Chemo assist for children mobile health application to manage chemotherapy-related symptoms in acute leukemia in Indonesia: a user-centered design approach.

BACKGROUND: A mobile health (mHealth) application can encourage parents and pediatric patients to be involved in caring for their child's health condition by providing the ability to identify and actively manage chemotherapy-related symptoms in their child. Several monitoring systems available today are diverse in features and system basis. This study aimed to develop and trial the Chemo Assist for Children (CAC) mHealth application for symptom management in children with acute lymphoblastic leukemia (ALL). METHODS: In this study, the development of the CAC application went through multiple phases and methods. Study phases included: (1) development of the application's feature based on the need assessment, (2) creation of content of application based on literature review, (3) develop prototyping of CAC, (4) expert review and feedback on the application content, (5) usability testing by targeted end-user. RESULTS: Based on need assessment, it was determined that parents with leukemia children were interested in symptom management of chemotherapy and preferred mobile applications. Therefore, a mHealth application was designed to include features to identify symptoms and provide recommendation strategies to manage the symptom. Usability evaluation by end-user revealed that mHealth is a valid, accessible, and appropriate application for users. CONCLUSIONS: The CAC mHealth application developed can meet the needs of technology users to identify symptoms and manage chemotherapy-related symptoms in children with ALL. The CAC mHealth application can accommodate data not recorded at out-of-hospital care, increase the independence of symptom management, and improve communication between parents of children with ALL and health workers.

Phylogenetic analysis of congenital rubella virus from Indonesia: a case report.

BACKGROUND: Rubella is a common inherited infection resulting in congenital cataracts and a significant cause of permanent vision loss in developing countries. In 2016, Indonesia had the highest number of congenital rubella syndrome (CRS) cases globally. Here, we report the first genotype of the rubella virus extracted from the eye lens from a child with congenital cataracts due to CRS. CASE PRESENTATION: A female neonate was delivered by an elective caesarean delivery with normal birth weight at term from a 24-year-old mother in the rural setting. The baby presented with bilateral congenital cataracts, small-moderate secundum atrial septal defect, severe supravalvular pulmonary stenosis, and profound bilateral hearing loss. She also had microcephaly and splenomegaly. The patient's serology showed persistent positive IgG for rubella virus at the age of four years and four months. Following extraction during cataract surgery, viral detection of the lenses identified the presence of rubella. Phylogenetic analysis confirmed that the virus was grouped into genotype 1E. CONCLUSIONS: Our study reports the first phylogenetic analysis of the rubella virus extracted from the eye lens of a child with CRS in Indonesia. The detection of the rubella virus from eye lenses is remarkably promising. Our findings also emphasize the importance of molecular epidemiology in tracking the origin of rubella infection toward achieving virus eradication.

Hospital-based surveillance of congenital rubella syndrome in Indonesia.

Congenital rubella syndrome (CRS) has serious consequences, such as miscarriage, stillbirth, and severe birth defects in infants, resulting from rubella virus infection during pregnancy. However, rubella vaccine has not yet been implemented in Indonesia. This study aimed (1) to estimate the incidence of CRS in Indonesia, (2) describe the clinical features of CRS at our referral hospital, and (3) pilot a CRS surveillance system to be extended to other hospitals. We conducted a 4-month prospective surveillance study of infants aged <1 year with suspected CRS in 2013 at an Indonesian hospital. Infants with suspected CRS were examined for rubella-specific IgM antibody or rubella IgG antibody levels. Of 47 suspected cases of CRS, 11/47 (23.4%), 9/47 (19.1%), and 27/47 (57.5%) were diagnosed as laboratory-confirmed, clinically compatible, and discarded CRS, respectively. The most common defects among laboratory-confirmed CRS cases were hearing impairment (100%), congenital cataracts (72.7%), microcephaly (72.7%), and congenital heart defects (45.5%). CONCLUSION: The number of laboratory-confirmed CRS cases among Indonesian infants is high. Furthermore, hearing impairment is the most common clinical feature of CRS in infants. Our findings indicate the importance of implementation of rubella vaccine in Indonesia. Conducting hospital-based surveillance of CRS in other hospitals in Indonesia may be appropriate. What is Known: •Congenital rubella syndrome (CRS) has serious consequences in infants resulting from rubella virus infection during pregnancy. •The incidence of CRS in most developed countries has greatly decreased since implementation of rubella vaccination. •Rubella vaccine has not yet been implemented in many developing countries. What is New: •The number of laboratory-confirmed CRS cases among Indonesian infants was high. •Implementation of rubella vaccine into immunization programs in Indonesia is important because of the high number of CRS cases. •Our study highlights the need for ongoing prospective surveillance of CRS in Indonesia.

Genetic exploration of Dravet syndrome: two case report.

BACKGROUND: Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental comorbidities. This article focuses on manifestations in two Indonesian children with Javanese ethnicity who experienced Dravet syndrome with an SCN1A gene mutation, presenting genetic analysis findings using next-generation sequencing. CASE PRESENTATION: We present a case series involving two Indonesian children with Javanese ethnicity whom had their first febrile seizure at the age of 3 months, triggered after immunization. Both patients had global developmental delay and intractable seizures. We observed distinct genetic findings in both our cases. The first patient revealed heterozygous deletion mutation in three genes (TTC21B, SCN1A, and SCN9A). In our second patient, previously unreported mutation was discovered at canonical splice site upstream of exon 24 of the SCN1A gene. Our patient's outcomes improved after therapeutic evaluation based on mutation findings When comparing clinical manifestations in our first and second patients, we found that the more severe the genetic mutation discovered, the more severe the patient's clinical manifestations. CONCLUSION: These findings emphasize the importance of comprehensive genetic testing beyond SCN1A, providing valuable insights for personalized management and tailored therapeutic interventions in patients with Dravet syndrome. Our study underscores the potential of next-generation sequencing in advancing genotype-phenotype correlations and enhancing diagnostic precision for effective disease management.

Neurological Manifestations of COVID-19 Associated Multisystem Inflammatory Syndrome in Children (MIS-C) in Yogyakarta, Indonesia.

OBJECTIVE: This observational cohort study aims to provide data on pediatric patients with neurological manifestations associated with multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease (Covid-19). METHODS: Patients aged <18 with neurologic symptoms and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from January, 2021 to January, 2022 at the Dr. Sardjito Hospital in Yogyakarta, Indonesia were evaluated. We used WHO diagnostic criteria to classify patients as MIS-C or non-MIS-C. Demographic information, symptoms, and outcomes were compared between MIS-C and non-MIS-C groups. RESULTS: Between January, 2021 and January, 2022, 74 pediatric patients were considered eligible. More than half of the patients were female (54.1%), and 24.3% presented with MIS-C. Length of hospitalization was significantly longer in MIS-C individuals (P=0.006). The commonest neurological findings were involuntary movements (43.2%) and paresis (27%). The commonest neuroimaging findings were meningoencephalitis (18.9%) and hydrocephalus (22.9%). Among all the variety of neurologic manifestations in non-MIS-C and MIS-C patients, a statistically significant result was found for fever (71.4% vs 100%; P=0.015), altered mental state (14.2% vs 50%, P=0.004), and paresis (33.9% vs 5.5%, P=0.030). CONCLUSION: MIS-C was found in 24% of our patients with acute neurologic symptoms, and most cases (51.8%) had positive SARS-CoV-2 antibody results.

Identification of the genetic basis of pediatric neurogenetic disorders at a tertiary referral hospital in Indonesia: Contribution of whole exome sequencing.

BACKGROUND: Neurogenetic disorders (NGDs) are complex Mendelian disorders that affect the neurological system. A molecular diagnosis will provide more information about pathophysiology, prognosis, and therapy, including future genetic therapy options. Whole-Exome Sequencing (WES) can rapidly discover the genetic basis in NGDs. OBJECTIVE: The purpose of this study was to assess the WES results and its value in diagnosing pediatric NGDs, especially those with unspecified clinical features. METHODS: A retrospective chart review was performed from May 2021- February 2023 in Dr. Sardjito General Hospital, a tertiary referral hospital in Yogyakarta, Indonesia. WES proband only was conducted on children aged 0 to 17 years old who met one or more of the following criteria: (1) epileptic encephalopathy and familial epilepsy; (2) complex neurodevelopmental phenotypes; (3) leukodystrophy; (4) movement disorders; and (5) neurocutaneous disorder. The WES was conducted in the certified laboratory, 3Billion, in Seoul, Korea. RESULTS: The diagnosis yield of WES in our study was 45% (9/20). We identified nine positive results, including eight pathogenic single nucleotide variants (SNVs) in 8 genes (KCNQ2, ARSA, UBE3A, IRF2BPL, ATM, MECP2, TSC2, and NF1), and one variant with uncertain significance (VUS) in the ADK gene that has not been able to explain the observed clinical features. Of the nine patients with positive WES results, five had missense mutations, three frameshift mutations, and one nonsense mutation. Additionally, we identified two suggestive copy number variants (CNVs) in 15q11.2q13.1 and 1p31.3. CONCLUSIONS: Whole-Exome Sequencing is an essential diagnostic tool for pediatric NGDs, especially those with unspecified clinical features. It ends multi-year diagnostic odysseys, provides personalized medicine therapy, and optimizes genetic counselling for these families.

Development and Evaluation of Internet-based Health Technology in Pediatric Oncology: A Scoping Review.

OBJECTIVE: There is an increased awareness to identify symptomatic experiences in children undergoing chemotherapy. An Internet-based health technology accessible and friendly for children and parents to report health problems during chemotherapy has been well-developed in developed countries. The purpose of this scoping review is to provide a comprehensive view of relevant research related to the emergence of health applications in pediatric oncology so that it can provide information for design and evaluation in the future. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines support this scoping review. To investigate the evidence on the development of Internet-based health technology, Science Direct, Scopus, PubMed, EBSCOHOST Medline, IEEEXplore, ProQuest, and Nature databases were searched between 2015 and 2021. RESULTS: 14 articles met the inclusion criteria with nine Internet-based health technologies. Moreover, four of nine mobile health apps use a theoretical foundation (SPARK for children and family member, Empower Stars!, THRIVE, and Facebook-based "Healthy Teens for Soaam"), three apps apply four stages of development and testing, and all apps have met the category of the degree of attachment of patients to the application. CONCLUSION: The effect of Internet-based health technology through a scientific process by paying attention to the underlying theories, user needs, developer passion, application testing, and evaluation methods is the key to success.

Estimation of Japanese encephalitis virus infection prevalence in mosquitoes and bats through nationwide sentinel surveillance in Indonesia.

Indonesia belongs to endemic areas of Japanese encephalitis (JE), yet data regarding the true risk of disease transmission are lacking. While many seroprevalence studies reported its classic enzootic transmission, data related to the role of bats in the transmission of JE virus are limited. This current study aimed to identify the potential role of bats in the local transmission of the JE virus to aid the ongoing active case surveillance in Indonesia, in order to estimate the transmission risk. Mosquitoes and bats were collected from 11 provinces in Indonesia. The detection of the JE virus used polymerase chain reaction (PCR). Maps were generated to analyze the JE virus distribution pattern. Logistic regression analysis was done to identify risk factors of JE virus transmission. JE virus was detected in 1.4% (7/483) of mosquito pools and in 2.0% (68/3,322) of bat samples. Mosquito species positive for JE virus were Culex tritaeniorhynchus and Cx. vishnui, whereas JE-positive bats belonged to the genera Cynopterus, Eonycteris, Hipposideros, Kerivoula, Macroglossus, Pipistrellus, Rousettus, Scotophilus and Thoopterus. JE-positive mosquitoes were collected at the same sites as the JE-positive bats. Collection site nearby human dwellings (AOR: 2.02; P = 0.009) and relative humidity of >80% (AOR: 2.40; P = 0.001) were identified as independent risk factors for JE virus transmission. The findings of the current study highlighted the likely ongoing risk of JE virus transmission in many provinces in Indonesia, and its potential implications on human health.

The role of whole exome sequencing in the UBE3A point mutation of Angelman Syndrome: A case report.

INTRODUCTION: Angelman Syndrome (AS) is a rare disorder with a relatively well-defined phenotype caused by lack of expression of the maternally inherited ubiquitin-protein ligase E3A (UBE3A) gene in the brain. This article describes the role of genetic testing using whole-exome sequencing (WES) in detecting rare AS variants, a point mutation in the UBE3A gene. CASE PRESENTATION: We describe a rarely reported clinical presentation of AS in a two year and ten months old girl with severe developmental delay, movement and balance disorder, frequent smiling, apparent happy demeanor, speech impairment, absence of seizure, lack of sleep, and abnormal food-related behavior. Physical examination showed microcephaly, with facial characteristics of AS, ataxia gait, and truncal hypotonia. The electroencephalogram showed medium amplitude rhythmic 2-3c/s. Brain Magnetic Resonance Imaging revealed microcephaly, corpus callosum dysgenesis, and heterotopia grey matter on the bilateral lateral ventricle. WES was conducted to search pathogenic variants and showed a heterozygous mutation in exon 9 of the UBE3A gene, c.1513C > T (p.Arg505Ter). CONCLUSION: Angelman syndrome is a neurodevelopmental disorder that has several underlying genetic etiologies. WES could detect a rare variant of Angelman syndrome, identified as the point mutation of the UBE3A gene, which cannot be seen with other modalities.

Dp71 and intellectual disability in Indonesian patients with Duchenne muscular dystrophy.

INTRODUCTIONS: Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive muscular disease marked by developmental delays due to mutations in the DMD gene, which encodes dystrophin. Brain comorbidity adds to the burden of limited mobility and significantly impacts patients' quality of life and their family. The changes of expression of dystrophin isoforms in the brain due to DMD gene mutations are thought to be related to the cognitive and neurobehavior profiles of DMD. OBJECTIVES: This cross-sectional study aimed to characterize cognitive and neurodevelopmental profiles of patients with DMD and to explore underlying genotype-phenotype associations. METHODS: Patients with DMD aged 5-18 years from Dr Sardjito Hospital and Universitas Gadjah Mada Academic Hospital from 2017-2022 were included. Multiplex ligation-dependent probe amplification and whole exome sequencing were used to determine mutations in the DMD genes. Cognitive function was measured by intelligence quotient testing using the Wechsler Intelligence Scale for Children and adaptive function tests with Vineland Adaptive Behavior Scales. The Autism Mental Status Exam and Abbreviated Conner's Rating Scale were used to screen for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD), respectively. RESULTS: The mean total IQ score of DMD patients was lower than that of the general population (80.6 ± 22.0 vs 100 ± 15), with intellectual disability observed in 15 boys (29.4%). Of the 51 patients with DMD, the Dp71 group had the lowest cognitive performance with a total IQ score (46 ± 24.8; p = 0.003), while the Dp427 group and Dp140 group's total IQ scores were 83.0 ± 24.6 and 84.2 ± 17.5 respectively. There were no DMD patients with ASD, while 4 boys (7.8%) had comorbidity with ADHD. CONCLUSION: Boys with DMD are at higher risk of intellectual disability. The risk appears to increase with mutations at the 3' end of the gene (Dp71 disruption). Moreover, Dp71 disruption might not be associated with ADHD and ASD in patients with DMD.

Predicting Candida Infection in Pediatric Intensive Care Unit using Candida Score in a Low-Resource Setting.

Candida infection was previously thought to be rare in intensive care. With the increased use of broad-spectrum antibiotics, the incidence of candida infection increased significantly. Case-control study was done in patients ≤18 years of age treated for 3 days or more in Pediatric Intensive Care Unit (PICU) Dr. Sardjito General Hospital, Yogyakarta from January 2014 to December 2016. Overall, 43 children were included in this study as a case group with positive candida culture and 43 children as a control group with no candida culture. Cut off point of candida score is ≥3 from our subjects. The area under curve (AUC) value for cut off ≥3 was moderate (0,72). Candida score ≥3 has an odd ratio (OR) 6.8 (95% CI 2.4-18.6) with P < .05. All of confounding factors in candida infection have no association with P > .05. Candida score can be used as predictor of candida infection in PICU.

The detection of Japanese encephalitis virus in Megachiropteran bats in West Kalimantan, Indonesia: A potential enzootic transmission pattern in the absence of pig holdings.

The West Kalimantan province in Borneo island, Indonesia belongs to endemic area of Japanese encephalitis (JE) that accounts for approximately 30% of total cases yearly. As the presence of pig holdings is uncommon in West Kalimantan, another reservoir host might have played a role in the local transmission of JE virus in this area. Current study aimed to identify the potential role of bats in the local transmission of JE by performing molecular detection of JE virus in bats and mosquitoes using RT-PCR. Sample collection was performed in 3 districts in West Kalimantan, covering 3 different ecosystems: forest, coastal, and residential areas. Bat collection was performed using mist net and harp net, while mosquito collection was carried out using animal-baited trap and human landing collection. A total of 373 blood samples from bats were tested for JE virus, among which 21 samples (5.6%) showed positive results, mainly from Cynopterus brachyotis (lesser short-nosed fruit bat) found in residential areas. Out of 53 mosquito pools, 3 JE-positive pools of Culex tritaeniorhynchus and Cx. vishnui were collected at the same location as JE-positive bats. Current study showed the first evidence of JE virus detection in several species of Megachiropteran bats in Indonesia, demonstrated the potential role of frugivorous bats in local transmission of JE in West Kalimantan. More aggressive measures are required in JE risk mitigation, particularly in initiating JE vaccination campaign and in avoiding disruption of bats' natural habitats through changes in land-use.

Congenital Rubella Syndrome Surveillance After Measles Rubella Vaccination Introduction in Yogyakarta, Indonesia.

BACKGROUND: Congenital rubella syndrome (CRS) is a fatal disease causing severe congenital defects. Indonesia had the highest CRS cases in the world in 2016 with a commitment to achieve elimination of rubella disease by 2020, through the campaign and introduction of measles rubella (MR) national vaccination program in 2017 and 2018. This study aimed to describe the impact of the national vaccination campaign by conducting surveillance of CRS cases and comparing the incidence of new CRS cases before and after the MR vaccination campaign. METHODS: From July 2015 to July 2020, we conducted surveillance of CRS in Yogyakarta. Suspected patients underwent complete clinical examinations. Serology was tested for the presence of IgM and IgG antibodies against rubella. Descriptive analysis was used to characterize the demographic and clinical characteristics of the cases before and after the MR vaccination campaign. RESULTS: The study involved 229 infants who were suspected for CRS. Laboratory-confirmed cases were found in 47 of them (20.86%). Most of the laboratory-confirmed cases (55.3%) were reported among 1-5 months old infants. Common clinical features among laboratory-confirmed cases included structural heart defects in 43 (91.4%). There was a significant decrease (60.9%) of CRS incidence from 0.39 per 1000 live births in the precampaign era to 0.08 in the postcampaign era (P = 0.00). CONCLUSION: There has been a significant declining number of CRS cases based on pre- and post-MR vaccination campaign in Yogyakarta, Indonesia. An effective surveillance system will help monitor the number of CRS cases.

Novel SCN1A mutations in Indonesian patients with severe myoclonic epilepsy in infancy.

BACKGROUND: Severe myoclonic epilepsy in infancy (SMEI) and borderline SMEI (SMEB) are caused by a mutation in SCN1A, which encodes a voltage-gated sodium channel alpha1-subunit protein. Although many mutations in SCN1A have been associated with clinical features of SMEI or SMEB from different ethnic groups, there have been no such reports from the South-East Asian populations so far. METHODS: Patients 1 and 2 were Indonesian children diagnosed as having SMEI and SMEB based on their clinical features. SCN1A was screened for mutations using a combination of polymerase chain reaction and denaturing high-performance liquid chromatography. Nucleotide substitutions were confirmed on direct sequencing. RESULTS: In patient 1, a G-to-A heterozygous transition was detected at nucleotide 4834 (c.4834G>A) in exon 25, leading to substitution of valine with isoleucine at amino acid position 1612 (p.V1612I) in the SCN1A protein. In patient 2 a T-to-G heterozygous transversion was identified at nucleotide 5266 (c.5266T>G) in exon 26, leading to substitution of cysteine with glycine at amino acid 1756 (p.C1756G) in the SCN1A protein. Both amino acid substitutions might disrupt these highly conserved regions in species from drosophila to human, leading to dysfunction of the protein. p.V1612I and p.C1756G were determined as disease-causing mutations due to their absence in the control population. CONCLUSION: The first cases of SMEI and SMEB are reported in South-East Asian populations. Two novel SCN1A mutations are also identified in these patients, p.V1612I and p.C1756G, which may lead to neuronal excitability or convulsions.

Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract in neonates. Three polymorphisms, rs2435357, within a conserved transcriptional enhancer of RET, and, rs7835688 and rs16879552, within intron 1 of NRG1, have been shown to be associated with isolated forms of HSCR. We wished to replicate these findings, and study the interactions between these variants, in Indonesian HSCR patients. METHODS: Sixty isolated HSCR patients and 124 controls were ascertained for this study. The three genetic markers were examined using TaqMan Genotyping Assays in genomic DNA for association studies. RESULTS: RET rs2435357 showed the strongest association with HSCR both by case-control analysis (p=2.5 × 10(-8)) and transmission disequilibrium test (p=4.2 × 10(-6)). NRG1 rs7835688 was modestly associated with HSCR only by case-control analysis (p=4.3 × 10(-3)), whereas rs16879552 demonstrated no association (p>0.097). Two locus analyses of variants showed significant interactions with increased and decreased disease risks of HSCR at NRG1 but conditional on rs2435357 genotype. CONCLUSIONS: RET and NRG1 variants are common susceptibility factors for HSCR in Indonesia. These common variants demonstrate that development of HSCR requires joint effects of RET and NRG1 early in gut development.

Generalized epilepsy with febrile seizures plus (GEFS+) spectrum: clinical manifestations and SCN1A mutations in Indonesian patients.

Generalized epilepsy with febrile seizures plus (GEFS+) is a childhood genetic epilepsy syndrome. GEFS+ includes a wide spectrum of clinical manifestations, and SCN1A mutations have frequently been reported among the GEFS+-related gene abnormalities. In this study, to clarify the distributions of the clinical subtypes, we analyzed 34 families with GEFS+ in Indonesia using the hospital records of the patients and questionnaires for the family members. The number of patients with febrile seizures plus (FS+), FS+ and afebrile generalized/partial seizures, borderline severe myoclonic epilepsy in infancy (SMEB) and severe myoclonic epilepsy in infancy (SMEI) were 9, 11, 7, and 7, respectively. Most patients had a family history of febrile seizures. Next, we performed molecular analyses to clarify the contributions of SCN1A mutations to the development of the GEFS+ subtypes. Only 3 of 34 probands showed SCN1A mutations. These mutations were two missense mutations, p.V1612I and p.C1756G, in two patients with SMEI and SMEB, and one silent mutation, p.G1762G, in a patient with FS+ and afebrile partial seizures. In conclusion, the majority of GEFS+ patients in Indonesia were not associated with SCN1A mutations. To detect the GEFS+-causing mutations, we must search and analyze other genes in these patients.