Study on the Protective Immunity Induced by Pseudotyped Baculovirus Expressing the E Protein of Tembusu Virus in Ducklings.

The Duck Tembusu virus (DTMUV), a pathogenic flavivirus, has been causing significant economic losses in the Chinese poultry industry since 2010. This virus can severely decrease egg production and inhibit the growth of laying ducks and ducklings. While many vaccines have been developed to prevent DTMUV infection, fresh outbreaks continue to occur, as few effective vaccines are available. The E glycoprotein of DTMUV is the primary target for inducing protective immunity in the natural host. Therefore, we conducted an investigation and successfully developed a recombinant baculovirus containing the DTMUV E gene. Ducklings were then vaccinated with the purified protein derived from this virus as a potential vaccine candidate. Our findings demonstrated that the E glycoprotein of DTMUV was highly expressed in Sf9 cells. The vaccination of ducklings with the recombinant baculovirus Bac-E resulted in the induction of strong humoral and cellular immune responses. Most significantly, we observed that the vaccine provided 100% protective immunity against lethal challenges with the DTMUV YY5 strain.

Predicting the Societal Value of Lecanemab in Early Alzheimer's Disease in Japan: A Patient-Level Simulation.

INTRODUCTION: Alzheimer's disease (AD), a neurodegenerative disorder that progresses from mild cognitive impairment (MCI) to dementia, is responsible for significant burden on caregivers and healthcare systems. In this study, data from the large phase III CLARITY AD trial were used to estimate the societal value of lecanemab plus standard of care (SoC) versus SoC alone against a range of willingness-to-pay (WTP) thresholds from a healthcare and societal perspective in Japan. METHODS: A disease simulation model was used to evaluate the impact of lecanemab on disease progression in early AD based on data from the phase III CLARITY AD trial and published literature. The model used a series of predictive risk equations based on clinical and biomarker data from the Alzheimer's Disease Neuroimaging Initiative and Assessment of Health Economics in Alzheimer's Disease II study. The model predicted key patient outcomes, including life years (LYs), quality-adjusted life years (QALYs), and total healthcare and informal costs of patients and caregivers. RESULTS: Over a lifetime horizon, patients treated with lecanemab plus SoC gained an additional 0.73 LYs compared with SoC alone (8.50 years vs. 7.77 years). Lecanemab, with an average treatment duration of 3.68 years, was found to be associated with a 0.91 increase in patient QALYs and a total increase of 0.96 when accounting for caregiver utility. The estimated value of lecanemab varied according to the WTP thresholds (JPY 5-15 million per QALY gained) and the perspective employed. From the narrow healthcare payer's perspective, it ranged from JPY 1,331,305 to JPY 3,939,399. From the broader healthcare payer's perspective, it ranged from JPY 1,636,827 to JPY 4,249,702, while from the societal perspective, it ranged from JPY 1,938,740 to JPY 4,675,818. CONCLUSION: The use of lecanemab plus SoC would improve health and humanistic outcomes with reduced economic burden for patients and caregivers with early AD in Japan.

A Path to Improved Alzheimer's Care: Simulating Long-Term Health Outcomes of Lecanemab in Early Alzheimer's Disease from the CLARITY AD Trial.

INTRODUCTION: Alzheimer's disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and one of the leading causes of death for elderly people in the USA. Lecanemab is a humanized IgG1 monoclonal antibody targeting amyloid protofibrils for the treatment of early AD [i.e., mild cognitive impairment (MCI) or mild AD dementia]. In a recent 18-month phase III trial, using a double-blind, placebo-controlled design, lecanemab treatment led to reduced brain amyloid burden and significant improvements in cognitive and functional abilities in individuals with early AD. METHODS: An evidence-based patient-level disease simulation model was updated to estimate the long-term health outcomes of lecanemab plus standard of care (SoC) compared to SoC alone in patients with early AD and evidence of brain amyloid burden, using recent phase III trial data and published literature. The disease progression is described by changes in the underlying biomarkers of AD, including measures of amyloid and tau, and their connection to the clinical presentation of the disease assessed through various patient-level scales of cognition and function. RESULTS: Lecanemab treatment was estimated to slow the progression of AD to moderate and severe stages and reduce the time spent in these more advanced states. In individuals with early AD, lecanemab plus SoC was associated with a gain of 0.71 quality-adjusted life-years (QALYs), a 2.95-year delay in mean time to progression to AD dementia, a reduction of 0.11 years in institutional care, and an additional 1.07 years in community care as shown in the base-case study. Improved health outcomes were demonstrated with lecanemab treatment when initiated earlier based on age, disease severity, or tau pathology, resulting in estimated gains in QALYs ranging from 0.77 to 1.09 years, compared to 0.4 years in the mild AD dementia subset, as shown by the model. CONCLUSION: The study findings demonstrate the potential clinical value of lecanemab for individuals with early AD by slowing down disease progression and prolonging time in earlier stages of disease, which significantly benefits not only patients and caregivers but also society overall. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03887455.

High expression of the classical swine fever virus (CSFV) envelope protein E2 by a single amino acid mutation and its embedded in the pseudorabies virus (PRV) vector for immunization.

Pseudorabies (PR) and classical swine fever (CSF) are economically important infectious diseases in pigs. Most pig farms in China are vaccinated against these two diseases. Gene-deleted pseudorabies virus (PRV) can be used to develop promising and economical multivalent live attenuated viral vector vaccines. It has been reported that recombinant PRV can express a truncated E2 protein (1-338 aa), but it has not been reported that recombinant PRV can express a full-length E2 protein. We constructed nine groups of E2 proteins with different expression forms and found that the E2 protein could be expressed in vitro only when the transmembrane region of E2 was removed and the signal peptide was added. Analysis of the transmembrane region of E2 revealed that the high hydrophobicity of the E2 transmembrane region was the main reason for its inability to express. By mutating an amino acid to reduce the hydrophobicity of the transmembrane region, it was found that the full-length mutant of E2 (E2FL-muta3 or E2FL-muta4) could be expressed. The expressed full-length mutant E2 could also localize to the cell membrane. Mice immunized with a PRV vector vaccine expressing E2FL-muta3 or E2FL-muta4 developed specific cellular immunity to the E2 protein and stimulated higher levels of E2 antibody than mice immunized with a PRV vector expressing truncated E2. After immunizing the rabbits, the lethal challenge by PRV-ZJ2013 and the febrile response elicited by CSFV were simultaneously prevented. These results suggest that rPRV-dTK/gE-E2FL-muta4 is a promising bivalent vaccine against CSFV and PRV infections.

Estimated Societal Value of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory, cognitive, and behavioral deficits, and brings significant economic burden on caregivers and healthcare systems. This study aims to estimate the long-term societal value of lecanemab plus standard of care (SoC) versus SoC alone, corresponding to a range of willingness-to-pay (WTP) thresholds based on the phase III CLARITY AD trial readouts from both the US payer and societal perspectives. METHODS: An evidence-based model was developed to simulate the effects of lecanemab on disease progression in early AD using interconnected predictive equations based on longitudinal clinical and biomarker data derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The model was informed with the results of the phase III CLARITY AD trial and published literature. Key model outcomes included patient life-years (LYs), quality-adjusted life-years (QALYs), and total costs of both the direct and indirect costs of patients and caregivers over a lifetime horizon. RESULTS: Patients treated with lecanemab plus SoC gained an additional 0.62 years of life versus SoC alone (6.23 years vs. 5.61 years). The mean time on lecanemab was 3.91 years, and the treatment was associated with an increase in patient QALYs of 0.61 and an increase in total QALYs of 0.64 when both patient and caregiver utilities were considered. The model estimated that the annual value of lecanemab for the US payer perspective was US$18,709-35,678 ($19,710-37,351 for societal perspective) at the WTP threshold of $100,000-200,000 per QALY gained, respectively. Scenario analyses of patient subgroups, time horizon, input sources, treatment stopping rules, and treatment dosing were conducted to explore the impact of alternative assumptions on the model results. CONCLUSION: The economic study suggested that lecanemab plus SoC would improve health and humanistic (quality of life) outcomes and reduce economic burden for patients and caregivers in early AD.

Inactivation Performance of Pseudorabies Virus as African Swine Fever Virus Surrogate by Four Commercialized Disinfectants.

This study was based on similar physicochemical characteristics of pseudorabies virus (PRV) and African swine fever virus (ASFV). A cellular model for evaluation of disinfectants was established with PRV as an alternative marker strain. In the present study, we evaluated the disinfection performance of commonly used commercialized disinfectants on PRV to provide a reference for the selection of good ASFV disinfectants. In addition, the disinfection (anti-virus) performances for four disinfectants were investigated based on the minimum effective concentration, onset time, action time, and operating temperature. Our results demonstrated that glutaraldehyde decamethylammonium bromide solution, peracetic acid solution, sodium dichloroisocyanurate, and povidone-iodine solution effectively inactivated PRV at concentrations 0.1, 0.5, 0.5, and 2.5 g/L on different time points 30, 5, 10, and 10 min, respectively. Specifically, peracetic acid exhibits optimized overall performance. Glutaraldehyde decamethylammonium bromide is cost effective but requires a long action time and the disinfectant activity is severely affected by low temperatures. Furthermore, povidone-iodine rapidly inactivates the virus and is not affected by environmental temperature, but its application is limited by a poor dilution ratio such as for local disinfection of the skin. This study provides a reference for the selection of disinfectants for ASFV.

Recombinant pseudorabies virus (PRV) expressing stabilized E2 of classical swine fever virus (CSFV) protects against both PRV and CSFV.

Pseudorabies (PR) and classical swine fever (CSF) are economically important infectious diseases of pigs. Most pig farms in China are immunized against these two diseases. Here, we describe a stabilized E2 protein as an immunogen inserted into the PRV genome as a bivalent live virus-vectored vaccine. The E2 protein has 48 variant sites, there are 2-5 candidate amino acids per variant site, and the relative energy contribution of each amino acid to E2 energy was calculated. Combined substitutions of amino acids at the neighbor variant site (neighbor substitution) were performed to obtain the E2 protein sequence with the lowest energy (stabilized E2). Multiple amino acid substitutions at 48 variant sites were performed, and the results were consistent with neighbor substitutions. The stabilized E2 sequence was obtained, and its energy decreased by 22 Rosetta Energy Units (REUs) compared with the original sequence. After the recombinant PRV expressing stabilized E2 of CSFV was constructed, the secretion efficiency of stabilized E2 was increased by 2.97 times, and the thermal stability was increased by 10.5 times. Immunization of mice resulted in a 2-fold increase in antibody production, and a balanced antibody level against subtype 1.1 and subtype 2.1d E2 was achieved. In rabbits immunized, the lethal challenge of PRV-ZJ and the fever response induced by CSFV could be prevented simultaneously. These findings suggest that rPRV-muta/287aaE2 is a promising bivalent vaccine against CSFV and PRV infections.

Isolation and Pathogenicity of a Novel Goose Astrovirus from Overfed Adult Landaise Geese in China.

Goose astrovirus (GAstV) is an important pathogen causing visceral gout and high mortality in goslings, which has broken out and spread across China. In 2021, a disease characterized by urate deposition on the visceral surface and 30% mortality occurred in commercial adult Landaise geese in Zhejiang Province, China. A systematic study identified an infecting astrovirus, designated ZJCX, that was efficiently isolated from a diseased goose with a chicken hepatocellular carcinoma cell line (LMH). In contrast to other GAstVs originating from goslings, ZJCX caused cytopathogenic effects in LMH cells, and the crystalline arrangement of viral particles was observed through transmission electron microscopy. Indeed, phylogenetic analysis and nucleotide homology comparison revealed that ZJCX isolate belongs to the genotype II cluster of GAstVs and displays 97.8-98.4% identity with other GAstV II strains. However, several specific mutations occurred in the polyprotein and capsid protein regions. Moreover, a pathogenicity assessment of ZJCX with a gosling model was conducted, and typical visceral gout was reproduced and led to 18% mortality. The viral loads of ZJCX in the blood, kidney, and liver were detected with specific primers after inoculation, which demonstrated that the kidney and liver presented viral loads peaking at seven days post-inoculation (dpi). Biochemical parameter examination showed that AST, ALT, γ-GT, UA, and BUN levels were significantly increased by GAstV, whereas body weight was reduced. Overall, this study indicated that the GAstV isolate could infect adult geese, and the results regarding the viral loads and biochemical parameters induced by ZJCX provide insight into GAstV pathogenicity.

Development and Evaluation of a Monoclonal Antibody-Based Blocking Enzyme-Linked Immunosorbent Assay for the Detection of Antibodies against Novel Duck Reovirus in Waterfowl Species.

The novel duck reovirus (NDRV) is an emerging pathogen that causes disease in various waterfowl species. Since the outbreak, it has caused huge economic losses to the duck industry in China. A rapid, reliable, and high-throughput method is required for epidemiological investigation and evaluation of vaccine immunogenicity. A good first step would be establishing an enzyme-linked immunosorbent assay (ELISA) that could detect NDRV antibodies in different breeds of ducks and geese from the serum and egg yolk. This study used a recombinant NDRV σB protein and a corresponding horseradish peroxidase (HRP)-labeled monoclonal antibody to develop a blocking ELISA (B-ELISA). The cutoff value of the B-ELISA was 37.01%. A total of 212 serum samples were tested by the B-ELISA, and the virus neutralization test (VNT) was the gold standard test. The sensitivity and specificity of the B-ELISA were 92.17% (106/115) and 97.94% (95/97), respectively. The agreement rates between the B-ELISA and VNT were 94.81% (kappa value, 0.896). The B-ELISA could specifically recognize anti-NDRV sera without cross-reacting with other positive serums for other major diseases in ducks and geese. The inter- and intra-assay coefficients of variation (CVs) of the B-ELISA and VNT assays were acceptable. In conclusion, the novel B-ELISA could be a rapid, simple, safe, and economically attractive alternative to the VNT in assessing duck flocks' immunity status and in epidemiological surveillance in multiple waterfowl species. IMPORTANCE NDRV disease is a new epidemic disease in waterfowl that first appeared in China. Compared with the classical DRV (CDRV), NDRV is associated with more severe symptoms, a higher mortality rate, and a broader host range. NDRV has become the prevalent genotype in China. At present, there are no commercially available diagnostic products for the NDRV disease. VNT, as the gold standard serologic test, is not only time-consuming and laborious, but also has high requirements for facilities and equipment, which is not suitable for clinical application. Conventional ELISA requires specific antispecies conjugates that are not currently available. B-ELISA not only has the advantage of higher analysis specificity, but also can be used to test specific antibodies against different waterfowl species, because no species-specific conjugates are required in such detection. Therefore, it is necessary to establish a B-ELISA for the detection of antibodies against NDRV in waterfowl species.

The Potential Value-Based Price of a Multi-Cancer Early Detection Genomic Blood Test to Complement Current Single Cancer Screening in the USA.

BACKGROUND: Multi-cancer early detection (MCED) testing could increase detection of cancer at early stages, when survival outcomes are better and treatment costs are lower, but is expected to increase screening costs. This study modeled an MCED test for 19 solid cancers in a US population and estimated the potential value-based price (the maximum price to meet a given willingness to pay) of the MCED test plus current single cancer screening (usual care) compared to usual care alone from a third-party payer perspective over a lifetime horizon. METHODS: A hybrid cohort-level state-transition and decision-tree model was developed to estimate the clinical and economic outcomes of annual MCED testing between age 50 and 79 years. The impact on time and stage of diagnosis was computed using an interception modeling approach, with the consequences of cancer modeled based on stage at diagnosis. The model parameters were mainly sourced from the literature, including a published case-control study to inform MCED test performance. All costs were inflated to 2021 US dollars. RESULTS: Multi-cancer early detection testing shifted cancer diagnoses to earlier stages, with a 53% reduction in stage IV cancer diagnoses, resulting in longer overall survival compared with usual care. Addition of MCED decreased per cancer treatment costs by $5421 and resulted in a gain of 0.13 and 0.38 quality-adjusted life-years across all individuals in the screening program and those diagnosed with cancer, respectively. At a willingness-to-pay threshold of $100,000 per quality-adjusted life-year gained, the potential value-based price of an MCED test was estimated at $1196. The projected survival of individuals diagnosed with cancer and the number of cancers detected at an earlier stage by MCED had the greatest impact on outcomes. CONCLUSIONS: An MCED test with high specificity would potentially improve long-term health outcomes and reduce cancer treatment costs, resulting in a value-based price of $1196 at a $100,000/quality-adjusted life-year willingness-to-pay threshold.

A Simulation Model to Evaluate the Potential Impact of Disease-Modifying Treatments on Burden of Illness in Alzheimer's Disease.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease that places a substantial burden on patients, caregivers, and society. The advent of disease-modifying treatments (DMTs) would represent a major advancement in the management of AD, particularly in early AD. It is important to understand the potential value of these therapies to individuals and society. METHODS: A modeling framework was developed to estimate the potential clinical and economic burden of AD in the USA by simulating the impact, relative to that of usual care, of a DMT with hypothesized availability beginning from 2022. The model assessed AD epidemiology, disease progression, and burden of illness from 2020 to 2050. Model outcomes included the total number of Americans with mild cognitive impairment (MCI) due to AD and mild, moderate, or severe AD dementia in community or residential care settings and their associated care costs, including direct medical and non-medical costs for healthcare resource use and indirect costs for caregiving. RESULTS: A hypothetical DMT was compared to the usual care under different effect scenarios based on delay in onset of AD (1, 3, and 5 years) and DMT uptake (25%, 50%, and 100%). A delay in the onset of AD by 5 years would reduce the prevalence of AD in 2050 by 6%, 12%, and 25%, resulting in savings of $0.783, $1.566, and $3.132 trillion from 2022 to 2050 for the 25%, 50%, and 100% uptake scenarios, respectively. CONCLUSION: This analysis demonstrated that DMTs that provide even small delays in the onset of AD can lead to an increase in disease-free years and sizable savings in the cost of care, providing significant benefits to patients, caregivers, and society.

Intergrated Transcriptomic and Proteomic Analysis Revealed the Differential Responses to Novel Duck Reovirus Infection in the Bursa of Fabricius of Cairna moschata.

The bursa of Fabricius is an immunologically organ against the invasion of duck reovirus (DRV), which is a fatal bird virus belonging to the Reoviridae family. However, responses of the bursa of Fabricius of Cairna moschata to novel DRV (NDRV) infection are largely unknown. Transcriptomes and proteomes of the samples from control and two NDRV strain (HN10 and JDm10) with different virulence were analyzed. Differentially expressed genes and differential accumulated proteins were enriched in the serine protease system and innate immune response clusters. Most of the immune-related genes were up-regulated under both JDm10/HN10 infections. However, the immune-related proteins were only accumulated under HN10 infection. For the serine protease system, coagulation factor IX, three chains of fibrinogen, and complements C8, C5, and C2s were significantly up-regulated by the HN10 infection, suggesting that the serine protease-mediated immune system might be involved in the resistance to NDRV infection. For the innate and adaptive immune system, RIG-I, MDA5, MAPK20, and IRF3 were significantly up-regulated, indicating their important roles against invaded virus. TLR-3 and IKBKB were only up-regulated in the liver cells, MAPK20 was only up-regulated in the bursa of Fabricius cells, and IRAK2 was only up-regulated in the spleen samples. Coagulation factor IX was increased in the bursa of Fabricius, not in the liver and spleen samples. The data provides a detailed resource for studying the proteins participating in the resistances of the bursa of Fabricius of duck to NDRV infections.

Novel epitopes identified from Tembusu virus NS3 protein induce cytotoxic T lymphocyte response.

Since 2010, Tembusu virus (TMUV) has spread widely in China, causing huge economic losses to the poultry industry. Due to the infectious and zoonotic nature of flaviviruses, their potential threat to public health is of great concern. Cellular immune responses usually play a critical role in combating viral infections. To study the molecular basis of cell immunity induced by TMUV, 14 cytotoxic T lymphocyte (CTL) epitope peptides of TMUV antigen E, NS1 and NS3 were predicted by bioinformatics tools. Their abilities to induce cellular immune responses were determined by IFN-γ ELISpot assay, and 4 peptides were found to exhibit highly significant responses upon stimulation. In addition, the cytotoxic activity induced by the epitope peptides was assessed by lactate dehydrogenase (LDH) release assay. Finally, among these peptides, we identified two murine TMUV NS3-derived H-2d-restricted CTL epitopes in BALB/c mice, which could be used to further study of epitope vaccines against TMUV infection.

Diagnostic Value and Cost-Effectiveness of Next-Generation Sequencing-Based Testing for Treatment of Patients with Advanced/Metastatic Non-Squamous Non-Small-Cell Lung Cancer in the United States.

The study evaluated the diagnostic value and cost-effectiveness of next-generation sequencing (NGS)-based testing versus various combinations of single-gene tests (SGTs) for selection of first-line treatment for patients with advanced/metastatic non-squamous non-small-cell lung cancer in the United States. A dynamic decision analysis model was developed comparing NGS versus SGT from a payer perspective. Inputs were obtained from published sources and included diagnostic performance, biomarker-positive disease rates, biomarker-directed recommendations for treatment, and survival outcomes. Costs were reported in 2020 US dollars. In the base case, NGS improved the detection of actionable biomarkers by 74.4%, increased the proportion of patients receiving biomarker-driven therapy by 11.9%, and decreased the proportion of patients with biomarker-positive disease receiving non-biomarker-driven first-line treatment by 40.5%. The incremental cost-effectiveness ratio per life-year gained of NGS testing versus SGT was $7224 (excluding post-diagnostic costs); the incremental cost-effectiveness ratio for NGS-directed therapy was $148,786 versus SGT-directed therapy. Sensitivity analyses confirmed the robustness of these findings; survival outcomes and targeted therapy costs had the greatest impact on results. Testing strategies with NGS are more comprehensive in the detection of actionable biomarkers and can improve the proportion of patients receiving biomarker-driven therapies. NGS testing may provide a cost-effective strategy for advanced/metastatic non-squamous non-small-cell lung cancer; however, the value of NGS-directed therapy varies by the willingness-to-pay threshold of the decision-maker.

The Potential Economic Value of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.

INTRODUCTION: Alzheimer's disease (AD) is a progressive, neurodegenerative disease that affects memory, thinking, and behavior and places a substantial economic burden on caregivers and healthcare systems. This early-phase study aimed to model lecanemab, a humanized monoclonal antibody targeting amyloid protofibrils, for patients with early AD, and estimate the potential value-based price (VBP) of lecanemab + standard of care (SoC) compared to SoC alone given an expected product profile of lecanemab informed by data from a phase II trial from payer and societal perspectives using a broad range of willingness-to-pay (WTP) thresholds in the USA. METHODS: A disease simulation model was used to capture how key AD pathology components relate to the clinical and economic presentation of AD. The effects of disease modification and early intervention on disease progression were simulated on the basis of BAN2401-G000-201 trial data as well as published literature. Model outcomes included patient and caregiver quality-adjusted life years (QALYs), total life years, and total care costs including direct medical and non-medical costs for healthcare resource use and indirect costs for caregiving over a lifetime horizon. RESULTS: Lecanemab + SoC was predicted to result in a gain of 0.61 QALYs (societal, 0.64) and a $8707 decrease in total non-treatment costs (societal, $11,214) vs. SoC alone for patients with early AD. For a WTP threshold range of $50,000 to $200,000 per QALY gained, the potential annual VBP of lecanemab was estimated at $9249 (societal, $10,400) to $35,605 (societal, $38,053), respectively. Other patient subsets, treatment stopping rules, and dosing regimens were used to assess the sensitivity of the VBP estimates. CONCLUSION: The early model predicted that lecanemab would potentially improve long-term health outcomes and reduce formal and informal care costs, resulting in a range of VBPs that reflect the value of lecanemab to society.

Long-Term Health Outcomes of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.

INTRODUCTION: Alzheimer's disease (AD) is a progressive, neurodegenerative disease and is the most common cause of dementia. Lecanemab is a humanized monoclonal antibody targeting amyloid protofibrils for the treatment of early AD. In the phase II BAN2401-G000-201 trial (NCT01767311), lecanemab reduced amyloid accumulated in the brain and slowed progression on key global and cognitive scales evaluating efficacy after 18 months of treatment. METHODS: A disease simulation model was used to predict the long-term clinical outcomes of lecanemab for patients with early AD [i.e., mild cognitive impairment (MCI) due to AD and mild AD dementia] on the basis of BAN2401-G000-201 trial data and published literature. The model captures the pathophysiology and management of AD, with a focus on simulating the effects of disease modification and early intervention on disease progression. The model compares lecanemab in addition to standard of care (SoC) versus SoC alone. RESULTS: Lecanemab treatment was estimated to slow the rate of disease progression, resulting in an extended duration of MCI due to AD and mild AD dementia and shortened duration in moderate and severe AD dementia. The mean time to mild, moderate, and severe AD dementia was longer for patients in the lecanemab + SoC group than for patients in the SoC group by 2.51, 3.13, and 2.34 years, respectively. On base-case analysis, lecanemab was associated with 0.73 incremental life years (LY) and 0.75 incremental quality-adjusted LYs (QALY), and the caregiver QALYs lost was reduced by 0.03 years. The model also predicted a lower lifetime probability of admission to institutional care in lecanemab + SoC versus SoC group (25% versus 31%). CONCLUSION: The model results demonstrate the potential clinical value of lecanemab for patients with early AD and how it can slow the rate of disease progression and reduce the lifetime probability for institutionalized care.

Ultraviolet-Infrared Mixing in Marginal Fermi Liquids.

When Fermi surfaces (FSs) are subject to long-range interactions that are marginal in the renormalization-group sense, Landau Fermi liquids are destroyed, but only barely. With the interaction further screened by particle-hole excitations through one-loop quantum corrections, it has been believed that these marginal Fermi liquids (MFLs) are described by weakly coupled field theories at low energies. In this Letter, we point out a possibility in which higher-loop processes qualitatively change the picture through UV-IR mixing, in which the size of the FS enters as a relevant scale. The UV-IR mixing effect enhances the coupling at low energies, such that the basin of attraction for the weakly coupled fixed point of a (2+1)-dimensional MFL shrinks to a measure-zero set in the low-energy limit. This UV-IR mixing is caused by gapless virtual Cooper pairs that spread over the entire FS through marginal long-range interactions. Our finding signals a possible breakdown of the patch description for the MFL and questions the validity of using the MFL as the base theory in a controlled scheme for non-Fermi liquids that arise from relevant long-range interactions.

Genomic and epidemiological characteristics provide insights into the phylogeographic spread of goose astrovirus in China.

Goose astrovirus (GAstV) is an emerging pathogen with a wide distribution in China that causes visceral gout and leads to significant economic losses in the goose industry. Here, 10 GAstV strains were isolated from different farms in southeast China. We performed an integrated analysis of the full-genome sequences of these new strains alongside comprehensive epidemiological surveillance information from the database. Interestingly, the results showed two distinct genotypes of GAstV, which were evolutionarily distant from each other. Group I GAstVs were closely related to DAstV IV, and group II strains were classified with duck astrovirus (DAstV) II and turkey astrovirus (TAstV) II. Further investigation showed that among the GAstV I strains, ZJC14 and AHDY differed from FLX. Comparative analysis of 58 available genomes clustered the GAstV II strains into two subgroups. We identified two major mutation sites, 456 (E/D) and 540 (L/Q), in the capsid protein, which were related to distinct subgroups according to evolution. GAstV II subgroup 1a strains are the predominant strains in the current prevalent epidemiology. Phylogeographic analysis based on 90 reported cases from 13 provinces revealed the complexity and severity of GAstV epidemics in China, within which Henan, Anhui and Jiangsu provinces have suffered great impacts. According to these phylogeographic investigations, following the initial introduction of GAstV from Hunan Province, the dispersal of GAstV with different subgenotypes on a nationwide scale may be explained by the live gosling trade. Our findings have important implications for the evolution and dispersal of GAstV and will contribute to understanding the potential risk of GAstV.

Distinct Whole Transcriptomic Profiles of the Bursa of Fabricius in Muscovy Ducklings Infected by Novel Duck Reovirus with Different Virulence.

Novel duck reovirus (NDRV) is a newly identified reovirus that brings about more severe damage on multiple organs and mortality in various species of waterfowl. We previously characterized the transcriptomic profiles responding to NDRV in the bursa of Fabricius of Muscovy ducklings, which is a major immunological organ against virus infection. However, the molecular mechanisms of variant cell responses in the bursa of Fabricius to NDRV with different virulence is unclear. Here, we conducted a whole transcriptomic analysis to study the effects of two strains, HN10 (virulent NDRV) and JDm10 (artificially attenuated NDRV), on the bursa of Fabricius of Muscovy ducklings. We harvested a large number of differentially expressed genes (DEGs) of the bursa of Fabricius specially induced by HN10 and JDm10, and we found that HN10 induced DEGs enriched in differentiation and development in multiple organs beyond JDm10. Moreover, the ceRNA regulatory network also indicated the different connections among mRNA, lncRNA and miRNA. Interestingly, we further noticed that a population of differential expressed miRNA could particularly target to transcripts of HN10 and JDm10. We took miR-24 as an example and observed that miR-24 could reduce the transcription of GLI family zinc finger 3 (Gli3) and membrane-associated guanylate kinase, WW and PDZ domain containing 1 (Magi1) via recognition 3' UTR of these two genes by a dual luciferase reporter gene assay in vitro. However, this effect could be compromised by HN10 infection or the ectopic over-expression of the putative miR-24 targeting regions in L1 and L3 fragments of HN10. Taken together, we examined and proposed a novel regulatory competitive mechanism between transcripts of NDRV and Muscovy ducklings for miRNA. These findings may advance the understanding of the molecular pathogenesis of NDRV in Muscovy ducklings, and help provide the potential targets for vaccine and drug development against NDRV.

Proteomic analysis of host cellular proteins co-immunoprecipitated with duck enteritis virus gC.

Duck enteritis virus (DEV), the causative agent of duck viral enteritis, causes a contagious, lethal viral disease in Anseriformes (waterfowls). In virus infection, host-virus interaction plays a crucial role in virus replication and pathogenesis. In our previous study, mRFP was fused with the C-terminus of DEV glycoprotein C (gC) to construct a fluorescent-tag DEV virus rgCRFP. In the current study, fluorescent fusion protein (gC-mRFP) was used as the proteomic probe. Co-immunoprecipitation and mass spectrometric analysis of proteins from rgCRFP-infected chicken embryo fibroblasts using commercial anti-RFP antibody led to the identification of a total of 21 gC interacting host proteins. Out of these 21 proteins, the interaction of seven host proteins (GNG2, AR1H1, PPP2CA, UBE2I, MCM5, NUBP1, HN1) with DEV gC protein was validated using membrane-bound split-ubiquitin yeast two-hybrid system (MbYTH) and bimolecular fluorescence complementation (BiFC) analyses. It indicated direct interaction between these proteins with DEV gC protein. This study has furthered the current understanding of DEV virus infection and pathogenesis. SIGNIFICANCE: gC is an crucial glycoprotein of duck enteritis virus that plays an important role in the viral life cycle. Uncovering the interaction between virus-host is very important to elucidate the pathogenic mechanism of the virus. In this study, host factors interacting with DEV gC have been discerned. And seven host proteins (GNG2, AR1H1, PPP2CA, UBE2I, MCM5, NUBP1, HN1) have been further validated to interact with DEV gC using MbYTH and BiFC analyses. These outcomes could shed light on how DEV manipulates the cellular machinery, which could further our understanding of DEV pathogenesis.