ABSTRACT Passive dengue surveillance systematically underestimates true disease burden, and this under‐ascertainment is spatially structured rather than random. In the Brazilian Amazon, municipalities with the weakest notification infrastructure tend to coincide with those presenting the most favorable environmental conditions for vector proliferation. This work investigates whether municipalities with more active surveillance can serve as a structural proxy to infer cases in less active regions, allowing for the identification of localities where notification capacity fails to reflect true transmission. Building on this framework, this study aimed to estimate municipality‐level dengue under‐ascertainment in Pará by disentangling surveillance capacity from true transmission intensity through a Bayesian spatiotemporal model. A BYM2‐ST model was fitted to dengue notification data from municipalities of Pará, from January 2018 to December 2024, integrating socioeconomic indicators and time‐varying climatic covariates. A spatial ascertainment ratio was derived for each municipality from the model, benchmarking observed notifications against the structurally expected counterfactual. The results showed that only 20.1% of municipalities reported notification counts within the expected range, while 40.3% showed statistically supported evidence of under‐ascertainment.
ABSTRACT The host genetic factors that resulted in the heterogeneous clinical outcomes of COVID‐19 remained poorly understood, especially in admixed populations that are underrepresented in global genomic studies. In this study, we investigated the genetic landscape associated with COVID‐19 severity using whole‐exome sequencing data from 325 Brazilian individuals recruited between 2020 and 2023. To prioritize variants related to disease severity, we applied a machine learning framework combining Support Vector Machine – Recursive Feature Elimination and SHAP interpretation. This approach encompasses 25 variants that contributed to the model's discrimination between severe and non‐severe cases (AUC = 0.94) in our cohort. Subsequently, logistic regression analyses adjusted for age, sex, principal components of ancestry, and significant comorbidities confirmed several loci associated with severity after correction for multiple testing (FDR < 0.05). The prioritized genes were grouped into biological axes, including mitochondrial bioenergetics, neuroimmune signaling, complement activation, and epithelial structural integrity. Variants in genes such as MUC16, SLC4A2, LAPS1, ARRDC2 , and CCSER1 showed associations with disease severity. Furthermore, functional annotation using CADD and regulatory exploration using GTEx suggested that several loci may influence gene regulation in lung, immune, and neural tissues. Instead of implicating single causal variants, our findings highlight pathway‐level genetic architectures that may contribute to the variability of the host response to COVID‐19. These findings provide exploratory insights into potential host genetic pathways that may be involved in disease variability in admixed environments. However, replication in independent cohorts and functional validation are still needed.
ABSTRACT Data on hepatitis B virus reactivation (HBVr) during tyrosine kinase inhibitor (TKI) therapy remain limited. We prospectively enrolled patients with chronic or resolved HBV receiving TKIs for lung cancer or chronic myeloid leukemia at one Taiwanese center (January 2023–March 2025). HBV DNA and liver enzymes were monitored 12‐weekly and HBsAg 24‐weekly. HBVr was defined by AASLD criteria, with APASL and EASL definitions applied secondarily. Among 79 patients (20 HBsAg‐positive, 59 resolved HBV), none received antiviral prophylaxis. Median follow‐up was 42 weeks (IQR, 19–65). HBVr occurred in 7 (8.9%; 95% CI, 4.4%–17.2%): 5 HBsAg‐positive (25.0%; 95% CI, 11.2%–46.9%), and 2 with resolved HBV (3.4%; 95% CI, 0.9%–11.5%). APASL and EASL definitions yielded 30.0% and 35.0% in HBsAg‐positive patients, with no additional events in resolved HBV. No HBVr‐associated hepatitis flare meeting the study definition was observed, although transient flares between assessments could not be excluded and deterioration in one fatal case was attributed clinically to sepsis. Median HBVr detection time was 19 weeks (IQR, 14–30). Week‐48 Kaplan–Meier HBVr incidence was 37.5% (95% CI, 17.0%–69.5%) in HBsAg‐positive and 5.6% (95% CI, 1.4%–21.2%) in resolved HBV (log‐rank p < 0.001); Aalen–Johansen estimates were 28.3% (95% CI, 9.5%–50.9%) and 4.3% (95% CI, 0.8%–13.2%), respectively. In exploratory Firth‐corrected regression, HBsAg positivity was associated with HBVr (HR, 6.95; 95% CI, 1.60–40.19), while osimertinib exposure was not. HBVr was common among HBsAg‐positive patients and less common but not negligible among those with resolved HBV receiving TKIs.
ABSTRACT We aimed to evaluate the association between IL10 variants and plasma IL‐10 levels and clinical outcomes in patients with severe COVID‐19 treated with corticosteroids. We studied 944 patients with severe COVID‐19 who were treated with corticosteroids. The clinical outcomes evaluated were in‐hospital mortality and the requirement of invasive mechanical ventilation (IMV). The variants IL10 rs1800872, rs1554286, rs3024505, and rs3122605 were determined using TaqMan SNP assays, and IL‐10 levels were measured by ELISA at the start of corticosteroid treatment (T1) and after 8 days (T2). The rs1800872‐TT ( p = 0.035, OR = 1.55, 95% CI = 1.03–2.33) and the rs1554286‐AA genotypes were associated with IMV ( p adj = 0.036, OR = 2.42, 95% CI = 1.12–5.95). IL‐10 levels were higher at T1 than at T2. At T2, IL‐10 levels were higher in non‐survivors (15.9 vs. 7.0 pg/mL, p < 0.001) and in patients requiring IMV (9.9 vs. 5.5 pg/mL, p < 0.001). Among non‐survivors, IL‐10 plasma levels did not decrease at T2. The alluvial plot revealed that 51.9% of patients in the highest IL‐10 tertile at T1 remained in the highest tertile at T2, with a mortality rate of 50%. IL10 rs1800872 and rs1554286 contribute to the risk of requiring IMV. Elevated IL‐10 levels after corticosteroid treatment were linked to in‐hospital mortality and IMV.
Treating respiratory viral infections remains challenging, necessitating exploration of novel therapeutic approaches. Alternative strategies, such as drug repurposing or combinations, are essential for treating them. This study evaluated the in vitro activities of the antivirals ribavirin, favipiravir, and oseltamivir, and the mucolytic drugs N-acetylcysteine (NAC) and erdosteine, alone or in combination, against Human Parainfluenza Virus (HPIV) and Respiratory Syncytial Virus (RSV). HPIV-2 and RSV were cultured in VERO and HEp-2 cell lines, respectively. Antiviral efficacy was assessed by calculating IC50 values using MTT and plaque reduction assays. For combination studies, synergy scores were analyzed using the SynergyFinder program. We investigated potential interactions underlying the synergistic activities using an in silico approach, that combined virtual screening and molecular docking. The IC50 values of ribavirin, favipiravir, and oseltamivir against HPIV-2 and RSV ranged from 4.46 to 14.1 & micro;g/mL, and the results from both methods were highly similar. All three antivirals' cytotoxicity was well above their C-max, and SIs were 12.43-36.69 for HPIV-2 and 15.88-38.12 for RSV. The ribavirin-oseltamivir combination synergy scores of 13.35 for HPIV-2 and 17.98 for RSV indicate clear synergism, while other combinations were additive. Docking analysis identified potential molecular interactions that may contribute to the antiviral activity of the ribavirin-oseltamivir combination against RSV and HPIV-2. Ribavirin, favipiravir, and oseltamivir showed good activity against HPIV-2 and RSV, and the ribavirin-oseltamivir combination exhibited strong synergistic interactions, suggesting promising therapeutic potential.
