The Fifth Residue of the Coat Protein of Turnip Mosaic Virus Is Responsible for Long-Distance Movement in a Local-Lesion Host and Aphid Transmissibility in a Systemic Host.

HC-Pro and coat protein (CP) genes of a potyvirus facilitate cell-to-cell movement and are involved in the systemic movement of the viruses. The interaction between HC-Pro and CP is mandatory for aphid transmission. Two turnip mosaic virus (TuMV) isolates, RC4 and YC5, were collected from calla lily plants in Taiwan. The virus derived from the infectious clone pYC5 cannot move systemically in Chenopodium quinoa plants and loses aphid transmissibility in Nicotiana benthamiana plants, like the initially isolated virus. Sequence analysis revealed that two amino acids, P5 and A206, of YC5 CP uniquely differ from RC4 and other TuMV strains. Recombination assay and site-directed mutagenesis revealed that the fifth residue of leucine (L) at the N-terminal region of the CP (TuMV-RC4), rather than proline (P) (TuMV-YC5), is critical to permit the systemic spread in C. quinoa plants. Moreover, the single substitution mutant YC5-CPP5L became aphid transmissible, similar to RC4. Fluorescence microscopy revealed that YC5-GFP was restricted in the petioles of inoculated leaves, whereas YC5-CPP5L-GFP translocated through the petioles of inoculated leaves, the main stem, and the petioles of the upper uninoculated leaves of C. quinoa plants. In addition, YC5-GUS was blocked at the basal part of the petiole connecting to the main stem of the inoculated C. quinoa plants, whereas YC5-CPP5L-GFP translocated to the upper leaves. Thus, a single amino acid, the residue L5 at the N-terminal region right before the 6DAG8 motif, is critical for the systemic translocation ability of TuMV in a local lesion host and for aphid transmissibility in a systemic host.

Inositol polyphosphates-regulated polyubiquitination of PHR1 by NLA E3 ligase during phosphate starvation response in Arabidopsis.

Phosphate (Pi) availability is a major factor limiting plant growth and development. The key transcription factor controlling Pi-starvation response (PSR) is PHOSPHATE STARVATION RESPONSE 1 (PHR1) whose transcript levels do not change with changes in Pi levels. However, how PHR1 stability is regulated at the post-translational level is relatively unexplored in Arabidopsis thaliana. Inositol polyphosphates (InsPn) are important signal molecules that promote the association of stand-alone SPX domain proteins with PHR1 to regulate PSR. Here, we show that NITROGEN LIMITATION ADAPTATION (NLA) E3 ligase can associate with PHR1 through its conserved SPX domain and polyubiquitinate PHR1 in vitro. The association with PHR1 and its ubiquitination is enhanced by InsP6 but not by InsP5. Analysis of InsPn-related mutants and an overexpression plant shows PHR1 levels are more stable in itpk4-1 and vih2-4/VIH1amiRNA but less stable in ITPK4 overexpression plants. Under Pi-deficient conditions, nla seedlings contain high PHR1 levels, display long root hair and accumulate anthocyanin in shoots phenocopying PHR1 overexpression plants. By contrast, NLA overexpression plants phenocopy phr1 whose phenotypes are opposite to those of nla. Our results suggest NLA functions as a negative regulator of Pi response by modulating PHR1 stability and the NLA/PHR1 association depends on InsPn levels.

Obesity as a clinical predictor for severe manifestation of dengue: a systematic review and meta-analysis.

BACKGROUND: Severe dengue often leads to poor clinical outcomes and high mortality; as a result, it is of vital importance to find prognostic factors associated with the severe form of dengue. Obesity is known to deteriorate many infectious diseases due to impaired immune responses. Several studies have suggested that obese patients with dengue infection tend to have more severe manifestations with poorer prognosis. However, a firm conclusion could not be drawn due to the varied results of these studies. Here, we aimed to conduct a systematic review and meta-analysis to investigate the association between obesity and dengue severity. METHODS: A literature search for relevant studies was conducted in PubMed, Embase, Ovid Medline and Cochrane from inception to September 9, 2022. The two main keywords were "dengue" and "obesity". Mantel-Haenszel method and random effects model was used to analyze the pooled odds ratio with 95% confidence intervals. RESULTS: A total of 15 article involving a total of 6,508 patients were included in the meta-analysis. Included patients in most studies were hospitalized pediatric patients. Only one study included adulthood data. Three cohort studies, four case-control studies, and one cross-sectional studies found a significant association between obesity and dengue severity. In contrast, three cohort studies, three case-control studies, and one cross-sectional study reported no significant relationship between obesity and dengue severity. Our analysis results showed that patient with obesity is 50% (OR = 1.50; 95%CI: 1.15-1.97) more likely to develop severe manifestation of dengue. CONCLUSION: This meta-analysis revealed that overweight could be a clinical predictor for severe disease for pediatric patients with dengue infection.

Modification of Papaya Ringspot Virus HC-Pro to Generate Effective Attenuated Mutants for Overcoming the Problem of Strain-Specific Cross Protection.

Cross protection application of HA5-1, an attenuated mutant of papaya ringspot virus (PRSV) HA strain from Hawaii, was withdrawn from Taiwan due to the narrow geographic strain specificity of HA5-1. Here, to overcome this problem, we created attenuated mutants of PRSV YK, a dominant severe strain from Taiwan, by mutating helper component protease (HC-Pro) at F7, R181, F206, and D397 residues critical for potyviral pathogenicity. PRSV YK HC-Pro R181I, F206L, and D397N single-mutant viruses induced mild symptoms, but their adverse effects on growth of papaya plants disqualified them as useful protective viruses. However, F7I single-mutant and F7I + F206L double-mutant viruses displayed mild symptoms followed by recovery, and they showed a zigzag pattern of accumulation in papaya plants, indicating their potential to trigger RNA silencing and retain partial antagonistic suppression of host defense. Although F7I + R181I and F7I + D397N double-mutant viruses caused symptomless infection, they accumulated barely above mock level and, thus, were not qualified as proper protective viruses. RNA silencing suppression (RSS) analysis by agroinfiltration in Nicotiana benthamiana plants revealed that the HC-Pro F7I and F7I + F206L mutant proteins were weaker in RSS ability than the wild-type protein. Under greenhouse conditions, F7I and F7I + F206L mutant viruses were genetically stable but not aphid transmissible. Compared with the HA5-1 mutant's low degree (10%) of protection to papaya plants, the F7I and F7I + F206L mutants provided complete (100%) protection to papaya and horn melon plants against strain YK. Thus, F7I and F7I + F206L mutants solve the problem of strain-specific protection and have great potential for control of PRSV in Taiwan.

Relationship between the Incidence of Dengue Virus Transmission in Traditional Market and Climatic Conditions in Kaohsiung City.

In 2014 and 2015, Southern Taiwan experienced two unprecedented outbreaks, with more than 10,000 laboratory-confirmed dengue cases in each outbreak. The present study was aimed to investigate the influence of meteorological and spatial factors on dengue outbreaks in Southern Taiwan and was conducted in Kaohsiung City, which is the most affected area in Taiwan. The distributed lag nonlinear model was used to investigate the role of climatic factors in the 2014 and 2015 dengue outbreaks. Spatial statistics in the Geographic Information System was applied to study the relationship between the dengue spreading pattern and locations of traditional markets (human motility) in the 2015 dengue outbreak. Meteorological analysis results suggested that the relative risk of dengue fever increased when the weekly average temperature was more than 15°C at lagged weeks 5 to 18. Elevated relative risk of dengue was observed when the weekly average rainfall was more than 150 mm at lagged weeks 12 to 20. The spatial analysis revealed that approximately 83% of dengue cases were located in the 1000 m buffer zone of traditional market, with statistical significance. These findings support the influence of climatic factors and human motility on dengue outbreaks. Furthermore, the study analysis may help authorities to identify hotspots and decide the timing for implementation of dengue control programs.

A Conserved Helix in the C-Terminal Region of Watermelon Silver Mottle Virus Nonstructural Protein S Is Imperative For Protein Stability Affecting Self-Interaction, RNA Silencing Suppression, and Pathogenicity.

In orthotospovirus, the nonstructural protein S (NSs) is the RNA-silencing suppressor (RSS) and pathogenicity determinant. Here, we demonstrate that a putative α-helix, designated H8, spanning amino acids 338 to 369 of the C-terminal region of the NSs protein, is crucial for self-interaction of watermelon silver mottle virus NSs protein and that the H8 affects RSS function. Co-immunoprecipitation, yeast two-hybrid, and bimolecular fluorescence complementation analyses revealed that the triple point mutation (TPM) of H8 amino acids Y338A, H350A, and F353A resulted in NSs protein self-interaction dysfunction. Transient expression of H8-deleted (ΔH8) and TPM NSs proteins in Nicotiana benthamiana plants by agroinfitration indicated that these proteins have weaker RSS activity and are far less stable than wild-type (WT) NSs. However, an electrophoretic mobility assay revealed that small interfering RNA (siRNA) binding ability of TPM NSs protein is not compromised. The pathogenicity assay of WT NSs protein expressed by the attenuated turnip mosaic virus vector restored severe symptoms in recombinant-infected N. benthamiana plants but not for ΔH8 or TPM proteins. Taken together, we conclude that the H8 helix in the C-terminal region of NSs protein is crucial for stabilizing NSs protein through self-interaction to maintain normal functions of RSS and pathogenicity, but not for NSs-siRNA binding activity.

Early Seroreversion After 2 Doses of Hepatitis A Vaccination in Human Immunodeficiency Virus-Positive Patients: Incidence and Associated Factors.

Serological responses (Seroresponse) and durability of hepatitis A virus (HAV) vaccination are reduced among human immunodeficiency virus (HIV)-positive patients. Incidence of and associated factors with early seroreversion (loss of seroresponse) among HIV-positive patients who have achieved seroresponses after two doses of HAV vaccination remain unclear. In this multicenter study, we followed HIV-positive adults who had mounted seroresponses after completing two doses of HAV vaccination during a recent outbreak of acute hepatitis A between 2015 and 2017, a 1:4 case-control study was conducted to identify factors associated with seroreversion. Case patients were those with seroreversion, and controls were those with similar follow-up durations who were able to maintain seroresponses. During the study period, 49 of the 1,256 patients (3.9%) seroreverted after a median follow-up of 611 days. In a case-control study, seroreversion was more likely to occur in patients with a higher weight (adjusted odds ratio [aOR], 1.703; 95% confidence interval [CI], 1.292-2.323, per 10-kg increment) and HIV viremia at the time of vaccination (aOR, 2.922; 95% CI, 1.067-7.924), whereas positive seroresponse at 6 months of HAV vaccination and higher CD4 lymphocyte counts at vaccination were inversely associated with early seroreversion with an aOR of 0.059 (95% CI, 0.020-0.154) and 0.837 (95% CI, 0.704-0.979, per 100-cell/mm3 increment), respectively, in multivariable analyses. Conclusion: During an outbreak setting, early seroreversion following two-dose HAV vaccination occurred in 3.9% of HIV-positive patients. Lower and delayed seroresponses to HAV vaccination, a higher weight, and HIV viremia and lower CD4 lymphocyte counts at the time of HAV vaccination were associated with early seroreversion. Regular monitoring of seroresponse and booster vaccination might be warranted, especially in HIV-positive adults with predictors of early seroreversion.

ELF18-INDUCED LONG-NONCODING RNA Associates with Mediator to Enhance Expression of Innate Immune Response Genes in Arabidopsis.

The plant immune response is a complex process involving transcriptional and posttranscriptional regulation of gene expression. Responses to plant immunity are initiated upon the perception of pathogen-associated molecular patterns, including peptide fragment of bacterial flagellin (flg22) or translation elongation factor Tu (elf18). Here, we identify an Arabidopsis thaliana long-noncoding RNA, designated ELF18-INDUCED LONG-NONCODING RNA1 (ELENA1), as a factor enhancing resistance against Pseudomonas syringe pv tomato DC3000. ELENA1 knockdown plants show decreased expression of PATHOGENESIS-RELATED GENE1 (PR1) and the plants are susceptible to pathogens. By contrast, plants overexpressing ELENA1 show elevated PR1 expression after elf18 treatment and display a pathogen resistance phenotype. RNA-sequencing analysis of ELENA1-overexpressing plants after elf18 treatment confirms increased expression of defense-related genes compared with the wild type. ELENA1 directly interacts with Mediator subunit 19a (MED19a) and affects enrichment of MED19a on the PR1 promoter. These results show that MED19a regulates PR1 expression through ELENA1. Our findings uncover an additional layer of complexity, implicating long-noncoding RNAs in the transcriptional regulation of plant innate immunity.

Prostasin Impairs Epithelial Growth Factor Receptor Activation to Suppress Dengue Virus Propagation.

BACKGROUND: Dengue virus (DENV), a common and widely spread arbovirus, causes life-threatening diseases, such as dengue hemorrhagic fever or dengue shock syndrome. There is currently no effective therapeutic or preventive treatment for DENV infection. METHODS: Next-generation sequencing analysis revealed that prostasin expression was decreased upon DENV infection. Prostasin expression levels were confirmed by real-time quantitative polymerase chain reaction in patients with dengue fever and a DENV-infected mice model. Short hairpin RNA against EGFR and LY294002 were used to investigate the molecular mechanism. RESULTS: Based on clinical studies, we first found relatively low expression of prostasin, a glycosylphosphatidyl inositol-anchored membrane protease, in blood samples from patients with dengue fever compared with healthy individuals and a high correlation of prostasin expression and DENV-2 RNA copy number. DENV infection significantly decreased prostasin RNA levels of in vivo and in vitro models. By contrast, exogenous expression of prostasin could protect ICR suckling mice from life-threatening DENV-2 infection. Mechanistic studies showed that inhibition of DENV propagation by prostasin was due to reducing expression of epithelial growth factor receptor, leading to suppression of the Akt/NF-κB-mediated cyclooxygenase-2 signaling pathway. CONCLUSION: Our results demonstrate that prostasin expression is a noteworthy clinical feature and a potential therapeutic target against DENV infection.

Regulation of flowering time by SPL10/MED25 module in Arabidopsis.

Several SQUAMASA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors are involved in plant developmental transition from vegetative to reproductive growth. However, the function of SPL10 in regulating floral transition is largely unknown. It is also not known which Mediator subunit mediates SPL10 transcriptional activity. Here, we used overexpression lines and knockout mutants to examine the role of SPL10 in flowering-time regulation and we investigated possible interactions of SPL10 with several mediator subunits in vitro and in vivo. Plants overexpressing SPL10 showed precocious flowering, whereas the triple loss-of-function mutants of SPL10 and its two homologous genes, SPL2 and SPL11, flowered late compared with wild-type plants. We found that SPL10 interacts with MED25, a subunit of the Mediator complex, which bridges transcription factors and RNA polymerase II to facilitate transcription initiation. Genetic analysis showed that MED25 acts downstream of SPL10 to execute SPL10-regulated floral transition. Furthermore, SPL10 was required for MED25 association with the promoters of two target genes, FUL and LFY. We provide evidence that SPL10 recruits MED25 to the promoters of target genes to regulate flowering time. Our results on the SPL10/MED25 module are relevant to the molecular mechanism of other SPL family members.

Potyviral Gene-Silencing Suppressor HCPro Interacts with Salicylic Acid (SA)-Binding Protein 3 to Weaken SA-Mediated Defense Responses.

The viral infection process is a battle between host defense response and pathogen antagonizing action. Several studies have established a tight link between the viral RNA silencing suppressor (RSS) and the repression of salicylic acid (SA)-mediated defense responses, nonetheless host factors directly linking an RSS and the SA pathway remains unidentified. From yeast two-hybrid analysis, we identified an interaction between the potyviral RSS helper-component proteinase (HCPro) and SA-binding protein SABP3. Co-localization and bimolecular fluorescence complementation analyses validated the direct in vivo interaction between Turnip mosaic virus (TuMV) HCPro and the Arabidopsis homologue of SABP3, AtCA1. Additionally, transient expression of TuMV HCPro demonstrated its ability to act as a negative regulator of AtCA1. When the plants of the AtCA1 knockout mutant line were inoculated with TuMV, our results indicated that AtCA1 is essential to restrict viral spreading and accumulation, induce SA accumulation, and trigger the SA pathway. Unexpectedly, the AtCA1 overexpression line also displayed a similar phenotype, suggesting that the constitutive expression of AtCA1 antagonizes the SA pathway. Taken together, our results depict AtCA1 as an essential regulator of SA defense responses. Moreover, the interaction of potyviral HCPro with this regulator compromises the SA pathway to weaken host defense responses and facilitate viral infection.

IL-28 and IL-29 as protective markers in subject with dengue fever.

About 400 million people every year are estimated to contract dengue virus infection, which causes prolonged morbidity and sometimes mortality. Interleukin (IL)-28 and IL-29 are relatively newly discovered cytokines and play an important role in our immune defense against pathogens, especially for viral infection. In the present study, we investigated serum IL-28 and IL-29 expression and the relationship to clinical and laboratory parameters in patients with dengue virus infection. Adult patients with dengue (n = 45) and control group (n = 24) were included prospectively. Clinical symptoms and laboratory data were collected from every patient. We investigated IL-28 and IL-29 levels in serum by ELISA. The concentrations of serum IL-28 and IL-29 were significantly higher in subjects with dengue when compared to those of control group. The patients with higher serum IL-28 and IL-29 levels had significantly lower ALAT and peripheral blood neutrophil percentage, but higher peripheral platelet, total white blood cell (WBC), monocyte, and lymphocyte counts. Patients with higher serum IL-28 and IL-29 levels also had more flu-like symptoms, but less vomiting. Increased level of IL-28 and IL-29 was associated with better liver function, platelet and WBC numbers and clinical symptom in subjects with dengue and could potentially serve as a protective marker.

Serum Galectin-9 and Galectin-3-Binding Protein in Acute Dengue Virus Infection.

Dengue fever is a serious threat for public health and induces various inflammatory cytokines and mediators, including galectins and glycoproteins. Diverse immune responses and immunological pathways are induced in different phases of dengue fever progression. However, the status of serum galectins and glycoproteins is not fully determined. The aim of this study was to investigate the serum concentration and potential interaction of soluble galectin-1, galectin-3, galectin-9, galectin-3 binding protein (galectin-3BP), glycoprotein 130 (gp130), and E-, L-, and P-selectin in patients with dengue fever in acute febrile phase. In this study, 317 febrile patients (187 dengue patients, 150 non-dengue patients that included 48 patients with bacterial infection and 102 patients with other febrile illness) who presented to the emergency department and 20 healthy controls were enrolled. Our results showed the levels of galectin-9 and galectin-3BP were significantly higher in dengue patients than those in healthy controls. Lower serum levels of galectin-1, galectin-3, and E-, L-, and P-selectin in dengue patients were detected compared to bacteria-infected patients, but not to healthy controls. In addition, strong correlation between galectin-9 and galectin-3BP was observed in dengue patients. In summary, our study suggested galectin-9 and galectin-3BP might be critical inflammatory mediators in acute dengue virus infection.

Establishment and Comparison of Two Different Diagnostic Platforms for Detection of DENV1 NS1 Protein.

Dengue virus (DENV) infection is currently at pandemic levels, with populations in tropical and subtropical regions at greatest risk of infection. Early diagnosis and management remain the cornerstone for good clinical outcomes, thus efficient and accurate diagnostic technology in the early stage of the disease is urgently needed. Serotype-specific monoclonal antibodies (mAbs) against the DENV1 nonstructural protein 1 (NS1), DA12-4, DA13-2, and DA15-3, which were recently generated using the hybridoma technique, are suitable for use in diagnostic platforms. Immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA) and Western blot analysis further confirmed the serotype specificity of these three monoclonal antibodies. The ELISA-based diagnostic platform was established using the combination of two highly sensitive mAbs (DA15-3 and DB20-6). The same combination was also used for the flow cytometry-based diagnostic platform. We report here the detection limits of flow cytometry-based and ELISA-based diagnostic platforms using these mAbs to be 0.1 and 1 ng/mL, respectively. The collected clinical patient serum samples were also assayed by these two serotyping diagnostic platforms. The sensitivity and specificity for detecting NS1 protein of DENV1 are 90% and 96%, respectively. The accuracy of our platform for testing clinical samples is more advanced than that of the two commercial NS1 diagnostic platforms. In conclusion, our platforms are suitable for the early detection of NS1 protein in DENV1 infected patients.

Mapping the CP-Transgene Insert in the Papaya Genome and Developing a Hermaphrodite Transgenic Hybrid with Broad-Spectrum Resistance to Papaya Ringspot Virus.

Papaya ringspot virus (PRSV) limits papaya production worldwide. Previously, we generated transgenic lines of hybrid Tainung No.2 (TN-2) carrying the coat protein (CP) gene of PRSV with broad resistance to PRSV strains. Unfortunately, all of them were female, unacceptable for growers and consumers in practical applications. With our reported flanking sequences and the newly released papaya genomic information, the CP-transgene insert was identified at a non-coding region in chromosome 3 of the papaya genome, and the flanking sequences were verified and extended. The female transgenic line 16-0-1 was first used for backcrossing with the parental Sunrise cultivar six times and then followed by selfing three times. With multi-level molecular markers developed from the PRSV CP transgene and the genomic flanking sequences, the presence and zygosity of the CP transgene were characterized at the seedling stage. Meanwhile, hermaphrodite genotype was identified by a sex-linked marker. With homozygotic transgene and horticultural properties of Sunrise, a selected hermaphrodite individual was propagated by tissue culture (TC) and used as maternal progenitor to cross with non-transgenic parental cultivar Thailand to generate a new hybrid cultivar TN-2 with a hemizygotic CP-transgene. Three selected hermaphrodite individuals of transgenic TN were micropropagated by TC, and they showed broad-spectrum resistance to different PRSV strains from Taiwan, Hawaii, Thailand, and Mexico under greenhouse conditions. The selected clone TN-2 #1, with excellent horticultural traits, also showed complete resistance to PRSV under field conditions. These selected TC clones of hermaphrodite transgenic TN-2 provide a novel cultivation system in Taiwan and elsewhere.

The association of obesity and dengue severity in hospitalized adult patients.

BACKGROUND: Obesity is associated with unfavorable outcomes for infectious diseases. Most researches exploring the association between nutritional status and dengue severity have focused on pediatric populations, with only few studies assessing adult patients. METHODS: Adult patients with laboratory-confirmed dengue admitted to a tertiary hospital in southern Taiwan between 2014 and 2015 were enrolled retrospectively. Demographics, comorbidities, clinical presentation, laboratory findings, and outcomes were obtained from case-record forms. Patients were categorized into obese group and nonobese group. The obese group comprised patients with a body mass index of ≥27.5 kg/m2. RESULTS: A total of 1417 hospitalized patients with dengue were evaluated. The mean age was 57.9 years (range: 18-92 years). The obese and nonobese groups comprised 333 (23.5%) and 1084 (76.5%) patients, respectively. The obese group included more patients with hypertension (85%, p < 0.001), diabetes mellitus (33%, p < 0.001), and congestive heart failure (6.3%, p = 0.049). Multivariate analysis revealed that the obese group had more petechiae (AOR: 1.353, 95% CI: 1.025-1.786, p = 0.033), more dyspnea (AOR: 1.380, 95% CI: 1.015-1.876, p = 0.040), and more severe hepatitis (AOR: 2.061, 95% CI: 1.050-4.048, p = 0.036). The obese group also had higher peak hematocrit values (44.1%, p < 0.001) and lower nadir platelet count (45.3 × 103/µL, p = 0.049) than the nonobese group. CONCLUSION: In adult patients with dengue, obese group had more petechiae, dyspnea, severe hepatitis, lower nadir of platelet count, and higher peak hematocrit level. We observed no difference in severe dengue or mortality between obese and nonobese group.

Grape Seed Proanthocyanidins Inhibit Replication of the Dengue Virus by Targeting NF-kB and MAPK-Mediated Cyclooxygenase-2 Expression.

Dengue virus (DENV) infection is a serious global health issue as it causes severe dengue hemorrhagic fever and dengue shock syndrome. Since no approved therapies are available to treat DENV infection, it is necessary to develop new agents or supplements that can do this. In this study, grape seed proanthocyanidins extract (GSPE), which is widely consumed as a dietary supplement, dose-dependently suppressed the replication of four DENV serotypes. The inhibitory mechanism demonstrated that GSPE downregulated DENV-induced aberrant cyclooxygenase-2 (COX-2) expression, revealing that the inhibitory effect of the GSPE on DENV replication involved targeting DENV-induced COX-2 expression. Mechanistic studies on signaling regulation have demonstrated that GSPE significantly reduced COX-2 expression by inactivating NF-κB and ERK/P38 MAPK signaling activities. Administrating GSPE to DENV-infected suckling mice reduced virus replication, mortality, and monocyte infiltration of the brain. In addition, GSPE substantially reduced the expression of DENV-induced inflammatory cytokines associated with severe dengue disease, including tumor necrosis factor-α, nitric oxide synthase, interleukin (IL)-1, IL-6, and IL-8, suggesting that GSPE has potential as a dietary supplement to attenuate DENV infection and severe dengue.

Effect of immunological non-response on incidence of Non-AIDS events in people living with HIV: A retrospective multicenter cohort study in Taiwan.

BACKGROUND: People living with HIV (PLWH) are susceptible to non-AIDS-related events, particularly those with immunological nonresponses (INRs) to highly active antiretroviral therapy (HAART). This study assessed the association of INRs with incident non-AIDS-related events among PLWH. METHODS: This multicenter retrospective cohort study enrolled PLWH who had newly diagnosed stage 3 HIV and received HAART between January 1, 2008, and December 31, 2019. The patients were divided into two groups according to their immunological responses on the 360th day after HAART initiation: INR and non-INR groups. Cox regression and sensitivity analyses were conducted to estimate the effects of INRs on overall and individual categories of non-AIDS-related events (malignancies, vascular diseases, metabolic disorders, renal diseases, and psychiatric disorders). Patient observation started on the 360th day after HAART initiation and continued until February 28, 2022, death, or an outcome of interest, whichever occurred first. RESULTS: Among the 289 included patients, 44 had INRs. Most of the included patients were aged 26-45 years (69.55%) and were men who have sex with men (89.97%). Many patients received HIV diagnoses between 2009 and 2012 (38.54%). INRs (vs. non-INRs) were associated with composite non-AIDS-related events (adjusted hazard ratio [aHR] = 1.80; 95% confidence interval [CI]: 1.19-2.73) and metabolic disorders (aHR = 1.75; 95% CI: 1.14-2.68). Sensitivity analyses revealed consistent results for each Cox regression model for both composite non-AIDS-related events and metabolic diseases. CONCLUSION: Clinicians should be vigilant and implement early intervention and rigorous monitoring for non-AIDS-related events in PLWH with INRs to HAART.

In-hospital mortality predictors among hospitalized adults and those with chronic kidney disease with dengue.

BACKGROUND: Accurately identifying risk factors that predict fatality in dengue is crucial for patient triage and clinical management. Our objective was to identify predictors of death associated with dengue and investigate the clinical characteristics and risk factors among patients with chronic kidney disease (CKD) who died from dengue. METHODS: A multicenter longitudinal observation study conducted from 2008 to 2019. RESULTS: A total of 1272 patients (113 who died and 1186 who recovered) diagnosed with dengue were included. Old age, CKD, and an elevated white blood cell count at hospital presentation were identified as independent predictors of in-hospital mortality among individuals infected with the dengue virus. In a subgroup analysis of 138 patients with CKD infected with dengue virus, 64 (46.3%) patients died, with 46 (33.3%) patients dying within 7 days after symptom onset. Among 64 fatal dengue patients with CKD, 34.4% were in stages 2 and 3 of kidney disease, 51.5% were in stages 4 and 5, and 14.1% had end stage renal disease as per the classification by Kidney Disease Improving Global Outcomes. Multivariate analysis revealed that initial altered consciousness, pulmonary edema, and leukocytosis during hospitalization were independently associated with in-hospital mortality in CKD patients infected with the dengue virus. Leukocytosis during hospitalization and severe hepatitis were independent risk factors for death within 7 days after dengue illness onset in CKD patients. CONCLUSIONS: This study offers valuable insights into predictors linked to fatality in dengue and reinforces the importance of optimizing patient triage to improve the quality of care.