Analysis of endothelial gene polymorphisms in Spanish patients with vascular dementia and Alzheimer´s disease.

There is increasing evidence for the involvement of blood-brain barrier (BBB) in vascular dementia (VaD) and Alzheimer´s disease (AD) pathogenesis. However, the role of endothelial function-related genes in these disorders remains unclear. We evaluated the association of four single-nucleotide polymorphisms (VEGF, VEGFR2 and NOS3) with diagnosis and rate of cognitive decline in AD and VaD in a Spanish case-control cohort (150 VaD, 147 AD and 150 controls). Participants carrying -604AA genotype in VEGFR2 (rs2071559) were less susceptible to VaD after multiple testing. Further analysis for VaD subtype revealed a significant difference between small-vessel VaD patients and controls, but not for large-vessel VaD patients. In addition, -2578A and -460C alleles in VEGF (rs699947 and rs833061) showed to decrease the risk of AD, whereas NOS3 (rs1799983) influenced disease progression. Our study supports previous findings of a deleterious effect of VEGFR2 reduced expression on small-vessel disease, but not on large-vessel disease; as well as a detrimental effect of down-regulating VEGF and eNOS in AD, affecting vascular permeability and neuronal survival. These data highlight the relevance of endothelial function and, therefore, BBB in both VaD and AD.

The metabolic effects of APOL1 in humans.

Harboring apolipoprotein L1 (APOL1) variants coded by the G1 or G2 alleles of the APOL1 gene increases the risk for collapsing glomerulopathy, focal segmental glomerulosclerosis, albuminuria, chronic kidney disease, and accelerated kidney function decline towards end-stage kidney disease. However, most subjects carrying APOL1 variants do not develop the kidney phenotype unless a second clinical condition adds to the genotype, indicating that modifying factors modulate the genotype-phenotype correlation. Subjects with an APOL1 high-risk genotype are more likely to develop essential hypertension or obesity, suggesting that carriers of APOL1 risk variants experience more pronounced insulin resistance compared to noncarriers. Likewise, arterionephrosclerosis (the pathological correlate of hypertension-associated nephropathy) and glomerulomegaly take place among carriers of APOL1 risk variants, and these pathological changes are also present in conditions associated with insulin resistance, such as essential hypertension, aging, and diabetes. Insulin resistance may contribute to the clinical features associated with the APOL1 high-risk genotype. Unlike carriers of wild-type APOL1, bearers of APOL1 variants show impaired formation of lipid droplets, which may contribute to inducing insulin resistance. Nascent lipid droplets normally detach from the endoplasmic reticulum into the cytoplasm, although the proteins that enable this process remain to be fully defined. Wild-type APOL1 is located in the lipid droplet, whereas mutated APOL1 remains sited at the endoplasmic reticulum, suggesting that normal APOL1 may participate in lipid droplet biogenesis. The defective formation of lipid droplets is associated with insulin resistance, which in turn may modulate the clinical phenotype present in carriers of APOL1 risk variants.

Evidence based policy making during times of uncertainty through the lens of future policy makers: four recommendations to harmonise and guide health policy making in the future.

The Covid-19 pandemic has not only outlined the importance of using evidence in the healthcare policy making process but also the complexity that exists between policymakers and the scientific community. As a matter of fact, scientific data is just one of many other concurrent factors, including economic, social and cultural, that may provide the rationale for policy making. The pandemic has also raised citizens' awareness and represented an unprecedented moment of willingness to access and understand the evidence underpinning health policies.This commentary provides policy recommendations to improve evidence-based policy making in health, through the lens of a young generation of public policy students and future policymakers, enrolled in a 24-hour course at Sciences Po Paris entitled "Evidence-based policy-making in health: theory and practice(s)".Four out of 11 recommendations were prioritised and presented in this commentary which target both policymakers and the scientific community to make better use of evidence-based policy making in health. First, policy makers and scientists should build trusting partnerships with citizens and engage them, especially those facing our target health care issues or systems. Second, while artificial intelligence raises new opportunities in healthcare, its use in contexts of uncertainty should be addressed by policymakers in terms of liability and ethics. Third, conflicts of interest must be disclosed as much as possible and effectively managed to (re) build a trust relationship between policymakers, the scientific community and citizens, implying the need for risk management tools and cross border disclosure mechanisms. Last, well-designed and secure health information systems need to be implemented, following the FAIR (findable, accessible, interoperable and reusable) principles for health data. This will take us a step further from data to 'policy wisdom'.Overall, these recommendations identified and formulated by students highlight some key issues that need to be rethought in the health policy cycle through elements like institutional incentives, cultural changes and dialogue between policy makers and the scientific community. This input from a younger generation of students highlights the importance of making the conversation on evidence-based policy making in health accessible to all generations and backgrounds.

Insulin Resistance is Associated with Clinical Manifestations of Diabetic Kidney Disease (Glomerular Hyperfiltration, Albuminuria, and Kidney Function Decline).

Clinical features of diabetic kidney disease include glomerular hyperfiltration, albuminuria, and kidney function decline towards End-Stage Kidney Disease (ESKD). There are presently neither specific markers of kidney involvement in patients with diabetes nor strong predictors of rapid progression to ESKD. Serum-creatinine-based equations used to estimate glomerular filtration rate are notoriously unreliable in patients with diabetes. Early kidney function decline, reduced glomerular filtration rate, and proteinuria contribute to identifying diabetic patients at higher risk for rapid kidney function decline. Unlike proteinuria, the elevation of urinary albumin excretion in the range of microalbuminuria is frequently transient in patients with diabetes and does not always predict progression towards ESKD. Although the rate of progression of kidney function decline is usually accelerated in the presence of proteinuria, histological lesions of diabetes and ESKD may occur with normal urinary albumin excretion. No substantial reduction in the rate of ESKD associated with diabetes has been observed during the last decades despite intensified glycemic control and reno-protective strategies, indicating that existing therapies do not target underlying pathogenic mechanisms of kidney function decline. Very long-term effects of sodium-glucose transporters- 2 inhibitors and glucagon-like peptide-1 analogs remain to be defined. In patients with diabetes, glucagon secretion is typically elevated and induces insulin resistance. Insulin resistance is consistently and strongly associated with clinical manifestations of diabetic kidney disease, suggesting that reduced insulin sensitivity participates in the pathogenesis of the disease and may represent a therapeutic objective. Amelioration of insulin sensitivity in patients with diabetes is associated with cardioprotective and kidney-protective effects.

Elastic tissue disruption is a major pathogenic factor to human vascular disease.

Elastic fibers are essential components of the arterial extracellular matrix. They consist of the protein elastin and an array of microfibrils that support the protein and connect it to the surrounding matrix. The elastin gene encodes tropoelastin, a protein that requires extensive cross-linking to become elastin. Tropoelastin is expressed throughout human life, but its expression levels decrease with age, suggesting that the potential to synthesize elastin persists during lifetime although declines with aging. The initial abnormality documented in human atherosclerosis is fragmentation and loss of the elastic network in the medial layer of the arterial wall, suggesting an imbalance between elastic fiber injury and restoration. Damaged elastic structures are not adequately repaired by synthesis of new elastic elements. Progressive collagen accumulation follows medial elastic fiber disruption and fibrous plaques are formed, but advanced atherosclerosis lesions do not develop in the absence of prior elastic injury. Aging is associated with arterial extracellular matrix anomalies that evoke those present in early atherosclerosis. The reduction of elastic fibers with subsequent collagen accumulation leads to arterial stiffening and intima-media thickening, which are independent predictors of incident hypertension in prospective community-based studies. Arterial stiffening precedes the development of hypertension. The fundamental role of the vascular elastic network to arterial structure and function is emphasized by congenital disorders caused by mutations that disrupt normal elastic fiber production. Molecular changes in the genes coding tropoelastin, lysyl oxidase (tropoelastin cross-linking), and elastin-associated microfibrils, including fibrillin-1, fibulin-4, and fibulin-5 produce severe vascular injury due to absence of functional elastin.

The assessment of cognitive and behavioural disturbances in vascular cognitive impairment (VCI) - recommendations of an expert working group.

With newer research-based classification systems, the term Vascular Cognitive Impairment (VCI) is now preferred to vascular dementia. VCI is an umbrella term that includes all forms of cognitive deficits ranging from mild cognitive impairment of vascular origin (VaMCI) to vascular dementia (VaD). The new VCI construct takes into account the fact that in addition to single strategic infarcts, multiple infarcts, and leukoaraiosis, there are other mechanisms of cerebrovascular disease such as chronic hypoperfusion that might account for the pattern of cognitive deficits associated with vascular dementia. The key to defining the spectrum of VCI is neuropsychological testing, bedside or office-based clinical examination, and neuroimaging. The lack of specific cognitive tools that are sufficiently sensitive to detect subtle deficits makes the assessment of cognitive impairment difficult. Prospective cross-sectional and longitudinal studies of VCI from different settings are therefore required. Although there have been few published reports, behavioural and psychological symptoms (BPS) are inherently present in VCI from the onset and during the course of the disease. Besides the type of population (i.e. clinical, community or nursing-home settings), the definition of VCI/VaD and the instruments used, and differences in the prevalence and pattern of BPS between various studies, could be due to other, often unconsidered, factors such as gender, age, education, use of medication and VCI/VaD severity.

Antibody-Dependent Enhancement of Severe Disease Is Mediated by Serum Viral Load in Pediatric Dengue Virus Infections.

BACKGROUND: Low preexisting anti-dengue virus (DENV) antibody levels are associated with elevated disease severity. While antibody-dependent enhancement of dengue is thought to be driven by viral load, this has not been conclusively shown. We evaluated the association between preinfection anti-DENV antibody titers, viral load, and disease severity among 133 dengue cases in a Nicaraguan pediatric cohort study. METHODS: Viral load was quantified in acute-phase serum by real-time reverse transcription polymerase chain reaction and analyzed in relation to preinfection antibody titer (measured by inhibition enzyme-linked immunosorbent assay) and dengue severity, categorized using 3 definitions. RESULTS: Higher viral load was significantly associated with dengue severity; for each increase of 1.0 log10 copies/mL, the odds of severe dengue increased approximately 50%, regardless of severity definition. Viral load at presentation and the odds of severe disease were highest among patients with low to intermediate preinfection antibody titers and lowest among those with the highest antibody titers. We showed the effect of preinfection antibody titer on disease severity was mediated by viral load for each of 3 dengue severity outcomes. CONCLUSIONS: This study demonstrates the association between preinfection anti-DENV antibody titer, serum viral load, and disease severity, and provides evidence for the mechanism of antibody-dependent enhancement in dengue cases.

The impact of vascular burden on behavioural and psychological symptoms in older adults with dementia: the BEVASDE study.

OBJECTIVES: Behavioural and psychological symptoms (BPS) worsen quality of life and increase institutionalization in dementia, but the relationship between BPS and vascular burden on neuroimaging is unclear. Our aim is to explore whether the profile of BPS differs between patients with large-vessel or cortical vascular dementia (cVaD), small-vessel or subcortical vascular dementia (sVaD) and Alzheimer's disease (AD). METHODS: The BEVASDE study comprised 806 demented patients (cVaD-136, sVaD-184, AD-486) recruited from outpatient consultations in Salamanca and Avila, Spain. The Clinical Dementia Rating Scale (CDR) and the 12-item Neuropsychiatric Inventory (NPI) were used to evaluate dementia severity and BPS. RESULTS: BPS were reported in 98.5%, 97.3% and 96.9% of the cVaD, sVaD and AD cases, respectively. The median NPI score was 36 in both cVaD and sVaD and 34 in AD, with a median number of four symptoms per patient. The most frequent disorders were depression (64.4%), apathy (61.8%) and sleep disturbance (60.5%). Multivariate regression analyses after controlling for possible confounders showed a higher risk of euphoria (p = 0.011), apathy (p = 0.007), irritability (p = 0.002) and sleep disturbance (p = 0.020) in cVaD than in AD and more apathy (p = 0.0001) and irritability (p = 0.0001) in sVaD than in AD. In contrast, AD subjects had a higher risk of delusions (p = 0.007) and hallucinations (p = 0.023) than patients with cVaD as well as more aberrant motor behaviour than both cVaD (p = 0.0001) and sVaD (p = 0.003). CONCLUSION: BPS are common in dementia and may help in differential diagnosis of the various subtypes. We should inquire about them and treat as necessary.

High Rates of New Delhi Metallo-ß-Lactamase Carbapenemase Genes in Multi-Drug Resistant Gram-Negative Bacteria in Nicaragua.

Antimicrobial resistance (AMR) is a global public health crisis. Much of the burden of AMR in resource-limited settings remains unknown. This pilot study characterized clinical isolates of multidrug-resistant Gram-negative rods (MDR-GNRs) from Nicaragua. New Delhi metallo-ß-lactamase (NDM) carbapenemase genes were detected in 60% of isolates. Enterobacteriaceae had the highest rates of NDM detection, with 92% (50/54 isolates) positive by polymerase chain reaction (PCR). Pulsed-field gel electrophoresis (PFGE) analysis revealed patterns of clustering among isolates by two factors: plasmid profiles and year of culture. These findings of very high rates of NDM-carbapenemase genes in MDR-GNRs from hospitals throughout Nicaragua are alarming. Further research is needed to determine clinical and epidemiologic factors associated with multidrug-resistant isolates and to guide interventions to limit further spread.

Age-dependent manifestations and case definitions of paediatric Zika: a prospective cohort study.

BACKGROUND: Paedeatric Zika remains an understudied topic. WHO and the Pan American Health Organization (PAHO) Zika case definitions have not been assessed in children. We aimed to characterise clinical profiles and evaluate the diagnostic performance of the WHO and PAHO case definitions in a large cohort of paediatric Zika cases. METHODS: From January, 2016 to February, 2017, encompassing the major 2016 Zika epidemic, participants in the Pediatric Dengue Cohort Study (PDCS) in Managua, Nicaragua, were encouraged to visit the study health centre at first indication of any illness. PDCS participants were aged 2-14 years, healthy at enrolment, and recruited before the initiation of the present study. Molecular and serological assays were used to test participants exhibiting any of four broad clinical profiles suspected of resulting from a symptomatic Zika virus infection. These clinical profiles were: fever and at least two of headache, retro-orbital pain, myalgia, arthralgia, rash, haemorrhagic manifestations, and leukopenia; fever and at least two of nausea or vomiting, rash, aches and pains, positive tourniquet test, leukopenia, and any dengue warning sign; undifferentiated fever without evident cause, with or without any other clinical finding; and afebrile rash with or without any other clinical finding. We characterised acute clinical findings (signs, symptoms, and complete blood counts) in both Zika cases and non-Zika cases. FINDINGS: We prospectively followed a cohort of about 3700 children, of which 1110 were deemed eligible for inclusion. Four participants with laboratory-confirmed Zika (three co-infections with dengue virus, one missing complete blood count data) and two participants who were non-Zika cases (missing complete blood count data) were excluded from analysis. We analysed 556 laboratory-confirmed Zika and 548 non-Zika cases. The WHO case definition captured 176 confirmed Zika cases, and the PAHO definition 109 confirmed Zika cases, who presented with the most clinical findings and a dengue-like clinical profile. The remaining two thirds of Zika cases, principally characterised by undifferentiated fever or afebrile rash, were missed. Among Zika cases, rash (n=440)-particularly generalised erythematous rash (n=334)-fever (n=333), leukopenia (n=217), and headache (n=203) were most common and peaked within 3 days of illness onset. The most common Zika presentation over the first week of illness was rash only (n=80). The sensitivity of Zika case definitions increased across paediatric age (from 11·3% to 56·1% for the WHO case definition and from 6·0% to 36·6% for the PAHO case definition), as the prevalence of most clinical findings (particularly arthralgia) increased with age, irrespective of previous dengue virus infection. Consequently, Zika manifested differently across paediatric age; older Zika cases presented with a dengue-like clinical profile while younger Zika cases presented with undifferentiated fever or afebrile rash. INTERPRETATION: We provide the most thorough description of paediatric Zika to date. Most paediatric Zika cases go undetected under the WHO and PAHO case definitions, suggesting that current standards for Zika case ascertainment require revision. Zika manifests with mild but differing clinical profiles across paediatric age, presenting major challenges to diagnosis, surveillance, and efforts to control future Zika epidemics. FUNDING: US National Institutes of Health.

Dietary habits contribute to define the risk of type 2 diabetes in humans.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) is a frequent disorder largely preventable. The aim of this review was to summarize information on the association between dietary habits and the risk of developing T2D. METHODS: We conducted a comprehensive literature search using the PubMed database from its inception to June, 2019. Articles were restricted to those written in English and concerning human subjects. Relevant manuscripts found in the list of references of the retrieved articles were also used in preparation for the review. RESULTS: Animal protein consumption increases the risk of T2D independently of body mass index. Intake of both unprocessed meat and processed meat is strongly and consistently associated with increased risk of developing T2D. In contrast, consumption of high-quality vegetable foods prevents the disease. High-quality plant foods include whole grains, nuts, legumes, fruits, and vegetables. Among less healthy plant-based foods are fruit juices, sweetened beverages, refined grains, potatoes, sweets, and desserts. Carbohydrate-restricted diets that encourage consumption of animal products promote T2D. Low intake of animal products is linked to high educational level so that well-informed individuals tend to consume diets with elevated content of vegetable food. According to the American Dietetic Association, "appropriately planned vegetarian diets including vegan diets are healthful, nutritionally adequate, and may provide health benefits in the prevention and treatment of certain diseases". CONCLUSIONS: restricting animal products while increasing healthy plant-based foods intake facilitates T2D prevention. To neutralize worldwide the burden of T2D and its devastating complications, animal products consumption should be limited or discontinued.

Clinical Features and Treatment in the Spectrum of Paroxysmal Dyskinesias: An Observational Study in South-West Castilla y Leon, Spain.

BACKGROUND: Paroxysmal dyskinesias (PxD) are a group of heterogeneous disorders characterized by intermittent episodes of involuntary movements. PxD include paroxysmal kinesigenic (PKD), nonkinesigenic (PNK), and exercise-induced (PED) varieties. OBJECTIVES: To define the phenotype of primary and secondary PxD forms. METHODS: Twenty-two patients with PxD (9 men/13 women) were evaluated in two hospitals in south-west Castilla y Leon, Spain. Clinical features of the episodes, causes, family history, and response to treatment were collected. RESULTS: Thirteen participants with primary PxD (6 men/7 women) and 9 with secondary PxD (3 men/6 women) were recruited. Nine patients belong to three nonrelated families (2 had PKD and 1 had PED). Mean age at onset in primary PKD cases was 10 years (range 5-23 years), earlier than in PNKD (24 years) and PED (20 years). Most primary PKD cases experienced daily episodes of duration <1 minute, which are more frequent and shorter attacks than in PNKD (1-2 per month, 5 minutes) and PED (1 per day, 15 minutes). The location of the involuntary movements varied widely; isolated dystonia was more common than mixed chorea and dystonia. All PKD patients who received antiepileptic treatment significantly improved. Levodopa and ketogenic diet proved to be effective in two patients with PED. Secondary forms presented a later mean age of onset (51 years). Six cases had PNKD, 1 had PKD, 1 both PNKD and PKD, and 1 had PED. Causes comprised vascular lesions, encephalitis, multiple sclerosis, peripheral trauma, endocrinopathies, and drugs such as selective serotonin reuptake inhibitors (SSRIs). CONCLUSION: The knowledge of the clinical features and spectrum of causes related to PxD is crucial to avoid delays in diagnosis and treatment, or even a nonorganic disorder diagnosis.

Subclinical vascular disease in patients with diabetes is associated with insulin resistance.

Patients with diabetes experience increased cardiovascular risk that is not fully explained by deficient glycemic control or traditional cardiovascular risk factors such as smoking and hypercholesterolemia. Asymptomatic patients with diabetes show structural and functional vascular damage that includes impaired vasodilation, arterial stiffness, increased intima-media thickness and calcification of the arterial wall. Subclinical vascular injury associated with diabetes predicts subsequent manifestations of cardiovascular disease, such as ischemic heart disease, peripheral artery disease and stroke. Noninvasive detection of subclinical vascular disease is commonly used to estimate cardiovascular risk associated to diabetes. Longitudinal studies in normotensive subjects show that arterial stiffness at baseline is associated with a greater risk for future hypertension independently of established risk factors. In patients with type 2 diabetes, vascular disease begins to develop during the latent phase of insulin resistance, long before the clinical diagnosis of diabetes. In contrast, patients with type 1 diabetes do not manifest vascular injury when they are first diagnosed due to insulin deficiency, as they lack the preceding period of insulin resistance. These findings suggest that insulin resistance plays an important role in the development of early vascular disease associated with diabetes. Cross-sectional and prospective studies confirm that insulin resistance is associated with subclinical vascular injury in patients with diabetes, independently of standard cardiovascular risk factors. Asymptomatic vascular disease associated with diabetes begins to occur early in life having been documented in children and adolescents. Insulin resistance should be considered a therapeutic target in order to prevent the vascular complications associated with diabetes.

Insulin resistance is associated with subclinical vascular disease in humans.

Insulin resistance is associated with subclinical vascular disease that is not justified by conventional cardiovascular risk factors, such as smoking or hypercholesterolemia. Vascular injury associated to insulin resistance involves functional and structural damage to the arterial wall that includes impaired vasodilation in response to chemical mediators, reduced distensibility of the arterial wall (arterial stiffness), vascular calcification, and increased thickness of the arterial wall. Vascular dysfunction associated to insulin resistance is present in asymptomatic subjects and predisposes to cardiovascular diseases, such as heart failure, ischemic heart disease, stroke, and peripheral vascular disease. Structural and functional vascular disease associated to insulin resistance is highly predictive of cardiovascular morbidity and mortality. Its pathogenic mechanisms remain undefined. Prospective studies have demonstrated that animal protein consumption increases the risk of developing cardiovascular disease and predisposes to type 2 diabetes (T2D) whereas vegetable protein intake has the opposite effect. Vascular disease linked to insulin resistance begins to occur early in life. Children and adolescents with insulin resistance show an injured arterial system compared with youth free of insulin resistance, suggesting that insulin resistance plays a crucial role in the development of initial vascular damage. Prevention of the vascular dysfunction related to insulin resistance should begin early in life. Before the clinical onset of T2D, asymptomatic subjects endure a long period of time characterized by insulin resistance. Latent vascular dysfunction begins to develop during this phase, so that patients with T2D are at increased cardiovascular risk long before the diagnosis of the disease.

Metabolic effects of glucagon in humans.

Diabetes is a common metabolic disorder that involves glucose, amino acids, and fatty acids. Either insulin deficiency or insulin resistance may cause diabetes. Insulin deficiency causes type 1 diabetes and diabetes associated with total pancreatectomy. Glucagon produces insulin resistance. Glucagon-induced insulin resistance promotes type 2 diabetes and diabetes associated with glucagonoma. Further, glucagon-induced insulin resistance aggravates the metabolic consequences of the insulin-deficient state. A major metabolic effect of insulin is the accumulation of glucose as glycogen in the liver. Glucagon opposes hepatic insulin action and enhances the rate of gluconeogenesis, increasing hepatic glucose output. In order to support gluconeogenesis, glucagon promotes skeletal muscle wasting to supply amino acids as gluconeogenic precursors. Glucagon promotes hepatic fatty acid oxidation to supply energy required to sustain gluconeogenesis. Hepatic fatty acid oxidation generates ß-hydroxybutyrate and acetoacetate (ketogenesis). Prospective studies reveal that elevated glucagon secretion at baseline occurs in healthy subjects who develop impaired glucose tolerance at follow-up compared with subjects who maintain normal glucose tolerance, suggesting a relationship between elevated glucagon secretion and development of impaired glucose tolerance. Prospective studies have identified animal protein consumption as an independent risk factor for type 2 diabetes and cardiovascular disease. Animal protein intake activates glucagon secretion inducing sustained elevations in plasma glucagon. Glucagon is a major hormone that causes insulin resistance. Insulin resistance is an established cardiovascular risk factor additionally to its pathogenic role in diabetes. Glucagon may be a potential link between animal protein intake and the risk of developing type 2 diabetes and cardiovascular disease.

Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua.

BACKGROUND: Zika virus (ZIKV) emerged in northeast Brazil in 2015 and spread rapidly across the Americas, in populations that have been largely exposed to dengue virus (DENV). The impact of prior DENV infection on ZIKV infection outcome remains unclear. To study this potential impact, we analyzed the large 2016 Zika epidemic in Managua, Nicaragua, in a pediatric cohort with well-characterized DENV infection histories. METHODS AND FINDINGS: Symptomatic ZIKV infections (Zika cases) were identified by real-time reverse transcription PCR and serology in a community-based cohort study that follows approximately 3,700 children aged 2-14 years old. Annual blood samples were used to identify clinically inapparent ZIKV infections using a novel, well-characterized serological assay. Multivariable Poisson regression was used to examine the relation between prior DENV infection and incidence of symptomatic and inapparent ZIKV infection. The generalized-growth method was used to estimate the effective reproduction number. From January 1, 2016, to February 28, 2017, 560 symptomatic ZIKV infections and 1,356 total ZIKV infections (symptomatic and inapparent) were identified, for an overall incidence of 14.0 symptomatic infections (95% CI: 12.9, 15.2) and 36.5 total infections (95% CI: 34.7, 38.6) per 100 person-years. Effective reproduction number estimates ranged from 3.3 to 3.4, depending on the ascending wave period. Incidence of symptomatic and total ZIKV infections was higher in females and older children. Analysis of the effect of prior DENV infection was performed on 3,027 participants with documented DENV infection histories, of which 743 (24.5%) had experienced at least 1 prior DENV infection during cohort follow-up. Prior DENV infection was inversely associated with risk of symptomatic ZIKV infection in the total cohort population (incidence rate ratio [IRR]: 0.63; 95% CI: 0.48, 0.81; p < 0.005) and with risk of symptomatic presentation given ZIKV infection (IRR: 0.62; 95% CI: 0.44, 0.86) when adjusted for age, sex, and recent DENV infection (1-2 years before ZIKV infection). Recent DENV infection was significantly associated with decreased risk of symptomatic ZIKV infection when adjusted for age and sex, but not when adjusted for prior DENV infection. Prior or recent DENV infection did not affect the rate of total ZIKV infections. Our findings are limited to a pediatric population and constrained by the epidemiology of the site. CONCLUSIONS: These findings support that prior DENV infection may protect individuals from symptomatic Zika. More research is needed to address the possible immunological mechanism(s) of cross-protection between ZIKV and DENV and whether DENV immunity also modulates other ZIKV infection outcomes such as neurological or congenital syndromes.

Epidemiological Evidence for Lineage-Specific Differences in the Risk of Inapparent Chikungunya Virus Infection.

In late 2013, chikungunya virus (CHIKV) was introduced into the Americas, leading to widespread epidemics. A large epidemic caused by the Asian chikungunya virus (CHIKV) lineage occurred in Managua, Nicaragua, in 2015. Literature reviews commonly state that the proportion of inapparent CHIKV infections ranges from 3 to 28%. This study estimates the ratio of symptomatic to asymptomatic CHIKV infections and identifies risk factors of infection. In October to November 2015, 60 symptomatic CHIKV-infected children were enrolled as index cases and prospectively monitored, alongside 236 household contacts, in an index cluster study. Samples were collected upon enrollment and on day 14 or 35 and tested by real-time reverse transcription-PCR (rRT-PCR), IgM capture enzyme-linked immunosorbent assays (IgM-ELISAs), and inhibition ELISAs to detect pre- and postenrollment CHIKV infections. Of 236 household contacts, 55 (23%) had experienced previous or very recent infections, 41 (17%) had active infections at enrollment, and 21 (9%) experienced incident infections. Vehicle ownership (multivariable-adjusted risk ratio [aRR], 1.58) increased the risk of CHIKV infection, whereas ≥4 municipal trash collections/week (aRR, 0.38) and having externally piped water (aRR, 0.52) protected against CHIKV infection. Among 63 active and incident infections, 31 (49% [95% confidence interval {CI}, 36%, 62%]) were asymptomatic, yielding a ratio of symptomatic to asymptomatic infections of 1:0.97 (95% CI, 1:0.56, 1:1.60). Although our estimate is outside the 3% to 28% range reported previously, Bayesian and simulation analyses, informed by a systematic literature search, suggested that the proportion of inapparent CHIKV infections is lineage dependent and that more inapparent infections are associated with the Asian lineage than the East/Central/South African (ECSA) lineage. Overall, these data substantially improve knowledge regarding chikungunya epidemics.IMPORTANCE Chikungunya virus (CHIKV) is an understudied threat to human health. During the 2015 chikungunya epidemic in Managua, Nicaragua, we estimated the ratio of symptomatic to asymptomatic CHIKV infections, which is important for understanding transmission dynamics and the public health impact of CHIKV. This index cluster study identified and monitored persons at risk of infection, enabling capture of asymptomatic infections. We estimated that 31 (49%) of 63 at-risk participants had asymptomatic CHIKV infections, which is significantly outside the 3% to 28% range reported in literature reviews. However, recent seroprevalence studies, including two large pediatric cohort studies in the same setting, had also found percentages of inapparent infections outside the 3% to 28% range. Bayesian and simulation analyses, informed by a systematic literature search, revealed that the percentage of inapparent infections in epidemic settings varies by CHIKV phylogenetic lineage. Our study quantifies and provides the first epidemiological evidence that chikungunya epidemic characteristics are strongly influenced by CHIKV lineage.

Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua.

Dengue virus (DENV) is the most prevalent human vector-borne viral disease. The force of infection (FoI), the rate at which susceptible individuals are infected in a population, is an important metric for infectious disease modeling. Understanding how and why the FoI of DENV changes over time is critical for developing immunization and vector control policies. We used age-stratified seroprevalence data from 12 years of the Pediatric Dengue Cohort Study in Nicaragua to estimate the annual FoI of DENV from 1994 to 2015. Seroprevalence data revealed a change in the rate at which children acquire DENV-specific immunity: in 2004, 50% of children age >4 years were seropositive, but by 2015, 50% seropositivity was reached only by age 11 years. We estimated a spike in the FoI in 1997-1998 and 1998-1999 and a gradual decline thereafter, and children age <4 years experienced a lower FoI. Two hypotheses to explain the change in the FoI were tested: (i) a transition from introduction of specific DENV serotypes to their endemic transmission and (ii) a population demographic transition due to declining birth rates and increasing life expectancy. We used mathematical models to simulate these hypotheses. We show that the initial high FoI can be explained by the introduction of DENV-3 in 1994-1998, and that the overall gradual decline in the FoI can be attributed to demographic shifts. Changes in immunity and demographics strongly impacted DENV transmission in Nicaragua. Population-level measures of transmission intensity are dynamic and thus challenging to use to guide vaccine implementation locally and globally.

Seroprevalence, risk factor, and spatial analyses of Zika virus infection after the 2016 epidemic in Managua, Nicaragua.

In 2015, a Zika epidemic in Brazil began spreading throughout the Americas. Zika virus (ZIKV) entered Managua, Nicaragua, in January 2016 and caused an epidemic that peaked in July-September 2016. ZIKV seropositivity was estimated among participants of pediatric (n = 3,740) and household (n = 2,147) cohort studies, including an adult-only subset from the household cohort (n = 1,074), in Managua. Seropositivity was based on a highly sensitive and specific assay, the Zika NS1 blockade-of-binding ELISA, which can be used in dengue-endemic populations. Overall seropositivity for the pediatric (ages 2-14), household (ages 2-80), and adult (ages 15-80) cohorts was 36, 46, and 56%, respectively. Trend, risk factor, and contour mapping analyses demonstrated that ZIKV seroprevalence increased nonlinearly with age and that body surface area was statistically associated with increasing seroprevalence in children. ZIKV seropositivity was higher in females than in males across almost all ages, with adjusted prevalence ratios in children and adults of 1.11 (95% CI: 1.02-1.21) and 1.14 (95% CI: 1.01-1.28), respectively. No household-level risk factors were statistically significant in multivariate analyses. A spatial analysis revealed a 10-15% difference in the risk of ZIKV infections across our 3-km-wide study site, suggesting that ZIKV infection risk varies at small spatial scales. To our knowledge, this is the largest ZIKV seroprevalence study reported in the Americas, and the only one in Central America and in children to date. It reveals a high level of immunity against ZIKV in Managua as a result of the 2016 epidemic, making a second large Zika epidemic unlikely in the near future.

Obesity Increases the Duration of Influenza A Virus Shedding in Adults.

Epidemiologic studies indicate that obesity increases the risk of severe complications and death from influenza virus infections, especially in elderly individuals. This work investigates the effect of obesity on the duration of viral shedding within household transmission studies in Managua, Nicaragua, over 3 seasons (2015-2017). Symptomatic obese adults were shown to shed influenza A virus 42% longer than nonobese adults (adjusted event time ratio [ETR], 1.42; 95% confidence interval [CI], 1.06-1.89); no association was observed with influenza B virus shedding duration. Even among paucisymptomatic and asymptomatic adults, obesity increased the influenza A shedding duration by 104% (adjusted ETR, 2.04; 95% CI, 1.35-3.09). These findings suggest that obesity may play an important role in influenza transmission.