Cost-benefit analysis of human adenovirus vaccine development in a Korean military setting.

BACKGROUND: Human adenovirus (HAdV) is a prevalent causative agent of acute respiratory disease (ARD) and is frequently responsible for outbreaks, particularly in military environments. Current vaccines do not effectively cover HAdV subtypes commonly found among Korean military personnel, highlighting the need for a new targeted vaccine. This study presents a cost-benefit analysis to evaluate the economic viability of developing and implementing such a vaccine within a military context. METHODS: We adopted a societal perspective for this cost-benefit analysis, which included estimating costs associated with vaccine development, production, and distribution over a projected timeline. We assumed a development period of five years, after which vaccine production and administration were initiated in the sixth year. The cost associated with vaccine development, production, and dispensation was considered. The benefits were calculated based on both direct and indirect cost savings from preventing HAdV infections through vaccination. All financial figures were expressed in 2023 US dollars. A sensitivity analysis was conducted to explore the impact of varying factors such as vaccination rate, incidence of infection, vaccine efficacy, and discount rate. RESULTS: For the base case scenario, we assumed a vaccination rate of 100 %, an incidence rate of 0.02, and a vaccine efficacy of 95 %, applying a 3 % discount rate. Initially, in the sixth year, the benefit-cost ratio stood at 0.71, suggesting a cost disadvantage at the onset of vaccination. However, this ratio improved to 1.32 in the following years, indicating a cost benefit from the seventh year onward. The cumulative benefit-cost ratio over a decade reached 2.72. The outcomes from the sensitivity analysis were consistent with these findings. CONCLUSION: Our cost-benefit analysis demonstrates that the introduction of an HAdV vaccine for the Korean military is economically advantageous, with substantial cost benefits accruing from the seventh year after the commencement of vaccination.

Prevalence and Burden of Human Adenovirus-Associated Acute Respiratory Illness in the Republic of Korea Military, 2013 to 2022.

BACKGROUND: Human adenovirus (HAdV) is a common cause of acute respiratory disease (ARD) and has raised significant concerns within the Korean military. Here, we conducted a comprehensive epidemiological analysis of HAdV-associated ARD by evaluating its prevalence, clinical outcomes, and prognosis. METHODS: We reviewed data from multiple sources, including the New Defense Medical Information System, Defense Medical Statistical Information System, Ministry of National Defense, Army Headquarters, Navy Headquarters, Air Force Headquarters, and Armed Forces Medical Command. We analyzed data of patients who underwent polymerase chain reaction (PCR) testing for respiratory viruses between January 2013 and July 2022 in all 14 Korean military hospitals. The analysis included the PCR test results, demographic characteristics, health care utilization, and prognosis including types of treatments received, incidence of pneumonia, and mortality. RESULTS: Among the 23,830 individuals who underwent PCR testing at Korean military hospitals, 44.78% (10,670 cases) tested positive for respiratory viruses. Across all military types and ranks, HAdV was the most prevalent virus, with a total of 8,580 patients diagnosed, among HAdV, influenza virus, human metapneumovirus, human parainfluenza virus, and human respiratory syncytial virus. HAdV-infected patients exhibited higher rates of healthcare use compared to non-HAdV-infected patients, including a greater number of emergency visits (1.04 vs. 1.02) and outpatient visits (1.31 vs. 1.27), longer hospitalizations (8.14 days vs. 6.84 days), and extended stays in the intensive care unit (5.21 days vs. 3.38 days). Furthermore, HAdV-infected patients had a higher proportion of pneumonia cases (65.79% vs. 48.33%) and greater likelihood of receiving advanced treatments such as high flow nasal cannula or continuous renal replacement therapy. CONCLUSION: Our findings indicate that HAdV posed a significant public health concern within the Korean military prior to the coronavirus disease 2019 (COVID-19) pandemic. Given the potential for a resurgence of outbreaks in the post-COVID-19 era, proactive measures, such as education, environmental improvements, and the development of HAdV vaccines, are crucial for effectively preventing future outbreaks.

Ultraviolet light-emitting diode-assisted highly sensitive room temperature NO2 gas sensors based on low-temperature solution-processed ZnO/TiO2 nanorods decorated with plasmonic Au nanoparticles.

Nanostructured semiconducting metal oxides such as SnO2, ZnO, TiO2, and CuO have been widely used to fabricate high performance gas sensors. To improve the sensitivity and stability of gas sensors, we developed NO2 gas sensors composed of ZnO/TiO2 core-shell nanorods (NRs) decorated with Au nanoparticles (NPs) synthesized via a simple low-temperature aqueous solution process, operated under ultraviolet irradiation to realize room temperature operation. The fabricated gas sensor with a 10 nm-thick TiO2 shell layer shows 9 times higher gas sensitivity and faster response and recovery times than ZnO NR-based gas sensors. This high performance of the fabricated gas sensor can be ascribed to band bending between the ZnO and TiO2 core-shell layers and the localized surface plasmon resonance effect of Au NPs with a sufficient Debye length of the TiO2 shell layer.

TiO2 Nanorods and Pt Nanoparticles under a UV-LED for an NO2 Gas Sensor at Room Temperature.

Because the oxides of nitrogen (NOx) cause detrimental effects on not only the environment but humans, developing a high-performance NO2 gas sensor is a crucial issue for real-time monitoring. To this end, metal oxide semiconductors have been employed for sensor materials. Because in general, semiconductor-type gas sensors require a high working temperature, photoactivation has emerged as an alternative method for realizing the sensor working at room temperature. In this regard, titanium dioxide (TiO2) is a promising material for its photocatalytic ability with ultraviolet (UV) photonic energy. However, TiO2-based sensors inevitably encounter a problem of recombination of photogenerated electron-hole pairs, which occurs in a short time. To address this challenge, in this study, TiO2 nanorods (NRs) and Pt nanoparticles (NPs) under a UV-LED were used as an NO2 gas sensor to utilize the Schottky barrier formed at the TiO2-Pt junction, thereby capturing the photoactivated electrons by Pt NPs. The separation between the electron-hole pairs might be further enhanced by plasmonic effects. In addition, it is reported that annealing TiO2 NRs can achieve noteworthy improvements in sensing performance. Elucidation of the performance enhancement is suggested with the investigation of the X-ray diffraction patterns, which implies that the crystallinity was improved by the annealing process.

Ongoing outbreak of human adenovirus-associated acute respiratory illness in the Republic of Korea military, 2013 to 2018.

BACKGROUND/AIMS: Human adenovirus type 55 (HAdV-55), an emerging epidemic strain, has caused several large outbreaks in the Korean military since 2014, and HAdV-associated acute respiratory illness (HAdV-ARI) has been continuously reported thereafter. METHODS: To evaluate the epidemiologic characteristics of HAdV-ARI in the Korean military, we analyzed respiratory virus polymerase chain reaction (RV-PCR) results, pneumonia surveillance results, and severe HAdV cases from all 14 Korean military hospitals from January 2013 to May 2018 and compared these data with nationwide RV surveillance data for the civilian population. RESULTS: A total of 14,630 RV-PCRs was performed at military hospitals. HAdV (45.4%) was the most frequently detected RV, followed by human rhinovirus (12.3%) and influenza virus (6.3%). The percentage of the military positive for HAdV was significantly greater than the percentage of civilians positive for HAdV throughout the study period, with a large outbreak occurring during the winter to spring of 2014 to 2015. The outbreak continued until the end of the study, and non-seasonal detections increased over time. The reported number of pneumonia patients also increased during the outbreak. Case fatality rate was 0.075% overall but 15.6% in patients with respiratory failure. The proportion of severe patients did not change significantly during the study period. CONCLUSION: A large HAdV outbreak is currently ongoing in the Korean military, with a trend away from seasonality, and HAdV-55 is likely the predominant strain. Persistent efforts to control the outbreak, HAdV type-specific surveillance, and vaccine development are required.

Seroprevalence of neutralizing antibodies against human adenovirus type 55 in the South Korean military, 2018-2019.

We conducted a seroprevalence study of a large ongoing outbreak of human adenovirus type 55 (HAdV-55) among the military in South Korea. Serum samples were collected between 2018 and 2019 from military-exposed (military group) and non-exposed (non-military group) populations. The plaque reduction neutralization test (PRNT) was used to assess neutralization activity against HAdV-55. A total of 100 sera was collected from the non-military group, of which 18.8% showed HAdV-55 neutralizing antibody activity. Ninety-six sera were tested from the military group, which had significantly higher prevalence of neutralizing antibodies (56.0%, P <0.001). A significantly higher proportion of the military group had PRNT titers ≥1:1,000 than the non-military group (85.7% vs. 50.0%, P = 0.004). Among the military group, 48.9% of active-duty soldiers had PRNT titers ≥1:5,000, while none of the discharged civilians did (P = 0.007). In conclusion, Koreans were exposed to HAdV-55 in their communities, but the exposure risk was higher among people in military service.

Ultraviolet Photoactivated Room Temperature NO2 Gas Sensor of ZnO Hemitubes and Nanotubes Covered with TiO2 Nanoparticles.

Prolonged exposure to NO2 can cause lung tissue inflammation, bronchiolitis fibrosa obliterans, and silo filler's disease. In recent years, nanostructured semiconducting metal oxides have been widely used to fabricate gas sensors because of their unique structure and surface-to-volume ratio compared to layered materials. In particular, the different morphologies of ZnO-based nanostructures significantly affect the detection property of NO2 gas sensors. However, because of the large interaction energy of chemisorption (1-10 eV), metal oxide-based gas sensors are typically operated above 100 °C, overcoming the energy limits to attain high sensitivity and fast reaction. High operating temperature negatively affects the reliability and durability of semiconductor-based sensors; at high temperature, the diffusion and sintering effects at the metal oxide grain boundaries are major factors causing undesirable long-term drift problems and preventing stability improvements. Therefore, we demonstrate NO2 gas sensors consisting of ZnO hemitubes (HTs) and nanotubes (NTs) covered with TiO2 nanoparticles (NPs). To operate the gas sensor at room temperature (RT), we measured the gas-sensing properties with ultraviolet illumination onto the active region of the gas sensor for photoactivation instead of conventional thermal activation by heating. The performance of these gas sensors was enhanced by the change of barrier potential at the ZnO/TiO2 interfaces, and their depletion layer was expanded by the NPs formation. The gas sensor based on ZnO HTs showed 1.2 times higher detection property than those consisting of ZnO NTs at the 25 ppm NO2 gas.

Electromagnetic field-induced converse cell growth during a long-term observation.

PURPOSE: Professional and public concern about the potential adverse effects of man-made electromagnetic fields (EMF) on the human body has dramatically expanded in recent years. Despite numerous attempts to investigate this issue, the long-standing challenge of reproducibility surrounding alternating EMF effects on human health remains unresolved. Our chief aim was to investigate a plausible mechanism for this phenomenon. MATERIALS AND METHODS: Growth of cultured human cancer cells, DU145 and Jurkat, exposed to power frequency magnetic field (MF) (60 Hz, 1 mT) for 3 days, was determined using a 2-(4-Iodophenyl)- 3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) assay and a trypan blue exclusion assay. This experiment was repeated at incubators long-term monitoring period up to 5.3 years. A periodogram analysis was performed to investigate periodic patterns in the MF and sham effects on cell growth. RESULTS: Unlike conventional assumptions, the MF effect on growth in both cell types was promotive or suppressive in a period-dependent manner. The converse cell growth induced by the MF was consistent in incubators, with little variation. CONCLUSIONS: Spatiotemporal evidence suggests that the period-dependent converse cell growth by the MF may contribute to the poor reproducibility and explain the adverse effects observed in previous experimental and epidemiological investigations. Additionally, the novel approach of this study may be applied to design features required to experimentally determine the effects of EMF on living organisms in a convincing manner.

HBxAPα/Rsf-1-mediated HBx-hBubR1 interactions regulate the mitotic spindle checkpoint and chromosome instability.

Hepatitis B virus (HBV) X protein (HBx), encoded by the HBV genome, is involved in the development of HBV-mediated liver cancer, whose frequency is highly correlated with chromosomal instability (CIN). We reported previously that HBx induces mitotic checkpoint dysfunction by targeting the human serine/threonine kinase BubR1 (hBubR1). However, the underlying mechanism remained unresolved. Here, we show that HBx protein-associated protein α (HBxAPα)/Rsf-1 associates with hBubR1 and HBx in the chromatin fraction during mitosis. Depletion of HBxAPα/Rsf-1 abolished the interaction between HBx and hBubR1, indicating that HBxAPα/Rsf-1 mediates these interactions. Knockdown of HBxAPα/Rsf-1 with small interfering RNA did not affect the recruitment of hBubR1 to kinetochores; however, it did significantly impair HBx targeting to kinetochores. A deletion mutant analysis revealed that two Kunitz domains of HBx, the Cdc20-binding domain of hBubR1 and full-length of HBxAPα/Rsf-1 were essential for these interactions. Thus, binding of HBx to hBubR1, stabilized by HBxAPα/Rsf-1, significantly attenuated hBubR1 binding to Cdc20 and consequently increased the rate of mitotic aberrations. Collectively, our data show that the HBx impairs hBubR1 function and induces CIN through HBxAPα/Rsf-1, providing a novel mechanism for induction of genomic instability by a viral pathogen in hepatocarcinogenesis.

Non-chromatographic Method for the Hepatitis B Virus X Protein Using Elastin-Like Polypeptide Fusion Protein.

OBJECTIVES: Hepatitis B virus (HBV) is a member of the hepadnavirus family. The HBV genome contains four genes designated as S, C, P, and X. The HBV X (HBx) gene encodes for a 16.5-kDa regulatory protein that enhances HBV replication and exerts multifunctional activities. The aim of this study is to describe the rapid and easy purification of HBx using ELP (elastin-like polypeptide) fusion protein. METHODS: The ELP-HBx fusion protein was overexpressed in Escherichia coli. Environmental sensitivity was demonstrated via turbidity and dynamic light scattering as a function of temperature. HBx was purified as an ELP fusion protein. ELPs are biopolymers of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly that undergo an inverse temperature phase transition. ELP follows in temperature and salt consistency, precipitation, and solution repetition (inverse transition cycling) with polypeptide, where it purifies the protein in a simple manner. RESULTS: Fusion proteins underwent supramolecular aggregation at 40 ℃ in 1 M NaCl and slowly resolubilized at subphysiologic temperatures. ELP domain proteolysis liberated a peptide of comparable size and immunoreactivity to the commercial HBx. CONCLUSION: This study suggests that HBx can be purified rapidly and easily using inverse transition cycling, and that this method can be applied in determination of HBx 3D structures and HBx stability study.

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression.

Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBx(Delta 68-117)) neither increased intracellular ROS levels nor induced COX-2 expression. HBx(68-117), which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calcium-dependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.

Depletion of BubR1 promotes premature centrosomal localization of cyclin B1 and accelerates mitotic entry.

The role of BubR1 has been established mainly in mitosis as an essential mitotic checkpoint protein although it is expressed throughout the cell cycle. To explore a possible role of BubR1 in regulating the G(2) phase of cell cycle, we have employed siRNA-mediated hBubR1 knockdown in HeLa cells. Here, we demonstrate that reducing BubR1 levels during the G(2) phase causes accelerated mitotic entry. As expected, BubR1 depletion leads to degradation of cyclin B(1) in the G(2) phase. Intriguingly, cyclin B(1) is prematurely targeted to centrosomes appearing at early G(2) phase in BubR1-depleted cells despite its low levels. This is in contrast to control cells where cyclin B(1) appears at the centrosomes in early prophase based on cell cycle-specific localization of CENP-F. Furthermore, cyclin B/Cdk1 kinase activity in early G(2) is aberrantly high in BubR1-depleted cells. Together, our results indicate that hBubR1 depletion triggers premature centrosomal localization of cyclin B(1) probably leading to premature mitotic entry. This study is the first to suggest a role of hBubR1 in controlling centrosome targeting of cyclin B(1) and timing of mitotic entry.

Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats.

Dysregulated Notch signaling accounts for the majority of acute T lymphoblastic leukemia/lymphoma (T-ALL) cases in humans. Here, we characterize lymphomas from Notch1IC transgenic rats, which develop T-ALL shortly after weaning, and show that they display a number of previously undocumented features. Starting from monoclonal thymic tumors, the CD4(+)CD8alphaalpha(+) lymphoma cells infiltrate the bone marrow and then spread to secondary lymphoid and non-lymphoid organs. However, major hallmarks of T-ALL cells in other murine models and human patients, such as constitutive NF-kappaB activity and increased levels of anti-apoptotic proteins, are remarkably absent in Notch1IC lymphomas. In contrast, CD30, a classic marker of Hodgkin lymphomas, is overexpressed in these tumors. Intriguingly, enforced Notch1 signaling up-regulates expression of Notch3, which has also been implicated in the pathogenesis of T-ALL. By blocking endogenous Notch signaling, we could demonstrate that Notch1IC is sufficient to induce sustained preTCR expression in transgenic thymocytes but not for their progression to the double-positive stage. This suggests that other Notch activities may also contribute to the phenotype of the transgenic rats. In summary, we anticipate this new animal model will help to further elucidate the role of Notch1 in the pathogenesis of T-ALL.