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Human Enterovirus 71 (EV71) has emerged as one of the predominant causative agents of hand, foot and mouth disease (HFMD) with global impact. Despite the inactivated vaccine being licensed, other vaccine candidates based on advanced technology platforms are under development. In this report, we rationally designed and constructed two DNA-launched live attenuated vaccine candidates (pDL-EV71) under the control of specific promoters. In vitro and in vivo transfection with pDL-EV71 driven by the CMV promoter successfully yielded fully infectious EV71. More importantly, the administration of pDL-EV71 did not cause clinical symptoms following intracranial or intramuscular inoculation in neonatal and IFNα/ßR-/- mice, demonstrating its safety profile. Moreover, a single-dose or two-dose immunization with pDL-EV71 elicited robust neutralizing antibodies against EV71 as well as an antigen-specific cellular response in mice. A single-dose immunization with 10 µg of pDL-EV71 conferred complete protection against lethal EV71 infection in neonates born to immunized maternal mice. Overall, our present results demonstrate that pDL-EV71 is a safe and effective vaccine candidate against EV71 for further development.

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We performed a comparative, retrospective analysis (March 2019-April 2023) of children diagnosed with non-polio enterovirus (NPEV) central nervous system (CNS) infections (n = 47 vs. 129 contemporaneous controls without NPEV, all <18 years old), requiring cerebrospinal fluid (CSF) testing upon presentation to hospital. We found that showed that admissions decreased during pandemic restrictions (13% vs. controls 33%, p = 0.003). The median age of children with NPEV was 41 days (IQR: 18-72), most were male (n = 76, 59%) and were less likely to present with symptoms of irritability (11% vs. controls 26%, p = 0.04), but more likely to be febrile (93% vs. controls 73%, p = 0.007), have higher respiratory rates (mean 44 bpm, SD 11, vs. controls 36 bpm, SD 14, p = 0.001), higher heart rates (mean 171 bpm, SD 27 vs. controls 141 bpm, SD 36, p < 0.001), higher CSF protein (median 0.66 g/L, interquartile range [IQR] 0.46-1.01, vs. controls 0.53 mg/mL, IQR 0.28-0.89, p = 0.04), higher CSF white cell count (WCC) (median WCC 9.5×106/L, IQR 1-16 vs. controls 3.15×106/L, IQR 2.7-3.6, p < 0.001), but lower CSF glucose (median 2.8 mmol/L, IQR 2.4-3.1 vs. controls 3.1 mmol/L, IQR 2.7-3.6, p < 0.001). Phylogenetic analysis showed that these NPEVs originated from Europe (EV A71, CV B4, E21, E6, CV B3, CV B5, E7, E11, E18), North America (CV B4, E18), South America (E6), Middle East (CV B5), Africa (CV B5, E18), South Asia (E15), East/Southeast Asia (E25, CV A9, E7, E11, E18), and Australia (CV B5).

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Background: The outbreak of foot and mouth disease (FMD) in Indonesia induces reproductive disorders in dairy cows that lead to economic losses to smallholder dairy farms. Aim: The study was to assess the influence of FMD on reproductive traits and evaluate the effect of gonadotropin hormone-releasing hormone (GnRH) administrations on the reproductive performance in FMD-infected dairy cows. Methods: The study was conducted in Jemowo village, Taman Sari sub-district, Boyolali district, Central Java, Indonesia. A total of 155 cows were used to identify the reproductive disorders on FMD-infected dairy cows aged 2-10 years old. Cows were raised in similar conditions and fed diets. A single dose of 2 ml GnRH was injected intramuscularly into 96 ovarian disorder cows. Reproductive performance was measured by service per conception (S/C), conception rate (CR), and pregnancy rate (PR). A descriptive study was conducted to demonstrate the results. Results: The study showed that 61.9% of FMD-infected cows had reproductive disorders, whereby 53.5% ovarian hypofunction, 4.52% silent heat, 1.94% repeat breeder, 1.29% ovarian atrophy, and 0.65% endometritis. FMD-infected cows injected with GnRH had a 98% reproductive recovery rate. Moreover, the S/C, CR, and PR of cows injected with GnRH were 2.02%, 51%, and 85%. Conclusion: GnRH administrations enhanced the reproductive traits of FMD-infected dairy cows indicated by the improvement of CR and PR.

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Hand, foot, and mouth disease (HFMD) is an acute infectious illness primarily caused by enteroviruses. The present study aimed to describe the epidemiological characteristics of hospitalized HFMD patients in a hospital in Henan Province (Zhengzhou, China), and to predict the future epidemiological parameters. In this study, we conducted a retrospective analysis of general demographic and clinical data on hospitalized children who were diagnosed with HFMD from 2014 to 2023. We used wavelet analysis to determine the periodicity of the disease. We also conducted an analysis of the impact of the COVID-19 epidemic on the detection ratio of severe illness. Additionally, we employed a Seasonal Difference Autoregressive Moving Average (SARIMA) model to forecast characteristics of future newly hospitalized HFMD children. A total of 19 487 HFMD cases were included in the dataset. Among these cases, 1515 (7.8%) were classified as severe. The peak incidence of HFMD typically fell between May and July, exhibiting pronounced seasonality. The emergence of COVID-19 pandemic changed the ratio of severe illness. In addition, the best-fitted seasonal ARIMA model was identified as (2,0,2)(1,0,1)12. The incidence of severe cases decreased significantly following the introduction of the vaccine to the market (χ2 = 109.9, p < 0.05). The number of hospitalized HFMD cases in Henan Province exhibited a seasonal and declining trend from 2014 to 2023. Non-pharmacological interventions implemented during the COVID-19 pandemic have led to a reduction in the incidence of severe illness.

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Foot-and-mouth disease (FMD) is one of the most important transboundary animal diseases caused by foot-and-mouth disease virus (FMDV), leading to significant economic losses worldwide. The first report of PanAsia lineage of FMDV in China was in 1999. Since 2011, 18 outbreaks attributed to PanAsia lineage viruses have been reported across 7 provinces or municipality in China. Phylogenetic analysis indicated that these PanAsia strains were clustered into three distinct clades (clade 1, clade 2, and clade 3), with nucleotide homology ranging from 91.4% to 100%. The outbreaks of FMD caused by clade 1 strains occurred around 1999 when this lineage was prevalent globally. Clade 2 strains dominated from 2011 to 2013, while clade 3 strains were prevalent during 2018-2019, sharing only 93% homology with clade 2 strains and 91% with clade 1 strains. Tracing analysis showed that these outbreaks represented 3 distinct introductions of PanAsia viruses into China. Virus neutralization tests (VNT) have demonstrated that current commercial vaccines are effective to protect susceptible animals against these strains (r1 > 0.3). However, the growing demand for livestock has promoted animal movement and encouraged the exchange of products, services, and materials between countries, thereby heightening the risk of exotic strain incursions. Therefore, it is imperative to reinforce border controls and limit animal movements among various Asian countries continually to reduce the risk of new transboundary diseases, such as FMD incursion. Additionally, PanAsia-2 strains need to be taken seriously to prevent its incursions, and the relevant vaccines against PanAsia-2 strains needs to be stockpiled in preparation for any possible incursion.

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Foot-and-mouth disease virus (FMDV) causes a contagious disease (FMD) in cloven-hoofed animals. For FMD-endemic countries, vaccination is critical for controlling disease but is rarely monitored, despite substantial funds spent on vaccine purchases. We evaluated antibody responses in cattle to two commercial vaccines each containing antigens of four FMDV serotypes. Sampling was done over 360 days, with serology for each serotype performed using commercially available solid phase competition ELISAs (SPCE) and with virus neutralization tests (VNT) employing regionally relevant test viruses. A primary course of each vaccine was administered to 37 calves, some of which received a second dose after 28 days. Using new production batches of vaccines, all calves received a booster vaccination 180 days post vaccination, while 10 additional naïve calves were also vaccinated using the new batches and followed up for ∼180 days. Simple and general linear models were used to compare antibody responses which varied substantially according to vaccine, dose regime, serotype, and test, but were mostly insufficient to ensure a high likelihood of adequate or sustained probable protection. One of the vaccines administered as a two-dose primary course of vaccination was superior to other options, but even then, data trajectories from VNT responses suggested probable protection of 75 % of calves for 6 months for only one virus serotype. Calves administered with the other vaccine and those given a single primary dose developed low levels of antibodies, offering predicted likely protection lasting less than two months. Individual SPCE results were weakly correlated (r2 = 0.48) to neutralization and associated likelihoods of protection but SPCE and VNT agreed on which vaccine and dose regime performed best. Our findings highlight gaps in immunogenicity of FMD vaccines used in East Africa and reinforce the importance of independent quality control studies to evaluate and improve commercial FMD vaccines and vaccination regimes.

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Background: Hand, foot, and mouth disease (HFMD) is a notable infectious disease predominantly affecting infants and children worldwide. Previous studies on HFMD have primarily focused on natural patterns, such as seasonality, but research on the influence of important social time points is lacking. Several studies have indicated correlations between birthdays and certain disease outcomes. Objective: This study aimed to explore the association between birthdays and HFMD. Methods: Surveillance data on HFMD from 2008 to 2022 in Yunnan Province, China, were collected. We defined the period from 6 days before the birthday to the exact birthday as the "birthday week." The effect of the birthday week was measured by the proportion of cases occurring during this period, termed the "birthday week proportion." We conducted subgroup analyses to present the birthday week proportions across sexes, age groups, months of birth, and reporting years. Additionally, we used a modified Poisson regression model to identify conditional subgroups more likely to contract HFMD during the birthday week. Results: Among the 973,410 cases in total, 116,976 (12.02%) occurred during the birthday week, which is 6.27 times the average weekly proportion (7/365, 1.92%). While the birthday week proportions were similar between male and female individuals (68,849/564,725, 12.19% vs 48,127/408,685, 11.78%; χ21=153.25, P<.001), significant differences were observed among different age groups (χ23=47,145, P<.001) and months of birth (χ211=16,942, P<.001). Compared to other age groups, infants aged 0-1 year had the highest birthday week proportion (30,539/90,709, 33.67%), which is 17.57 times the average weekly proportion. Compared to other months, patients born from April to July and from October to December, the peak months of the HFMD epidemic, had higher birthday week proportions. Additionally, a decreasing trend in birthday week proportions from 2008 to 2022 was observed, dropping from 33.74% (3914/11,600) to 2.77% (2254/81,372; Cochran-Armitage trend test: Z=-102.53, P<.001). The results of the modified Poisson regression model further supported the subgroup analyses findings. Compared with children aged >7 years, infants aged 0-1 year were more likely to contract HFMD during the birthday week (relative risk 1.182, 95% CI 1.177-1.185; P<.001). Those born during peak epidemic months exhibited a higher propensity for contracting HFMD during their birthday week. Compared with January, the highest relative risk was observed in May (1.087, 95% CI 1.084-1.090; P<.001). Conclusions: This study identified a novel "birthday week effect" of HFMD, particularly notable for infants approaching their first birthday and those born during peak epidemic months. Improvements in surveillance quality may explain the declining trend of the birthday week effect over the years. Higher exposure risk during the birthday period and potential biological mechanisms might also account for this phenomenon. Raising public awareness of the heightened risk during the birthday week could benefit HFMD prevention and control.

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In a case of unilateral acute idiopathic maculopathy (UAIM) following hand, foot, and mouth disease, we aim to discuss the decreased perfusion of choriocapillaris secondary to systemic inflammation as shown by optical coherence tomography angiography (OCTA) and to assess the prognostic significance of bacillary layer detachment (BALAD). A 33-year-old male presented with a decrease of vision in the right eye (OD) for 5 days preceding viral prodromal symptoms and vesicular lesions on bilateral palms and soles along with vesicles and ulcers on the oral mucosa. The best-corrected visual acuity was finger counting at 1 meter distance in OD and 20/20 in his left eye (OS). Dilated fundus examination revealed a circular white-grey dome-shaped elevated lesion at the macula indicative of serous retinal detachment in OD. Spectral-domain optical coherence tomography demonstrated BALAD associated with adjacent subretinal and intraretinal fluid along with pigment epithelium detachment and disruption of ellipsoid and interdigitation zones. OCTA showed decreased choriocapillaris perfusion. All the investigations were normal in OS. The resolution of BALAD occurred during the first 2 days, which was followed by gradual improvement of choriocapillaris flow that lasted 2 months. UAIM is associated with hand, foot, and mouth disease. OCTA demonstrates both qualitative and quantitative data by detecting alterations in the choriocapillaris flow, which could be monitored during the disease course.

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Introduction: Coxsackievirus A6 (CV-A6) has emerged as the predominant epidemic strain responsible for hand, foot and mouth disease (HFMD). CV-A6 infection can result in severe clinical manifestations, including encephalitis, meningitis, and potentially life-threatening central nervous system disorders. Our previous research findings demonstrated that neonatal mice infected with CV-A6 exhibited limb weakness, paralysis, and ultimately succumbed to death. However, the underlying mechanism of CV-A6-induced nervous system injury remains elusive. Numerous reports have highlighted the pivotal role of miRNAs in various viral infections. Methods: Separately established infection and control groups of mice were used to create miRNA profiles of the brain tissues before and after CV-A6 transfection, followed by experimental verification, prediction, and analysis of the results. Results: At 2 days post-infection (dpi), 4 dpi, and 2dpi vs 4dpi, we identified 175, 198 and 78 significantly differentially expressed miRNAs respectively using qRT-PCR for validation purposes. Subsequently, we predicted target genes of these differentially expressed miRNAs and determined their potential targets through GO (Gene Ontology) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Finally, we verified the miRNA-mRNA pairing via double luciferase experiments while confirming functional enrichment of target genes through Western Blotting analyses. Discussion: The results from this study suggest that transcriptional regulation, neuronal necrosis, pro-inflammatory cytokine release, and antiviral immunity are all implicated in the pathogenesis of central nervous system injury in mice infected with CV-A6. Brain injury resulting from CV-A6 infection may involve multiple pathways, including glial cell activation, neuronal necrosis, synaptic destruction, degenerative diseases of the nervous system. It can even encompass destruction of the blood-brain barrier, leading to central nervous system injury. The dysregulated miRNAs and signaling pathways discovered in this study provide valuable insights for further investigations into the pathogenesis of CV-A6.

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Hand, foot, and mouth disease (HFMD) is a prevalent acute infectious disease caused by enteroviruses, presenting substantial public health challenges in Shanghai, especially among children. The dynamic nature of HFMD's etiology necessitates an ongoing evaluation of its epidemiological and virological trends to inform effective control strategies. This study aims to investigate the epidemiological patterns and viral evolution of HFMD in Fengxian District, Shanghai, China, with a focus on shifts in predominant viral strains over a 14-year period. We conducted a retrospective analysis of HFMD cases reported to the National Notifiable Disease Reporting System in Fengxian District from January 1, 2009 to December 31, 2022. Epidemiological trends, strain prevalence, and demographic impacts were assessed. A total of 27,272 HFMD cases were documented during the study period, with incidence showing pronounced seasonal fluctuations-peaking in spring and summer and a lesser peak in autumn. The disease incidence demonstrated significant positive correlations with several meteorological variables: daily average temperature (r = 0.30, P < 0.05), relative humidity (r = 0.20, P < 0.05), wind speed (r = 0.17, P < 0.05), and precipitation (r = 0.17, P < 0.05). Geographically, Nanqiao Town, Fengcheng Town, and Xidu Subdistrict reported the highest incidence rates. The demographic analysis revealed a male-to-female ratio of 1.60:1, predominantly affecting children aged 1-3 years. Prior to 2017, Enterovirus 71 (EV71) and Coxsackievirus A16 (CoxA16) were the primary detected strains; post-2017, Coxsackievirus A6 (CoxA6) emerged as the dominant strain. Statistical analysis confirmed significant year-to-year variations in virus detection rates, with decreasing trends for EV71 and other enteroviruses and an increasing trend for CoxA6. The findings indicate a distinct seasonal incidence of HFMD in Fengxian District. This study underscores the need for targeted public health education, enhanced surveillance, and proactive measures in childcare facilities to mitigate disease spread during peak seasons. Moreover, the evolving viral landscape warrants accelerated efforts in vaccine development against new strains to reduce HFMD incidence.

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The most preferred method for the detection of foot-and-mouth disease (FMD) viral antigen and identification of viral serotype is the enzyme-linked immunosorbent assay (ELISA). Diagnostic tests with high sensitivity are necessary both to distinguish infected vaccinated animals and execute disease control programs for the identification of the carrier animals. The current strategies for the detection of FMD virus are mainly based on the capture antibody (sandwich) ELISA test. The usage of laying pullets as an animal bioreactor for the production of specific egg yolk antibodies (IgY) has increased in recent years due to its high yield, affinity, low price, and quick production turnover. The present study aimed to produce a concentrated and purified IgY polyclonal antibody to design a capture antibody ELISA kit against the FMD virus (FMDV) serotype A. At first, laying hens were immunized with inactivated FMDV serotype virus, and then, on days 14, 21, and 28 following vaccination, the eggs and sera were collected. Afterward, the IgY polyclonal antibodies were extracted and purified from the chicken egg yolk using a polyethylene glycol 6000-ethanol precipitation procedure. Extracts were filtered, purified by ion exchange chromatography, and dialyzed. The purified IgY concentration, estimated by Bradford assay, confirmed its presence by SDS-PAGE and Western blot and also its specific immune reaction by Ouchterlony double immunodiffusion and Dot blot tests. Moreover, for achieving the optimum concentration of antigen/antibody (sera) in sandwich ELISA, a checkerboard titration test was set up based on indirect ELISA results. Eventually, 119 previously confirmed samples (including 80 positive and 39 negative) by both real-time polymerase chain reaction (quantitative PCR, qPCR) and a commercial ELISA kit were used for evaluation of the sensitivity and accuracy of our developed Capture antibody ELISA kit. In this manner, the sensitivity and specificity of our designed kit were 100% and 98%, respectively. Accordingly, the present developed capture ELISA kit based on IgY had high sensitivity and specificity for FMD virus detection and it could be used in the future for both commercial detecting and serotyping applications.

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This study characterised type O foot-and-mouth disease (FMD) viruses recovered from outbreaks that were reported between 2010 and 2019 in the Republic of Korea. We used 96 newly generated whole-genome sequences (WGS) along with 131 already published WGSs from samples collected from countries in East and Southeast Asia. We identified at least eight independent introductions of O/SEA/Mya-98 and O/ME-SA/Ind-2001e FMDV strains into the Republic of Korea during the study period, which were closely related to the sequences of viruses circulating in the East and Southeast Asia neighbourhood with over 97 % nucleotide identity. Spatial-temporal transitions of O/SEA/Mya-98 lineage viruses recovered from the largest outbreak (2014-16) showed that after initial cases were detected within a 15-day period in July 2014, a single introduction of the same virus during December 2014 generated extensive forward virus transmission between farms that lasted until March 2016. We estimated that secondary transmissions were responsible for infection on 44 % FMD affected farms, over a total of 14 generations of infection. We eastimated a median evolutionry rate of 2.51 × 10-5 nt/site/day, which is similar for other FMD epidemic scenarios. These findings suggest that regular incursions of different FMDV lineages into the Republic of Korea have posed a continuous threat from endemic countries of East and Southeast Asia. These data highlight the importance of active cooperation and information exchange on FMD situation within Asian countries and assessment about the likely risk routes of virus movement is highly necessary to prevent further incursion and virus spread of FMDV in the Republic of Korea.

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Zinc finger protein 36 (ZFP36) is a key regulator of inflammatory and cytokine production. However, the interplay between swine zinc-finger protein 36 (sZFP36) and foot-and-mouth disease virus (FMDV) has not yet been reported. Here, we demonstrate that overexpression of sZFP36 restricted FMDV replication, while the knockdown of sZFP36 facilitated FMDV replication. To subvert the antagonism of sZFP36, FMDV decreased sZFP36 protein expression through its non-structural protein 3C protease (3Cpro). Our results also suggested that 3Cpro-mediated sZFP36 degradation was dependent on its protease activity. Further investigation revealed that both N-terminal and C-terminal-sZFP36 could be degraded by FMDV and FMDV 3Cpro. In addition, both N-terminal and C-terminal-sZFP36 decreased FMDV replication. Moreover, sZFP36 promotes the degradation of FMDV structural proteins VP3 and VP4 via the CCCH-type zinc finger and NES domains of sZFP36. Together, our results confirm that sZFP36 is a host restriction factor that negatively regulates FMDV replication.IMPORTANCEFoot-and-mouth disease (FMD) is an infectious disease of animals caused by the pathogen foot-and-mouth disease virus (FMDV). FMD is difficult to prevent and control because there is no cross-protection between its serotypes. Thus, we designed this study to investigate virus-host interactions. We first demonstrate that swine zinc-finger protein 36 (sZFP36) impaired FMDV structural proteins VP3 and VP4 to suppress viral replication. To subvert the antagonism of sZFP36, FMDV and FMDV 3Cpro downregulate sZFP36 expression to facilitate FMDV replication. Taken together, the present study reveals a previously unrecognized antiviral mechanism for ZFP36 and elucidates the role of FMDV in counteracting host antiviral activity.

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Foot and mouth disease (FMD) is a highly contagious infection caused by FMD-virus (FMDV) that affects livestock worldwide with significant economic impact. The main strategy for the control is vaccination with FMDV chemically inactivated with binary ethylenimine (FMDVi). In FMDV infection and vaccination, B cell response plays a major role by providing neutralizing/protective antibodies in animal models and natural hosts. Extracellular vesicles (EVs) and small EVs (sEVs) such as exosomes are important in cellular communication. EVs secreted by antigen-presenting cells (APC) like dendritic cells (DCs) participate in the activation of B and T cells through the presentation of native antigen membrane-associated to B cells or by transferring MHC-peptide complexes to T cells and even complete antigens from DCs. In this study, we demonstrate for the first time that APC activated with the FMDVi O1 Campos vaccine-antigens secrete EVs expressing viral proteins/peptides that could stimulate FMDV-specific immune response. The secretion of EVs-FMDVi is a time-dependent process and can only be isolated within the first 24 h post-activation. These vesicles express classical EVs markers (CD9, CD81, and CD63), along with immunoregulatory molecules (MHC-II and CD86). With an average size of 155 nm, they belong to the category of EVs. Studies conducted in vitro have demonstrated that EVs-FMDVi express antigens that can stimulate a specific B cell response against FMDV, including both marginal zone B cells (MZB) and follicular B cells (FoB). These vesicles can also indirectly or directly affect T cells, indicating that they express both B and T epitopes. Additionally, lymphocyte expansion induced by EVs-FMDVi is greater in splenocytes that have previously encountered viral antigens in vivo. The present study sheds light on the role of EVs derived from APC in regulating the adaptive immunity against FMDV. This novel insight contributes to our current understanding of the immune mechanisms triggered by APC during the antiviral immune response. Furthermore, these findings may have practical implications for the development of new vaccine platforms, providing a rational basis for the design of more effective vaccines against FMDV and other viral diseases.

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Epidemic models serve as a useful analytical tool to study how a disease behaves in a given population. Individual-level models (ILMs) can incorporate individual-level covariate information including spatial information, accounting for heterogeneity within the population. However, the high-level data required to parameterize an ILM may often be available only for a sub-population of a larger population (e.g., a given county, province, or country). As a result, parameter estimates may be affected by edge effects caused by infection originating from outside the observed population. Here, we look at how such edge effects can bias parameter estimates for within the context of spatial ILMs, and suggest a method to improve model fitting in the presence of edge effects when some global measure of epidemic severity is available from the unobserved part of the population. We apply our models to simulated data, as well as data from the UK 2001 foot-and-mouth disease epidemic.

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Modelling epidemics is crucial for understanding the emergence, transmission, impact and control of diseases. Spatial individual-level models (ILMs) that account for population heterogeneity are a useful tool, accounting for factors such as location, vaccination status and genetic information. Parametric forms for spatial risk functions, or kernels, are often used, but rely on strong assumptions about underlying transmission mechanisms. Here, we propose a class of non-parametric spatial disease transmission model, fitted within a Bayesian Markov chain Monte Carlo (MCMC) framework, allowing for more flexible assumptions when estimating the effect on spatial distance and infection risk. We focus upon two specific forms of non-parametric spatial infection kernel: piecewise constant and piecewise linear. Although these are relatively simple forms, we find them to produce results in line with, or superior to, parametric spatial ILMs. The performance of these models is examined using simulated data, including under circumstances of model misspecification, and then applied to data from the UK 2001 foot-and-mouth disease.

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Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals responsible for economic losses that amount to >$20 billion annually. Rapid recognition of FMD cases provides vital information to guide control programmes. A range of point-of-need amplification technologies have been developed which allow sensitive detection of the causative virus (FMDV) in the field at locations remote from laboratories. Here we describe a novel system to detect FMDV RNA using loop-mediated isothermal amplification (LAMP). This test was evaluated using a panel of FMDV isolates (n = 79) and RNA standards demonstrating capability to amplify viral genome directly from clinical material in the absence of nucleic acid extraction. This extraction-free RT-LAMP assay was transferred to a bespoke closed-system lateral flow test (LFT) that was used in combination with a low-cost hand-held heater. Our results show that the RT-LAMP-LFT assay retains a high level of diagnostic and analytical sensitivity when using direct clinical material, with a limit of detection under 80 copies per reaction. Together, our data support the potential for the use of this assay at the point-of-need to facilitate rapid feedback on the status of suspect cases.

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Background: In the past 10 years, the number of hand, foot, and mouth disease (HFMD) cases reported in Guangzhou, China, has averaged about 60,000 per year. It is necessary to conduct an in-depth analysis to understand the epidemiological pattern and related influencing factors of HFMD in this region. Objective: This study aims to describe the epidemiological characteristics and spatiotemporal distribution of HFMD cases in Guangzhou from 2013 to 2022 and explore the relationship between sociodemographic factors and HFMD incidence. Methods: The data of HFMD cases in Guangzhou come from the Infectious Disease Information Management System of the Guangzhou Center for Disease Control and Prevention. Spatial analysis and space-time scan statistics were used to visualize the spatiotemporal distribution of HFMD cases. Multifactor ordinary minimum regression model, geographically weighted regression, and geographically and temporally weighted regression were used to analyze the influencing factors, including population, economy, education, and medical care. Results: From 2013 to 2022, a total of 599,353 HFMD cases were reported in Guangzhou, with an average annual incidence rate of 403.62/100,000. Children aged 5 years and younger accounted for 93.64% (561,218/599,353) of all cases. HFMD cases showed obvious bimodal distribution characteristics, with the peak period from May to July and the secondary peak period from August to October. HFMDs in Guangzhou exhibited a spatial aggregation trend, with the central urban area showing a pattern of low-low aggregation and the peripheral urban area demonstrating high-high aggregation. High-risk areas showed a dynamic trend of shifting from the west to the east of peripheral urban areas, with coverage first increasing and then decreasing. The geographically and temporally weighted regression model results indicated that population density (ß=-0.016) and average annual income of employees (ß=-0.007) were protective factors for HFMD incidence, while the average number of students in each primary school (ß=1.416) and kindergarten (ß=0.412) was a risk factor. Conclusions: HFMD cases in Guangzhou were mainly infants and young children, and there were obvious differences in time and space. HFMD is highly prevalent in summer and autumn, and peripheral urban areas were identified as high-risk areas. Improving the economic level of peripheral urban areas and reducing the number of students in preschool education institutions are key strategies to controlling HFMD.

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Background: Hand, foot, and mouth disease (HFMD) is a global public health concern, notably within the Asia-Pacific region. Recently, the primary pathogen causing HFMD outbreaks across numerous countries, including China, is coxsackievirus (CV) A6, one of the most prevalent enteroviruses in the world. It is a new variant that has undergone genetic recombination and evolution, which might not only induce modifications in the clinical manifestations of HFMD but also heighten its pathogenicity because of nucleotide mutation accumulation. Objective: The study assessed the epidemiological characteristics of HFMD in China and characterized the molecular epidemiology of the major pathogen (CV-A6) causing HFMD. We attempted to establish the association between disease progression and viral genetic evolution through a molecular epidemiological study. Methods: Surveillance data from the Chinese Center for Disease Control and Prevention from 2021 to 2023 were used to analyze the epidemiological seasons and peaks of HFMD in Henan, China, and capture the results of HFMD pathogen typing. We analyzed the evolutionary characteristics of all full-length CV-A6 sequences in the NCBI database and the isolated sequences in Henan. To characterize the molecular evolution of CV-A6, time-scaled tree and historical population dynamics regarding CV-A6 sequences were estimated. Additionally, we analyzed the isolated strains for mutated or missing amino acid sites compared to the prototype CV-A6 strain. Results: The 2021-2023 epidemic seasons for HFMD in Henan usually lasted from June to August, with peaks around June and July. The monthly case reporting rate during the peak period ranged from 20.7% (4854/23,440) to 35% (12,135/34,706) of the total annual number of cases. Analysis of the pathogen composition of 2850 laboratory-confirmed cases identified 8 enterovirus serotypes, among which CV-A6 accounted for the highest proportion (652/2850, 22.88%). CV-A6 emerged as the major pathogen for HFMD in 2022 (203/732, 27.73%) and 2023 (262/708, 37.01%). We analyzed all CV-A6 full-length sequences in the NCBI database and the evolutionary features of viruses isolated in Henan. In China, the D3 subtype gradually appeared from 2011, and by 2019, all CV-A6 virus strains belonged to the D3 subtype. The VP1 sequences analyzed in Henan showed that its subtypes were consistent with the national subtypes. Furthermore, we analyzed the molecular evolutionary features of CV-A6 using Bayesian phylogeny and found that the most recent common ancestor of CV-A6 D3 dates back to 2006 in China, earlier than the 2011 HFMD outbreak. Moreover, the strains isolated in 2023 had mutations at several amino acid sites compared to the original strain. Conclusions: The CV-A6 virus may have been introduced and circulating covertly within China prior to the large-scale HFMD outbreak. Our laboratory testing data confirmed the fluctuation and periodic patterns of CV-A6 prevalence. Our study provides valuable insights into understanding the evolutionary dynamics of CV-A6.

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Enterovirus 71 (EV-71) has strong neurotropism, and it is the main pathogen causing severe hand, foot, and mouth disease (HFMD). In clinical observations, significant differences were observed in the severity and prognosis of HFMD among children who were also infected with EV-71. Genetic differences among individuals could be one of the important causes of differences in susceptibility to EV-71-induced HFMD. As P-selectin glycoprotein ligand-1 (PSGL-1) is an important receptor of EV-71, the correlation between single-nucleotide polymorphisms (SNPs) in PSGL-1 and the susceptibility to severe HFMD following EV-71 infection is worth studying. Given the role of PSGL-1 in immunity, the correlations between PSGL-1 SNPs and the immune status after EV-71 infection are also worth studying. Meanwhile, PSGL-1 variable number of tandem repeats (VNTR) represents a research hotspot in cardiovascular and cerebrovascular diseases, but PSGL-1 VNTR polymorphism has not been investigated in HFMD caused by EV-71 infection. In this study, specific gene fragments were amplified by polymerase chain reaction, and PSGL-1 VNTR sequences were genotyped using an automatic nucleic acid analyzer. The correlations of PSGL-1 VNTR polymorphism with the susceptibility to EV-71-associated severe HFMD and the post-infection immune status were analyzed. The PSGL-1 VNTR A allele was identified as a susceptible SNP for severe HFMD. The risk of severe HFMD was higher for AA + AB genotype carriers than for BB genotype carriers. The counts of peripheral blood lymphocyte subsets were lower in AA + AB genotype carries than in BB genotype carries. In conclusion, PSGL-1 VNTR polymorphism is associated with the susceptibility to EV-71-induced severe HFMD and the immune status after infection. PSGL-1 VNTR might play a certain role in the pathogenesis of severe cases.

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