[Research updates of osteoimmunomodulation in osteogenesis].

The gold-standard for bone substitution of large bone defects continues to be autogenous bone graft. Artificial bone substitutes are difficult to replace the autogenous bone grafting due to excessive immune response, fast biodegradation characteristics and inappropriate biocompatibility. Given these drawbacks, osteoimmunology and its advanced functional biomaterials have gained growing attention in recent years. Immune system plays an essential role during bone healing via regulating the shift from inflammatory to anti-inflammation phenotype, and inflammatory cytokines response. The inflammatory reaction mainly include infiltration of immune cells (such as macrophages, neutrophils, T cells, B cells, etc) and release of inflammatory factors (such as IL-1ß, IL-6, TNF-α, etc.) at the bone defects, which subsequently affect the step-wised process of bone healing rejuvenation. Hence, advanced bone biomaterials with immunomodulatory properties is of great significance for the treatment of patients with recalcitrant bone defects, especially for delayed healing or non-union. The reciprocal mechanism of immuno-modulated bone healing, however, is not fully understood and more research is required in the future.

Advances of Blood Coagulation Factor XIII in Bone Healing.

The biologic process of bone healing is complicated, involving a variety of cells, cytokines, and growth factors. As a result of bone damage, the activation of a clotting cascade leads to hematoma with a high osteogenic potential in the initial stages of healing. A major factor involved in this course of events is clotting factor XIII (FXIII), which can regulate bone defect repair in different ways during various stages of healing. Autografts and allografts often have defects in clinical practice, making the development of advanced materials that support bone regeneration a critical requirement. Few studies, however, have examined the promotion of bone healing by FXIII in combination with biomaterials, in particular, its effect on blood coagulation and osteogenesis. Therefore, we mainly summarized the role of FXIII in promoting bone regeneration by regulating the extracellular matrix and type I collagen, bone-related cells, angiogenesis, and platelets, and described the research progress of FXIII = related biomaterials on osteogenesis. This review provides a reference for investigators to explore the mechanism by which FXIII promotes bone healing and the combination of FXIII with biomaterials to achieve targeted bone tissue repair.

Caregivers: the potential infection resources for the sustaining epidemic of hand, foot, and mouth disease/herpangina in Guangdong, China?

BACKGROUND: Although several measures have been taken to control hand foot and mouth disease (HFMD) and herpangina (HA), these two diseases have been prevalent in China for 10 years with high incidence. We suspected that adults' inapparent infection might be the cause of the continued prevalence of HFMD/HA infection in mainland China. METHODS: To explore the role of adults (especially caregivers) in the transmission process of HFMD/HA among children, 330 HFMD/HA cases and 330 healthy children (controls) were selected for a case-control study. Then, data were analyzed by logistic regression. RESULTS: Single-variable analyses revealed that caregivers who tested positive for enterovirus was a significant risk factor of HFMD/HA transmission to children (adjusted odds ratio (OR) = 9.22; 95% CI, 1.16 to 73.23). In the final multivariable model, caregiver behavior, such as cooling children's food with mouth (OR = 1.85; 95% CI, 1.11 to 3.08) and feeding children with their own tableware (OR = 2.19; 95% CI, 1.07 to 4.45), significantly increased the risk of transmitting HFMD/HA to children. On the contrary, washing hands before feeding children reduced such risk. CONCLUSIONS: These results implied that the caregivers might be the infectious source or carriers of enterovirus. Therefore, preventing or treating the caregivers' enterovirus infection and improving their hygiene habits, especially when they are in contact with children, could provide a breakthrough for the effective control of HFMD/HA.

Lack of effective home quarantine: The cause of the continuing prevalence of hand, foot, and mouth disease in China?

BACKGROUND: Home quarantine as a non-pharmaceutical measure is a key strategy for preventing the spread of hand, foot, and mouth disease (HFMD) and herpangina (HA). However, the status of home quarantine remains unclear. This study aimed to provide a theoretical basis for the prevention and control of the HFMD and HA by investigating the situation and determining the factors influencing home quarantine in children with HFMD or HA. METHODS: The convenience sampling method was used in this cross-sectional study involving parents whose children suffered from HFMD or HA in 2019. An online questionnaire tool was used to collect demographic information, socioeconomic status, clinical factors, sources of advice, and details of home quarantine. Logistic regression analysis was used to explore the factors influencing of home quarantine. RESULTS: A total of 3145 parents answered the electronic questionnaire; among them, 317 had children diagnosed with HFMD or HA in 2019. After quality control, 298 questionnaires were included in the analysis. The whole compliance rate of home quarantine for HFMD and HA was 59.1%. Results of multivariate logistic regression analysis indicated that having grandparents as the primary caregiver (OR=2.53, 95% CI: 1.20-5.43) was a risk factor of home-quarantine noncompliance, whereas doctor's notification (OR=0.35, 95% CI: 0.18-0.67) and advice from parents of other infected children (OR=0.53, 95% CI: 0.31-0.91) can increase the compliance with home quarantine. CONCLUSIONS: Home-quarantine measures for HFMD and HA were not well implemented. The caregivers, doctor's notification, and advice from parents of other infected children were associated with home-quarantine compliance. Corresponding measures should be taken to regulate home quarantine.

Interactions between climate factors and air pollution on daily HFMD cases: A time series study in Guangdong, China.

BACKGROUND: Prior studies have shown that climate factors and air pollution are associated with hand, foot, and mouth disease (HFMD) epidemics. However, the interaction between air pollution and climate factors remains unknown. METHODS: Daily HFMD counts from 2009 through 2012 in Guangdong were collected. We used distributed lag non-linear models to assess the associations of climate factors and air pollution on HFMD cases. The effects of climate factors were stratified by air pollution stratum to examine the interaction effect of air quality index (AQI) and temperature, as well as relative humidity. In addition, we explored the variability across gender groups. RESULTS: We observed associations between HFMD cases and environmental factors, including temperature, relative humidity, and AQI. The highest relative risks (RR) were observed at the middle level of temperature and AQI, and high level of relative humidity. The effects for the interaction between AQI and climate factors on HFMD cases were also statistically observed. Compared with low level temperatures (≤23.5 °C), high level temperatures (>23.5 °C) had a RR of 1.486 (95%CI: 1.469,1.503) on days with "good" air quality (AQI ≤ 46), and RR of 1.013 (95%CI: 1.003,1.023) on days with "moderate" air quality (AQI > 46). For relative humidity, the high level (>77%) had a RR of 1.082 (95%CI: 1.076,1.089) on days with "good" air quality, and RR of 1.039 (95%CI: 1.033,1.046) on days with "moderate" air quality. The associations and the interactions remained robust for males and females. CONCLUSIONS: Our findings indicate that climate factors and air pollution imposed lagged and non-linear effects on HFMD epidemics. The effects of climate factors on health potentially vary by AQI. Our study is practical and useful for targeted prevention and control, and provides environmental-based evidence.

Bayesian spatiotemporal analysis for association of environmental factors with hand, foot, and mouth disease in Guangdong, China.

Hand, foot, and mouth disease (HFMD) remains a significant public health and economic burden in parts of China, particularly Guangdong Province. Although the association between meteorological factors and HFMD has been well documented, significant gaps remain in our understanding of the potential impact of environmental factors. Using county-level monthly HFMD data from China CDC and environmental data from multiple sources, we used spatiotemporal Bayesian models to evaluate the association between HFMD and environmental factors including vegetation index, proportion of artificial surface, road capacity, temperature and humidity, and assessed the spatial and temporal dynamic of the association. Statistically significant correlation coefficients from -0.056 to 0.36 (all P < 0.05) were found between HFMD incidence and all environmental factors. The contributions of these factors for HFMD incidence were estimated to be 16.32%, 12.31%, 14.61%, 13.53%, and 2.63%. All environmental factors including vegetation index (Relative Risk: 0.889; Credible Interval: 0.883-0.895), artificial surface (1.028; 1.022-1.034), road capacity (1.033; 1.028-1.038), temperature (1.039; 1.028-1.05), and relative humidity (1.015; 1.01-1.021) were statistically retained in the final spatiotemporal model. More comprehensive environmental factors were identified as associating with HFMD incidence. Taking these environmental factors into consideration for prevention and control strategy might be of great practical significance.

Predicting the hand, foot, and mouth disease incidence using search engine query data and climate variables: an ecological study in Guangdong, China.

OBJECTIVES: Hand, foot, and mouth disease (HFMD) has caused a substantial burden in China, especially in Guangdong Province. Based on the enhanced surveillance system, we aimed to explore whether the addition of temperate and search engine query data improves the risk prediction of HFMD. DESIGN: Ecological study. SETTING AND PARTICIPANTS: Information on the confirmed cases of HFMD, climate parameters and search engine query logs was collected. A total of 1.36 million HFMD cases were identified from the surveillance system during 2011-2014. Analyses were conducted at aggregate level and no confidential information was involved. OUTCOME MEASURES: A seasonal autoregressive integrated moving average (ARIMA) model with external variables (ARIMAX) was used to predict the HFMD incidence from 2011 to 2014, taking into account temperature and search engine query data (Baidu Index, BDI). Statistics of goodness-of-fit and precision of prediction were used to compare models (1) based on surveillance data only, and with the addition of (2) temperature, (3) BDI, and (4) both temperature and BDI. RESULTS: A high correlation between HFMD incidence and BDI (r=0.794, p<0.001) or temperature (r=0.657, p<0.001) was observed using both time series plot and correlation matrix. A linear effect of BDI (without lag) and non-linear effect of temperature (1 week lag) on HFMD incidence were found in a distributed lag non-linear model. Compared with the model based on surveillance data only, the ARIMAX model including BDI reached the best goodness-of-fit with an Akaike information criterion (AIC) value of -345.332, whereas the model including both BDI and temperature had the most accurate prediction in terms of the mean absolute percentage error (MAPE) of 101.745%. CONCLUSIONS: An ARIMAX model incorporating search engine query data significantly improved the prediction of HFMD. Further studies are warranted to examine whether including search engine query data also improves the prediction of other infectious diseases in other settings.

Estimating the basic reproduction rate of HFMD using the time series SIR model in Guangdong, China.

Hand, foot, and mouth disease (HFMD) has caused a substantial burden of disease in China, especially in Guangdong Province. Based on notifiable cases, we use the time series Susceptible-Infected-Recovered model to estimate the basic reproduction rate (R0) and the herd immunity threshold, understanding the transmission and persistence of HFMD more completely for efficient intervention in this province. The standardized difference between the reported and fitted time series of HFMD was 0.009 (<0.2). The median basic reproduction rate of total, enterovirus 71, and coxsackievirus 16 cases in Guangdong were 4.621 (IQR: 3.907-5.823), 3.023 (IQR: 2.289-4.292) and 7.767 (IQR: 6.903-10.353), respectively. The heatmap of R0 showed semiannual peaks of activity, including a major peak in spring and early summer (about the 12th week) followed by a smaller peak in autumn (about the 36th week). The county-level model showed that Longchuan (R0 = 33), Gaozhou (R0 = 24), Huazhou (R0 = 23) and Qingxin (R0 = 19) counties have higher basic reproduction rate than other counties in the province. The epidemic of HFMD in Guangdong Province is still grim, and strategies like the World Health Organization's expanded program on immunization need to be implemented. An elimination of HFMD in Guangdong might need a Herd Immunity Threshold of 78%.

Enterovirus 71 Neutralizing Antibodies Seroepidemiological Research among Children in Guangzhou, China between 2014 and 2015: A Cross-Sectional Study.

A hand-foot-mouth disease outbreak occurred in 2014 around Guangdong. The purpose of this study was investigating the status and susceptibility of infectious neutralizing antibodies to enterovirus 71 among children so as to provide scientific evidence for the population immunity level of hand-foot-mouth disease and prepare for enterovirus 71 vaccination implementation. Serum specimens were collected from children in communities from January 2014 to March 2015 in Guangzhou. A total of 197 serum samples from children 1-5 years old were collected for this cross-sectional study via non-probabilistic sampling from the database of Chinese National Science and Technique Major Project. Neutralization activity was measured via micro neutralization test in vitro. The positive rate of enterovirus 71 neutralizing antibodies was 59.4%, whereas the geometric mean titre was 1:12.7. A statistically significant difference in true positive rates was found between different age groups but not between different genders. Being the most susceptible population of hand-foot-mouth disease, children under 3 years of age are more likely to be infected with enterovirus 71, and the immunity of children increases with increasing age. Further cohort studies should be conducted, and measures for prevention and vaccination should be taken.

A Case-control Study on Risk Factors for Severe Hand, Foot and Mouth Disease.

The objective of this study was to identify potential risk factors for severe hand, foot and mouth disease (HFMD). In this case-control study, 459 severe HFMD patients and 246 mild HFMD patients from Guangdong province and Henan province, China were included. Data comprising demographic characteristics, clinical symptoms and signs, laboratory findings and other factors were collected. Univariate analysis revealed 30 factors associated with severe cases. Further multivariate analysis indicated four independent risk factors: fatigue (p < 0.01, odd ratio [OR] = 204.7), the use of glucocorticoids (p = 0.03, OR = 10.44), the use of dehydrant drugs (p < 0.01, OR = 73.7) and maculopapular rash (p < 0.01, OR = 84.4); and one independent protective factor: herpes or ulcers in mouth (p = 0.01, OR = 0.02). However, more systematic research and validation are needed to understand the underlying risk factors for severe HFMD.

Quantifying the adverse effect of excessive heat on children: An elevated risk of hand, foot and mouth disease in hot days.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a common childhood infection and has become a major public health issue in China. Considerable research has focused on the role of meteorological factors such as temperature and relative humidity in HFMD development. However, no studies have specifically quantified the impact of another major environmental agent, excessive heat, on HFMD. The current study was designed to help address this research gap. METHODS: Case-based HFMD surveillance data and daily meteorological data collected between 2010 and 2012 was obtained from China CDC and the National Meteorological Information Center, respectively. Distributed lag nonlinear models were applied to assess the impact of excessive heat on HFMD and its variability across social-economic status and age groups. RESULTS: After controlling the effects of several potential confounders, the commonly hot days were found to positively affect the HFMD burdens with the relative risk (RR) peaking at around 6 days of lag. The RR of HFMD in the Pearl-River Delta Region was generally higher and persisted longer than that in the remaining developing areas. Regarding the inter-age group discrepancy, children aged 3-6 years old had the highest risk of HFMD under conditions of excessive heat whereas those greater than 6 years old had the lowest. The lag structure of the impact of the extremely hot days was quite similar to that of the commonly hot days, although the relative effect of these two kinds of conditions of excessive heat might vary across regions. CONCLUSIONS: This study indicated significantly facilitating effects of excessive heat on HFMD especially among those aged 3-6 and from developed areas. Results from the current study were particularly practical and important for developing area-and-age-targeted control programs in the context of climate change and urbanization.

Boosted regression tree model-based assessment of the impacts of meteorological drivers of hand, foot and mouth disease in Guangdong, China.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a common childhood infection and has become a major public health issue in China. Considerable research has focused on the role of meteorological factors in HFMD development. Nonlinear relationship, delayed effects and collinearity problems are key issues for achieving robust and accurate estimations in this kind of weather-health relationship explorations. The current study was designed to address these issues and assess the impact of meteorological factors on HFMD in Guangdong, China. METHODS: Case-based HFMD surveillance data and daily meteorological data collected between 2010 and 2012 was obtained from China CDC and the National Meteorological Information Center, respectively. After a preliminary variable selection, for each dataset boosted regression tree (BRT) models were applied to determine the optimal lag for meteorological factors at which the variance of HFMD cases was most explained, and to assess the impacts of these meteorological factors at the optimal lag. RESULTS: Variance of HFMD cases was explained most by meteorological factors about 1 week ago. Younger children and those from the Pearl-River Delta Region were more sensitive to weather changes. Temperature had the largest contribution to HFMD epidemics (28.99-71.93%), followed by precipitation (6.52-16.11%), humidity (3.92-17.66%), wind speed (3.84-11.37%) and sunshine (6.21-10.36%). Temperature between 10°C and 25°C, as well as humidity between 70% and 90%, had a facilitating effect on the epidemic of HFMD. Sunshine duration above 9h and wind speed below 2.5m/s also contributed to an elevated risk of HFMD. The positive relationship between HFMD and precipitation reversed when the daily amount of rainfall exceeded 25 mm. CONCLUSIONS: This study indicated significantly facilitating effects of five meteorological factors within some range on the epidemic of HFMD. Results from the current study were particularly important for developing early warning and response system on HFMD in the context of global climate change.

Assessing the impact of humidex on HFMD in Guangdong Province and its variability across social-economic status and age groups.

Humidex is a meteorological index that combines the impacts of temperature and humidity, and is directly comparable with dry temperature in degrees Celsius. However, to date, no research has focused on the effect of humidex on hand, foot and mouth disease (HFMD). The current study was designed to address this research need. Case-based HFMD surveillance data and daily meteorological data collected between 2010 and 2012 was obtained from the China CDC and the National Meteorological Information Center, respectively. Distributed lag nonlinear models were applied to assess the impact of humidex on HFMD among children under 15 years oldin Guangdong, and its variability across social-economic status and age groups. We found that relative risk (RR) largely increased with humidex. Lag-specific and cumulative humidex-RR curves for children from the Pearl-River Delta Region as well as older children were more likely to show two-peak distribution patterns. One RR peak occurred at a humidex of between 15 and 20, and the other occurred between 30 and 35. This study provides a comprehensive picture of the impact of humidex on HFMD incidence in Guangdong Province. Results from the present study should be important in the development of area-and-age-targeted control programs.

The threshold effects of meteorological factors on Hand, foot, and mouth disease (HFMD) in China, 2011.

We explored the threshold effects of meteorological factors on hand, foot and mouth disease (HFMD) in mainland China to improve the prevention and early warning. Using HFMD surveillance and meteorological data in 2011, we identified the threshold effects of predictors on the monthly incidence of HFMD and predicted the high risk months, with classification and regression tree models (CART). The results of the classification tree showed that there was an 82.35% chance for a high risk of HFMD when the temperature was greater than 24.03 °C and the relative humidity was less than 60.9% during non-autumn seasons. According to the heatmap of high risk prediction, the HFMD incidence in most provinces was beyond the normal level during May to August. The results of regression tree showed that when the temperature was greater than 24.85 °C and the relative humidity was between 80.59% and 82.55%, the relative risk (RR) of HFMD was 3.49 relative to monthly average incidence. This study provided quantitative evidence for the threshold effects of meteorological factors on HFMD in China. The conditions of a temperature greater than 24.85 °C and a relative humidity between 80.59% and 82.55% would lead to a higher risk of HFMD.

Hand-Washing: The Main Strategy for Avoiding Hand, Foot and Mouth Disease.

Epidemics of hand, foot and mouth disease (HFMD) among children have caused concern in China since 2007. We have conducted a retrospective study to investigate risk factors associated with HFMD. In this non-matching case-control study, 99 HFMD patients and 126 control from Guangdong Province were enlisted as participants. Data comprising demographic, socio-economic, clinical and behavior factors were collected from children's parents through face-to-face interviews by trained interviewers using a standardized questionnaire. Results of the primary logistic regression analyses revealed that age, history of cold food consumption, hand-washing routines, and airing out bedding were significantly associated with HFMD cases. Results of further multivariate analysis indicated that older age (OR = 0.44, 95% CI: 0.34-0.56) and hand-washing before meals (OR = 0.3, 95% CI: 0.13-0.70) are protective factors, whereas airing out bedding more than thrice a month (OR = 4.55, 95% CI: 1.19-17.37) was associated with increased risk for HFMD. Therefore, hand-washing should be recommended to prevent HFMD, and the potential threat of airing out bedding should be carefully considered. However, further studies are needed to examine other possible risk factors.

Children's Caregivers and Public Playgrounds: Potential Reservoirs of Infection of Hand-foot-and-mouth Disease.

Hand-foot-and-mouth disease (HFMD) is a common infectious disease, which has led to millions of clinical cases and hundreds of deaths every year in China. This study aimed to exploring the effects on HFMD transmission of children's caregivers and public area, as well as trying to locate the potential reservoirs of infections in primary cases. Total children's 257 samples (98 children's caregivers and 159 environmental samples) were tested for the presence of universal enterovirus, enterovirus 71, coxsackie virus A6 and A16 by real-time fluorescence quantitative polymerase chain reaction (qPCR). 5.84% (15/257, 95% confidence interval [CI]: 2.98%, 8.70%) of total samples had positive results of enterovirus. The enterovirus positive rates of children's caregiver samples and environmental samples were respectively 7.14% (7/98, 95% CI: 2.04%, 12.24%), and 5.03% (8/159, 95% CI: 1.63%, 8.43%); 7.61% (7/92, 95% CI: 2.21%, 13.01%) of wiping samples from playgrounds and 1.49% (1/67, 95% CI: 0, 7.00%) of air samples in indoor market places had positive result of enterovirus. High positive rates of enterovirus in children's caregivers and from playgrounds indicated that they would be potential reservoirs of HFMD infection, as children might be infected via contacting with asymptomatic-infected individuals or exposure of contaminated surface of public facilities.

Enterovirus 71 vaccine: close but still far.

BACKGROUND: Enterovirus 71 (EV71), a member of the Enterovirus genus of the Picornaviridae family, is one of the causative pathogens of hand-foot-and-mouth disease (HFMD) and the most common etiological agent isolated from HFMD patients complicated with neurological disorders. EV71 has become an increasingly important neurotropic enterovirus in the post-poliomyelitis eradication era. Effective antiviral agents and vaccines against this virus are currently still under development. We reviewed publications on the development of EV71 vaccines in order to provide an overview of the field. METHODS: Fifty-five articles on EV71 vaccine development, published from 1974 to 2009, were collected from Sun Yat-sen University library and reviewed. RESULTS: Various types of vaccine have been developed for EV71. In results published to date, all vaccines for EV71 under development appear to elicit an immune response in rodents or in monkeys. According to the established regulatory standards, it may be relatively easy to acquire a license to use the inactivated virus in order to meet the immediate demands for EV71 control . With regard to the attenuated vaccine, it is critical to increase the genetic stability before clinical use, due to the risk of virulent revertants. The virus-like particle (VLP) vaccine, not only conserving the conformational epitopes, but also having no risk of virulent revertants, is another promising vaccine candidate for EV71, but needs further development. The VP1 capsid protein is the backbone antigen protein for developing subunit vaccine and epitope vaccine; these remain viable potential vaccine strategies worthy of further study and development. CONCLUSIONS: The conservation of the three-dimensional structure is important for the EV71 inactivated vaccine and VLP vaccine to induce a strong immune response. To develop EV71 vaccines with a high protection efficacy, strategies such as the use of adjuvant, strong promoters, tissue-specific promoters, and addition of mucosal immune adjuvant should be considered.