Feasibility of wearable monitors to detect heart rate variability in children with hand, foot and mouth disease.

Hand foot and mouth disease (HFMD) is caused by a variety of enteroviruses, and occurs in large outbreaks in which a small proportion of children deteriorate rapidly with cardiopulmonary failure. Determining which children are likely to deteriorate is difficult and health systems may become overloaded during outbreaks as many children require hospitalization for monitoring. Heart rate variability (HRV) may help distinguish those with more severe diseases but requires simple scalable methods to collect ECG data.We carried out a prospective observational study to examine the feasibility of using wearable devices to measure HRV in 142 children admitted with HFMD at a children's hospital in Vietnam. ECG data were collected in all children. HRV indices calculated were lower in those with enterovirus A71 associated HFMD compared to those with other viral pathogens.HRV analysis collected from wearable devices is feasible in a low and middle income country (LMIC) and may help classify disease severity in HFMD.

Rapid detection of four major HFMD-associated enteroviruses by multiplex HiFi-LAMP assays.

Hand, foot, and mouth disease (HFMD) caused by various enteroviruses is a major public health concern globally. Human enterovirus 71(EVA71), coxsackievirus A16 (CVA16), coxsackievirus A6 (CVA6), and coxsackievirus A10 (CVA10) are four major enteroviruses responsible for HFMD. Rapid, accurate, and specific point-of-care (POC) detection of the four enteroviruses is crucial for the prevention and control of HFMD. Here, we developed two multiplex high-fidelity DNA polymerase loop-mediated isothermal amplification (mHiFi-LAMP) assays for simultaneous detection of EVA71, CVA16, CVA6, and CVA10. The assays have good specificity and exhibit high sensitivity, with limits of detection (LOD) of 11.2, 49.6, 11.4, and 20.5 copies per 25 µL reaction for EVA71, CVA16, CVA6, and CVA10, respectively. The mHiFi-LAMP assays showed an excellent clinical performance (sensitivity 100.0%, specificity 83.3%, n = 47) when compared with four singleplex RT-qPCR assays (sensitivity 93.1%, specificity 100%). In particular, the HiFi-LAMP assays exhibited better performance (sensitivity 100.0%, specificity 100%) for CVA16 and CVA6 than the RT-qPCR assays (sensitivity 75.0-92.3%, specificity 100%). Furthermore, the mHiFi-LAMP assays detected all clinical samples positive for the four enteroviruses within 30 min, obviously shorter than about 1-1.5 h by the RT-qPCR assays. The new mHiFi-LAMP assays can be used as a robust point-of-care testing (POCT) tool to facilitate surveillance of HFMD at rural and remote communities and resource-limited settings.

Atypical cutaneous findings of hand-foot-mouth disease in children: A systematic review.

INTRODUCTION: Hand-foot-mouth disease (HFMD) is a common childhood infectious disease. Atypical skin findings of HFMD, often associated with coxsackievirus A6 (CVA6), were first reported in 2008, with increasing reports worldwide since. Atypical lesions of HFMD often involve sites beyond the palms and soles and tend to have unusual, polymorphic morphology. METHODS: A systematic review was conducted on clinical features and outcomes of pediatric HFMD with atypical cutaneous manifestations. RESULTS: Eighty-five studies were included, representing 1359 cases with mean age 2.4 years and a male predominance of 61%. The most reported morphologies were vesicles (53%), papules (49%), and bullae (36%). Other morphologies included eczema herpeticum-like (19%), purpuric/petechial (7%), and Gianotti Crosti-like (4%). Common atypical sites included the arms and/or legs (47%), face (45%), and trunk (27%). CVA6 was identified in 63% of cases. Symptoms resolved in a mean of 10 days. Overall, 16% of cases received treatment, most commonly with acyclovir, intravenous antibiotics, or topical steroids. The most common complications were nail changes (21%) and desquamation (4%) which occurred a mean of 3 and 2 weeks after symptoms, respectively. CONCLUSION: Due to unusual morphologies resembling other conditions, HFMD with atypical cutaneous findings may be misdiagnosed, leading to inappropriate and unnecessary investigations, hospitalization, and treatment. Greater awareness of atypical presentations of HFMD is warranted to improve patient care and counseling on infection control precautions.

Application value of EV/EV71/CA16-SAT detection in children with hand-foot-mouth disease.

The objective of this work was to explore the application value of a new type of fluorescent nucleic acid isothermal amplification (SAT) to detect EV/EV71/CA16-SAT in children with hand-foot-mouth disease (HFMD). For this purpose, from March 2017 to September 2019, Chengdu Children's Specialized Hospital collected throat swabs from children with clinical manifestations of hand, foot and mouth disease, and used SAT technology to screen and detect universal enterovirus (EV) nucleic acid (There were 1860 children with EV-RNA) positive. Patients who are EV-RNA positive at any time: first use the same throat swab specimen to detect EV71/CA16-RNA; secondly, collect venous blood and use the colloidal gold method to detect IgM antibodies in EV71/CA16 serum. The patients with positive EV71/CA16-RNA or EV71/CA16-IgM (or both) were repeated the above two methods 2 weeks and 4 weeks after standard treatment for review and comprehensive analysis. Results showed that 763 cases were enrolled for the first time: 59.76% were male and 40.24% were female; the age ranged from 1 month to 13 years, of which 69.06% were from 1 to 4 years old; CA16-RNA positive 56.23%, EV71-RNA positive 21.89%, CA16/EV71 -RNA were all positive in 1.57%; CA16-IgM was positive in 64.48%, EV71-IgM was positive in 54.26%, and CA16/EV71-IgM were both positive in 18.74%. After 2 weeks, 722 cases were reexamined: 26.73% were positive for CA16-RNA, 7.89% were positive for EV71-RNA, 0.28% were both positive for CA16/EV71-RNA; 66.21% were positive for CA16-IgM, 51.52% were positive for EV71-IgM, and IgM were all positive in 17.73%. Four weeks later, 489 cases were reexamined: among them, CA16-RNA positive 5.73% of which were positive for EV71 color RNA (0.005%), and 12.68% of them were all positive for EV71lym. The strategy of combining SAT technology and colloidal gold method to detect EV/EV71/CA16 nucleic acid (RNA) and serum IgM antibody in children HFMD can improve the early detection rate and accuracy of HFMD; According to the comprehensive analysis of the detection results of children with HFMD at the early stage, 2 weeks and 4 weeks of the present study, it is suggested that EV/EV71/CA16-SAT nucleic acid detection can be used to judge the prognosis, follow-up treatment, set isolation time, return students to school, and community management in children with HFMD. and prevention and control have more clinical application value.

Emerging concerns of atypical hand foot and mouth disease caused by recombinant Coxsackievirus A6 variants in Henan, China.

An increasing number of studies have reported that atypical hand, foot, and mouth disease (HFMD) is becoming a new concern for children's health. At present, there is no official definition for atypical HFMD, but some studies have defined that it occurs at anatomic sites not listed in the definition of HFMD issued by the World Health Organization. Several pathogens have been reported to cause atypical HFMD, such as Coxsackievirus (CV)A6. As one of the most prevalent enteroviruses in the world, CVA6 seems to affect a wider range of children and causes more severe and prolonged illness than other enteroviruses. The early lesions of atypical HFMD are very similar to the clinical presentations of other diseases, such as eczema, which poses a challenge for clinicians aiming to identify and diagnose HFMD in a timely manner. Here, we report on six atypical HFMD patients caused by recombinant CVA6 variants, and the atypical manifestations include eczema coxsackium, large herpes, rice-like red papules and herpes, purpuric rash, and onychomadesis, as well as and large red herpes on scalp, perianal, testicles, shoulders and neck, and other atypical eruption sites, hoping to draw the attention of other pediatricians. This study will provide scientific guidance for timely diagnosis of HFMD to prevent serious complications.

A hybrid model for hand-foot-mouth disease prediction based on ARIMA-EEMD-LSTM.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a common infectious disease that poses a serious threat to children all over the world. However, the current prediction models for HFMD still require improvement in accuracy. In this study, we proposed a hybrid model based on autoregressive integrated moving average (ARIMA), ensemble empirical mode decomposition (EEMD) and long short-term memory (LSTM) to predict the trend of HFMD. METHODS: The data used in this study was sourced from the National Clinical Research Center for Child Health and Disorders, Chongqing, China. The daily reported incidence of HFMD from 1 January 2015 to 27 July 2023 was collected to develop an ARIMA-EEMD-LSTM hybrid model. ARIMA, LSTM, ARIMA-LSTM and EEMD-LSTM models were developed to compare with the proposed hybrid model. Root mean square error (RMSE), mean absolute error (MAE) and coefficient of determination (R2) were adopted to evaluate the performances of the prediction models. RESULTS: Overall, ARIMA-EEMD-LSTM model achieved the most accurate prediction for HFMD, with RMSE, MAPE and R2 of 4.37, 2.94 and 0.996, respectively. Performing EEMD on the residual sequence yields 11 intrinsic mode functions. EEMD-LSTM model is the second best, with RMSE, MAPE and R2 of 6.20, 3.98 and 0.996. CONCLUSION: Results showed the advantage of ARIMA-EEMD-LSTM model over the ARIMA model, the LSTM model, the ARIMA-LSTM model and the EEMD-LSTM model. For the prevention and control of epidemics, the proposed hybrid model may provide a more powerful help. Compared with other three models, the two integrated with EEMD method showed significant improvement in predictive capability, offering novel insights for modeling of disease time series.

Potential relevance of salivary legumain for the clinical diagnostic of hand, foot, and mouth disease.

The fight against hand, foot, and mouth disease (HFMD) remains an arduous challenge without existing point-of-care (POC) diagnostic platforms for accurate diagnosis and prompt case quarantine. Hence, the purpose of this salivary biomarker discovery study is to set the fundamentals for the realization of POC diagnostics for HFMD. Whole salivary proteome profiling was performed on the saliva obtained from children with HFMD and healthy children, using a reductive dimethylation chemical labeling method coupled with high-resolution mass spectrometry-based quantitative proteomics technology. We identified 19 upregulated (fold change = 1.5-5.8) and 51 downregulated proteins (fold change = 0.1-0.6) in the saliva samples of HFMD patients in comparison to that of healthy volunteers. Four upregulated protein candidates were selected for dot blot-based validation assay, based on novelty as biomarkers and exclusions in oral diseases and cancers. Salivary legumain was validated in the Singapore (n = 43 healthy, 28 HFMD cases) and Taiwan (n = 60 healthy, 47 HFMD cases) cohorts with an area under the receiver operating characteristic curve of 0.7583 and 0.8028, respectively. This study demonstrates the feasibility of a broad-spectrum HFMD POC diagnostic test based on legumain, a virus-specific host systemic signature, in saliva.

A review on current diagnostic tools and potential optical absorption spectroscopy for HFMD detection.

Hand, Foot, and Mouth Disease (HFMD) is an outbreak infectious disease that can easily spread among children under the age of five. The most common causative agents of HFMD are enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), but infection caused by EV71 is more associated with fatalities due to severe neurological disorders. The present diagnosis methods rely on physical examinations by the doctors and further confirmation by laboratories detection methods such as viral culture and polymerase chain reaction. Clinical signs of HFMD infection and other childhood diseases such as chicken pox, and allergies are similar, yet the genetics and pathogenicity of the viruses are substantially different. Thus, there is an urgent need for an early screening of HFMD using an inexpensive and user-friendly device that can directly detect the causative agents of the disease. This paper reviews current HFMD diagnostic methods based on various target types, such as nucleic acid, protein, and whole virus. This was followed by a thorough discussion on the emerging sensing technologies for HFMD detection, including surface plasmon resonance, electrochemical sensor, and surface enhanced Raman spectroscopy. Lastly, optical absorption spectroscopic method was critically discussed and proposed as a promising technology for HFMD screening and detection.

Dual-attention-based recurrent neural network for hand-foot-mouth disease prediction in Korea.

Hand-foot-mouth disease (HFMD) is a viral disease that occurs primarily in children. Meteorological factors have a significant impact on its popularity annually in Korea. This study proposes a new HFMD prediction model using a dual-attention-based recurrent neural network (DA-RNN) and important weather factors for HFMD in Korea. First, suspected cases of HFMD in each state were predicted using meteorological factors from the DA-RNN. Second, the weather factors were divided into six categories: temperature, wind, rainfall, day length, humidity, and air pollution to conduct sensitivity analysis. Because of this prediction, the proposed model showed the best performance in predicting the number of suspected HFMD cases in a week compared with other RNN methods. Sensitivity analysis showed that air pollution and rainfall play an important role in HFMD in Korea. This model provides information for HFMD prevention and control and can be extended to predict other infectious diseases.

Hand, Foot, and Mouth Disease in Children: Clinical Characteristics of an Outbreak in Novi Sad, Serbia.

Hand, foot, and mouth disease (HFMD) is a relatively common mild viral infection that usually affects young children, mainly occurring during the late spring, early summer, and fall months. It is most commonly caused by members of the human enterovirus (HEV) genus. Recently, HFMD has received renewed attention because of evidence that this disease could have clinical, epidemiological, and etiological characteristics different from those initially associated with it. HFMD may be associated with neurologic or cardiopulmonary complications and can, rarely, lead to death. Our study was a retrospective analysis on 83 children (<18 years of age) who were clinically diagnosed with HFMD at the Department of Dermatology of the Institute for Child and Youth Health Care of Vojvodina, in a single, tertiary-care university hospital in Novi Sad, Vojvodina province, Serbia, for the time period from January 2016 to December 2017. During the study period, HFMD was diagnosed in 83 children. Our results suggest that the outbreak of HFMD occurred in younger children (average age 3.10 years), who seem to be the most susceptible age group for HFMD infection. Taking into account that the diagnosis of HFMD is usually clinical, we believe that it is important for health professionals to be well-informed about the clinical features and the course of the disease. Good personal hygiene and the implementation of a surveillance system can help stop the spread of the disease and prevent outbreaks.

Evaluation of models for multi-step forecasting of hand, foot and mouth disease using multi-input multi-output: A case study of Chengdu, China.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a public health concern that threatens the health of children. Accurately forecasting of HFMD cases multiple days ahead and early detection of peaks in the number of cases followed by timely response are essential for HFMD prevention and control. However, many studies mainly predict future one-day incidence, which reduces the flexibility of prevention and control. METHODS: We collected the daily number of HFMD cases among children aged 0-14 years in Chengdu from 2011 to 2017, as well as meteorological and air pollutant data for the same period. The LSTM, Seq2Seq, Seq2Seq-Luong and Seq2Seq-Shih models were used to perform multi-step prediction of HFMD through multi-input multi-output. We evaluated the models in terms of overall prediction performance, the time delay and intensity of detection peaks. RESULTS: From 2011 to 2017, HFMD in Chengdu showed seasonal trends that were consistent with temperature, air pressure, rainfall, relative humidity, and PM10. The Seq2Seq-Shih model achieved the best performance, with RMSE, sMAPE and PCC values of 13.943~22.192, 17.880~27.937, and 0.887~0.705 for the 2-day to 15-day predictions, respectively. Meanwhile, the Seq2Seq-Shih model is able to detect peaks in the next 15 days with a smaller time delay. CONCLUSIONS: The deep learning Seq2Seq-Shih model achieves the best performance in overall and peak prediction, and is applicable to HFMD multi-step prediction based on environmental factors.

Hand, Foot, and Mouth Disease Outbreak What You Need to Know.

HFMD is an obvious disease in children mostly below the age of five constituting a public health challenge to Asian-Pacific and developing countries majorly. This disease is often caused by enterovirus 71 (EV71) and Coxsackievirus A16. HFMD is a mild degree fever and general illness which manifests for about 10 days. Young age, male gender, poor hygiene, and high social contacts are some risk factors. HFMD can be diagnosed clinically by isolating the virus from stool and pharynx and identifying it on Light microscopic examination. Polymerase Chain Reaction Assay is a gold standard for confirming the virus from swabbed lesions. Late confirmation could lead to severe complications. There are no specific treatments and vaccines licensed for general use in the treatment of various serotypes of HFMD. The major strategy to prevent and control this disease is to strictly follow the WHO 8 guidelines to curb the spread of the disease.

75-year-old man • recent history of hand-foot-mouth disease • discolored fingernails and toenails lifting from the proximal end • Dx?

► recent history of hand-foot-mouth disease ► discolored fingernails and toenails lifting from the proximal end.

Ultrasensitive amperometric determination of hand, foot and mouth disease based on gold nanoflower modified microelectrode.

Given the widespread use of point-of-care testing for diagnosis of disease, micro-scale electrochemical deoxyribonucleic acid (DNA) biosensors have become a promising area of research owing to its fast mass transfer, high current density and rapid response. In this study, a gold nanoparticles modified gold microelectrode (AuNPs/Au-Me) was constructed to determine the hand, foot and mouth disease (HFMD)-related gene. The noble metal nanoparticles modification yielded ca. 7.4-fold increase in electroactive surface area of microelectrode, and the signal for HFMD-related gene was largely magnified. Under optimal conditions, the biosensor exhibited salient selectivity and sensitivity with a low detection limit of 0.3 fM (S/N = 3), which is sufficient for clinical diagnosis of HFMD. Additionally, the developed AuNPs/Au-Me was successfully applied to determining the polymerase chain reaction (PCR) amplified products of target gene. Thus, the electrochemical DNA biosensor possesses great potential in early-stage diagnosis and long-term monitoring of various disease.