[Relationship between clopidogrel resistance and genetic variability in Kawasaki disease children with coronary artery lesions].

Objective: To analyze the distribution of clopidogrel metabolism-related gene variability in Kawasaki disease (KD) children with coronary artery lesions (CAL) across different age groups and the impact of genetic variability on the efficacy of clopidogrel antiplatelet therapy. Methods: A retrospective cohort study was conducted. Clinical data were collected from 46 KD children with CAL who were hospitalized in the Cardiovascular Center of Children's Hospital of Fudan University between January 2021 and August 2022 and were treated with clopidogrel, including gender, age, body mass index, course of KD, CAL severity grade, and baseline platelet count. According to their age, the children were divided into ≥2-year-old group and <2-year-old group. Their platelet responsiveness was assessed by adenosine diphosphate-induced platelet inhibition rate (ADPi) calculated via thromboelastography, and children were categorized into high on-treatment platelet reactivity (HTPR) and normal on-treatment platelet reactivity (NTPR) groups. Genotypes of CYP2C19, PON1 and ABCB1 were detected. The t test, one-way analysis of variance and Chi-square test were used for intergroup comparison. Results: Among the 46 KD children with CAL, 34 were male and 12 were female; 37 were ≥2-year-old and 9 were <2-year-old; 25 cases were in the HTPR group and 21 cases were in the NTPR group, with 19 HTPR and 18 NTPR in the ≥2-year-old group, and 6 HTPR and 3 NTPR in the <2-year-old group. Genetic analysis showed that 92 alleles among the 46 children, with frequencies of CYP2C19*1, CYP2C19*2, CYP2C19*3, CYP2C19*17, PON1 192Q, PON1 192R, ABCB1 3435C, ABCB1 3435T at 59% (54/92), 32% (29/92), 9% (8/92), 1% (1/92), 36% (36/92), 64% (59/92), 63% (58/92) and 37% (34/92), respectively. Analysis of the impact of genotype on ADPi revealed that in children aged ≥2 years, those with CYP2C19*1/*3 genotype had significantly lower ADPi than those with CYP2C19*1/*1 genotype ((34±15)% vs. (61±29)%, t=2.18, P=0.036). There were also no significant difference in ADPi among children with PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes ((40±22)% vs. (52±33)% vs. (65±27)%, F=2.17, P=0.130), or among those with ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((55±34)% vs. (60±27)% vs. (49±24)%, F=0.33, P=0.719). In <2-year-old group, there were no significant differences in ADPi across CYP2C19*1/*1, CYP2C19*1/*2 and CYP2C19*2*2 genotypes ((40±20)% vs. (53±37)% vs. (34±16)%, F=0.37, P>0.05). There were no significant differences in ADPi across CYP2C19*1/*1 and CYP2C19*1/*3 genotypes ((44±27)% vs. (42±20)%, t=0.08, P>0.05). There were no significant differences in ADPi across PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes (45% vs. (55±27)% vs. (24±5)%, F=1.83, P>0.05). There were no significant differences in ADPi across ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((36±16)% vs. (50±35)% vs. 45%, F=0.29, P>0.05). The risk analysis of HTPR in different genotypes revealed that in children aged ≥2 years, carrying at least 1 or 2 loss-of-function alleles of CYP2C19 was a risk factor for HTPR (OR=4.69, 10.00, 95%CI 1.11-19.83, 0.84-119.32, P=0.033, 0.046, respectively), and PON1 192R homozygosity and carrying at least one PON1 192R allele were protective factors against HTPR (OR=0.08, 0.13, 95%CI 0.01-0.86, 0.01-1.19, P=0.019, 0.043, respectively). Conclusion: KD children aged ≥2 years carrying CYP2C19 loss-of-function alleles and PON1 192Q are more likely to develop HTPR.

[Periconceptional maternal homocysteine and birth weight outcomes in offspring: a prospective cohort study].

Objective: To quantify the associations between periconceptional maternal homocysteine (HCY) and offspring's birth weight and risk of small for gestational age (SGA) infant. Methods: The 19 984 mother-child pairs in this prospective cohort study were recruited from the Shanghai preconception cohort; the infants were delivered from 1st September 2016 to 11th November 2022. A standardized questionnaire was used to collect the mothers' demographic information, medical history, dietary supplement use, and maternal complications during pregnancy, and their serum samples were collected. Serum HCY, folate, and vitamin B12 were measured using chemiluminescent microparticle immunoassay based on serum sample drawn at enrollment. Birth weight data were obtained from medical records. Multiple imputation methods were applied to handle missing data in key variables. Multivariable linear regression and Poisson regression models were used to analyze the relationship between maternal HCY concentration during the periconceptional period and the birth weight and SGA risk of the offspring. Results: A total of 9 452 pairs were enrolled preconceptionally and the remaining 10 532 pairs were enrolled in early pregnancy. The proportion of mothers whose pregnancy age was greater than 35 years was 9.2% (1 832/19 984), the proportion of primiparous women was 76.5% (15 283/19 984), the proportion of pre-pregnancy overweight and obesity was 14.0% (2 804/19 984), the proportion of using folic acid supplements before pregnancy was 21.4% (4 272/19 984), and the proportion of those who supplemented with folic acid during early pregnancy was 85.2% (8 976/10 532); gestational diabetes mellitus was in 6.2% (1 245/19 984), gestational hypertensive syndrome in 3.6% (711/19 984). The birth weight of the offspring was (3 297±468) g, and there were 1 962 SGA children (9.8%). The HCY concentration in the overall population in appropriate for gestational age during the periconceptional period was (7.9±3.2) µmol/L, with (8.3±3.7) µmol/L in the preconception subgroup and (7.3±2.4) µmol/L in the early pregnancy subgroup. After adjustment for the covariates of perinatal demographic information, adverse pregnancy outcomes, serum folate and vitamin B12, increased maternal periconceptional HCY was significantly associated with lower offspring birth weight (ß=-2.30, 95%CI -4.43--0.16, P=0.035). Only the early pregnancy subgroup was significantly associated with lower offspring birth weight (ß=-7.39, 95%CI-11.50--3.21, P<0.001). No association was found between peripregnancy HCY and offspring SGA risk. However, elevated HCY in early pregnancy was associated with an increased risk of SGA in the offspring (RR=1.05, 95%CI 1.01-1.08, P=0.002). Periconceptional vitamin B12 was a mediator of the association between HCY and offspring birth weight, accounting for 16.5%, 41.2% and 5.4% of its total effect in the overall periconceptional population, the pre-pregnancy subgroup and the early pregnancy subgroup, respectively. Conclusions: Maternal periconceptional HCY level is associated with lower birth weight in offspring, but not with the risk of SGA. Elevated maternal HCY in early pregnancy subgroup may be associated with increased risk of SGA in offspring.

[Hospitalization costs of pediatric community-acquired pneumonia in Shanghai].

Objective: To investigate the epidemiology and hospitalization costs of pediatric community-acquired pneumonia (CAP) in Shanghai. Methods: A retrospective case summary was conducted on 63 614 hospitalized children with CAP in 59 public hospitals in Shanghai from January 2018 to December 2020. These children's medical records, including their basic information, diagnosis, procedures, and costs, were extracted. According to the medical institutions they were admitted, the patients were divided into the children's hospital group, the tertiary general hospital group and the secondary hospital group; according to the age, they were divided into <1 year old group, 1-<3 years old group, 3-<6 years old group, 6-<12 years old group and 12-18 years old group; according to the CAP severity, they were divided into severe pneumonia group and non-severe pneumonia group; according to whether an operation was conducted, the patients were divided into the operation group and the non-operation group. The epidemiological characteristics and hospitalization costs were compared among the groups. The χ2 test or Wilcoxon rank sum test was used for the comparisons between two groups as appropriate, and the Kruskal-Wallis H test was conducted for comparisons among multiple groups. Results: A total of 63 614 hospitalized children with CAP were enrolled, including 34 243 males and 29 371 females. Their visiting age was 4 (2, 6) years. The length of stay was 6 (5, 8) days. There were 17 974 cases(28.3%) in the secondary hospital group, 35 331 cases (55.5%) in the tertiary general hospital group and 10 309 cases (16.2%) in the children's hospital group. Compared with the hospitalizations cases in 2018 (27 943), the cases in 2019 (29 009) increased by 3.8% (1 066/27 943), while sharply declined by 76.2% (21 281/27 943) in 2020 (6 662). There were significant differences in the proportion of patients from other provinces and severe pneumonia cases, and the hospitalization costs among the children's hospital, secondary hospital and tertiary general hospital (7 146 cases(69.3%) vs. 2 202 cases (12.3%) vs. 9 598 cases (27.2%), 6 929 cases (67.2%) vs. 2 270 cases (12.6%) vs. 9 397 cases (26.6%), 8 304 (6 261, 11 219) vs. 1 882 (1 304, 2 796) vs. 3 195 (2 364, 4 352) CNY, χ2=10 462.50, 9 702.26, 28 037.23, all P<0.001). The annual total hospitalization costs of pediatric CAP from 2018 to 2020 were 110 million CNY, 130 million CNY and 40 million CNY, respectively. And the cost for each hospitalization increased year by year, which was 2 940 (1 939, 4 438), 3 215 (2 126, 5 011) and 3 673 (2 274, 6 975) CNY, respectively. There were also significant differences in the hospitalization expenses in the different age groups of <1 year old, 1-<3 years old, 3-<6 years old, 6-<12 years old and 12-18 years old (5 941 (2 787, 9 247) vs. 2 793 (1 803, 4 336) vs. 3 013 (2 070, 4 329) vs. 3 473 (2 400, 5 097) vs. 4 290 (2 837, 7 314) CNY, χ2=3 462.39, P<0.001). The hospitalization cost of severe pneumonia was significantly higher than that of non-severe cases (5 076 (3 250, 8 364) vs. 2 685 (1 780, 3 843) CNY, Z=109.77, P<0.001). The cost of patients who received operation was significantly higher than that of whom did not (10 040 (4 583, 14 308) vs. 3 083 (2 025, 4 747) CNY, Z=44.46, P<0.001). Conclusions: The number of children hospitalized with CAP in Shanghai decreased significantly in 2020 was significantly lower than that in 2018 and 2019.The proportion of patients from other provinces and with severe pneumonia are mainly admitted in children's hospitals. Hospitalization costs are higher in children's hospitals, and also for children younger than 1 year old, severe cases and patients undergoing operations.

[Early histological changes detected by confocal microscopy in patients with advanced keratoconus receiving collagen cross-linking therapy].

Objective: To investigate the early histological changes by confocal microscopy of patients with advanced keratoconus receiving collagen cross-linking therapy. Methods: In this prospective case series study, confocal microscopy was used to observe 23 patients (32 eyes) who were diagnosed with advanced keratoconus and treated with collagen cross-linking at the Department of Ophthalmology, Chinese PLA General Hospital from September 2017 to March 2019, aged (26±10) year. All patients were examined before and at 1 week, 1 month and 3 months after the therapy. The tissue structure changes, the density of nerve fibers, stromal cells and endothelial cells, and the depth of the corneal stroma were recorded and compared. The overall differences at different times were compared by repeated measurement analysis of variance or Friedman test, and the pairwise comparison was corrected by LSD-t test or Bonferroni test. Results: One week after collagen cross-linking, the epithelial cells were in the repair stage, showing an increased nucleolar size and an enhanced reflection, and the activated cells could be detected under the epithelium. The superficial corneal stroma was swollen and spongiform, while the deep corneal stroma was patchy or cord-like, scattered and with a strong reflection. One month after the therapy, epithelial cells recovered, subepithelial nerves began to grow, the superficial corneal stroma still showed a spongy structure, and the reflection was further enhanced. The activation of the deep corneal stroma exhibited as thicker plaques or cord-like structure. Three months after the therapy, the continuous elongation of single nerve fibers could be detected occasionally. There was statistically significant difference in the density of nerve fibers before and early after the therapy (F=233.30, P<0.001). Compared with the preoperative value [(14.60±2.57) mm/mm2], the density of subepithelial nerve fibers decreased significantly in the early postoperative period, which was (0.51±0.31), (3.65±2.21) and (8.50± 4.02) mm/mm2, respectively, at 1 week, 1 month and 3 months, and there were significant differences between different time points (all P<0.05). There was also statistically significant differences in the density of anterior stromal cells before and early after the therapy (χ2=92.48, P<0.001). Compared with the preoperative value [347.00(345.00,395.75) cells/mm2] the density of anterior stromal cells decreased significantly in the early postoperative period, which was 2.00(1.00,5.75), 2.50(1.00,5.75) and 79.00(64.25,94.00) cells/mm2, respectively, at 1 week, 1 month and 3 months, and there were significant differences between different time points (all P<0.05). Within 3 months after the therapy, the depth of the corneal stroma observed by confocal microscopy ranged from 245 to 536 µm, with an average of (400.56±86.12) µm. Histologically, the depth of the corneal stroma ranged from 245 to 536 µm [average, (402.13±89.20) µm], from 251 to 527 µm [average, (399.88±85.92) µm] and from 259 to 530 µm [average, (399.69±85.94) µm] at 1 week, 1 month and 3 months, respectively, with no significant difference (F=0.797, P=0.455). There was no significant difference in the density of posterior stromal cells [(260.6±33.2) cells/mm2 preoperatively, (264.4±44.5) cells/mm2 at 1 week, (263.9±37.6) cells/mm2 at 1 month and (266.3±40.2) cells/mm2 at 3 months] and endothelial cells [(2 707±152.6) cells/mm2 preoperatively, (2 704±148.5) cells/mm2 at 1 week, (2 705±152.6) cells/mm2 at 1 month and (2 704±150.1) cells/mm2 at 3 months] between different time points (F=1.380, 1.011; P=0.259, 0.351). Conclusions: Confocal microscopy is able to clearly document the early morphological characteristics after collagen cross-linking in the treatment of keratoconus, including the epithelial and subepithelial nerve injury repair, the spongiform superficial corneal stroma, the patchy or cord-like deep corneal stroma, and the relatively stable stromal depth change.

[Retrospective analysis of infliximab in the treatment of Kawasaki disease].

Objective: To investigate the efficacy and safety of infliximab (IFX) therapy for children with Kawasaki disease. Methods: Sixty-eight children with Kawasaki disease who received IFX therapy in Children's Hospital of Fudan University from January 2014 to April 2021 were enrolled. The indications for IFX administration, changes in laboratory parameters before and after IFX administration, response rate, drug adverse events and complications and outcomes of coronary artery aneurysms (CAA) were retrospectively analyzed. Comparisons between groups were performed with unpaired Student t test or Mann-Whitney U test or chi-square test. Results: Among 68 children with Kawasaki disease, 52 (76%) were males and 16 (24%) were females. The age of onset was 2.1 (0.5, 3.8) years. IFX was administered to: (1) 35 children (51%) with persistent fever who did not respond to intravenous immunoglobulin (IVIG) or steroids, 28 of the 35 children (80%) developed CAA before IFX therapy; (2) 32 children (47%) with continuous progression of CAA; (3) 1 child with persistent arthritis. In all cases, IFX was administered as an additional treatment (the time from the onset of illness to IFX therapy was 21 (15, 30) days) which consisted of second line therapy in 20 (29%), third line therapy in 20 (29%), and fourth (or more) line therapy in 28 (41%). C-reactive protein (8 (4, 15) vs. 16 (8, 43) mg/L, Z=-3.38, P=0.001), serum amyloid protein A (17 (10, 42) vs. 88 (11, 327) mg/L, Z=-2.36, P=0.018) and the percentage of neutrophils (0.39±0.20 vs. 0.49±0.21, t=2.63, P=0.010) decreased significantly after IFX administration. Fourteen children (21%) did not respond to IFX and received additional therapies mainly including steroids and cyclophosphamide. There was no significant difference in gender, age at IFX administration, time from the onset of illness to IFX administration, the maximum coronary Z value before IFX administration, and the incidence of systemic aneurysms between IFX-sensitive group and IFX-resistant group (all P>0.05). Infections occurred in 11 cases (16%) after IFX administration, including respiratory tract, digestive tract, urinary tract, skin and oral infections. One case had Calmette-Guérin bacillus-related adverse reactions 2 months after IFX administration. All of these adverse events were cured successfully. One child died of CAA rupture, 6 children were lost to follow up, the remaining 61 children were followed up for 6 (4, 15) months. No CAA occurred in 7 children before and after IFX treatment, while CAA occurred in 54 children before IFX treatment. CAA regressed in 23 (43%) children at the last follow-up, and the diameter of coronary artery recovered to normal in 10 children. Conclusion: IFX is an effective and safe therapeutic choice for children with Kawasaki disease who are refractory to IVIG or steroids therapy or with continuous progression of CAA.

[The distribution and variance of neonatal pulse oxygen saturation at different altitudes].

Objective: To analyze the distribution and variance of neonatal pulse oxygen saturation (SpO2) at different altitudes in China, and provide a new evidence for the screening of NCHD at high altitudes. Methods: Based on the database of National Screening Project of NCHD, the distribution of SpO2 values was described in 26 766 newborns at altitudes of 0-100 m, 600-700 m, 900-1 100 m, 1 400-1 600 m, 1 900-2 100 m, and 2 200-2 500 m. One-way analysis of variance was used to analyze the differences among SpO2 values in newborns at different altitudes. Results: The average SpO2 values of right hand in newborns at altitudes of 0-100 m, 600-700 m, 900-1 100 m, 1 400-1 600 m, 1 900-2 100 m and 2 200-2 500 m were 97.7%±1.4%, 97.1%±1.1%, 96.1%±1.3%, 96.0%±1.7%, 95.9%±1.7% and 95.5%±2.4%, respectively. And corresponding average SpO2 values of either foot were 97.7%±1.4%, 96.9%±1.1%, 96.3%±1.4%, 96.0%±1.7%, 95.6%±1.8% and 95.2%±2.7%, respectively. There were statistically significant differences in the average SpO2 values of newborns at different altitudes (right hand: F=1 248.35, P<0.001; either foot: F=1 280.45, P<0.001). The SpO2 of newborns tended to be lower with the increase of altitudes (P-trend<0.001). Conclusion: SpO2 values in newborns were negatively associated with the altitudes, which indicated that the cut-off value of screening for NCHD at sea level might not be applicable to newborns at higher altitudes. Thus, it is worthwhile to conducted studies on the normal values of SpO2 and the cut-off value of screening for NCHD in newborns at high altitudes.

[Clinical effect of adding hMG to the follicular phase long protocol for standard group with normal ovarian reserve function].

Objective: To investigate the impact of adding human menopausal gonadotropin (hMG) for in vitro fertilization-embryo transfer pregnancy outcomes in a standard population of non-advanced age with normal ovarian reserve function using a long follicular phase protocol. Methods: Clinical data of 489 patients with normal ovarian reserve function, who were admitted from January 2018 to January 2020 in the Affiliated Hospital of Guizhou Medical University and underwent in vitro fertilization for the first time with the long follicular phase protocol in fresh cycles, were retrospectively analyzed. The patients were divided into three groups according to whether or not to add urine-derived hMG and the timing of addition: non-addition group (group A), medium-term hMG group (group B1), whole course hMG group (group B2); the laboratory parameters of each group were observed, and the effect of ovulation induction drugs and pregnancy outcomes were compared. Results: The ages of B1 and B2 groups were significantly higher than that of group A (P=0.019 and P=0.011). The basal FSH level of group B2 was significantly higher than those of group A and group B1 (P<0.01 and P=0.006), and the basal FSH/LH ratio of group B2 was significantly higher than that of group B1 (P=0.009). Antral follicle counts of group A and group B1 were significantly higher than that of group B2 (P=0.007 and P=0.017). The superior embryo rate of group B2 [(47±27)%] was significantly higher than that of group A (P=0.017). The embryo implantation rate of group B1 was significantly lower than those of group A and group B2 (P=0.043 and P<0.01). The clinical pregnancy rate of group B2 [76.7% (155/202)] was significantly higher than those of group A (P=0.039) and group B1 (P<0.01). The live-birth rate of group B2 [67.3% (136/202)] was significantly higher than those of group A (P=0.017) and group B1 (P=0.001). Conclusions: For non-advanced aged patients with normal ovarian reserve function, the long protocol of follicular phase is suitable for those with relatively low ovarian reserve function. Adding hMG in the whole course of ovulation induction after gonadotropin-releasing hormone agonist reduction could improve the pregnancy outcomes by improving the quality of embryos.

China's experience in COVID-19 prevention and control among children in its different regions.

OBJECTIVE: To summarize the experience of three Chinese cities (Wuhan, Shanghai and Haikou) and provide a reference for global efforts to combat COVID-19 spread among children. MATERIALS AND METHODS: Through collecting the measures and outcomes of preventing and controlling COVID-19 in China's three hospitals, we compared the effect of different strategies. RESULTS: From January to March 2020, the number of suspected and confirmed COVID-19 cases in Wuhan increased exponentially, and Wuhan Children's Hospital as a whole was transformed into a designated quarantine and treatment facility, which is the "Wuhan Model". Shanghai has more children's hospitals with better capabilities to tackle public health emergency. Besides, it is far away from Wuhan and had a small caseload. Children's Hospital of Fudan University, a facility in Shanghai to treat pediatric infectious diseases, is famous for its well-equipped building for infectious disease treatment and professional medical team, and therefore no major transformation was required. That is the "Shanghai Model". Haikou is located on an island. Amid the outbreak, large numbers of tourists and travelers from Hubei had already arrived in Haikou. Hainan Women and Children's Medical Center, as the only pediatric care hospital in Hainan Province, did not have a separate building for infectious disease treatment. After a citywide survey of the medical resources and facilities available, a temporarily idle hospital 3 kilometers away from Hainan Women and Children's Medical Center was requisitioned as the quarantine and treatment facility for pediatric cases. That is the "Hainan Model". The three models enabled the treatment of all suspected and confirmed cases and no fatality was reported. CONCLUSIONS: The COVID-19 coping strategies for children should be designed according to the existing conditions of the local children's hospitals and the risk levels of the epidemic.

[Efficacy of percutaneous transluminal renal angioplasty for pediatric renovascular hypertension: a meta-analysis].

Objective: To evaluate the efficacy and the related factors of percutaneous transluminal renal angioplasty (PTRA) for pediatric renovascular hypertension (RVH) by a systematic review and meta-analysis. Methods: A systematic search was performed on international and domestic databases (Pubmed, Excerpt Medical Database (EMBASE), Cochrane library, Clinical trial.gov, Medline, China Biology Medicine (CBM), China national knowledge infrastructure (CNKI), VIP database and Wanfang) which included studies on PTRA for pediatric RVH from the establishment of the databases to March 2019. Key words of "pediatric" "children" "renal artery stenosis" "renovascular hypertension" "angioplasty" and "intervention" were used. Meta-analysis was made on the rate of technical success, clinical blood pressure improvement, complication and restenosis of PTRA as well as the predictors of its efficacy. The data consolidation, analysis of heterogeneity and sensitivity, and publication bias were performed using Comprehensive meta analyst and Open meta analyst software. Results: Seventeen observational non-controlled studies comprising 384 patients with RVH who underwent PTRA were identified. The technical success rate of PTRA was 93.9% (95% confidence interval (CI) 89.3%-97.5%). The improvement rate of blood pressure was 68.4% (95%CI 57.2%-78.7%), and the cure rate was 40.0% (95%CI 25.0%-55.8%). The subsequent subgroup analysis showed that there was no significant difference in the improvement rate of blood pressure after PTRA among the patients with RVH caused by fibromuscular dysplasia, Takayasu arteritis and neurofibromatosis type 1, respectively (P>0.05). The improvement rate of blood pressure in patients with combined lesions in renal artery branches was significantly lower than that in patients with lesions only in main renal artery (RR=1.659, 95%CI 1.023-2.689, P=0.040). It was found that 25.5% (95% CI 19.3%-32.2%) of patients required repeat procedure because of restenosis of lesions. Procedural complication of PTRA occurred in 8.3% (95%CI 3.5%-14.4%) of patients. In terms of clinical blood pressure improvement rate after PTRA, there was heterogeneity among the enrolled studies, but the results of meta-analysis were robust with low risk of publication bias (t=1.690, 95%CI -0.363-3.124, P=0.110). Conclusion: The result of the Meta-analysis suggests that PTRA may provide a safe and effective treatment for pediatric RVH, and patients with stenosis of renal arterial branches are associated with relatively poor clinical outcomes.