Cystic fibrosis in a female adolescent carrying c.263T>G (p.Leu88X) and c.2977G>T (p.Asp993Tyr) mutation

Cystic fibrosis (CF) is a chronic progressive autosomal recessive disease and caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. CFTR gene encodes an ion channel involved in salt and water transport in multiple organs including lung, pancreas and reproductive tract. To date, more than 2,000 mutations of CFTR gene have been identified. Because the age of onset and the severity of symptoms may vary greatly, a diagnosis of CF can be challenging. Although CF is common in Caucasians, it is extremely rare in Koreans. A few cases of CF have been reported in Korean children since 1988. Here, we report a 13-year-old girl carrying c.263T>G (p.Leu88X) and c.2977G>T (p.Asp993Tyr). Furthermore, we reviewed 22 Korean cystic fibrosis cases reported in the literature.

Risk Factors and Comorbidities Associated With the Allergic Rhinitis Phenotype in Children According to the ARIA Classification

PURPOSE: Data are lacking on the association between the allergic rhinitis (AR) phenotype and sensitization to specific allergens or bronchial hyperresponsiveness (BHR) in children. We here investigated risk factors and comorbidities, including sensitization to specific allergens and BHR, for the AR phenotype by AR and its Impact on Asthma (ARIA) classification in a general population-based birth cohort study. METHODS: We enrolled 606 children aged 7 years from the Panel Study of Korean Children. The AR phenotype was assigned in accordance with the ARIA classification in children. Skin prick tests and Provocholine provocation test were performed. Risk factors and comorbidities for AR phenotypes were then analyzed. RESULTS: The prevalence of mild and moderate to severe AR in our study cohort was 37.2% and 8.8%, respectively. Recent use of analgesics or antipyretics and current cat ownership were associated with the risk of mild persistent AR. Sensitizations to Dermatophagoides Pteronyssinus (Der p), Japanese hop and cat were associated with moderate to severe persistent AR. Children with moderate to severe AR had a higher risk of current asthma and BHR compared to mild AR cases (adjusted odds ratio [aOR], 5.26; 95% confidence interval [CI], 1.77–15.62). Moderate to severe AR with allergic sensitization was associated with the highest risk of BHR (aOR, 11.77; 95% CI, 3.40–40.74). CONCLUSIONS: Moderate to severe-persistent AR is more closely related to respiratory comorbidities and sensitizations than mild AR. Stratifying the AR phenotype by ARIA classification may assist in disease management.

Associated Factors for Asthma Severity in Korean Children: A Korean Childhood Asthma Study

PURPOSE: Childhood asthma has a considerable social impact and economic burden, especially in severe asthma. This study aimed to identify the proportion of childhood asthma severity and to evaluate associated factors for greater asthma severity. METHODS: This study was performed on 667 children aged 5–15 years with asthma from the nationwide 19 hospitals in the Korean childhood Asthma Study (KAS). Asthma was classified as mild intermittent, mild persistent, and moderate/severe persistent groups according to the National Asthma Education and Prevention Program recommendations. Multinomial logistic regression models were used to identify the associated factors for greater asthma severity. RESULTS: Mild persistent asthma was most prevalent (39.0%), followed by mild intermittent (37.6%), moderate persistent (22.8%), and severe persistent asthma (0.6%). Onset later than 6 years of age (adjusted odds ratio [aOR], 1.69 for mild persistent asthma; aOR, 1.92 for moderate/severe persistent asthma) tended to increase asthma severity. Exposure to environmental tobacco smoke (aOR, 1.53 for mild persistent asthma; aOR, 1.85 for moderate/severe persistent asthma), and current dog ownership with sensitization to dog dander (aOR, 5.86 for mild persistent asthma; aOR, 6.90 for moderate/severe persistent asthma) showed increasing trends with greater asthma severity. Lower maternal education levels (aOR, 2.32) and no usage of an air purifier in exposure to high levels of outdoor air pollution (aOR, 1.76) were associated with moderate/severe persistent asthma. CONCLUSIONS: Modification of identified environmental factors associated with greater asthma severity might help better control childhood asthma, thereby reducing the disease burden due to childhood asthma.

Seasonal patterns and etiologies of croup in children during the period 2010–2015: A multicenter retrospective study

PURPOSE: Croup is known to have epidemics in seasonal and biennial trends, and to be strongly associated with epidemics of parainfluenza virus. However, seasonal and annual epidemics of croup have not been clearly reported in Korea. This study aimed to examine the seasonal/annual patterns and etiologies of childhood croup in Korea during a consecutive 6-year period. METHODS: Pediatric croup data were collected from 23 centers in Korea from 1 January 2010 to 31 December 2015. Electronic medical records, including multiplex reverse transcription polymerase chain reaction (RT-PCR) results, demographics and clinical information were cross-sectionally reviewed and analyzed. RESULTS: Overall, 2,598 childhood croup patients requiring hospitalization were identified during the study period. Among them, a total of 927 who underwent RT-PCR were included in the analysis. Males (61.5%) predominated, and most (63.0%) of them were younger than 2 years of age (median, 19 months; interquartile range, 11–31 months). Peak hospitalization occurred in 2010 and 2012 in even-numbered years, and parainfluenza virus (PIV, 39.7%) was the most common cause of childhood croup requiring hospitalization, followed by respiratory syncytial virus (14.9%), human rhinovirus (12.5%), Mycoplasma pneumonaie (10.6%), and human coronavirus (7.3%). CONCLUSION: It is concluded that croup hospitalization has a biennial pattern in even-numbered years. PIV may be the most common cause of childhood croup; however, croup epidemics could be attributed to other viruses.

Indoor pet ownership in infancy is a risk factor for the development of sensitization to pets and asthma in childhood

PURPOSE: It is controversial whether indoor pet exposure is either a risk or protective factor developing sensitization to pet allergens or asthma. Therefore, we investigated whether indoor pet ownership entails a risk for the development of asthma and sensitization in childhood. METHODS: The Panel Study of Korean Children (PSKC) is a general-population-based birth cohort study that recruited 2,078 mother-baby dyads in Korea between April and July of 2008. Among 1,577 children who were followed up in 2015, 559 underwent skin prick tests, spirometry and bronchial provocation tests using Provocholine. Having a cat or a dog and the prevalence of asthma were evaluated by using self-reported questionnaires and physicians’ medical records. RESULTS: During infancy, the rate of dog ownership was 4.5% (71 of 1,574) and that of cat ownership was 0.5% (8 of 1,574). Of the subjects, 7.9% (n=109) currently had at least 1 dog and 2.5% (n=34) had at least 1 cat. Pet ownership during infancy was associated with sensitization to cats or dogs (adjusted odds ratio [aOR], 4.24; 95% confidence interval [CI], 1.29–13.98), wheezing within 12 months (aOR, 5.56; 95% CI, 1.65–18.75) and current asthma (wheezing episode in the last 12 months+diagnosed asthma by physicians) (aOR, 6.36; 95% CI, 1.54–26.28). In contrast, pet ownership during the last 12 months was not associated with sensitization to cats or dogs or current asthma. CONCLUSION: Indoor pet exposure during infancy can be critical for developing sensitization to cats or dogs and asthma in childhood. Avoidance of pet exposure in early life may reduce sensitization to cats or dogs and development of asthma.

Prevalence, Risk Factors and Cutoff Values for Bronchial Hyperresponsiveness to Provocholine in 7-Year-Old Children

BACKGROUND: A US Food and Drug Administration (FDA)-approved drug methacholine chloride (Provocholine®) was recently introduced to Korea where it is now widely used in clinical practice. We aimed to evaluate the prevalence, risk factors and cutoff value of bronchial hyperresponsiveness (BHR) to Provocholine in 7-year-old children. METHODS: Six hundred and thirty-three children from the Panel Study on Korean Children who visited 16 regional hospitals were evaluated. Skin prick tests, spirometry and bronchial provocation tests for Provocholine as well as a detailed history and physical examinations were performed. The bronchial provocation test was reliably performed on 559 of these children. RESULTS: The prevalence of ever-diagnosed asthma via medical records was 7.7%, and that of current asthma (wheezy episode in the last 12 months + diagnosed asthma by physicians) was 3.2%. The prevalence of BHR to Provocholine was 17.2% and 25.8%, respectively, for a PC20 < 8 and < 16 mg/mL. The risk factors for BHR (PC20 < 16 mg/mL) were atopic dermatitis diagnosis and current dog ownership, whereas those for current asthma were allergy rhinitis diagnosis, a history of bronchiolitis before the age of 3, recent use of analgesics/antipyretics and maternal history of asthma. The BHR prevalence trend showed an increase along with the increased immunoglobulin E (IgE) quartile. The cutoff value of PC20 for the diagnosis of current asthma in children at age 7 was 5.8 mg/mL (sensitivity: 47.1%, specificity: 87.4%). CONCLUSIONS: BHR to Provocholine (PC20 < 8 mg/mL) was observed in 17.2% of 7-year-olds children from the general population and the cutoff value of PC20 for the diagnosis of current asthma was 5.8 mg/mL in this age group. The risk factors for BHR and current asthma showed discrepancies suggesting different underlying mechanisms. Bronchial provocation testing with Provocholine will be a useful clinical tool in the future.

Mycoplasma pneumoniae pneumonia in children: Clinical characteristics and risk factors of refractory pneumonia by age

PURPOSE: It is thought that Mycoplasma pneumoniae infection is more prevalent and causes more severe pneumonia in school-age children and young adults than in preschool children; however, recent studies suggest that the infection may be underdiagnosed and more severe in preschool children. This study investigated the clinical characteristics of Mycoplasma pneumoniae pneumonia (MPP) and the risk factors of refractory MPP (RMPP) by age. METHODS: We retrospectively reviewed the medical records of 353 children admitted due to MPP from January 2015 to December 2016. Demographics, clinical information, laboratory data and radiological findings were collected from all patients in this study. The patients were divided into 2 groups by the age of 6 years. Also, both preschool ( 722 IU/L (odds ratio [OR], 3.02; 95% confidence interval [CI], 1.44–6.50) and ferritin >177 ng/mL (OR, 5.38; 95% CI, 1.61–19.49) were significant risk factors for RMPP, while LDH >645 IU/L (OR, 4.12; 95% CI, 1.64–10.97) and ferritin >166 ng/mL (OR, 5.51; 95% CI, 1.59–22.32) were so in school-age children. CONCLUSION: Clinical features of MPP were significantly different between preschool and school-age children. LDH and ferritin may be significant factors of RMPP in preschool and school-age children.

Clinical characteristics of acute lower respiratory tract infections according to respiratory viruses in hospitalized children without underlying disease during the last 3 years / 영남의대학술지

BACKGROUND: Respiratory viruses play a significant role in the etiology of acute respiratory infections and exacerbation of chronic respiratory illnesses. This study was conducted to identify the epidemiological and clinical characteristics of children with acute viral lower respiratory infections.METHODS: This study investigated 1,168 children diagnosed with acute viral lower respiratory tract infections (RTIs) between January 2012 and December 2014. Specimens of respiratory viruses were collected using a nasopharyngeal swab and analyzed by reverse transcriptase polymerase chain reaction. We retrospectively reviewed the medical records and analyzed the clinical features of children hospitalized for acute lower respiratory infections.RESULTS: Respiratory syncytial virus (RSV), the main cause of infection in children aged <5 years, was the most commonly detected pathogen in children with bronchiolitis and pneumonia, and resulted in high proportions of children requiring oxygen treatment and intensive care unit admission. Rhinovirus was preceded by RSV as the second most common cause of bronchiolitis and pneumonia, and was detected most frequently in the children aged ≥6 years. In addition, asthma was predominantly caused by rhinovirus in children aged ≥6 years, whereas croup was mostly caused by parainfluenza virus in those aged <5 years. Rhinovirus infection (p < 0.001) and history of asthma (p=0.049) were identified as significant risk factors for readmission within a month.CONCLUSION: We identified the epidemiological and clinical characteristics of respiratory viruses in children with acute lower respiratory infections during the last 3 years. Our findings may provide useful clinical insight to comprehend the acute viral lower RTIs in children.

Clinical characteristics of acute lower respiratory tract infections according to respiratory viruses in hospitalized children without underlying disease during the last 3 years / 영남의대학술지

BACKGROUND: Respiratory viruses play a significant role in the etiology of acute respiratory infections and exacerbation of chronic respiratory illnesses. This study was conducted to identify the epidemiological and clinical characteristics of children with acute viral lower respiratory infections. METHODS: This study investigated 1,168 children diagnosed with acute viral lower respiratory tract infections (RTIs) between January 2012 and December 2014. Specimens of respiratory viruses were collected using a nasopharyngeal swab and analyzed by reverse transcriptase polymerase chain reaction. We retrospectively reviewed the medical records and analyzed the clinical features of children hospitalized for acute lower respiratory infections. RESULTS: Respiratory syncytial virus (RSV), the main cause of infection in children aged <5 years, was the most commonly detected pathogen in children with bronchiolitis and pneumonia, and resulted in high proportions of children requiring oxygen treatment and intensive care unit admission. Rhinovirus was preceded by RSV as the second most common cause of bronchiolitis and pneumonia, and was detected most frequently in the children aged ≥6 years. In addition, asthma was predominantly caused by rhinovirus in children aged ≥6 years, whereas croup was mostly caused by parainfluenza virus in those aged <5 years. Rhinovirus infection (p < 0.001) and history of asthma (p=0.049) were identified as significant risk factors for readmission within a month. CONCLUSION: We identified the epidemiological and clinical characteristics of respiratory viruses in children with acute lower respiratory infections during the last 3 years. Our findings may provide useful clinical insight to comprehend the acute viral lower RTIs in children.

Diffuse panbronchiolitis in an adolescent female

Diffuse panbronchiolitis (DPB) is a progressive inflammatory respiratory disease of unknown cause mainly occurring in East Asian people. Studies on causes of the disease point to a genetic predisposition unique to Asians, but the cause remains unknown. If untreated, DPB progresses to bronchiectasis, respiratory failure, and death. The age of patients at onset of the disease varies from young to elderly people with a peak at 40-60 years. A few cases of DPB have been reported in Korean adults since 1992; however, the case of DPB in children is uncommon. Herein, we describe a 16-year-old girl with DPB who presented with chronic cough and sputum.

A Patient with IgA Nephropathy: 5 Years after Complete Remission of Minimal Change Nephrotic Syndrome / 이화의대지

A 37-year-old male patient was admitted with generalized edema as the main symptom. A blood test confirmed hypoalbuminemia and hyperlipidemia, and a urine test confirmed severe albuminuria. A renal biopsy was conducted, which revealed a diagnosis of minimal change disease. Although the patient experienced complete remission of minimal change nephrotic syndrome after oral prednisolone and cyclophosphamide treatment, he is readmitted due to bilateral leg edema 5 years later since minimal change nephrotic syndrome was completely cured. The patient is diagnosed with IgA nephropathy. Although the exact mechanisms of IgA nephropathy in this patient remain unclear, this case represents an extremely rare development, and is separate from the remission of minimal change nephrotic syndrome.

Clinical Study of a Newly Diagnosed Case of Gitelman Syndrome in a Patient Monitored for Liddle Syndrome

A 55-year-old man who had been monitored for Liddle syndrome in the nephrology division for 15 years visited again Inje University Sanggye Paik Hospital for a newly developed electrolyte disorder. Because his blood pressure was normal and he showed hypomagnesemia and hypokalemia, a renal clearance test and renal biopsy were conducted for suspected Gitelman syndrome. The patient was diagnosed with Gitelman syndrome, which has been previously reported 12 cases in South Korea. The renal clearance test revealed a disorder of the Na-Cl cotransporter (NCCT) in the distal tubule, while the renal biopsy revealed partial expression of NCCT, typical of Gitelman syndrome. Currently, the patient is being monitored, and is receiving oral administration of calcium and magnesium.

The First Successful Heart-Lung Transplant in a Korean Child with Humidifier Disinfectant-Associated Interstitial Lung Disease

From 2006 to 2011, an outbreak of a particular type of childhood interstitial lung disease occurred in Korea. The condition was intractable and progressed to severe respiratory failure, with a high mortality rate. Moreover, in several familial cases, the disease affected young women and children simultaneously. Epidemiologic, animal, and post-interventional studies identified the cause as inhalation of humidifier disinfectants. Here, we report a 4-year-old girl who suffered from severe progressive respiratory failure. She could survive by 100 days of extracorporeal membrane oxygenation support and finally, underwent heart-lung transplantation. This is the first successful pediatric heart-lung transplantation carried out in Korea.

A Multicenter Retrospective Case Study of Anaphylaxis Triggers by Age in Korean Children

PURPOSE: Although anaphylaxis is recognized as an important, life-threatening condition, data are limited regarding its triggers in different age groups. We aimed to identify anaphylaxis triggers by age in Korean children. METHODS: We performed a retrospective review of medical records for children diagnosed with anaphylaxis between 2009 and 2013 in 23 secondary or tertiary hospitals in South Korea. RESULTS: A total of 991 cases (mean age=5.89±5.24) were reported, with 63.9% involving patients younger than 6 years of age and 66% involving male children. Food was the most common anaphylaxis trigger (74.7%), followed by drugs and radiocontrast media (10.7%), idiopathic factors (9.2%), and exercise (3.6%). The most common food allergen was milk (28.4%), followed by egg white (13.6%), walnut (8.0%), wheat (7.2%), buckwheat (6.5%), and peanut (6.2%). Milk and seafood were the most common anaphylaxis triggers in young and older children, respectively. Drug-triggered anaphylaxis was observed more frequently with increasing age, with antibiotics (34.9%) and nonsteroidal anti-inflammatory drugs (17.9%) being the most common causes. CONCLUSIONS: The most common anaphylaxis trigger in Korean children was food. Data on these triggers show that their relative frequency may vary by age.

Dynamics of Gut Microbiota According to the Delivery Mode in Healthy Korean Infants

Microbial colonization of the infant gut is unstable and shows a wide range of diversity between individuals. Gut microbiota play an important role in the development of the immune system, and an imbalance in these organisms can affect health, including an increased risk of allergic diseases. Microbial colonization of young infants is affected by the delivery mode at birth and the consequent alterations of gut microbiota in early life affect the development of allergic diseases. We investigated the effects of the delivery mode on the temporal dynamics of gut microbiota in healthy Korean infants. Fecal samples were collected at 1-3 days, 1 month, and 6 months after birth in six healthy infants. Microbiota were characterized by 16S rRNA shotgun sequencing. At the first and third days of life, infants born by vaginal delivery showed a higher richness and diversity of gut microbiota compared with those born by cesarean section. However, these differences disappeared with age. The Bacteroides genus and Bacteroidetes phylum were abundant in infants born by vaginal delivery, whereas Bacilli and Clostridium g4 were increased in infants born by cesarean section. The Firmicutes phylum and Bacteroides genus showed convergent dynamics with age. This study demonstrated the effect of delivery mode on the dynamics of gut microbiota profiles in healthy Korean infants.

A study of the use of home mechanical ventilator and medical insurance

PURPOSE: Use of a home mechanical ventilator can shorten the hospitalization duration of children with chronic respiratory failure requiring long-term use of a mechanical ventilator. In this study, the researchers analyzed patients who had used a home mechanical ventilator. METHODS: From January 2009 to July 2014, we retrospectively investigated 15 patients under 18 years of age, from 2 hospitals, and their use of home mechanical ventilators. RESULTS: The median age of the patients was 55 months. Ten children were male, and 5 were female. As for the type of mechanical ventilators, 10 used a pressure type, 3 used a volume type, and 2 used a volume-mask type. Analysis of underlying diseases revealed that 10 children had neuromuscular disease, 3 had pulmonary disease, and 2 suffered from hypoxic ischemic encephalopathy. The number of patients who were discharged from the hospital with a home mechanical ventilator was 13. One child died of sepsis irrespective of the mechanical ventilator. Six patients had health insurance. But 9 did not. The group with insurance had the possibility of being discharged earlier than the group without. On readmission, the length of hospitalization was also reduced in patients who had used a home mechanical ventilator. CONCLUSION: Use of a mechanical ventilator at home is helpful in patients who need long-term use of a mechanical ventilator due to neuromuscular disease, chronic pulmonary diseases, and accidents because complications are rare and insurance coverage is feasible.

The cause of hemoptysis according to age and the amount of hemoptysis in children

PURPOSE: Studies on hemoptysis is rare because hemoptysis is an uncommon symptom in children. The aim of this study was to identify the causes of hemoptysis in children. METHODS: Medical chart review of patients with hemoptysis was retrospectively conducted at 2 tertiary hospitals from November 2008 to December 2014. Patients were divided into 3 groups according to age. The amount of hemoptysis was categorized as mild (<20 mL/day), moderate (20–99 mL/day), and massive (≥100 mL/day). RESULTS: A total of 59 patients were identified, and their mean age was 11.0±5.6 years. Among the causes of hemoptysis, respiratory tract infection was most common. Other causes included vasculitis syndrome, neoplasm in the airway, idiopathic pulmonary hemosiderosis, cardiac disease, and bronchiectasis. According to age, a significant difference was identified between the age groups in children with pneumonia (<6 years vs. 12–18 years, P=0.001). Differences were verified between the age groups in children with tuberculosis (<6 years vs. 12–18 years and 6–11 years vs. 12–18 years, P=0.023). According to amounts of hemoptysis, no significant difference was identified regardless of the causes. CONCLUSION: This study showed that the causes of hemoptysis in children were heterogeneous and the respiratory tract infection was most common. In children with hemoptysis, the age of onset and the amount of hemoptysis are needed to be considered for more precise diagnosis and more proper management of the underlying cause of hemoptysis.

Erratum: Acknowledgments Correction. The cause of hemoptysis according to age and the amount of hemoptysis in children

Acknowledgments section for grant support was misprinted unintentionally.

The Association of Lung Function, Bronchial Hyperresponsiveness, and Exhaled Nitric Oxide Differs Between Atopic and Non-atopic Asthma in Children

PURPOSE: Although many previous studies have attempted to identify differences between atopic asthma (AA) and non-atopic asthma (NAA), they have mainly focused on the difference of each variable of lung function and airway inflammation. The aim of this study was to evaluate relationships between lung function, bronchial hyperresponsiveness (BHR), and the exhaled nitric oxide (eNO) levels in children with AA and NAA. METHODS: One hundred and thirty six asthmatic children aged 5-15 years and 40 normal controls were recruited. Asthma cases were classified as AA (n=100) or NAA (n=36) from skin prick test results. Lung function, BHR to methacholine and adenosine-5'-monophosphate (AMP), eNO, blood eosinophils, and serum total IgE were measured. RESULTS: The AA and NAA cases shared common features including a reduced small airway function and increased BHR to methacholine. However, children with AA showed higher BHR to AMP and eNO levels than those with NAA. When the relationships among these variables in the AA and NAA cases were evaluated, the AA group showed significant relationships between lung function, BHR to AMP or methacholine and eNO levels. However, the children in the NAA group showed an association between small airway function and BHR to methacholine only. CONCLUSIONS: These findings suggest that the pathogenesis of NAA may differ from that of AA during childhood in terms of the relationship between lung function, airway inflammation and BHR.

Interactions Between Innate Immunity Genes and Early-Life Risk Factors in Allergic Rhinitis

PURPOSE: Allergic rhinitis (AR) is a common chronic disease. Many factors could affect the development of AR. We investigated early-life factors, such as delivery mode, feeding method, and use of antibiotics during infancy, which could affect the development of AR. In addition, how interactions between these factors and innate gene polymorphisms influence the development of AR was investigated. METHODS: A cross-sectional study of 1,828 children aged 9-12 years was conducted. Three early-life factors and AR were assessed by a questionnaire. Skin prick tests were done. Polymorphisms of TLR4 (rs1927911) and CD14 (rs2569190) were genotyped. RESULTS: Use of antibiotics during infancy increased the risk of AR (aOR [95% CI] 1.511 [1.222-2.037]) and atopic AR (aOR [95% CI], 1.565 [1.078-2.272]). There were synergistic interactions between caesarean delivery, formula feeding, and use of antibiotics in the rate of atopic AR (aOR [95% CI], 3.038 [1.256-7.347]). Additional analyses revealed that the risk for the development of AR or atopic AR subjects with the TLR4 CC genotype were highest when all the 3 early-life factors were present (aOR [95% CI], 5.127 [1.265-20.780] for AR; 6.078 [1.499-24.649] for atopic AR). In addition, the risk for the development of AR or atopic AR in subjects with the CD14 TT genotype were highest when all the 3 early-life factors were present (aOR [95% CI], 5.960 [1.421-15.002] for AR; 6.714 [1.440-31.312] for atopic AR). CONCLUSIONS: Delivery mode, feeding method, and use of antibiotics during infancy appeared to have synergistic interactions in the development of AR. Gene-environment interactions between polymorphism of innate genes and early- life risk factors might affect the development of AR.