Effect of Severe Fever With Thrombocytopenia Syndrome Virus Genotype on Disease Severity, Viral Load, and Cytokines in South Korea.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by Bandavirus dabieense (SFTS virus [SFTSV]). Recently, at least 6 different genotypes of SFTSV have been identified, with genotypes A, D, and F dominant in China and B dominant in Japan and Korea. This study investigated the effect of SFTSV genotypes circulating in South Korea on disease severity, viral load, and cytokine profile. Methods: We prospectively enrolled 70 patients with SFTS from July 2015 to June 2022. Serial plasma samples were obtained during hospitalization and analyzed. Viral load was measured by real-time reverse-transcription polymerase chain reaction. Partial sequences of the viral genome were analyzed for genotyping. Plasma concentrations of 17 cytokines were measured by multiplex-bead immunoassay. Results: Of 70 samples, 51 could be genotyped. Genotype B was predominant (80.4%) and other genotypes were uncommon. Intensive care unit admission rates (51.2% vs 50.0%) and mortality rates (26.8% vs 40.0%) did not show any significant differences between genotype B and non-B genotypes. The initial viral load did not show any significant differences (3.59 vs 3.64 log copies/µL), whereas viral load measured at hospital day 3-4 tended to be higher in genotype B than non-B genotypes (3.83 vs 1.83 log copies/µL, P = .07). Additionally, the plasma concentrations of interferon-α, interleukin 10, and interferon-γ-induced protein 10, which are closely related to mortality in cases of SFTS, did not show any significant differences. Conclusions: SFTSV genotype B was the prevalent genotype in South Korea, with no genotype-specific difference in clinical outcomes, initial viral load, or cytokine profiles.

Viral, Immunologic, and Laboratory Parameters in Patients With and Without Post-Acute Sequelae of SARS-CoV-2 Infection (PASC).

BACKGROUND: The pathophysiological mechanisms underlying the post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) are not well understood. Our study aimed to investigate various aspects of theses mechanisms, including viral persistence, immunological responses, and laboratory parameters in patients with and without PASC. METHODS: We prospectively enrolled adults aged ≥ 18 years diagnosed with coronavirus disease 2019 (COVID-19) between August 2022 and July 2023. Blood samples were collected at three time-points: within one month of diagnosis (acute phase) and at 1 month, and 3 months post-diagnosis. Following a recent well-designed definition of PASC, PASC patients were defined as those with a questionnaire-based PASC score ≥ 12 persisting for at least 4 weeks after the initial COVID-19 diagnosis. RESULTS: Of 57 eligible COVID-19 patients, 29 (51%) had PASC, and 28 (49%) did not. The PASC group had significantly higher nucleocapsid protein (NP) antigenemia 3 months after COVID-19 diagnosis (P = 0.022). Furthermore, several cytokines, including IL-2, IL-17A, VEGF, RANTES, sCD40L, IP-10, I-TAC, and granzyme A, were markedly elevated in the PASC group 1 and/or 3 month(s) after COVID-19 diagnosis. In contrast, the median values of several serological markers, including thyroid markers, autoimmune indicators, and stress-related hormones, were within the normal range. CONCLUSION: Levels of NP antigen and of various cytokines involved in immune responses become significantly elevated over time after COVID-19 diagnosis in PASC patients compared to non-PASC patients. This suggests that PASC is associated with prolonged immune dysregulation resulting from heightened antigenic stimulation.

The DNA-PAINT palette: a comprehensive performance analysis of fluorescent dyes.

DNA points accumulation for imaging in nanoscale topography (DNA-PAINT) is a super-resolution fluorescence microscopy technique that achieves single-molecule 'blinking' by transient DNA hybridization. Despite blinking kinetics being largely independent of fluorescent dye choice, the dye employed substantially affects measurement quality. Thus far, there has been no systematic overview of dye performance for DNA-PAINT. Here we defined four key parameters characterizing performance: brightness, signal-to-background ratio, DNA-PAINT docking site damage and off-target signal. We then analyzed 18 fluorescent dyes in three spectral regions and examined them both in DNA origami nanostructures, establishing a reference standard, and in a cellular environment, targeting the nuclear pore complex protein Nup96. Finally, having identified several well-performing dyes for each excitation wavelength, we conducted simultaneous three-color DNA-PAINT combined with Exchange-PAINT to image six protein targets in neurons at ~16 nm resolution in less than 2 h. We thus provide guidelines for DNA-PAINT dye selection and evaluation and an overview of performances of commonly used dyes.

The cost-effectiveness of integrating simplified HCV testing into HIV pre-exposure prophylaxis (PrEP) and treatment services among men who have sex with men in Taiwan.

Background: Simplified hepatitis C virus (HCV) testing integrated into existing HIV services has the potential to improve HCV diagnoses and treatment. We evaluated the cost-effectiveness of integrating different simplified HCV testing strategies into existing HIV pre-exposure prophylaxis (PrEP) and treatment services among men who have sex with men (MSM) in Taiwan. Methods: Mathematical modeling was used to assess the cost-effectiveness of integrating simplified HCV tests (point-of-care antibody, reflex RNA, or immediate point-of-care RNA) with HCV treatment into existing HIV prevention and care for MSM from a healthcare perspective. The impact of increasing PrEP and HIV treatment coverage among MSM in combination with these HCV testing strategies was also considered. We reported lifetime costs (2022 US dollars) and quality-adjusted life years (QALYs) and calculated incremental cost-effectiveness ratios (ICERs) with a 3% annual discounting rate. Findings: Point-of-care HCV antibody and reflex RNA testing are cost-effective compared to current HCV testing in all PrEP and HIV treatment coverage scenarios (ICERs <$32,811/QALY gained). Immediate point-of-care RNA testing would be only cost-effective compared to the current HCV testing if coverage of HIV services remained unchanged. Point-of-care antibody testing in an unchanged HIV services coverage scenario and all simplified HCV testing strategies in scenarios that increased both HIV PrEP and treatment coverage form an efficient frontier, indicating best value for money strategies. Interpretation: Our findings support the integration of simplified HCV testing and people-centered services for MSM and highlight the economic benefits of integrating simplified HCV testing into existing services for MSM alongside HIV PrEP and treatment. Funding: This study was made possible as part of a research-funded PhD being undertaken by HJW under the UNSW Sydney Scientia scholarship and was associated with the Rapid Point of Care Research Consortium for infectious disease in the Asia Pacific (RAPID), which is funded by an NHMRC Centre for Research Excellence. JG is supported by a National Health and Medical Research Council Investigator Grant (1176131).

Alleviation of preeclampsia-like symptoms through PlGF and eNOS regulation by hypoxia- and NF-κB-responsive miR-214-3p deletion.

Preeclampsia is caused by placental hypoxia and systemic inflammation and is associated with reduced placental growth factor (PlGF) and endothelial nitric oxide synthase (eNOS) levels. The molecular signaling axes involved in this process may play a role in the pathogenesis of preeclampsia. Here, we found that hypoxic exposure increased hypoxia-inducible factor-1α (HIF-1α)/Twist1-mediated miR-214-3p biogenesis in trophoblasts, suppressing PlGF production and trophoblast invasion. TNF-α stimulation increased NF-κB-dependent miR-214-3p expression in endothelial cells, impairing eNOS expression and causing endothelial dysfunction. Synthetic miR-214-3p administration to pregnant mice decreased PlGF and eNOS expression, resulting in preeclampsia-like symptoms, including hypertension, proteinuria, and fetal growth restriction. Conversely, miR-214-3p deletion maintained the PlGF and eNOS levels in hypoxic pregnant mice, alleviating preeclampsia-like symptoms and signs. These findings provide new insights into the role of HIF-1/Twist1- and NF-κB-responsive miR-214-3p-dependent PlGF and eNOS downregulation in the pathogenesis of preeclampsia and establish miR-214-3p as a therapeutic or preventive target for preeclampsia and its complications.

Impact of simplified HCV diagnostic strategies on the HCV epidemic among men who have sex with men in the era of HIV oral pre-exposure prophylaxis in Taiwan: a modelling study.

INTRODUCTION: Simplified hepatitis C virus (HCV) diagnostic strategies have the potential to improve HCV diagnoses and treatment. We aimed to investigate the impact of simplified HCV diagnostic strategies on HCV incidence and its effect on HCV diagnosis and treatment among men who have sex with men (MSM) regardless of HIV status and use of HIV pre-exposure prophylaxis (PrEP) in Taiwan. METHODS: A compartmental deterministic model was developed to describe the natural history of HCV disease progression, the HCV care cascade and the HIV status and PrEP using among MSM. The model was calibrated to available data for HCV and HIV epidemiology and population demographics in Taiwan. We simulated the epidemic from 2004 and projected the impact of simplified testing strategies on the HCV epidemic among MSM over 2022-2030. RESULTS: Under the current testing approach in Taiwan, total HCV incidence would increase to 12.6 per 1000 person-years among MSM by 2030. Single-visit point-of-care RNA testing had the largest impact on reducing the number of new HCV infections over 2022-2030, with a 31.1% reduction (interquartile range: 24.9%-32.8%). By 2030, single-visit point-of-care HCV testing improved HCV diagnosis to 90.9%, HCV treatment to 87.7% and HCV cure to 81.5% among MSM living with HCV. Compared to status quo, prioritized simplified HCV testing for PrEP users and MSM living with diagnosed HIV had considerable impact on the broader HCV epidemic among MSM. A sensitivity analysis suggests that reinfection risk would have a large impact on the effectiveness of each point-of-care testing scenario. CONCLUSIONS: Simplified HCV diagnostic strategies could control the ongoing HCV epidemic and improve HCV testing and treatment among Taiwanese MSM. Single-visit point-of-care RNA testing would result in large reductions in HCV incidence and prevalence among MSM. Efficient risk-reduction strategies will need to be implemented alongside point-of-care testing to achieve HCV elimination among MSM in Taiwan.

Controlling COVID-19 outbreaks in the correctional setting: A mathematical modelling study.

Correctional centres (termed here 'prisons') are at high risk of COVID-19 and have featured major outbreaks worldwide. Inevitable close contacts, frequent inmate movements, and a disproportionate burden of co-morbidities mean these environments need to be prioritised in any public health response to respiratory pathogens such as COVID-19. We developed an individual-based SARS-CoV-2 transmission model for the prison system in New South Wales, Australia - incorporating all 33 correctional centres, 13,458 inmates, 578 healthcare and 6,909 custodial staff. Potential COVID-19 disease outbreaks were assessed under various mitigation strategies, including quarantine on entry, isolation of cases, rapid antigen testing of staff, as well as immunisation.Without control measures, the model projected a peak of 472 new infections daily by day 35 across the prison system, with all inmates infected by day 120. The most effective individual mitigation strategies were high immunisation coverage and prompt lockdown of centres with infected inmates which reduced outbreak size by 62-73%. Other than immunisation, the combination of quarantine of inmates at entry, isolation of proven or suspected cases, and widespread use of personal protective equipment by staff and inmates was the most effective strategy. High immunisation coverage mitigates the spread of COVID-19 within and between correctional settings but is insufficient alone. Maintaining quarantine and isolation, along with high immunisation levels, will allow correctional systems to function with a low risk of outbreaks. These results have informed public health policy for respiratory pathogens in Australian correctional systems.

Preparing correctional settings for the next pandemic: a modeling study of COVID-19 outbreaks in two high-income countries.

Introduction: Correctional facilities are high-priority settings for coordinated public health responses to the COVID-19 pandemic. These facilities are at high risk of disease transmission due to close contacts between people in prison and with the wider community. People in prison are also vulnerable to severe disease given their high burden of co-morbidities. Methods: We developed a mathematical model to evaluate the effect of various public health interventions, including vaccination, on the mitigation of COVID-19 outbreaks, applying it to prisons in Australia and Canada. Results: We found that, in the absence of any intervention, an outbreak would occur and infect almost 100% of people in prison within 20 days of the index case. However, the rapid rollout of vaccines with other non-pharmaceutical interventions would almost eliminate the risk of an outbreak. Discussion: Our study highlights that high vaccination coverage is required for variants with high transmission probability to completely mitigate the outbreak risk in prisons.

Scale-up of Direct-Acting Antiviral Treatment in Prisons Is Both Cost-effective and Key to Hepatitis C Virus Elimination.

Background: The Surveillance and Treatment of Prisoners With Hepatitis C (SToP-C) study demonstrated that scaling up of direct-acting antiviral (DAA) treatment reduced hepatitis C virus (HCV) transmission. We evaluated the cost-effectiveness of scaling up HCV treatment in statewide prison services incorporating long-term outcomes across custodial and community settings. Methods: A dynamic model of incarceration and HCV transmission among people who inject drugs (PWID) in New South Wales, Australia, was extended to include former PWID and those with long-term HCV progression. Using Australian costing data, we estimated the cost-effectiveness of scaling up HCV treatment in prisons by 44% (as achieved by the SToP-C study) for 10 years (2021-2030) before reducing to baseline levels, compared to a status quo scenario. The mean incremental cost-effectiveness ratio (ICER) was estimated by comparing the differences in costs and quality-adjusted life-years (QALYs) between the scale-up and status quo scenarios over 40 years (2021-2060) discounted at 5% per annum. Univariate and probabilistic sensitivity analyses were performed. Results: Scaling up HCV treatment in the statewide prison service is projected to be cost-effective with a mean ICER of A$12 968/QALY gained. The base-case scenario gains 275 QALYs over 40 years at a net incremental cost of A$3.6 million. Excluding DAA pharmaceutical costs, the mean ICER is reduced to A$6 054/QALY. At the willingness-to-pay threshold of A$50 000/QALY, 100% of simulations are cost-effective at various discount rates, time horizons, and changes of treatment levels in prison and community. Conclusions: Scaling up HCV testing and treatment in prisons is highly cost-effective and should be considered a priority in the national elimination strategy. Clinical Trials Registration: NCT02064049.

Cytokine and Chemokine Profiles in Acute Severe Fever with Thrombocytopenia Syndrome and Scrub Typhus in South Korea.

In East Asia, severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus, which are common endemic tick- and mite-mediated diseases sharing common clinical manifestations, are becoming public health concerns. However, there are limited data on the comparative immunopathogenesis between the two diseases. We compared the cytokine profiles of SFTS and scrub typhus to further elucidate immune responses that occur during the disease courses. We prospectively enrolled 44 patients with confirmed SFTS and 49 patients with scrub typhus from July 2015 to December 2020. In addition, 10 healthy volunteers were enrolled as healthy controls. A cytometric bead array was used to analyze plasma samples for 16 cytokines. A total of 68 plasma samples, including 31 (45.6%) from patients with SFTS and 37 (54.4%) from patients with scrub typhus, were available for cytokine measurement. There were three cytokine expression patterns: increased levels in both SFTS and scrub typhus (interleukin 6 [IL-6], IL-10, interferon gamma induced protein 10 [IP-10], and granulocyte-macrophage colony-stimulating factor [GM-CSF]), highest levels in SFTS (interferon alpha [IFN-α], IFN-γ, granulocyte-CSF [G-CSF], monocyte chemotactic protein 1 [MCP-1], macrophage inflammatory protein 1α [MIP-1α], and IL-8), and distinct levels in scrub typhus (IL-12p40, tumor necrosis factor alpha [TNFα], IL-1ß, regulated on activation and normally T-cell expressed and secreted [RANTES], IL-17A, and vascular endothelial growth factor [VEGF]). Although patients with acute SFTS and scrub typhus exhibited partly shared expression patterns of cytokines related to disease severity, the different profiles of cytokines and chemokines might contribute to higher mortality in SFTS than in scrub typhus. Discrete patterns of helper T cell-related cytokines and VEGF might reflect differences in CD4 T-cell responses and vascular damage between these diseases.

Optimizing point-of-care testing strategies for diagnosis and treatment of hepatitis C virus infection in Australia: a model-based cost-effectiveness analysis.

Background: Timely diagnosis and treatment of hepatitis C virus (HCV) is critical to achieve elimination goals. This study evaluated the cost-effectiveness of point-of-care testing strategies for HCV compared to laboratory-based testing in standard-of-care. Methods: Cost-effectiveness analyses were undertaken from the perspective of Australian Governments as funders by modelling point-of-care testing strategies compared to standard-of-care in needle and syringe programs, drug treatment clinics, and prisons. Point-of-care testing strategies included immediate point-of-care HCV RNA testing and combined point-of-care HCV antibody and reflex RNA testing for HCV antibody positive people (with and without consideration of previous treatment). Sensitivity analyses were performed to investigate the cost per treatment initiation with different testing strategies at different HCV antibody prevalence levels. Findings: The average costs per HCV treatment initiation by point-of-care testing, from A$890 to A$1406, were up to 35% lower compared to standard-of-care ranging from A$1248 to A$1632 depending on settings. The average costs per treatment initiation by point-of-care testing for three settings ranged from A$1080 to A$1406 for RNA, A$960-A$1310 for combined antibody/RNA without treatment history consideration, and A$890-A$1189 for combined antibody/RNA with treatment history consideration. When HCV antibody prevalence was <74%, combined point-of-care HCV antibody and point-of-care RNA testing were the most cost-effective strategies. Modest increases in treatment uptake by 8%-31% were required for immediate point-of-care HCV RNA testing to achieve equivalent cost per treatment initiation compared to standard-of-care. Interpretation: Point-of-care testing is more cost-effective than standard of care for populations at risk of HCV. Testing strategies combining point-of-care HCV antibody and RNA testing are likely to be cost-effective in most settings. Funding: National Health and Medical Research Council.

Removing hepatitis C antibody testing for Australian blood donations: A cost-effectiveness analysis.

BACKGROUND AND OBJECTIVES: The risk of transfusion-transmitted hepatitis C virus (HCV) infections is extremely low in Australia. This study aims to conduct a cost-effectiveness analysis of different testing strategies for HCV infection in blood donations. MATERIALS AND METHODS: The four testing strategies evaluated in this study were universal testing with both HCV antibody (anti-HCV) and nucleic acid testing (NAT); anti-HCV and NAT for first-time donations and NAT only for repeat donations; anti-HCV and NAT for transfusible component donations and NAT only for plasma for further manufacture; and universal testing with NAT only. A decision-analytical model was developed to assess the cost-effectiveness of alternative HCV testing strategies. Sensitivity analysis and threshold analysis were conducted to account for data uncertainty. RESULTS: The number of potential transfusion-transmitted cases of acute hepatitis C and chronic hepatitis C was approximately zero in all four strategies. Universal testing with NAT only was the most cost-effective strategy due to the lowest testing cost. The threshold analysis showed that for the current practice to be cost-effective, the residual risks of other testing strategies would have to be at least 1 HCV infection in 2424 donations, which is over 60,000 times the baseline residual risk (1 in 151 million donations). CONCLUSION: The screening strategy for HCV in blood donations currently implemented in Australia is not cost-effective compared with targeted testing or universal testing with NAT only. Partial or total removal of anti-HCV testing would bring significant cost savings without compromising blood recipient safety.

Diagnostic Usefulness of Varicella Zoster Virus-Specific Immunoglobulin (Ig) A and IgG in Patients With Herpes Zoster.

BACKGROUND: Whether varicella zoster virus (VZV) antibody titer could discriminate patients with herpes zoster (HZ) from healthy controls (HCs) is unclear. We evaluated the diagnostic usefulness of VZV-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies in patients with confirmed HZ. METHODS: Study subjects comprised patients with confirmed HZ by salivary VZV DNA positivity and control age- and sex-matched HCs. Saliva was collected and concurrent blood samples were obtained on the first visit day (acute phase) and after 4 weeks (convalescent phase) from 44 HZ patients. All 44 healthy volunteers provided blood and saliva samples once. RESULTS: The median VZV IgA titers in acute-phase (5.2 mIU/mL, P < 0.001) and convalescent-phase (15.8 mIU/mL, P < 0.001) serum samples from HZ patients were significantly higher than those in HCs (1.35 mIU/mL). VZV IgA positivity was detected in about 20% of acute phase serum and convalescent-phase serum of HZ patients. The median VZV IgG antibody titers of HZ patients during acute (1,471.0 mIU/mL, P < 0.001) and convalescent (4,934.7 mIU/mL, P < 0.001) phases were significantly higher than the median titer reported for HCs (591.6 mIU/mL). A four-fold or higher increase in VZV IgG antibody titer was observed in 36.4% of HZ patients. CONCLUSION: VZV IgA positivity or four-fold or higher increase in VZV IgG antibody titers were not detected in a satisfactory proportion of HZ-infected patients. However, the titer of VZV IgA or IgG antibody particularly in convalescent-phase sera may discriminate HZ patients from HCs.

Comparison of the rapidity of SARS-CoV-2 immune responses between primary and booster vaccination for COVID-19.

BACKGROUND/AIMS: The rapidity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific memory B or T cell response in vaccinated individuals is important for our understanding of immunopathogenesis of coronavirus disease 2019 (COVID-19). We therefore compared the timing of adequate immune responses between the first and booster doses of COVID-19 vaccines in infection-naïve healthcare workers. METHODS: We enrolled healthcare workers who received two doses of either the BNT162b2 vaccine or the ChAdOx1 vaccine, all of whom received the BNT162b2 vaccine as the booster (the third) dose. Spike 1 (S1)-immunoglobulin G (IgG) antibodies and interferon gamma producing T cell responses were measured at 0, 7, 14, and 21 days after the first dose, and at 0 and between 2 to 7 days after the booster dose. RESULTS: After the first-dose vaccination, the S1-IgG antibody responses were elicited within 14 days in the BNT162b2 group and within 21 days in the ChAdOx1 group. After the booster dose, the S1-IgG antibody responses were elicited within 5 days in both groups. The SARS-CoV-2-specific T cell responses appeared at 7 days after the first dose and at 4 days after the booster dose. CONCLUSION: SARS-CoV-2-specific immune responses by memory B cells and T cells may be expected to appear around 4 to 5 days after the booster dose.

Comparison of antibody responses after the 1st and 2nd doses of COVID-19 vaccine with those of patients with mild or severe COVID-19.

BACKGROUND/AIMS: Data comparing the antibody responses of different coronavirus disease 2019 (COVID-19) vaccine platforms according to dose with natural severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection-induced antibody responses are limited. METHODS: Blood samples from adult patients with mild and severe COVID-19 and healthcare workers who received ChAdOx1 nCoV-19 vaccine (2nd dose at 12-week intervals) and BNT162b2 vaccine (2nd dose at 3-week intervals) were collected and compared by immunoglobulin G immune responses to SARS-CoV-2 specific spike protein using an in-house-developed enzyme-linked immunosorbent assay. RESULTS: A total of 53 patients, including 12 and 41 with mild and severe COVID-19, respectively, were analyzed. In addition, a total of 73 healthcare workers, including 37 who received ChAdOx1 nCoV-19 and 36 who received BNT162b2, were enrolled. Antibody responses after the first and second doses of the ChAdOx1 nCoV-19 vaccine or the first dose of the BNT162b2 vaccine were similar to those in convalescent patients with mild COVID-19, but lower than those in convalescent patients with severe COVID-19, respectively. However, after the second dose of the BNT162b2 vaccine, the antibody response was comparable to that in convalescent patients with severe COVID-19. CONCLUSION: Our data suggest that the second dose of mRNA vaccination may be more beneficial in terms of long-term immunity and prevention of SARS-CoV-2 variant infection than a single dose of COVID-19 vaccination or homologous second challenge ChAdOx1 nCoV-19.