The impact of the demographic transition on dengue in Thailand: Insights from a statistical analysis and mathematical modeling

Background: An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics. Methods and Findings: Using data from each of the 72 provinces of Thailand, we looked for associations between force of infection (a measure of hazard, defined as the rate per capita at which susceptible individuals become infected) and demographic and climactic variables. We estimated the force of infection from the age distribution of cases from 1985 to 2005. We find that the force of infection has declined by 2% each year since a peak in the late 1970s and early 1980s. Contrary to recent findings suggesting that the incidence of DHF has increased in Thailand, we find a small but statistically significant decline in DHF incidence since 1985 in a majority of provinces. The strongest predictor of the change in force of infection and the mean force of infection is the median age of the population. Using mathematical simulations of dengue transmission we show that a reduced birth rate and a shift in the population's age structure can explain the shift in the age distribution of cases, reduction of the force of infection, and increase in the periodicity of multiannual oscillations of DHF incidence in the absence of other changes. Conclusions: Lower birth and death rates decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals. The increase in the proportion of the population that is immune increases the likelihood that an infectious mosquito will feed on an immune individual, reducing the force of infection. Though the force of infection has decreased by half, we find that the critical vaccination fraction has not changed significantly, declining from an average of 85% to 80%. Clinical guidelines should consider the impact of continued increases in the age of dengue cases in Thailand. Countries in the region lagging behind Thailand in the demographic transition may experience the same increase as their population ages. The impact of demographic changes on the force of infection has been hypothesized for other diseases, but, to our knowledge, this is the first observation of this phenomenon

Inflammatory cytokines, goblet cell hyperplasia and altered lung mechanics in Lgl1+/- mice

<p>Abstract</p> <p>Background</p> <p>Neonatal lung injury, a leading cause of morbidity in prematurely born infants, has been associated with arrested alveolar development and is often accompanied by goblet cell hyperplasia. Genes that regulate alveolarization and inflammation are likely to contribute to susceptibility to neonatal lung injury. We previously cloned <it>Lgl1</it>, a developmentally regulated secreted glycoprotein in the lung. In rat, O₂toxicity caused reduced levels of <it>Lgl1</it>, which normalized during recovery. We report here on the generation of an <it>Lgl1 </it>knockout mouse in order to determine whether deficiency of <it>Lgl1 </it>is associated with arrested alveolarization and contributes to neonatal lung injury.</p> <p>Methods</p> <p>An <it>Lgl1 </it>knockout mouse was generated by introduction of a neomycin cassette in exon 2 of the <it>Lgl1 </it>gene. To evaluate the pulmonary phenotype of <it>Lgl1</it>^+/-mice, we assessed lung morphology, <it>Lgl1 </it>RNA and protein, elastin fibers and lung function. We also analyzed tracheal goblet cells, and expression of mucin, interleukin (IL)-4 and IL-13 as markers of inflammation.</p> <p>Results</p> <p>Absence of <it>Lgl1 </it>was lethal prior to lung formation. Postnatal <it>Lgl1</it>^+/-lungs displayed delayed histological maturation, goblet cell hyperplasia, fragmented elastin fibers, and elevated expression of T_H2 cytokines (IL-4 and IL-13). At one month of age, reduced expression of <it>Lgl1 </it>was associated with elevated tropoelastin expression and altered pulmonary mechanics.</p> <p>Conclusion</p> <p>Our findings confirm that <it>Lgl1 </it>is essential for viability and is required for developmental processes that precede lung formation. <it>Lgl1</it>^+/-mice display a complex phenotype characterized by delayed histological maturation, features of inflammation in the post-natal period and altered lung mechanics at maturity. <it>Lgl1 </it>haploinsufficiency may contribute to lung disease in prematurity and to increased risk for late-onset respiratory disease.</p

The Crystal Structure of PPIL1 Bound to Cyclosporine A Suggests a Binding Mode for a Linear Epitope of the SKIP Protein

BACKGROUND: The removal of introns from pre-mRNA is carried out by a large macromolecular machine called the spliceosome. The peptidyl-prolyl cis/trans isomerase PPIL1 is a component of the human spliceosome and binds to the spliceosomal SKIP protein via a binding site distinct from its active site. PRINCIPAL FINDINGS: Here, we have studied the PPIL1 protein and its interaction with SKIP biochemically and by X-ray crystallography. A minimal linear binding epitope derived from the SKIP protein could be determined using a peptide array. A 36-residue region of SKIP centred on an eight-residue epitope suffices to bind PPIL1 in pull-down experiments. The crystal structure of PPIL1 in complex with the inhibitor cyclosporine A (CsA) was obtained at a resolution of 1.15 A and exhibited two bound Cd(2+) ions that enabled SAD phasing. PPIL1 residues that have previously been implicated in binding of SKIP are involved in the coordination of Cd(2+) ions in the present crystal structure. Employing the present crystal structure, the determined minimal binding epitope and previously published NMR data, a molecular docking study was performed. In the docked model of the PPIL1.SKIP interaction, a proline residue of SKIP is buried in a hydrophobic pocket of PPIL1. This hydrophobic contact is encircled by several hydrogen bonds between the SKIP peptide and PPIL1. CONCLUSION: We characterized a short, linear epitope of SKIP that is sufficient to bind the PPIL1 protein. Our data indicate that this SKIP peptide could function in recruiting PPIL1 into the core of the spliceosome. We present a molecular model for the binding mode of SKIP to PPIL1 which emphasizes the versatility of cyclophilin-type PPIases to engage in additional interactions with other proteins apart from active site contacts despite their limited surface area

Comparison of the diagnostic accuracy of commercial NS1-based diagnostic tests for early dengue infection

<p>Abstract</p> <p>Background</p> <p>We compared the diagnostic accuracy and reproducibility of commercially available NS1-based dengue tests and explored factors influencing their sensitivities.</p> <p>Methods</p> <p>Paired analysis of 310 samples previously characterized as positive (n = 218) and negative (n = 92) for viral isolation and/or RT-PCR and/or IgM seroconversion. Masked samples were tested by two observers with Platelia™ Dengue NS1 Ag, second generation Pan-E™ Dengue Early ELISA, SD Dengue NS1 Ag ELISA, Dengue NS1 Ag STRIP™, and SD BIOLINE™ Dengue Duo (NS1/IgM/IgG).</p> <p>Results</p> <p>SD BIOLINE™ NS1/IgM/IgG had the highest sensitivity (80.7% 95%CI 75-85.7) with likelihood ratios of 7.4 (95%CI 4.1-13.8) and 0.21 (95%CI 0.16-0.28). The ELISA-format tests showed comparable sensitivities; all below 75%. STRIP™ and SD NS1 had even lower sensitivities (<65%). The sensitivities significantly decreased in samples taken after 3 days of fever onset, in secondary infections, viral serotypes 2 and 4, and severe dengue. Adding IgM or IgG to SD NS1 increased its sensitivity in all these situations.</p> <p>Conclusions</p> <p>The simultaneous detection of NS1/IgM/IgG would be potentially useful for dengue diagnosis in both endemic and non endemic areas. A negative result does not rule out dengue. Further studies are required to assess the performance and impact of early laboratory diagnosis of dengue in the routine clinical setting.</p

Verifying causes of death in Thailand: rationale and methods for empirical investigation

Background: Cause-specific mortality statistics by age and sex are primary evidence for epidemiological research and health policy. Annual mortality statistics from vital registration systems in Thailand are of limited utility because about 40% of deaths are registered with unknown or nonspecific causes. This paper reports the rationale, methods, and broad results from a comprehensive study to verify registered causes in Thailand.Methods: A nationally representative sample of 11,984 deaths was selected using a multistage stratified cluster sampling approach, distributed across 28 districts located in nine provinces of Thailand. Registered causes were verified through medical record review for deaths in hospitals and standard verbal autopsy procedures for deaths outside hospitals, the results of which were used to measure validity and reliability of registration data. Study findings were used to develop descriptive estimates of cause-specific mortality by age and sex in Thailand.Results: Causes of death were verified for a total of 9,644 deaths in the study sample, comprised of 3,316 deaths in hospitals and 6,328 deaths outside hospitals. Field studies yielded specific diagnoses in almost all deaths in the sample originally assigned an ill-defined cause of death at registration. Study findings suggest that the leading causes of death in Thailand among males are stroke (9.4%); transport accidents (8.1%); HIV/AIDS (7.9%); ischemic heart diseases (6.4%); and chronic obstructive lung diseases (5.7%). Among females, the leading causes are stroke (11.3%); diabetes (8%); ischemic heart disease (7.5%); HIV/AIDS (5.7%); and renal diseases (4%).Conclusions: Empirical investigation of registered causes of death in the study sample yielded adequate information to enable estimation of cause-specific mortality patterns in Thailand. These findings will inform burden of disease estimation and economic evaluation of health policy choices in the country. The development and implementation of research methods in this study will contribute to improvements in the quality of annual mortality statistics in Thailand. Similar research is recommended for other countries where the quality of mortality statistics is poor

Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse

Recent clinical evidence suggests important role of lipid and amino acid metabolism in early pre-autoimmune stages of type 1 diabetes pathogenesis. We study the molecular paths associated with the incidence of insulitis and type 1 diabetes in the Non-Obese Diabetic (NOD) mouse model using available gene expression data from the pancreatic tissue from young pre-diabetic mice. We apply a graph-theoretic approach by using a modified color coding algorithm to detect optimal molecular paths associated with specific phenotypes in an integrated biological network encompassing heterogeneous interaction data types. In agreement with our recent clinical findings, we identified a path downregulated in early insulitis involving dihydroxyacetone phosphate acyltransferase (DHAPAT), a key regulator of ether phospholipid synthesis. The pathway involving serine/threonine-protein phosphatase (PP2A), an upstream regulator of lipid metabolism and insulin secretion, was found upregulated in early insulitis. Our findings provide further evidence for an important role of lipid metabolism in early stages of type 1 diabetes pathogenesis, as well as suggest that such dysregulation of lipids and related increased oxidative stress can be tracked to beta cells

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Burden of disease in Thailand: changes in health gap between 1999 and 2004

<p>Abstract</p> <p>Background</p> <p>Continuing comprehensive assessment of population health gap is essential for effective health planning. This paper assessed changes in the magnitude and pattern of disease burden in Thailand between 1999 and 2004. It further drew lessons learned from applying the global burden of disease (GBD) methods to the Thai context for other developing country settings.</p> <p>Methods</p> <p>Multiple sources of mortality and morbidity data for both years were assessed and used to estimate Disability-Adjusted Life Years (DALYs) loss for 110 specific diseases and conditions relevant to the country's health problems. Causes of death from national vital registration were adjusted for misclassification from a verbal autopsy study.</p> <p>Results</p> <p>Between 1999 and 2004, DALYs loss per 1,000 population in 2004 slightly decreased in men but a minor increase in women was observed. HIV/AIDS maintained the highest burden for men in both 1999 and 2004 while in 2004, stroke took over the 1999 first rank of HIV/AIDS in women. Among the top twenty diseases, there was a slight increase of the proportion of non-communicable diseases and two out of three infectious diseases revealed a decrease burden except for lower respiratory tract infections.</p> <p>Conclusion</p> <p>The study highlights unique pattern of disease burden in Thailand whereby epidemiological transition have occurred as non-communicable diseases were on the rise but burden from HIV/AIDS resulting from the epidemic in the 1990s remains high and injuries show negligent change. Lessons point that assessing DALY over time critically requires continuing improvement in data sources particularly on cause of death statistics, institutional capacity and long term commitments.</p

Long-term air pollution exposure and self-reported morbidity: A longitudinal analysis from the Thai cohort study (TCS)

[Background] Several studies have shown the health effects of air pollutants, especially in China, North American and Western European countries. But longitudinal cohort studies focused on health effects of long-term air pollution exposure are still limited in Southeast Asian countries where sources of air pollution, weather conditions, and demographic characteristics are different. The present study examined the association between long-term exposure to air pollution and self-reported morbidities in participants of the Thai cohort study (TCS) in Bangkok metropolitan region (BMR), Thailand. [Methods] This longitudinal cohort study was conducted for 9 years from 2005 to 2013. Self-reported morbidities in this study included high blood pressure, high blood cholesterol, and diabetes. Air pollution data were obtained from the Thai government Pollution Control Department (PCD). Particles with diameters ≤10 μm (PM₁₀), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), ozone (O₃), and carbon monoxide (CO) exposures were estimated with ordinary kriging method using 22 background and 7 traffic monitoring stations in BMR during 2005–2013. Long-term exposure periods to air pollution for each subject was averaged as the same period of person-time. Cox proportional hazards models were used to examine the association between long-term air pollution exposure with self-reported high blood pressure, high blood cholesterol, diabetes. Results of self-reported morbidity were presented as hazard ratios (HRs) per interquartile range (IQR) increase in PM₁₀, O₃, NO₂, SO₂, and CO. [Results] After controlling for potential confounders, we found that an IQR increase in PM₁₀ was significantly associated with self-reported high blood pressure (HR = 1.13, 95% CI: 1.04, 1.23) and high blood cholesterol (HR = 1.07, 95%CI: 1.02, 1.12), but not with diabetes (HR = 1.05, 95%CI: 0.91, 1.21). SO₂ was also positively associated with self-reported high blood pressure (HR = 1.22, 95%CI: 1.08, 1.38), high blood cholesterol (HR = 1.20, 95%CI: 1.11, 1.30), and diabetes (HR = 1.21, 95%CI: 0.92, 1.60). Moreover, we observed a positive association between CO and self-reported high blood pressure (HR = 1.07, 95%CI: 1.00, 1.15), but not for other diseases. However, self-reported morbidities were not associated with O₃ and NO₂. [Conclusions] Long-term exposure to air pollution, especially for PM₁₀ and SO₂ was associated with self-reported high blood pressure, high blood cholesterol, and diabetes in subjects of TCS. Our study supports that exposure to air pollution increases cardiovascular disease risk factors for younger population