emotional domains of the Problem List. Distress was mostly related to physical symptoms (pain, fatigue) and emotional issues (worry, fears, sadness, nervousness). Patients with actionable distress generally reported more problems across all their visits. Actionable distress was associated with higher odds of the composite outcome measure of hospitalization or visiting the ED, within both the next 3 months (OR = 1.37; 95% CI = 1.19, 1.58; p < 0.001) and 6 months (OR = 1.19; 95% CI = 1.03, 1.37; p = 0.019). CONCLUSION: Patients with significant distress had marked utilization of ED and inpatient services. DT scores are a source of untapped data in the EHR that can highlight patients in need of intervention, including palliative care and cancer support services.

Treatment-Related Changes in Left Atrial Structure in Atrial Fibrillation: Findings From the CABANA Imaging Substudy.

[Figure: see text].

Implementation and Impact of a Risk-Stratified Prostate Cancer Screening Algorithm as a Clinical Decision Support Tool in a Primary Care Network.

BACKGROUND: Implementation methods of risk-stratified cancer screening guidance throughout a health care system remains understudied. OBJECTIVE: Conduct a preliminary analysis of the implementation of a risk-stratified prostate cancer screening algorithm in a single health care system. DESIGN: Comparison of men seen pre-implementation (2/1/2016-2/1/2017) vs. post-implementation (2/2/2017-2/21/2018). PARTICIPANTS: Men, aged 40-75 years, without a history of prostate cancer, who were seen by a primary care provider. INTERVENTIONS: The algorithm was integrated into two components in the electronic health record (EHR): in Health Maintenance as a personalized screening reminder and in tailored messages to providers that accompanied prostate-specific antigen (PSA) results. MAIN MEASURES: Primary outcomes: percent of men who met screening algorithm criteria; percent of men with a PSA result. Logistic repeated measures mixed models were used to test for differences in the proportion of individuals that met screening criteria in the pre- and post-implementation periods with age, race, family history, and PSA level included as covariates. KEY RESULTS: During the pre- and post-implementation periods, 49,053 and 49,980 men, respectively, were seen across 26 clinics (20.6% African American). The proportion of men who met screening algorithm criteria increased from 49.3% (pre-implementation) to 68.0% (post-implementation) (p < 0.001); this increase was observed across all races, age groups, and primary care clinics. Importantly, the percent of men who had a PSA did not change: 55.3% pre-implementation, 55.0% post-implementation. The adjusted odds of meeting algorithm-based screening was 6.5-times higher in the post-implementation period than in the pre-implementation period (95% confidence interval, 5.97 to 7.05). CONCLUSIONS: In this preliminary analysis, following implementation of an EHR-based algorithm, we observed a rapid change in practice with an increase in screening in higher-risk groups balanced with a decrease in screening in low-risk groups. Future efforts will evaluate costs and downstream outcomes of this strategy.

Overcoming underpowering: Trial simulations and a global rank end point to optimize clinical trials in children with heart disease.

BACKGROUND: Randomized controlled trials (RCTs) in children with heart disease are challenging and therefore infrequently performed. We sought to improve feasibility of perioperative RCTs for this patient cohort using data from a large, multicenter clinical registry. We evaluated potential enrollment and end point frequencies for various inclusion cohorts and developed a novel global rank trial end point. We then performed trial simulations to evaluate power gains with the global rank end point and with use of planned covariate adjustment as an analytic strategy. METHODS: Data from the Society of Thoracic Surgery-Congenital Heart Surgery Database (STS-CHSD, 2011-2016) were used to support development of a consensus-based global rank end point and for trial simulations. For Monte Carlo trial simulations (n = 50,000/outcome), we varied the odds of outcomes for treatment versus placebo and evaluated power based on the proportion of trial data sets with a significant outcome (P < .05). RESULTS: The STS-CHSD study cohort included 35,967 infant index cardiopulmonary bypass operations from 103 STS-CHSD centers, including 11,411 (32%) neonatal cases and 12,243 (34%) high-complexity (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category ≥4) cases. In trial simulations, study power was 21% for a mortality-only end point, 47% for a morbidity and mortality composite, and 78% for the global rank end point. With covariate adjustment, power increased to 94%. Planned covariate adjustment was preferable to restricting to higher-risk cohorts despite higher event rates in these cohorts. CONCLUSIONS: Trial simulations can inform trial design. Our findings, including the newly developed global rank end point, may be informative for future perioperative trials in children with heart disease.

Rationale and design of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial.

For decades, physicians have administered corticosteroids in the perioperative period to infants undergoing heart surgery with cardiopulmonary bypass (CPB) to reduce the postoperative systemic inflammatory response to CPB. Some question this practice because steroid efficacy has not been conclusively demonstrated and because some studies indicate that steroids could have harmful effects. STRESS is a randomized, placebo-controlled, double-blind, multicenter trial designed to evaluate safety and efficacy of perioperative steroids in infants (age < 1 year) undergoing heart surgery with CPB. Participants (planned enrollment = 1,200) are randomized 1:1 to methylprednisolone (30 mg/kg) administered into the CPB pump prime versus placebo. The trial is nested within the existing infrastructure of the Society of Thoracic Surgeons Congenital Heart Surgery Database. The primary outcome is a global rank score of mortality, major morbidities, and hospital length of stay with components ranked commensurate with their clinical severity. Secondary outcomes include several measures of major postoperative morbidity, postoperative hospital length of stay, and steroid-related safety outcomes including prevalence of hyperglycemia and postoperative infectious complications. STRESS will be one of the largest trials ever conducted in children with heart disease and will answer a decades-old question related to safety and efficacy of perioperative steroids in infants undergoing heart surgery with CPB. The pragmatic "trial within a registry" design may provide a mechanism for conducting low-cost, high-efficiency trials in a heretofore-understudied patient population.

Early cardiac dysfunction in children and young adults with perinatally acquired HIV.

OBJECTIVE: To define the prevalence of early cardiac dysfunction in children and young adults with perinatally acquired HIV and predictors of cardiac function. DESIGN: Cross-sectional design. METHODS: Early cardiac dysfunction was defined as left ventricular (LV) global longitudinal strain z-score less than -2 or myocardial performance index at least 0.5 with normal LV ejection fraction. Regression models were fitted to assess the relationship between measures of cardiac function and HIV RNA levels, clinical variables, and markers of inflammation. RESULTS: Six hundred and forty-three individuals (mean age 14.1 ±â€Š5.2 years) were enrolled. The average time on combination antiretroviral treatment was 6.8 ±â€Š3.6 years. Nearly 28% of individuals met criteria for early cardiac dysfunction. Individuals with early cardiac dysfunction were older (15.3 vs. 13.5 years, P < 0.001), had more frequently detectable HIV RNA (52.5 vs. 41.7%, P = 0.018), were more likely exposed to azidothymidine or zidovudine (ZDV) (55.6 vs. 41.2%, P = 0.002), and had higher median level of plasma IL-6 concentrations (1.00 vs. 0.88 pg/ml, P = 0.011). Multivariable models show LV ejection fraction negatively associated with HIV RNA levels [ß -0.18; 95% confidence interval (CI) -0.33, -0.03] and ZDV exposure (ß -1.75; 95% CI -2.62, -0.88) and positively associated with proportion of life on combination antiretroviral treatment (ß 2.65; 95% CI 0.90, 4.41). Higher myocardial performance index was positively associated with serum inflammation marker (IL-6 ß 0.01; 95% CI 0.0001, 0.001). Left ventricular global longitudinal strain was not significantly associated with clinical and laboratory variables of interest. CONCLUSION: Over one-quarter of children and young adults living with HIV demonstrated evidence of cardiac dysfunction, which may be associated with increasing levels of systemic inflammation.

Myocardial Viability and Long-Term Outcomes in Ischemic Cardiomyopathy.

BACKGROUND: The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear. METHODS: Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years. RESULTS: CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P = 0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death. CONCLUSIONS: The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH ClinicalTrials.gov number, NCT00023595.).

Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos.

Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.

Myocardial viability and long-term outcomes in ischemic cardiomyopathy

BACKGROUND: The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear. METHODS: Among 601 patients who had coronary artery disease that was amenable to coronaryartery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photonemission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years. RESULTS: CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P=0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death. CONCLUSIONS: The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH ClinicalTrials.gov number, NCT00023595.). (AU)

Femoral Artery Atherosclerosis Is Associated With Physical Function Across the Spectrum of the Ankle-Brachial Index: The San Diego Population Study.

BACKGROUND: The ankle-brachial index (ABI) is inadequate to detect early-stage atherosclerotic disease, when interventions to prevent functional decline may be the most effective. We determined associations of femoral artery atherosclerosis with physical functioning, across the spectrum of the ABI, and within the normal ABI range. METHODS AND RESULTS: In 2007-2011, 1103 multiethnic men and women participated in the San Diego Population Study, and completed all components of the summary performance score. Using Doppler ultrasound, superficial and common femoral intima media thickness and plaques were ascertained. Logistic regression was used to assess associations of femoral atherosclerosis with the summary performance score and its individual components. Models were adjusted for demographics, lifestyle factors, comorbidities, lipids, and kidney function. In adjusted models, among participants with a normal-range ABI (1.00-1.30), the highest tertile of superficial intima media thickness was associated with lower odds of a perfect summary performance score of 12 (odds ratio=0.56 [0.36, 0.87], P=0.009), and lower odds of a 4-m walk score of 4 (0.34 [0.16, 0.73], P=0.006) and chair rise score of 4 (0.56 [0.34, 0.94], P=0.03). Plaque presence (0.53 [0.29, 0.99], P=0.04) and greater total plaque burden (0.61 [0.43, 0.87], P=0.006) were associated with worse 4-m walk performance in the normal-range ABI group. Higher superficial intima media thickness was associated with lower summary performance score in all individuals (P=0.02). CONCLUSIONS: Findings suggest that use of femoral artery atherosclerosis measures may be effective in individuals with a normal-range ABI, especially, for example, those with diabetes mellitus or a family history of peripheral artery disease, when detection can lead to earlier intervention to prevent functional declines and improve quality of life.

Disaggregating the evidence linking biodiversity and ecosystem services.

Ecosystem services (ES) are an increasingly popular policy framework for connecting biodiversity with human well-being. These efforts typically assume that biodiversity and ES covary, but the relationship between them remains remarkably unclear. Here we analyse >500 recent papers and show that reported relationships differ among ES, methods of measuring biodiversity and ES, and three different approaches to linking them (spatial correlations, management comparisons and functional experiments). For spatial correlations, biodiversity relates more strongly to measures of ES supply than to resulting human benefits. For management comparisons, biodiversity of 'service providers' predicts ES more often than biodiversity of functionally unrelated taxa, but the opposite is true for spatial correlations. Functional experiments occur at smaller spatial scales than management and spatial studies, which show contrasting responses to scale. Our results illuminate the varying dynamics relating biodiversity to ES, and show the importance of matching management efforts to the most relevant scientific evidence.

Do pollinators contribute to nutritional health?

Despite suggestions that animal pollinators are crucial for human nutritional health, no studies have actually tested this claim. Here, we combined data on crop pollination requirements, food nutrient densities, and actual human diets to predict the effects of pollinator losses on the risk of nutrient deficiency. In four developing countries and across five nutrients, we found that 0 to 56% of populations would become newly at risk if pollinators were removed. Increases in risk were most pronounced for vitamin A in populations with moderate levels of total nutrient intake. Overall, the effects of pollinator decline varied widely among populations and nutrients. We conclude that the importance of pollinators to human nutrition depends critically on the composition of local diets, and cannot be reliably predicted from global commodity analyses. We identify conditions under which severe health effects of pollinator loss are most likely to occur.

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.

Recasting the theory of mosquito-borne pathogen transmission dynamics and control.

Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. That framework, especially Macdonald's formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases. A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross-Macdonald assumption of homogeneous transmission in a well-mixed population. Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory. Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement. Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.

A systematic review of mathematical models of mosquito-borne pathogen transmission: 1970-2010.

Mathematical models of mosquito-borne pathogen transmission originated in the early twentieth century to provide insights into how to most effectively combat malaria. The foundations of the Ross-Macdonald theory were established by 1970. Since then, there has been a growing interest in reducing the public health burden of mosquito-borne pathogens and an expanding use of models to guide their control. To assess how theory has changed to confront evolving public health challenges, we compiled a bibliography of 325 publications from 1970 through 2010 that included at least one mathematical model of mosquito-borne pathogen transmission and then used a 79-part questionnaire to classify each of 388 associated models according to its biological assumptions. As a composite measure to interpret the multidimensional results of our survey, we assigned a numerical value to each model that measured its similarity to 15 core assumptions of the Ross-Macdonald model. Although the analysis illustrated a growing acknowledgement of geographical, ecological and epidemiological complexities in modelling transmission, most models during the past 40 years closely resemble the Ross-Macdonald model. Modern theory would benefit from an expansion around the concepts of heterogeneous mosquito biting, poorly mixed mosquito-host encounters, spatial heterogeneity and temporal variation in the transmission process.

An age-structured extension to the vectorial capacity model.

BACKGROUND: Vectorial capacity and the basic reproductive number (R(0)) have been instrumental in structuring thinking about vector-borne pathogen transmission and how best to prevent the diseases they cause. One of the more important simplifying assumptions of these models is age-independent vector mortality. A growing body of evidence indicates that insect vectors exhibit age-dependent mortality, which can have strong and varied affects on pathogen transmission dynamics and strategies for disease prevention. METHODOLOGY/PRINCIPAL FINDINGS: Based on survival analysis we derived new equations for vectorial capacity and R(0) that are valid for any pattern of age-dependent (or age-independent) vector mortality and explore the behavior of the models across various mortality patterns. The framework we present (1) lays the groundwork for an extension and refinement of the vectorial capacity paradigm by introducing an age-structured extension to the model, (2) encourages further research on the actuarial dynamics of vectors in particular and the relationship of vector mortality to pathogen transmission in general, and (3) provides a detailed quantitative basis for understanding the relative impact of reductions in vector longevity compared to other vector-borne disease prevention strategies. CONCLUSIONS/SIGNIFICANCE: Accounting for age-dependent vector mortality in estimates of vectorial capacity and R(0) was most important when (1) vector densities are relatively low and the pattern of mortality can determine whether pathogen transmission will persist; i.e., determines whether R(0) is above or below 1, (2) vector population growth rate is relatively low and there are complex interactions between birth and death that differ fundamentally from birth-death relationships with age-independent mortality, and (3) the vector exhibits complex patterns of age-dependent mortality and R(0) ∼ 1. A limiting factor in the construction and evaluation of new age-dependent mortality models is the paucity of data characterizing vector mortality patterns, particularly for free ranging vectors in the field.