Genomic epidemiology of CVA10 in Guangdong, China, 2013-2021.

Hand, Foot and Mouth Disease (HFMD) is a highly contagious viral illness primarily affecting children globally. A significant epidemiological transition has been noted in mainland China, characterized by a substantial increase in HFMD cases caused by non-Enterovirus A71 (EV-A71) and non-Coxsackievirus A16 (CVA16) enteroviruses (EVs). Our study conducts a retrospective examination of 36,461 EV-positive specimens collected from Guangdong, China, from 2013 to 2021. Epidemiological trends suggest that, following 2013, Coxsackievirus A6 (CVA6) and Coxsackievirus A10 (CVA10) have emerged as the primary etiological agents for HFMD. In stark contrast, the incidence of EV-A71 has sharply declined, nearing extinction after 2018. Notably, cases of CVA10 infection were considerably younger, with a median age of 1.8 years, compared to 2.3 years for those with EV-A71 infections, possibly indicating accumulated EV-A71-specific herd immunity among young children. Through extensive genomic sequencing and analysis, we identified the N136D mutation in the 2 A protein, contributing to a predominant subcluster within genogroup C of CVA10 circulating in Guangdong since 2017. Additionally, a high frequency of recombination events was observed in genogroup F of CVA10, suggesting that the prevalence of this lineage might be underrecognized. The dynamic landscape of EV genotypes, along with their potential to cause outbreaks, underscores the need to broaden surveillance efforts to include a more diverse spectrum of EV genotypes. Moreover, given the shifting dominance of EV genotypes, it may be prudent to re-evaluate and optimize existing vaccination strategies, which are currently focused primarily target EV-A71.

Molecular surveillance of coxsackievirus A16 in southern China, 2008-2019.

A national surveillance system on hand, foot, and mouth disease (HFMD) was launched in 2008 in China. Since then, millions of HFMD cases have been reported each year, with enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), and coxsackievirus A6 (CV-A6) as the major causative pathogens. Long-term surveillance of viral infection rates and genetic changes is essential for understanding the disease epidemiology pattern. Here, we analyzed molecular surveillance data on CV-A16 covering a period of 12 years (2008-2019) in Guangdong, China, one of the regions reporting the largest number of HFMD cases. Full VP1 sequences of 456 strains were determined to examine the genetic diversity and changes in the distribution of CV-A16 variants. Our study revealed an irregular pattern of CV-A16 infections in Guangdong. Different from the cyclic epidemics observed in some Asia-Pacific regions, there was a continuously high CV-A16 infection rate from 2008 to 2014, and after a period of lower epidemic activity in 2015-2017, an upsurge of CV-A16 infection was observed in 2018-2019. Cocirculation of subgenotypes B1a and B1b was observed, but while subgenotype B1a was predominant from 2008 to 2012, it appears to have been replaced by B1b, which has circulated as the predominant subgenotype since 2013. Phylogenetic analysis showed that most of the circulating CV-A16 strains are endemic, with occasional transmission between neighboring regions. The re-emergence of B1a in 2016-2019 in Guangdong was likely the result of introduction(s) from Southeast Asia. These results highlight the importance of continuous molecular surveillance from different areas, which will improve our understanding of the origin of the epidemic and facilitate the development of strategies for HFMD disease control.

Epidemiology and HBGA-susceptibility investigation of a G9P[8] rotavirus outbreak in a school in Lechang, China.

Rotaviruses cause severe gastroenteritis in infants, in which the viruses interact with human histo-blood group antigens (HBGAs) as attachment and host susceptibility factors. While gastroenteritis outbreaks caused by rotaviruses are uncommon in adolescents, we reported here one that occurred in a middle school in China. Rectal swabs and saliva samples were collected from symptomatic and asymptomatic students, and samples were also collected from the environment. Using PCR, followed by DNA sequencing, a single G9P[8] rotavirus strain was identified as the causative agent. The attack rate of the outbreak was 13.5% for boarders, which was significantly higher than that of day students (1.8%). Person-to-person transmission was the most plausible transmission mode. The HBGA phenotypes of the individuals in the study were determined by enzyme immunoassay, using saliva samples, while recombinant VP8* protein of the causative rotavirus strain was produced for HBGA binding assays to evaluate the host susceptibility. Our data showed that secretor individuals had a significantly higher risk of infection than nonsecretors. Accordingly, the VP8* protein bound nearly all secretor saliva samples, but not those of nonsecretors, explaining the observed infection of secretor individuals only. This is the first single-outbreak-based investigation showing that P[8] rotavirus infected only secretors. Our investigation also suggests that health education of school students is an important countermeasure against an outbreak of communicable disease.

Protective effect of exclusive breastfeeding against hand, foot and mouth disease.

BACKGROUND: Infants who are exclusively breastfed receive natural protection against some infectious agents. This study examined whether there was protective effect of exclusive breastfeeding on the occurrence of hand, foot and mouth disease, which was an emerging infectious disease among children in China. METHODS: A community-based case-control study was carried out among children age 4 years or younger in Guangdong Province, China. Cases were newly diagnosed hand, foot and mouth disease. Controls were randomly sampled from healthy children from the nearby village. Unconditional logistic regression model was used to estimate the odds ratio (OR) for exclusive breastfeeding after adjusting for potential confounding factors. RESULTS: A total of 316 cases and 566 controls were included in the analysis. Significantly beneficial effect of exclusive breastfeeding during the first 6 months was observed for hand, foot and mouth disease occurrence. The overall OR was 0.63 (95% CI: 0.47-0.85) for exclusive breastfeeding compared with mixed feeding type. The age-specific analyses indicated that the protective effect persisted till the age of 28 months. CONCLUSIONS: This study suggests that exclusive breastfeeding might have protective effect against HFMD infection among the children within 28 months of age.

The impact of enterovirus A71 vaccination program on hand, foot, and mouth disease in Guangdong, China: A longitudinal surveillance study.

Enterovirus A71 (EV71) vaccination program was introduced in 2016 in China. Based on a longitudinal surveillance dataset from 2012 to 2019 in Guangdong, China, we estimated the impact of the EV71 vaccination program on hand, foot, and mouth disease (HFMD) incidence, by using a counterfactual prediction made from synthetic control approach integrated with a Bayesian time-series model. We observed a relative reduction of 41.4% for EV71-associated HFMD cases during the post-vaccination period of 2017-2019, corresponding to 26,226 cases averted. The reduction of EV71-associated HFMD cases raised with the elevation of EV71 vaccine coverage by year. We found an indirect effect for the children aged 6-14 years who were less likely to be vaccinated. Whereas, the EV71 vaccine may not protect against non-EV71-associated HFMD. This study provides a template for ongoing public health surveillance of EV71 vaccine effectiveness with a counterfactual study design. Our results show strong evidence of the EV71 vaccination program working on reducing EV71-associated HFMD in real-world settings. The finding will benefit policy-making of EV71 vaccination and the prevention of HFMD.

Novel ocular findings in oculodentodigital dysplasia (ODDD): a case report and literature review.

BACKGROUND: Oculodentodigitaldysplasia (ODDD; MIM no. 164200) is a rare hereditary disorder caused by mutations in the gene GJA1.Ocular disorders included microcornea, cornea opacity and glaucoma. However, few studies described fundus findings. MATERIALS AND METHODS: Ophthalmic examination included visual acuity measurement, intraocular pressure (IOP) measurements, slit-lamp biomicroscopy, B-scan ultrasonography, Ultrasound biomicroscopy (UBM), spectral-domain optical coherence tomography (SD-OCT), ERG and retcam fluorescein angiogram. In addition, blood samples were taken from this patient for mutation analyze of GJA1. RESULT: The ophthalmic features of this patient were microcornea, cornea opacity, glaucoma as expected. Interestingly, the patient had a normal axial length with refractive status of emmetropia, but extremely retinal dysplasia and severe choroid thinning was noted. Flash electroretinogram (ERG) was extinguished in both eyes. This study identified a novel mutation c.91A>T in the GJA1 gene associated with fundus abnormalities. Bioinformatics and structural modeling suggested the mutation to be pathogenic. CONCLUSION: Our research expanded not only the mutation spectrum, but also the clinical characteristics of ODDD. To the best of our knowledge, this is the first report on anatomical and functional chorioretinal changes in ODDD patients. These novel ocular features highlight the importance of fundus morphological and functional evaluation in ODDD. ABBREVIATIONS: ODDD: oculodentodigital dysplasia; OCT: optical coherence tomography; ERG: electroretinogram; TACT: teller acuity card test; UBM: ultrasound biomicroscopy; MW: molecular weights; AL: axial length; Cx43: connexin 43; RPE: retinal pigment epithelium; RGCs: retinal ganglion cells; FEVR: familial exudative vitreoretinopathy; ROP: retinopathy of prematurity.

Evaluating the transmission routes of hand, foot, and mouth disease in Guangdong, China.

Although it is an enteroviral infectious disease, recent studies suggest that respiratory transmission might play a role in the transmission of hand, foot, and mouth disease (HFMD). We evaluated the transmission modes (respiratory and fecal-oral transmission) of HFMD among children using a case-control study in Guangdong, China. Our analyses suggested that fecal-oral transmission might be the principal transmission mode of HFMD among children in the study area, and handwashing habits of the children and their parents should be emphasized to control this infection.

Giant cell rich osteosarcoma of the mandible with abundant spindle cells and osteoclast-like giant cells mimicking malignancy in giant cell tumor.

Giant cell rich osteosarcoma is a relatively unusual histological form of osteosarcoma, common lesion usually presenting in the long bones of the appendicular skeleton. The occurrence in the mandible is exceptional rare. Histologically, this tumor tends to be a highly anaplastic, pleomorphic tumor in which the tumor cells may be: plasmacytoid, fusiform, ovoid, small round cells, clear cells, mono-or multinucleated giant cells, or, spindle cells. Herein, we present a case with the sternum and first thoracic vertebra metastasis from primary giant cell rich osteosarcoma of the mandible in a 28 year-old Chinese female. The tumor was predominantly composed of abundant spindle cells with marked atypia and numerous osteoclast-like giant cells reminiscent of malignancy in giant cell tumor. The unusual histological appearance can pose a great diagnostic challenge. It may be easily misdiagnosed, especially if the specimen is limited or from fine-needle aspiration.

The Epidemiological Study of Coxsackievirus A6 revealing Hand, Foot and Mouth Disease Epidemic patterns in Guangdong, China.

Enterovirus A71 (EVA71) and Coxsackievirus A16 (CVA16) are regarded as the two major causative pathogens in hand, foot and mouth disease (HFMD) epidemics. However, CVA6, previously largely ignored, became the predominant pathogen in China in 2013. In this study, we describe the epidemiological trends of CVA6 during the annual HFMD outbreaks from 2008 to 2013 in Guangdong, China. The study results show that CVA6 has been one of three major causative agents of HFMD epidemics since 2009. The periodic rotation and dominance of the three pathogens, EVA71, CVA16 and CVA6, may have contributed to the continuously increasing HFMD epidemics. Moreover, phylogenetic analysis of the VP1 gene shows that major circulating CVA6 strains collected from 2009 to 2013 are distinct from the earlier strains collected before 2009. In conclusion, the discovery from this research investigating epidemiological trends of CVA6 from 2008 to 2013 explains the possible pattern of the continuous HFMD epidemic in China. The etiological change pattern also highlights the need for improvement for pathogen surveillance and vaccine strategies for HFMD control in China.

Antitumor activity of celastrol nanoparticles in a xenograft retinoblastoma tumor model.

BACKGROUND: Celastrol, a Chinese herbal medicine, has shown antitumor activity against various tumor cell lines. However, the effect of celastrol on retinoblastoma has not yet been analyzed. Additionally, the poor water solubility of celastrol restricts further therapeutic applications. The goal of this study was to evaluate the effect of celastrol nanoparticles (CNPs) on retinoblastoma and to investigate the potential mechanisms involved. METHODS: Celastrol-loaded poly(ethylene glycol)-block-poly(ɛ-caprolactone) nanopolymeric micelles were developed to improve the hydrophilicity of celastrol. The 2-(2-methoxy-4- nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulf-ophenyl)-2H tetrazolium monosodium salt (WST-8) assay was used to determine the inhibitory effect of CNPs on SO-Rb 50 cell proliferation in vitro. Immunofluorescence was used to evaluate the apoptotic effect of CNPs on nuclear morphology, and flow cytometry was used to quantify cellular apoptosis. The expression of Bcl-2, Bax, NF-κB p65, and phospo-NF-κB p65 proteins was assessed by Western blotting. A human retinoblastoma xenograft model was used to evaluate the inhibitory effects of CNPs on retinoblastoma in NOD-SCID mice. Hematoxylin and eosin staining was used to assess the apoptotic effects of CNPs on retinoblastoma. RESULTS: CNPs inhibit the proliferation of SO-Rb 50 cells in a dose- and time-dependent manner with an IC(50) of 17.733 µg/mL (celastrol-loading content: 7.36%) after exposure to CNPs for 48 hours. CNPs induce apoptosis in SO-Rb 50 cells in a dose-dependent manner. The expression of Bcl-2, NF-κB p65, and phospo-NF-κB p65 proteins decreased after exposure to CNPs 54.4 µg/mL for 48 hours. Additionally, the Bax/Bcl-2 ratio increased, whereas the expression of Bax itself was not significantly altered. CNPs inhibit the growth of retinoblastoma and induce apoptosis in retinoblastoma cells in mice. CONCLUSION: CNPs inhibit the growth of retinoblastoma in mouse xenograft model by inducing apoptosis in SO-Rb 50 cells, which may be related to the increased Bax/Bcl-2 ratio and the inhibition of NF-κB. CNPs may represent a potential alternative treatment for retinoblastoma.

[Survey on the recessive infection of pathogen to hand-foot-mouth disease among healthy adults and children in Guangdong province].

OBJECTIVE: To understand the pathogen-carrying status of hand-foot-mouth disease (HFMD) among healthy people in Guangdong province. METHODS: Stool specimens were collected randomly on 7 age groups from 7 cities in Guangdong province. Real-time RT-PCR was used to detect enterovirus (EV), enterovirus 71 (EV71) and coxsackie virus A16 (CA16). RESULTS: Altogether, 1285 stool specimens were collected. The positive rates of EV71, CA16 and other enterovirus were 0.39% (5/1285), 0.23% (3/1285) and 7.00% (90/1285), respectively. The highest EV71 positive rate (1.79%) was among the 4-6-year-old group, followed by the age group 0 - 3 with positive rate as 0.67%. EV71 was not found among the rest age groups. The highest CA16 positive rate (1.35%) was among the 4 - 6 year-olds group, but the CA16 was not found among the rest age groups. EV71 was only found among native population, with the positive-rate as 0.47%. CA16-positive rate was 0.19% among the native population and 0.85% among floating population, with no significant difference found (P > 0.05). The EV71 positive rate was 0.36% among rural residents and 0.54% among urban residents, but with no significant difference (P > 0.05). All CA16 was found among the urban residents. CONCLUSION: Recessive infection of EV71 and CA16 were only found among 0-6 year-old group but not found among other groups, which suggested that the approaches on prevention and control should be targeted to all children especially on pre-school children.

An enterovirus 71 epidemic in Guangdong Province of China, 2008: epidemiological, clinical, and virogenic manifestations.

Enterovirus 71 (EV71) is shown to be a major causative agent in outbreaks of hand, foot, and mouth disease (HFMD) reported in Guangdong (GD) Province of China in 2008. A total of 48,876 HFMD cases (131 severe and 21 fatal) were reported to the GD HFMD web-based surveillance system, which covers 871 clinics. The main causes of death included central nervous system damage, heart failure, and pulmonary edema. The incidence rate was 52 per 100,000, and the epidemic peak appeared in May and June. EV71 was found in 59% and coxsackievirus A16 in 26% of 936 laboratory-confirmed cases. Other viruses are likely to be responsible for the remaining 15% of cases. Of the 185 EV71 cases collected, 62% were mild, 27% were severe, and the remaining 11% were fatal. A total of 17 EV71 isolates were subjected to nucleotide sequencing of the entire VP1 gene. Phylogenetic analysis showed that the GD EV71 strains belonged to the C4 subgenotype and that EV71 circulates at a national rather than a regional level. A Comparison with the VP1 gene from a different clinical case showed that there was no obvious virulence determinant in this locus. Furthermore, this study found that most deaths occurred in rural areas, thereby indicating that delayed diagnosis and incorrect treatment may play an important role.