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    Major histocompatibility complex class I Chain-related A and B (MICA and MICB) gene, allele, and haplotype associations with dengue infections in ethnic thais
    (2020-09-01)
    Luangtrakool, Panpimon
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    Vejbaesya, Sasijit
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    Luangtrakool, Komon
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    Ngamhawornwong, Somporn
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    Apisawes, Kusuma
    Background. Major histocompatibility complex class I chain-related (MIC) A and B (MICA and MICB) are polymorphic stress molecules recognized by natural killer cells. This study was performed to analyze MIC gene profiles in hospitalized Thai children with acute dengue illness. Methods. MIC allele profiles were determined in a discovery cohort of patients with dengue fever or dengue hemorrhagic fever (DHF) (n = 166) and controls (n = 149). A replication cohort of patients with dengue (n = 222) was used to confirm specific MICB associations with disease. Results. MICA*045 and MICB*004 associated with susceptibility to DHF in secondary dengue virus (DENV) infections (odds ratio [OR], 3.22; [95% confidence interval (CI), 1.18-8.84] and 1.99 [1.07-2.13], respectively), and MICB*002 with protection from DHF in secondary DENV infections (OR, 0.41; 95% CI,.21-.68). The protective effect of MICB*002 against secondary DHF was confirmed in the replication cohort (OR, 0.43; 95% CI,.22-.82) and was stronger when MICB*002 is present in individuals also carrying HLA-B*18, B*40, and B*44 alleles which form the B44 supertype of functionally related alleles (0.29, 95% CI,.14-.60). Conclusions. Given that MICB*002 is a low expresser of soluble proteins, these data indicate that surface expression of MICB*002 with B44 supertype alleles on DENV-infected cells confer a protective advantage in controlling DENV infection using natural killer cells.
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    Individual, Household, and Community Drivers of Dengue Virus Infection Risk in Kamphaeng Phet Province, Thailand
    (2022-10-15)
    Ribeiro Dos Santos, Gabriel
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    Buddhari, Darunee
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    Iamsirithaworn, Sopon
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    Khampaen, Direk
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    Ponlawat, Alongkot
    Background: Dengue virus (DENV) often circulates endemically. In such settings with high levels of transmission, it remains unclear whether there are risk factors that alter individual infection risk. Methods: We tested blood taken from individuals living in multigenerational households in Kamphaeng Phet province, Thailand for DENV antibodies (N = 2364, mean age 31 years). Seropositivity ranged from 45.4% among those 1-5 years old to 99.5% for those >30 years. Using spatially explicit catalytic models, we estimated that 11.8% of the susceptible population gets infected annually. Results: We found that 37.5% of the variance in seropositivity was explained by unmeasured household-level effects with only 4.2% explained by spatial differences between households. The serostatus of individuals from the same household remained significantly correlated even when separated by up to 15 years in age. Conclusions: These findings show that despite highly endemic transmission, persistent differences in infection risk exist across households, the reasons for which remain unclear.
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    Targeted orexin and hypothalamic neuropeptides for migraine
    (2018-02-13)
    Strother, Lauren C.
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    Supronsinchai, Weera
    The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central role in the migraine syndrome from the earliest stages of the attack. The hypothalamus hosts many key neuropeptide systems that have been postulated to play a role in this pathophysiology. Such neuropeptides include but are not exclusive too orexins, oxytocin, neuropeptide Y, and pituitary adenylate cyclase activating protein, which will be the focus of this review. Each of these peptides has its own unique physiological role and as such many preclinical studies have been conducted targeting these peptide systems with evidence supporting their role in migraine pathophysiology. Preclinical studies have also begun to explore potential therapeutic compounds targeting these systems with some success in all cases. Clinical efficacy of dual orexin receptor antagonists and intranasal oxytocin have been tested; however, both have yet to demonstrate clinical effect. Despite this, there were limitations in these cases and strong arguments can be made for the further development of intranasal oxytocin for migraine prophylaxis. Regarding neuropeptide Y, work has yet to begun in a clinical setting, and clinical trials for pituitary adenylate cyclase activating protein are just beginning to be established with much optimism. Regardless, it is becoming increasingly clear the prominent role that the hypothalamus and its peptide systems have in migraine pathophysiology. Much work is required to better understand this system and the early stages of the attack to develop more targeted and effective therapies aimed at reducing attack susceptibility with the potential to prevent the attack all together.
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    Household immunity and individual risk of infection with dengue virus in a prospective, longitudinal cohort study
    (2024-01-01)
    Hamins-Puértolas, Marco
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    Buddhari, Darunee
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    Salje, Henrik
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    Cummings, Derek A.T.
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    Fernandez, Stefan
    Although it is known that household infections drive the transmission of dengue virus (DENV), it is unclear how household composition and the immune status of inhabitants affect the individual risk of infection. Most population-based studies to date have focused on paediatric cohorts because more severe forms of dengue mainly occur in children, and the role of adults in dengue transmission is understudied. Here we analysed data from a multigenerational cohort study of 470 households, comprising 2,860 individuals, in Kamphaeng Phet, Thailand, to evaluate risk factors for DENV infection. Using a gradient-boosted regression model trained on annual haemagglutination inhibition antibody titre inputs, we identified 1,049 infections, 90% of which were subclinical. By analysing imputed infections, we found that individual antibody titres, household composition and antibody titres of other members in the same household affect an individual’s risk of DENV infection. Those individuals living in households with high average antibody titres, or households with more adults, had a reduced risk of infection. We propose that herd immunity to dengue acts at the household level and may provide insight into the drivers of the recent change in the shifting age distribution of dengue cases in Thailand.
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    Transcriptional and clonal characterization of B cell plasmablast diversity following primary and secondary natural DENV infection
    (2020-04-01)
    Waickman, Adam T.
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    Gromowski, Gregory D.
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    Rutvisuttinunt, Wiriya
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    Li, Tao
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    Siegfried, Hayden
    Antibody-mediated humoral immunity is thought to play a central role in mediating the immunopathogenesis of acute DENV infection, but limited data are available on the diversity, specificity, and functionality of the antibody response at the molecular level elicited by primary or secondary DENV infection. In order to close this functional gap in our understanding of DENV-specific humoral immunity, we utilized high-throughput single cell RNA sequencing to investigate B cells circulating in both primary and secondary natural DENV infections. We captured full-length paired immunoglobulin receptor sequence data from 9,027 B cells from a total of 6 subjects, including 2,717 plasmablasts. In addition to IgG and IgM class-switched cells, we unexpectedly found a high proportion of the DENV-elicited plasmablasts expressing IgA, principally in individuals with primary DENV infections. These IgA class-switched cells were extensively hypermutated even in individuals with a serologically confirmed primary DENV infection. Utilizing a combination of conventional biochemical assays and high-throughput shotgun mutagenesis, we determined that DENV-reactive IgA class-switched antibodies represent a significant fraction of DENV-reactive Igs generated in response to DENV infection, and that they exhibit a comparable epitope specificity to DENV-reactive IgG antibodies. These results provide insight into the molecular-level diversity of DENV-elicited humoral immunity and identify a heretofore unappreciated IgA plasmablast response to DENV infection.
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    Migraine and its psychiatric comorbidities: The role of the amygdala
    (2018-01-01)
    Wanasuntronwong, Aree
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    Psychiatric comorbidities are common among patients with migraine. These comorbidities can compromise the quality of life of patients and may affect the result of treatment. The prevalence is higher in patients with migraine who overuse abortive medication. The mechanisms underlying these comorbidities remain unclear, but the amygdala is likely to be involved in their pathogenesis. This brain area has important functions in integrating sensory experiences with unpleasant emotions. The central amygdala plays a general integrative role in autonomic functions related to pain, and receives input from the outer layers of the trigeminal nucleus caudalis via the lateral parabrachial nucleus. A recent study showed that neurons in lateral parabrachial nucleus are activated more strongly by noxious stimulation of the face than of the hind paw. Increased excitability of laterocapsular division of the central nucleus of the amygdala has been observed in animals with cortical spreading depression, an electrophysiological phenomenon underlying the aura phase of migraine. Chronic treatment with analgesics further increases the neuronal excitability in the central nucleus of the amygdala and increases cortical spreading depression-evoked expression of Fos in the trigeminal nucleus caudalis and amygdala. These preclinical evidences imply the role of amygdala in pathogenesis of comorbid depression and anxiety commonly observed in patients with migraine.
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    Neurobiology of migraine progression
    (2022-08-01) ;
    Rapoport, Alan
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    Chronic migraine is one of the most devastating headache disorders. The estimated prevalence is 1.4–2.2% in the population. The factors which may predispose to the process of migraine progression include high frequency of migraine attacks, medication overuse, comorbid pain syndromes, and obesity. Several studies showed that chronic migraine results in the substantial anatomical and physiological changes in the brain. Despite no clear explanation regarding the pathophysiologic process leading to the progression, certain features such as increased sensory sensitivity, cutaneous allodynia, impaired habituation, identify the neuronal hyperexcitability as the plausible mechanism. In this review, we describe two main mechanisms which can lead to this hyperexcitability. The first is persistent sensitization caused by repetitive and prolonged trigeminal nociceptive activation. This process results in changes in several brain networks related to both pain and non-pain behaviours. The second mechanism is the decrease in endogenous brainstem inhibitory control, hence increasing the excitability of neurons in the trigeminal noceptive system and cerebral cortex. The combination of increased pain matrix connectivity, including hypothalamic hyperactivity and a weak serotonergic system, may contribute to migraine chronification.
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    Correlation between reported dengue illness history and seropositivity in rural Thailand
    (2021-06-01)
    Buddhari, Darunee
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    Anderson, Kathryn B.
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    Gromowski, Gregory D.
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    Jarman, Richard G.
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    Iamsirithaworn, Sopon
    In the latest World Health Organization (WHO) recommendation for Dengvaxia implementation, either serological testing or a person’s history of prior dengue illness may be used as supporting evidence to identify dengue virus (DENV)-immune individuals eligible for vaccination, in areas with limited capacity for laboratory confirmation. This analysis aimed to estimate the concordance between self-reported dengue illness histories and seropositivity in a prospective cohort study for dengue virus infection in Kamphaeng Phet province, a dengue-endemic area in northern Thailand. The study enrolled 2,076 subjects from 516 multigenerational families, with a median age of 30.6 years (range 0–90 years). Individual and family member dengue illness histories were obtained by questionnaire. Seropositivity was defined based on hemagglutination inhibition (HAI) assays. Overall seropositivity for DENV was 86.5% among those aged 9–45 years, which increased with age. 18.5% of participants reported a history of dengue illness prior to enrollment; 30.1% reported a previous DENV infection in the family, and 40.1% reported DENV infection in either themselves or a family member. Relative to seropositivity by HAI in the vaccine candidate group, the sensitivity and specificity of individual prior dengue illness history were 18.5% and 81.6%, respectively; sensitivity and specificity of reported dengue illness in a family member were 29.8% and 68.0%, and of either the individual or a family member were 40.1% and 60.5%. Notably, 13.4% of individuals reporting prior dengue illness were seronegative. Given the high occurrence of asymptomatic and mild DENV infection, self-reported dengue illness history is poorly sensitive for prior exposure and may misclassify individuals as ‘exposed’ when they were not. This analysis highlights that a simple, highly sensitive, and highly specific test for determining serostatus prior to Dengvaxia vaccination is urgently needed.
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    Stakeholder perspectives on skills required for health technology developers: a qualitative study in Thailand
    (2025-01-01)
    Phaisawang, Sranya
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    ; ;
    Background: Throughout history, medical education has developed in response to societal changes and advances in biological research and technology. Health technology, encompassing devices, medicines, vaccines, and digital health systems, is transforming healthcare with increased effectiveness and efficiency. Thailand, a popular medical tourism destination, intends to shift its focus to high-quality healthcare services and advanced technologies for long-term economic sustainability. This study identifies necessary skills for health technology developers to help create a technology-driven healthcare ecosystem and prepare human capital in the field. Methods: In this qualitative study, in-depth interviews with diverse stakeholders in health and health technology industries were conducted to investigate the role of health technology in future healthcare and the skills required for health technology developers. Qualitative Content Analysis was carried out. Participants included national health policy makers, university presidents, hospital directors, and health technology company administrators. The study utilized the electronic Delphi method for ranking skills through multiple interview rounds, ensuring thorough evaluation of significant topics. Results: This study involved interviews with sixteen stakeholders in health technology, focusing on its importance and impact on future healthcare. Participants discussed three major areas of technology: molecular technologies, biomedical engineering technologies, and health information technologies. Delocalization, personalization, and digitalization are key components of healthcare transformation. The challenges and skills needed for health technology developers were categorized into four domains including, Health Science, Health Technology, Product Development & Design and Marketing & Entrepreneurship. Conclusion: Our study revealed the significance of technology in healthcare transformation. We identified four skill categories that health technology developers must possess. (1) Health Science, (2) Health Technology, (3) Product Development & Design, and (4) Marketing & Entrepreneurship were among these domains. A systematic strategy for developing these skills is a crucial success factor in human capital preparation for future technology-driven healthcare.
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    Linking multiple serological assays to infer dengue virus infections from paired samples using mixture models
    (2025-12-20)
    Hamins-Puértolas, Marco
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    Buddhari, Darunee
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    Salje, Henrik
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    Huang, Angkana T.
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    Hunsawong, Taweewun
    Dengue virus (DENV) is an increasingly important human pathogen, with already half of the globe’s population living in environments with transmission potential. Since many cases are missed by direct detection methods (RT-PCR or antigen tests), serological assays play an important role in the diagnostic process. However, individual assays can suffer from low sensitivity and specificity and interpreting results from multiple assays remains challenging, particularly because interpretations from multiple assays may differ, creating uncertainty over how to generate finalized interpretations. We develop a Bayesian mixture model that can jointly model data from multiple paired serological assays, to infer infection events. We first test the performance of our model using simulated data. We then apply our model to 677 pairs of acute and convalescent serum collected as a part of illness and household investigations across two longitudinal cohort studies in Kamphaeng Phet, Thailand, including data from 232 RT-PCR confirmed infections (gold standard). We compare the classification of the new model to prior standard interpretations that independently utilize information from either the hemagglutination inhibition assay (HAI) or the enzyme-linked immunosorbent assay (EIA). We find that additional serological assays improve accuracy of infection detection for both simulated and real world data. Models incorporating paired IgG and IgM data as well as those incorporating IgG, IgM, and HAI data consistently have higher accuracy when using PCR confirmed infections as a gold standard (87–90% F1 scores, a combined metric of sensitivity and specificity) than currently implemented cut-point approaches (82–84% F1 scores). Our results provide a probabilistic framework through which multiple serological assays across different platforms can be leveraged across sequential serum samples to provide insight into whether individuals have recently experienced a DENV infection. These methods are applicable to other pathogen systems where multiple serological assays can be leveraged to quantify infection history.