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Utilities and Limitations of the World Health Organization 2009 Warning Signs for Adult Dengue Severity
Tun-Linn Thein equal contributor ,Victor C. Gan equal contributor,David C. Lye,Chee-Fu Yung,Yee-Sin Leo
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002023
Abstract: Background In 2009, the World Health Organization (WHO) proposed seven warning signs (WS) as criteria for hospitalization and predictors of severe dengue (SD). We assessed their performance for predicting dengue hemorrhagic fever (DHF) and SD in adult dengue. Method DHF, WS and SD were defined according to the WHO 1997 and 2009 dengue guidelines. We analyzed the prevalence, sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of WS before DHF and SD onset. Results Of 1507 cases, median age was 35 years (5th–95th percentile, 17–60), illness duration on admission 4 days (5th–95th percentile, 2–6) and length of hospitalization 5 days (5th–95th percentile, 3–7). DHF occurred in 298 (19.5%) and SD in 248 (16.5%). Of these, WS occurred before DHF in 124 and SD in 65 at median of two days before DHF or SD. Three commonest warning signs were lethargy, abdominal pain/tenderness and mucosal bleeding. No single WS alone or combined had Sn >64% in predicting severe disease. Specificity was >90% for both DHF and SD with persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, clinical fluid accumulation, and any 3 or 4 WS. Any one of seven WS had 96% Sn but only 18% Sp for SD. Conclusions No WS was highly sensitive in predicting subsequent DHF or SD in our confirmed adult dengue cohort. Persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, and clinical fluid accumulation, as well as any 3 or 4 WS were highly specific for DHF or SD.
Predictive Value of Proteinuria in Adult Dengue Severity
Farhad F. Vasanwala equal contributor,Tun-Linn Thein equal contributor,Yee-Sin Leo ,Victor C. Gan,Ying Hao,Linda K. Lee,David C. Lye
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0002712
Abstract: Background Dengue is an important viral infection with different presentations. Predicting disease severity is important in triaging patients requiring hospital care. We aim to study the value of proteinuria in predicting the development of dengue hemorrhagic fever (DHF), utility of urine dipstick test as a rapid prognostic tool. Methodology and principal findings Adult patients with undifferentiated fever (n = 293) were prospectively enrolled at the Infectious Disease Research Clinic at Tan Tock Seng Hospital, Singapore from January to August 2012. Dengue infection was confirmed in 168 (57%) by dengue RT-PCR or NS1 antigen detection. Dengue cases had median fever duration of 6 days at enrolment. DHF was diagnosed in 34 cases according to the WHO 1997 guideline. Dengue fever (DF) patients were predominantly younger and were mostly seen in the outpatient setting with higher platelet level. Compared to DF, DHF cases had significantly higher peak urine protein creatinine ratio (UPCR) during clinical course (26 vs. 40 mg/mmol; p<0.001). We obtained a UPCR cut-off value of 29 mg/mmol based on maximum AUC in ROC curves of peak UPCR for DF versus DHF, corresponding to 76% sensitivity and 60% specificity. Multivariate analysis with other readily available clinical and laboratory variables increased the AUC to 0.91 with 92% sensitivity and 80% specificity. Neither urine dipstick at initial presentation nor peak urine dipstick value during the entire illness was able to discriminate between DF and DHF. Conclusions Proteinuria measured by a laboratory-based UPCR test may be sensitive and specific in prognosticating adult dengue patients.
Risk Factors for Fatality among Confirmed Adult Dengue Inpatients in Singapore: A Matched Case-Control Study
Tun-Linn Thein, Yee-Sin Leo, Dale A. Fisher, Jenny G. Low, Helen M. L. Oh, Victor C. Gan, Joshua G. X. Wong, David C. Lye
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081060
Abstract: Objectives To identify demographic, clinical and laboratory risk factors for death due to dengue fever in adult patients in Singapore. Methods Multi-center retrospective study of hospitalized adult patients with confirmed dengue fever in Singapore between 1 January 2004 and 31 December 2008. Non-fatal controls were selected by matching age and year of infection with fatal cases. World Health Organization 1997, 2009 criteria were applied to define dengue hemorrhagic fever (DHF), warning signs and severe dengue. Statistical significance was assessed by conditional logistic regression modeling. Results Significantly more fatal cases than matched controls had pre-existing co-morbid conditions, and presented with abdominal pain/tenderness. Median pulse rates were significantly higher while myalgia was significantly less frequent in cases. . Fatal cases also had higher leucocyte counts, platelet counts, serum sodium, potassium, urea, creatine and bilirubin levels on admission compared to controls. There was no statistical significant difference between the prevalence of DHF and hematocrit level among cases and controls. Multivariate analysis showed myalgia and leucocyte count at presentation were independent predictors of fatality (adjusted odds ratios 0.09 and 2.94 respectively). None of the controls was admitted to intensive care unit (ICU) or given blood transfusion, while 71.4% and 28.6% of fatal cases received ICU admission and blood transfusion. Conclusions Absence of myalgia and leucocytosis on admission were independently associated with fatality in our matched case-control study. Fatalities were also commonly associated with co-morbidities and clinicians should be alarmed if dengue patients fulfilled severe dengue case definition on admission.
Challenges in Dengue Fever in the Elderly: Atypical Presentation and Risk of Severe Dengue and Hospita-Acquired Infection
Emily K. Rowe ,Yee-Sin Leo,Joshua G. X. Wong,Tun-Linn Thein,Victor C. Gan,Linda K. Lee,David C. Lye
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0002777
Abstract: Background/methods To better understand dengue fever in the elderly, we compared clinical features, World Health Organization (WHO) dengue classification and outcomes between adult (<60) and elderly (≥60) dengue patients. We explored the impact of co-morbidity and hospital-acquired infection (HAI) on clinical outcomes in the elderly. All patients managed at the Communicable Disease Centre, Singapore, between 2005 and 2008 with positive dengue polymerase chain reaction (PCR) or who fulfilled WHO 1997 or 2009 probable dengue criteria with positive dengue IgM were included. Results Of the 6989 cases, 295 (4.4%) were elderly. PCR was positive in 29%. The elderly suffered more severe disease with more dengue haemorrhagic fever (DHF) (29.2% vs. 21.4%) and severe dengue (SD) (20.3% vs. 14.6%) (p<0.05). Classic dengue symptoms were more common in the adult group. The elderly were less likely to fulfill WHO 1997 (93.6% vs. 96.4%) (p = 0.014), but not WHO 2009 probable dengue (75.3% vs. 71.5%). Time to dengue diagnosis was similar. There was no significant difference in the frequency of warning signs between the two groups, but the elderly were more likely to have hepatomegaly (p = 0.006) and malaise/lethargy (p = 0.033) while the adults had significantly more mucosal bleeding (p<0.001). Intensive care admission occurred in 15 and death in three, with no age difference. Notably, the elderly stayed in hospital longer (median 5 vs. 4 days), and suffered more pneumonia (3.8% vs. 0.7%) and urinary infection (1.9% vs. 0.3%) (p = 0.003). Predictors of excess length of stay were age (adjusted odds ratio [aOR] 2.01, 95% confidence interval [CI] 1.37–2.88), critical illness (aOR 5.13, 95%CI 2.59–9.75), HAI (aOR 12.06, 95%CI 7.39–19.9), Charlson score (aOR 6.9, 95%CI 2.02–22.56) and severe dengue (DHF/dengue shock syndrome/SD) (aOR 2.24, 95%CI 1.83–2.74). Conclusion Elderly dengue patients present atypically and are at higher risk of DHF, SD and HAI. Aside from dengue severity, age, co-morbidity and HAI were associated with longer hospital stay.
Granzyme A Produced by γ9δ2 T Cells Induces Human Macrophages to Inhibit Growth of an Intracellular Pathogen
Charles T. Spencer equal contributor,Getahun Abate equal contributor,Isaac G. Sakala equal contributor,Mei Xia,Steven M. Truscott,Christopher S. Eickhoff,Rebecca Linn,Azra Blazevic,Sunil S. Metkar,Guangyong Peng,Christopher J. Froelich,Daniel F. Hoft
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003119
Abstract: Human γ9δ2 T cells potently inhibit pathogenic microbes, including intracellular mycobacteria, but the key inhibitory mechanism(s) involved have not been identified. We report a novel mechanism involving the inhibition of intracellular mycobacteria by soluble granzyme A. γ9δ2 T cells produced soluble factors that could pass through 0.45 μm membranes and inhibit intracellular mycobacteria in human monocytes cultured below transwell inserts. Neutralization of TNF-α in co-cultures of infected monocytes and γ9δ2 T cells prevented inhibition, suggesting that TNF-α was the critical inhibitory factor produced by γ9δ2 T cells. However, only siRNA- mediated knockdown of TNF-α in infected monocytes, but not in γ9δ2 T cells, prevented mycobacterial growth inhibition. Investigations of other soluble factors produced by γ9δ2 T cells identified a highly significant correlation between the levels of granzyme A produced and intracellular mycobacterial growth inhibition. Furthermore, purified granzyme A alone induced inhibition of intracellular mycobacteria, while knockdown of granzyme A in γ9δ2 T cell clones blocked their inhibitory effects. The inhibitory mechanism was independent of autophagy, apoptosis, nitric oxide production, type I interferons, Fas/FasL and perforin. These results demonstrate a novel microbial defense mechanism involving granzyme A-mediated triggering of TNF-α production by monocytes leading to intracellular mycobacterial growth suppression. This pathway may provide a protective mechanism relevant for the development of new vaccines and/or immunotherapies for macrophage-resident chronic microbial infections.
Prevention and Treatment of Venous Thromboembolism with New Oral Anticoagulants: A Practical Update for Clinicians
Nay Min Tun,Thein Hlaing Oo
Thrombosis , 2013, DOI: 10.1155/2013/183616
Prevention and Treatment of Venous Thromboembolism with New Oral Anticoagulants: A Practical Update for Clinicians
Nay Min Tun,Thein Hlaing Oo
Thrombosis , 2013, DOI: 10.1155/2013/183616
Abstract: Traditional anticoagulants, such as warfarin and enoxaparin, have several limitations, including parenteral administration, need for laboratory monitoring, and ongoing dose adjustment, which may limit optimal patient care. Newer oral anticoagulants, such as direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban), have been developed to overcome these drawbacks, and thereby improve patient care. Several of these agents have been approved for use in the prevention and treatment of venous and/or systemic thromboembolism. The objective of this paper is to provide an overview of the available clinical trial data for these new oral anticoagulants in the prevention and treatment of venous thromboembolism and a practical update for clinicians. 1. Introduction Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the exact incidence of VTE is not known, it is estimated to affect 900,000 patients each year in the United States [1]. Approximately one-third of these cases are fatal pulmonary emboli, and the remaining two-thirds are nonfatal episodes of symptomatic DVT or PE [1]. VTE is the second most common cause of extended hospital stay and the third most common cause of in-hospital mortality [2]. Because it causes considerable morbidity and mortality, VTE places a substantial burden on healthcare resources [3, 4]. Without thromboprophylaxis, the incidence of hospital-acquired DVT based on objective diagnostic screening is 10–40% among medical or general surgical patients and 40–60% among patients who have undergone major orthopedic surgery such as total knee replacement (TKR), total hip replacement (THR), and hip fracture surgery [5]. Patients with cancer are at a greater risk of new or recurrent VTE than patients without cancer. VTE risk is 3- to 5-fold higher in cancer patients who are undergoing surgery and 6.5-fold higher in cancer patients receiving chemotherapy than in patients who do not have cancer [6, 7]. The efficacy of traditional anticoagulants in preventing VTE in patients undergoing major orthopedic surgery and in hospitalized acutely ill medical patients is well established [5, 8–11]. However, these agents have several limitations that may limit optimal patient care, such as their parenteral administration, need for laboratory monitoring, and ongoing dose adjustment (Table 1) [12–16]. Newer oral anticoagulants, such as direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g.,
250 MHz to 30 GHz, Unilateral Circuitmodel for Ingap/GaAs Hbt
Than Tun Thein;Choi Look Law;Kai Fu
PIER C , 2012, DOI: 10.2528/PIERC11101702
Abstract: A unilateral circuit model, which precisely predicts small signal response over a wide range of frequencies and bias points, is quantitatively analyzed and presented. The shortfall of current unilateral assumption and transformation technique is presented. A complete and explicit analysis is provided to develop a compact unilateral circuit model. The model is intended to predict input reflection, forward transmission and output reflection coefficients over wide range of frequencies. The technique is validated by transforming bilateral a small signal model of 3 x 3 μm x 40 μm, InGaP/GaAs HBT into its unilateral equivalent over the frequency range of 250 MHz to 30 GHz. The accuracy of the technique is corroborated at various bias conditions; collector current from 3 mA to 150 mA and collector-emitter voltage from 1 V to 5 V. Simulated results show very good agreement between small signal responses of transformed unilateral and bilateral circuit models.
Frequency Domain Dynamic Thermal Analysis in GaAs Hbt for Power Amplifier Applications
Than Tun Thein;Choi Look Law;Kai Fu
PIER , 2011, DOI: 10.2528/PIER11050301
Abstract: Dynamic temperature distributions in GaAs HBT are numerically analyzed in frequency domain as a function of power dissipation, frequency and space. Complete thermal characteristics, including frequency-dependent thermal impedance and phase lag behavior, are presented. The analysis is also extended for arbitrary periodic or aperiodic pulse heating operation to predict junction temperature of a Power Amplifier (PA) with non-constant envelope input signal. Dynamic junction temperatures of a single finger 2 μm x 20 μm GaAs HBT are predicted for square pulse envelope signal input with power levels varying with up to 10 dB above a nominal average level of 40 mW and with pulse widths ranging from 10 ns to 100 μs. With the input envelope signal amplitude of 10 dB above the average, the analytical results show that junction temperature rises from room temperature of 27C to 39C when heated by 10 ns pulse, increase to 36C by 100ns pulse, 105C by 1μs pulse and to 198C by 100 μs pulse. A novel setup is developed for nano-second pulsed measurements, and the analysis is validated through time domain on wafer pulsed measurements at three different power levels: 0 dB, 3 dB, and 6 dB above the average level. Results show that analytical results track well with measured junction temperature within the accuracy of ±5C over the entire measurement set.
Multiple Loci Are Associated with White Blood Cell Phenotypes
Michael A. Nalls equal contributor ,David J. Couper equal contributor,Toshiko Tanaka equal contributor,Frank J. A. van Rooij equal contributor,Ming-Huei Chen equal contributor,Albert V. Smith equal contributor,Daniela Toniolo equal contributor,Neil A. Zakai equal contributor,Qiong Yang,Andreas Greinacher,Andrew R. Wood,Melissa Garcia,Paolo Gasparini,Yongmei Liu,Thomas Lumley,Aaron R. Folsom,Alex P. Reiner,Christian Gieger,Vasiliki Lagou,Janine F. Felix,Henry V?lzke,Natalia A. Gouskova,Alessandro Biffi,Angela D?ring,Uwe V?lker,Sean Chong,Kerri L. Wiggins,Augusto Rendon,Abbas Dehghan,Matt Moore,Kent Taylor,James G. Wilson,Guillaume Lettre,Albert Hofman,Joshua C. Bis,Nicola Pirastu,Caroline S. Fox,Christa Meisinger,Jennifer Sambrook,Sampath Arepalli,Matthias Nauck,Holger Prokisch,Jonathan Stephens,Nicole L. Glazer,L. Adrienne Cupples,Yukinori Okada,Atsushi Takahashi,Yoichiro Kamatani,Koichi Matsuda,Tatsuhiko Tsunoda,Toshihiro Tanaka,Michiaki Kubo,Yusuke Nakamura,Kazuhiko Yamamoto,Naoyuki Kamatani,Michael Stumvoll,Anke T?njes,Inga Prokopenko,Thomas Illig,Kushang V. Patel,Stephen F. Garner,Brigitte Kuhnel,Massimo Mangino,Ben A. Oostra,Swee Lay Thein,Josef Coresh,H.-Erich Wichmann,Stephan Menzel,JingPing Lin,Giorgio Pistis,André G. Uitterlinden,Tim D. Spector,Alexander Teumer,Gudny Eiriksdottir,Vilmundur Gudnason,Stefania Bandinelli,Timothy M. Frayling,Aravinda Chakravarti,Cornelia M. van Duijn,David Melzer,Willem H. Ouwehand,Daniel Levy,Eric Boerwinkle,Andrew B. Singleton
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002113
Abstract: White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
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