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06 November 2020, Volume 35 Issue 11 Previous Issue    Next Issue

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Expert consensus on the diagnosis and treatment of macrophage activation syndrome related to childhood rheumatism（Ⅰ）— general introduction Rheumatic Immunology Group of Pediatric Branch of Chinese Medical Doctor Association，China Children’s Immunity and Health Alliance，Editorial Committee of Chinese Journal of Practical Pediatrics 2020, 35(11): 825-831.  DOI: 10.19538/j.ek2020110601 Abstract ( )

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Expert consensus on the diagnosis and treatment of macrophage activation syndrome related to childhood rheumatism（Ⅱ）—systemic juvenile idiopathic arthritis Rheumatic Immunology Group of Pediatric Branch of Chinese Medical Doctor Association，China Children’s Immunity and Health Alliance，Editorial Committee of Chinese Journal of Practical Pediatrics 2020, 35(11): 831-834.  DOI: 10.19538/j.ek2020110602 Abstract ( )

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Expert consensus on the diagnosis and treatment of macrophage activation syndrome related to childhood rheumatism（Ⅲ）— systemic lupus erythematosus Rheumatic Immunology Group of Pediatric Branch of Chinese Medical Doctor Association，China Children’s Immunity and Health Alliance，Editorial Committee of Chinese Journal of Practical Pediatrics 2020, 35(11): 834-838.  DOI: 10.19538/j.ek2020110603 Abstract ( )

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Expert consensus on the diagnosis and treatment of macrophage activation syndrome related to childhood rheumatism（Ⅳ）— juvenile dermatomyositis Rheumatic Immunology Group of Pediatric Branch of Chinese Medical Doctor Association，China Children’s Immunity and Health Alliance，Editorial Committee of Chinese Journal of Practical Pediatrics 2020, 35(11): 838-841.  DOI: 10.19538/j.ek2020110604 Abstract ( )

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Expert consensus on the diagnosis and treatment of macrophage activation syndrome related to childhood rheumatism（Ⅴ）— Kawasaki disease Rheumatic Immunology Group of Pediatric Branch of Chinese Medical Doctor Association，China Children’s Immunity and Health Alliance，Editorial Committee of Chinese Journal of Practical Pediatrics 2020, 35(11): 841-845.  DOI: 10.19538/j.ek2020110605 Abstract ( )

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Interpretation of Revision of Diagnostic Guidelines for Kawasaki Disease（6th revised edition） PAN Si-lin*，LIU Fang，LUO Gang 2020, 35(11): 846-849.  DOI: 10.19538/j.ek2020110606 Abstract ( )   Kawasaki disease（KD） is an acute nonspecific generalized vasculitis in childhood. About 25% of untreated KD patients may develop coronary artery dilatation or aneurysm，which may lead to ischemic heart disease or sudden death，and it has become the leading cause of acquired heart disease in children in most developed areas worldwide. Because the diagnosis of KD mainly depends on clinical features，early diagnosis of KD，especially incomplete KD，is still a big challenge. The authors interpret the key points of Revision of Diagnostic Guidelines for Kawasaki Disease（6th revised edition） delivered by the Scientific Committee of the Japanese Circulation Society，and compared with the Scientific Statement for KD diagnosis by  the American Heart Association（2017），aiming to improve the diagnostic level of KD in domestic clinical practice.

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Application prospect of medical artificial intelligence in fetal echocardiography PAN Si-lin，LUO Gang 2020, 35(11): 850-853.  DOI: 10.19538/j.ek2020110607 Abstract ( )   As a new technology，medical artificial intelligence（AI） is developing rapidly in the field of medical imaging. AI is in the primary stage of echocardiography application. Some automatic software of ultrasonic system can achieve image recognition，automatic extraction and standardized measurement，such as left ventricular ejection fraction and valve function. The particularity of fetal heart anatomy，involuntary movements，change in fetal posture and the difference in the ultrasound doctors’ professional competence increase the difficulty of fetal heart examination. AI will help to optimize the clinical application of fetal echocardiography. Classification，staging and prognosis evaluation of fetal heart disease will be the future direction of AI development.

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Relationship between serum 25（OH）D3 and cardiovascular risk factors in children LUO Ye-tao*，QU Ping，CHEN Min，et al 2020, 35(11): 854-860.  DOI: 10.19538/j.ek2020110608 Abstract ( )   Objective　To explore the relationship between serum 25-hydroxyvitamin D3（VD） and cardiovascular risk factors in children. Methods　A total of 260 school-age children were randomly selected from the 1212 children cohorts established in Chongqing from 2014 to 2016. The data of biochemical tests，physical activity，physical examination and demographic information were collected. One hundred and sixty-eight of them met the criteria and were included in the study. According to the serum VD quartile（P25＝34.98，P75＝45.80），the children were divided into the serum VD low group（＜35 nmol/L，42 cases），medium group（35 to 45 nmol/L，76 cases） and high （＞45 nmol/L，49 cases） group. Covariance analysis and multivariate logistic regression model were used to analyze the correlation of serum VD with the cardiovascular risk factors including obesity，hypertension and metabolic syndrome. Results　Children with obesity，hyperglycemia，hypertriglycerides and metabolic syndrome had lower average serum VD than those without obesity，hyperglycemia，hypertriglycerides and metabolic syndrome（34.9±7.2 vs. 43.4±9.8，35.8±7.5 vs. 41.0±9.9，35.8±9.5 vs. 41.0±9.7，34.7±7.5 vs. 41.0± 9.8 nmol/L，respectively，P＜0.05）. The correlation coefficients of serum VD with  high density lipoprotein cholesterol，systolic blood pressure，BMI and waist circumference were 0.225，-0.289，-0.379 and -0.484，respectively（all P＜0.05），after adjusting for age，gender，breastfeeding duration，birth weight，time of daily physical activity，family income and parents’ education level. The risk（OR） of obesity，hyperglycemia，hypertriglycerides and metabolic syndrome in children with serum VD＜35 nmol/L was 14.5（95%CI：4.3-49.6），4.6（95%CI：1.1-20.5），4.1（95%CI：1.1-15.8） and 6.1（95%CI：1.1-35.9） times of those children with serum VD＞ 45 nmol/L （all P＜0.05）. After adjusting BMI，serum VD was not associated with hyperglycemia，hypertriglycerides or metabolic syndrome. Conclusion　The lower serum VD of children in Chongqing is related to cardiovascular risk factors. The prevention of cardiovascular disease should start from childhood，and VD supplementation should be provided in childhood.

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Changes and significance of serum PⅠCP and PⅢNP levels in children with chronic heart failure MU Shu-jing，FENG Song，CHEN Xiao-guang，et al 2020, 35(11): 861-865.  DOI: 10.19538/j.ek2020110609 Abstract ( )   To explore the changes and significance of the carboxy- terminal propeptide of typeⅠprocollagen（PⅠCP） and the amino-terminal propeptide of type Ⅲ procollagen（PⅢNP） in children with chronic heart failure（CHF）. Methods　A total of 28 children with CHF admitted between February 2018 and June 2019 to the First Affiliated Hospital of Zhengzhou University were included in the heart failure group，including 15 males and 13 females，with a median age of 1.00（0.63，5.50） years old. Heart failure group was divided as 8 cases in the heart function class Ⅱ group，11 cases in the heart function class Ⅲ group，and 9 cases in the heart function class Ⅳ group. Seventeen healthy children were included as the control group，including 12 males and 5 females，with a median age of 3.88（2.36，5.38） years old. There was no statistical difference in age or gender of children in each group（P＞0.05）. The levels of serum PⅠCP and PⅢNP were measured by enzyme-linked immunosorbent assay. The left ventricular ejection fraction and other related indexes were measured by cardiac echocardiography，and the data was statistically analyzed by SPSS25.0 software. Results　The level of serum PⅠCP and PⅢNP in children with CHF before treatment was significantly higher than that in the control group，and the level of serum PⅢNP was significantly lower after treatment for 10 weeks（P＜0.05）；the level of serum PⅠCP and PⅢNP in children with CHF in grade Ⅳ group was significantly higher than that in grade Ⅱ group and the control group，and the difference was statistically significant（P＜0.05）. The levels of serum PⅠCP and PⅢNP were positively correlated with cardiac function，NT-proBNP level，LVEDd and LVMI，and negatively correlated with LVEF and LVFS. Conclusion　The serum PⅠCP and PⅢNP is involved in the occurrence and development of CHF myocardial fibrosis in children，and can help the clinical diagnosis，grading of cardiac function and treatment effect assessment of children with CHF.

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Efficacy of Saccharomyces boulardii in the prevention of diarrhea secondary to pneumonia in children：A randomized controlled multicenter clinical study Clinical Research Collaboration Group on the Prevention of Diarrhea Secondary to Pneumonia in Children by Saccharomyces boulardii 2020, 35(11): 866-871.  DOI: 10.19538/j.ek2020110610 Abstract ( )   Objective　To evaluate the clinical efficacy of Saccharomyces boulardii in preventing diarrhea secondary to pneumonia in children. Methods　A multi-center，randomized，open and blank control study was conducted，and 499 children aged 1 month to 6 years old with pneumonia were enrolled，who were treated in 18 hospitals in Zhejiang province from August 2014 to December 2017. The children were randomly divided into control group and study group by random number table. The study group was treated with antibiotics plus symptomatic treatment plus Saccharomyces boulardii orally，while the control group was treated with antibiotics plus symptomatic treatment. The usage of Saccharomyces boulardii was 1 pack/time，1 time/day for children aged from 1 month to 3 years old and 1 pack/time，2 times/day for children aged from 3 to 6 years old. The children were followed up until 14 d after withdrawal of antibiotics. Observe and record the times of bowel movement and stool property. The results，such as the incidence of diarrhea，the antibiotic use time，the hospitalization time，the hospital costs and adverse drug reactions，were observed and recorded. Results　Totally 499 cases were randomly divided into two groups，among which report of 434 cases were received，and 370 cases were included for effect analysis（192 cases in the study group，178 cases in the control group）. There was no significant difference in general information between the two groups. The overall incidence of secondary diarrhea in the study group was lower than that in the control group（P＝0.017 < 0.05）. There was no significant difference between the two groups in terms of the antibiotic use time，hospitalization time or hospital costs. Stratified analysis of age found that when the age of children was less than or equal to 1 year old，there was no significant difference in the incidence of diarrhea between the two groups，but when the age of children was more than 1 year old，the incidence of diarrhea in the study group was significantly lower than that in the control group（P＝0.006 < 0.05）. Stratified analysis of antibiotics showed there was no significant difference in the incidence of diarrhea between the two groups. Multivariate Logistic regression analysis showed that the age and duration of antibiotic treatment were risk factors，but Saccharomyces boulardii was a protective factor. No drug-related adverse events were observed in both groups. Conclusion　Saccharomyces boulardii can prevent diarrhea secondary to pneumonia in children without obvious adverse reactions.

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Clinical characteristics and risk factors of peptic ulcer perforation in children ZHANG Jing，WANG Yue-sheng，LI Xiao-qin，et al 2020, 35(11): 872-876.  DOI: 10.19538/j.ek2020110611 Abstract ( )   Objective　To explore the clinical characteristics and risk factors of peptic ulcer with perforation in children，and to provide reference for clinical intervention. Methods　The clinical data of 688 cases of peptic ulcer diagnosed by endoscopy in Department of Gastroenterology，Children’s Hospital Affiliated to Zhengzhou University，from December 2014 to December 2019 were analyzed retrospectively. All the cases were divided as 47 cases of peptic ulcer with perforation group and 641 cases of peptic ulcer group. Demographic factors，incidence rate，clinical features，etiology，symptoms，endoscopic or surgical treatment and clinical outcome were analyzed. Risk factors for perforation of peptic ulcer were analyzed by multivariate logistic regression analysis. Results　A total of 14916 cases of gastroscopy were collected in the study，and 688 cases（4.61%） of peptic ulcer were screened，among which 47 cases（6.83%） were complicated with perforation. There were 412 boys and 276 girls，with a median age of 8.5 years（1 month to 14 years old）. A total of 485 cases（70.49%） lived in rural areas；353 cases（51.31%） had no family history；424 cases（61.63%） had no peritoneal stimulation sign；228 cases（33.14%） had gastric antrum ulcers；264 cases（38.37%） had duodenal bulb ulcers；in 461 cases（67.01%） the diameter of ulcers was  less than 10 mm；465 cases（67.59%） had single ulcer；the causes of ulcer were mainly infection of Helicobacter pylori（Hp）（306 cases，44.48%） and nonsteroidal anti-inflammatory drugs（NSAID）（109 cases，15.84%）. The average age of perforation group was significantly lower than that of non-perforation group［（5.3±1.2） years old vs.（9.8±3.5） years old，P＜0.001］；ulcers with perforation were mostly found in rural children（38 cases，80.85%）；fever，WBC and CRP were more likely to occur in perforation group，and there were significant differences between the two groups（P＜0.05）；gastric antrum and duodenal bulb were the most common sites of perforation，which were similar to those of ulcer；the diameters of ulcers were more than or equal to 10 mm in perforation group（35 cases，74.47%），and the proportion of multiple ulcer in perforation group（33 cases，70.21%） was significantly higher than that in non-perforation group（P＜0.001）；the main cause of peptic ulcer perforation in children was HP infection（28 cases，59.57%） and NSAID（8 cases，17.02%）. The prognosis of laparotomy was good，but the hospitalization period of laparoscopy was shortened. Multivariate Logistic regression analysis indicated that age，ulcer location，ulcer size and etiology were independent risk factors for perforation. Conclusion　There are complicated risk factors for peptic ulcer complicated with perforation. Early diagnosis and reasonable treatment can effectively shorten the course of disease and improve the prognosis.

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Analysis of pathogen and high risk factors for poor prognosis in newborns with ventilator-associated pneumonia DING Li，SONG Wei，ZHU Xue-ping 2020, 35(11): 877-880.  DOI: 10.19538/j.ek2020110612 Abstract ( )   Objective　To analyze the pathogen and high risk factors for poor prognosis in newborns with ventilator-associated pneumonia（VAP） in Neonatal Intensive Care Unit（NICU）. Methods　The clinical data of 236 newborns with VAP admitted from August 2012 to August 2019 to the NICU，Children’s Hospital of Soochow University，were analyzed retrospectively. According to the prognosis，the patients were divided into the group with good prognosis and the group with poor prognosis. The clinical characteristics and pathogen of the two groups were compared，and the risk factors for poor prognosis were analyzed. Results　（1）Among the 236 children with VAP，182 were in the good prognosis group and 54 were in the bad prognosis group. A total of 258 strains of pathogenic bacteria were cultured from the airway secretions of the two groups，and 240 strains（93.02%） were gram-negative bacteria. Klebsiella pneumoniae，Stenotrophomonas maltophilia，Acinetobacter baumannii，Enterobacter cloacae and Pseudomonas aeruginosa were the main pathogens in the two groups. Klebsiella pneumoniae was the most common pathogen in the group with good prognosis，and Acinetobacter baumannii was the most common pathogen in the group with poor prognosis. （2）The incidence of invasive ventilator use time＞5 d，relapse after using ventilator or withdrawing ventilator，fever，hypokalemia，hyponatremia，hypochloridemia，atelectasis，pulmonary hemorrhage and the minimum serum albumin ≤30 g/L during mechanical ventilation in the group with poor prognosis was significantly higher than that of the other group（P＜0.05）. （3）Multivariate Logistic regression analysis showed that relapse after using ventilator or withdrawing ventilator，hyponatremia，hypochloridemia and the minimum serum albumin ≤30 g/L during mechanical ventilation were independent high risk factors for poor prognosis. Conclusion　Acinetobacter baumannii is the main pathogen in VAP neonates with poor prognosis. The prognosis of children with VAP can be improved by reducing relapse after using ventilator or withdrawing ventilator，correcting electrolyte disorders in time and increasing nutritional reserves.

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Clinical value of multiple PCR detection for influenza-like cases in children: A report of 94 cases SHI Da-wei*，ZHANG Yan-ru，DONG Yan，et al 2020, 35(11): 881-884.  DOI: 10.19538/j.ek2020110613 Abstract ( )   Objective　To investigate the clinical value of multiple PCR method in detecting pathogens in influenza-like cases in children and to understand the distribution of respiratory pathogens in pediatric influenza-like cases. Methods　A total of 94 throat swabs of childhood flu-like cases admitted from November 2018 to February 2019 in Beijing area were collected. Multiple PCR method was used to detect influenza A virus，influenza A virus-H1N1，influenza A virus-H3N2，influenza B，parainfluenza virus，RSV，human adenovirus，human rhinovirus，human bocavirus，human metapneumovirus，human coronavirus，mycoplasma pneumonia and chlamydia gene. Results　Of the 94 specimens，78（82.98%） were detected pathogens，of which one pathogen was detected in 69 cases（73.40%），and 2 pathogens in 9 cases（9.57%）. Fifty-two（55.32%） of 94 specimens were detected influenza pathogens and 26 cases（27.66%） detected non-flu pathogens. The number of single pathogens detected was 31 cases of InfA-H1N1，10 cases of InfA-H3N2，9 cases of RSV，7 cases of HMPV，3 cases of InfA，HRV and HADV each，and 1 case of InfB，HCoV and MP each. Of the 9 specimens with 2 pathogens detected，6 were with influenza combined with other viruses（HRV，HADV，RSV，HCoV，HMPV），1 with H1N1 and H3N2，and 2 with RSV，HRV and HCoV，HADV，respectively. Conclusion　Influenza-like cases caused by non-influenza pathogenic microorganisms are common. Multiple PCR detection can help to understand the pathogen distribution and mixed infection in influenza-like cases.

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Clinical features and pathogens of children with bronchopulmonary dysplasia rehospitalized due to lower respiratory tract infection in the first 2 years：An analysis of 52 cases ZENG Ling-jian，XIE Xiao-hong，CHEN Xin，et al 2020, 35(11): 885-890.  DOI: 10.19538/j.ek2020110614 Abstract ( )   Objective　To discuss the clinical features and pathogens of rehospitalization caused by lower respiratory tract infection in the first 2 years of BPD patients. Methods　The neonatal rehospitalization data within the first 2 years of 52 BPD patients admitted between January 2012 and December 2016 to Children’s Hospital of Chongqing Medical University were analyzed retrospectively. Results　There were 137 cases of rehospitalization in the first 2 years of 52 BPD patients due to lower respiratory tract infection. The main manifestations were cough，short of breath，wheezing，cyanosis and rales in the lung. The incidence of wheezing was higher in the second year（χ2＝10.715，P＝0.001） significantly. RSV accounting for 67.3%（33/49） and PIV3 accounting for 22.4%（11/49） were the main virus pathogens. The 3 most common bacteria pathogens were Klebsiella pneumoniae accounting for 28.2%（31/110），Streptococcus pneumoniae accounting for 15.5%（17/110），and Haemophilus influenzae accounting for 8.2%（9/110）. Among them，Klebsiella pneumoniae was dominant in the first year of life and Streptococcus pneumoniae was dominant in more than 1 to 2 years old patients. The resistance rate of Klebsiella pneumoniae to ceftazidime，piperaciratazobtan and meropenem was 64.5%，54.8% and 7.1%. The resistance rate to cefotaxime and amoxicillin of Streptococcus pneumoniae were 8.0% and 6.3%. Klebsiella pneumoniae detection was significantly elevated in severe pneumonia. The median length of hospital stay was 8.0（7.0 to 12.0） days with 2 years. A total of 77.4%（106/137） of rehospitalized cases needed oxygen supplement，among which 21.7%（23/106） required mechanical ventilation. Methylprednisolone usage rate in wheezing children in the first and second year was 42.2%（27/64） and 56.5%（13/23）. Conclusion　The incidence of wheezing has an increasing trend over time in readmitted BPD patients under 2 years old. RSV is the main virus pathogen. Klebsiella pneumoniae plays a most common bacteria role in the early time and is replaced by Streptococcus gradually. Klebsiella pneumoniae is more likely to cause more severe pneumonia，and ESBL-producing Klebsiella pneumoniae accounts for a higher proportion in the cases. Ceftazidime and piperaciratazobtan are recommended，even meropenem when necessary. Rehospitalized BPD patients are usually more severe，and have a high rate of oxygen use，but the use of methylprednisolone do not increase along with the incidence of wheezing.

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Clinical data，genetic mutation and prognosis analysis of cblB type methylmalonic acidemia：A report of 4 patients SHUAI Rui-xue*，YU Yue，HAN Lian-shu，et al 2020, 35(11): 891-895.  DOI: 10.19538/j.ek2020110615 Abstract ( )   Objective　To investigate the clinical characteristics and prognosis of cblB type methylmalonic acidemia（MMA）by analyzing the clinical manifestation，genetic mutation types，biochemical results，therapeutic efficacy and prognosis. Methods　The clinical data of 4 patients with cblB type MMA diagnosed in Department of Pediatric Endocrinology and Genetic Metabolism，Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine，from May 2016 to December 2019 were analyzed retrospectively. The clinical data included the clinical characteristics，biochemical results，genetic sequencing data and treatment. Gesell developmental diagnosis scale and Bayley scale of infant development were used to evaluate the developmental condition of 3 patients. Results　Four patients（1 male，3 females） were diagnosed by screening newborns. During the follow-up，1 patient was lost，who had jaundice，acidosis，hypoglycemia and hypokalemia after birth. The other 3 patients were followed up to 13-43 months of age. Six mutations were identified by genetic sequencing，of which c.383T＞C（p.L128P） was a novel mutation. Two patients with a type of gene mutation which was correlated with late onset were vitamin B12-responsive. Nevertheless，for patient who carried a novel mutation，vitamin B12 treatment was ineffective. All three patients with early treatment were developing normally or at borderline state. Conclusion　The clinical phenotype of cblB type MMA is with obvious heterogeneity. The condition may be mild or severe. Some patients are clinically vitamin B12-responsive. Newborn screening is essential to the early diagnosis， treatment and outcome of patients.

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Griffiths Mental Development Scales-Chinese（GDS-C） applied to children with attention deficit hyperactivity disorder for structural patterns analysis of development MAO Zheng-huan，DU Yu，WANG Hui，et al 2020, 35(11): 896-900.  DOI: 10.19538/j.ek2020110616 Abstract ( )   Objective　Use the Griffiths Mental Development Scales-Chinese（GDS-C） to evaluate the developmental level of children with attention deficit hyperactivity disorder（ADHD），and analyze the structural patterns of each subscale to guide the formulation of effective rehabilitation interventions programs. Methods　A total of 28 children，who met the DSM-Ⅴ diagnostic criteria for ADHD and were treated from April 2018 to April 2019 in Department of Rehabilitation，the Children’s Hospital，Zhejiang University School of Medicine，were selected as ADHD group，and 28 healthy children of the same sex and age（±1 month） were matched as control group. Both groups were evaluated by GDS-C，and the differences of scores in locomotor，personal-social，hearing and speech，hand and eye coordination，performance and practical reasoning subscales and the total developmental quotient between the two groups were compared；meanwhile，the structural patterns of each subscale were analyzed. Results　The scores of each subscale and the total developmental quotient of ADHD group were lower than those of the control group，and the score differences in locomotor，personal-social，and hand-eye coordination subscales and the total developmental quotient between two groups were statistically significant（t＝-7.07，-4.75，-7.60，-7.65，P＜0.05）. Comparison of the structural patterns analysis of each subscale：ADHD group had lower scores than the healthy group in the ability of physical energy and strength，depth perception，gross physical coordination ability and coarse visual motor coordination of the locomotor subscale，communication skills，housework skills and dressing and self-care of the personal-social subscale，memory the hearing-speech subscale，shape recognition，creativity and bilateral coordination of the hand-eye coordination subscale，and visual spatial reasoning of performance subscale（P＜0.05）. Conclusion　Griffiths Mental Development Scales-Chinese（GDS-C） can be used to assess the comprehensive development of ADHD children. The development of children with ADHD is behind that of normal children，manifesting in subscales of locomotor，personal-social and hand-eye coordination. Based on the assessment results and structural patterns analysis，the individualized training strategies of appropriate levels for ADHD children can be developed.

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Pediatric systemic lupus erythematosus complicated with rhino-orbito cerebral mucormycosis：A report of 1 case and literature review CUI Shu-hua，WANG Yue，XING Wei，et al 2020, 35(11): 901-904.  DOI: 10.19538/j.ek2020110617 Abstract ( )

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Progress of clinical diagnosis and treatment of children’s parainfluenza virus infection TIAN Shu-feng, DENG Ji-kui 2020, 35(11): 905-908.  DOI: 10.19538/j.ek2020110618 Abstract ( )

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Systemic onset juvenile idiopathic arthritis complicated with macrophage activation syndrome and reversible posterior leukoencephalopathy syndrome：A report of 1 case WEN Qiu-yue，ZHANG Wei 2020, 35(11): 909-912.  DOI: 10.19538/j.ek2020110619 Abstract ( )