[A 10-year retrospective analysis of spectrums and treatment options of orthostatic intolerance and sitting intolerance in children].

OBJECTIVE: To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical treatment options. METHODS: The medical records including history, physical examination, laboratory examination, and imagological examination of children were retrospectively studied in Peking University First Hospital from 2012 to 2021. All the children who met the diagnostic criteria of OI and SI were enrolled in the study. The disease spectrums underlying OI and SI and treatment options during the last 10 years were analyzed. RESULTS: A total of 2 110 cases of OI and SI patients were collected in the last 10 years, including 943 males (44.69%) and 1 167 females (55.31%) aged 4－18 years, with an average of (11.34±2.84) years. The overall case number was in an increasing trend over the year. In the OI spectrum, postural tachycardia syndrome (POTS) accounted for 826 cases (39.15%), followed by vasovagal syncope (VVS) (634 cases, 30.05%). The highest proportion of SI spectrum was sitting tachycardia (STS) (8 cases, 0.38%), followed by sitting hypertension (SHT) (2 cases, 0.09%). The most common comorbidity of OI and SI was POTS coexisting with STS (36 cases, 1.71%). The highest proportion of treatment options was autonomic nerve function exercise (757 cases, 35.88%), followed by oral rehydration salts (ORS) (687 cases, 32.56%), metoprolol (307 cases, 14.55%), midodrine (142 cases, 6.73%), ORS plus metoprolol (138 cases, 6.54%), and ORS plus midodrine (79 cases, 3.74%). The patients with POTS coexisting with VVS were more likely to receive pharmacological intervention than the patients with POTS and the patients with VVS (41.95% vs. 30.51% vs. 28.08%, χ2= 20.319, P < 0.01), but there was no significant difference in the proportion of treatment options between the patients with POTS and the patients with VVS. CONCLUSION: POTS and VVS in children are the main underlying diseases of OI, while SI is a new disease discovered recently. The number of children with OI and SI showed an increasing trend. The main treatment methods are autonomic nerve function exercise and ORS. Children with VVS coexisting with POTS were more likely to take pharmacological treatments than those with VVS or POTS only.

The role of ancillary features for diagnosing hepatocellular carcinoma on CT: based on the Liver Imaging Reporting and Data System version 2017 algorithm.

AIM: To investigate the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) version 2017 for diagnosing hepatocellular carcinoma (HCC), by using major features only and combined major and ancillary features on computed tomography (CT). MATERIALS AND METHODS: A total of 147 HCC, 35 non-HCC malignancy, and 37 benign lesions in 205 patients at high risk of HCC were evaluated retrospectively, and the diagnostic performance of LI-RADS for diagnosing HCC were compared between using major features only and adopting major and ancillary features in combination. RESULTS: When using LR-5 as a predictor for diagnosing HCC, the diagnostic specificity (90.3% versus 91.7%), positive predictive value (92.3% versus 93.3%), and accuracy (68% versus 68.8%) were increased based on major and ancillary features in combination than just using major features on CT. When using LR-4/5 as a predictor for diagnosing HCC, the diagnostic sensitivity (78.9% versus 85.7%), negative predictive value (64.4% versus 72%), and accuracy (78.5% versus 82.2%) were increased while preserving a high specificity (77.8% versus 75%), according to major and ancillary features in combination rather than just using major features on CT. The LI-RADS categories of 8.7% (19/219) lesions were adjusted by adding the ancillary features on CT. CONCLUSION: Adding the ancillary features visible on CT can improve the diagnostic performance of the LI-RADS v2017 algorithm for diagnosing HCC, especially for LR-3 lesions.

[Effects of estradiol on the day of human chorionic gonadotropin administration on adverse perinatal outcomes].

Objective: To investigate the association between estradiol on the day of human chorionic gonadotropin (HCG) administration and birth outcomes among singleton live births following fresh embryo transfers. Methods: Based on the clinical reproduction medicine management system of the First Affiliated Hospital of Nanjing Medical University, this retrospective cohort study collected data of fresh embryo transfer cycles during January 2013 and December 2016, including pregnant women's age, body mass index (BMI), type and cause of infertility, assisted reproductive therapy indicators (fertilization mode, ovulation stimulation protocol, estradiol levels on HCG administration day), adverse birth outcomes[small for gestational age (SGA), premature and low birth weight (LBW)], etc.. A total of 2 060 women with singleton pregnancy (2 061 fresh embryo transfer cycles) were enrolled. Multivariate logistic regression was used to analyze the association between estradiol on HCG administration day and singletons' adverse birth outcomes. Results: The age and BMI of the 2 060 pregnant women were (29.63±3.92) years old and (22.29±2.86) kg/m2. Incidences of SGA, premature and LBW were 9.8% (201/2 061), 6.9% (143/2 061) and 3.5% (73/2 061), respectively. After adjusting for confounders, the risk of LBW in 4 000-4 499 pg/ml group was significantly elevated when compared to estradiol<1 500 pg/ml group [OR (95%CI): 4.42 (1.13-17.24)]. A protective effect of premature was observed in estradiol≥4 500 pg/ml group [OR (95%CI): 0.50 (0.25-0.97)]. Conclusion: The high level of estradiol on HCG administration day might be a risk factor for LBW, but a protective factor for premature.

[Hemodynamic changes in standing-up test of children and adolescents with postural tachycardia syndrome].

OBJECTIVE: To explore the hemodynamic changes in standing-up test of children and adolescents with postural tachycardia syndrome (POTS) and to compare hemodynamic parameters of POTS patients with decreased cardiac index (CI) and those with not-decreased CI. METHODS: A retrospective study was conducted to show the trends of CI, total peripheral vascular resistance index (TPVRI), heart rate and blood pressure in standing-up test of 26 POTS patients and 12 healthy controls, and to compare them between the two groups. The POTS patients were divided into two groups based on CI decreasing or not in standing-up test, namely decreased CI group (14 cases) and not-decreased CI group (12 cases). The trends of the above mentioned hemodynamic parameters in standing-up test were observed and compared between decreased CI group and not-decreased CI group. RESULTS: In standing-up test for all the POTS patients, CI (F=6.936, P=0.001) and systolic blood pressure (F=6.049, P<0.001) both decreased significantly, and heart rate increased obviously (F=113.926, P<0.001). However, TPVRI (F=2.031, P=0.138) and diastolic blood pressure (F=2.018, P=0.113) had no significant changes. For healthy controls, CI (F=3.646, P=0.016), heart rate (F=43.970, P<0.001), systolic blood pressure (F=4.043, P=0.020) and diastolic blood pressure (F=8.627, P<0.001) all increased significantly in standing-up test. TPVRI (F=1.688, P=0.190) did not change obviously. The changing trends of CI (F=6.221, P=0.001), heart rate (F=6.203, P<0.001) and systolic blood pressure (F=7.946, P<0.001) over time were significantly different between the patients and healthy controls, however, no difference was found in TPVRI and diastolic blood pressure (P > 0.05). Among the POTS patients, CI was significantly different between decreased CI group and not-decreased CI group (F=14.723, P<0.001). Systolic blood pressure of the former decreased obviously (F=8.010, P<0.001), but it did not change obviously in the latter (F=0.612, P=0.639). Furthermore, none of the changes of TPVRI, heart rate and diastolic blood pressure in standing-up test were significantly different between the two groups (P > 0.05). Age was an independent factor for decreased CI patients (P=0.013, OR=2.233; 95% CI, 1.183 to 4.216). CONCLUSION: POTS patients experience vital hemodynamic changes in standing-up test, part of them suffering from decreased CI, but others from not-decreased CI. Age is an independent factor for patients suffering from decreased CI.

[Analysis on factors related to spontaneous reduction in twin pregnancy following assisted reproductive technology].

Objective: To explorer factors related to spontaneous reduction in twin pregnancy following assisted reproductive technology. Methods: 2 848 twin pregnant women with treatment of vitro fertilization-embryo transfer (IVF-ET) or intra cytoplasmic sperm injection (ICSI) cycles were enrolled at Assisted Reproductive Centre of the First Affiliated Hospital of Nanjing Medical University, Nanjing Maternity Hospital and Shengjing Hospital of China Medical University from January 2013 to December 2016 respectively. Basic features of subjects, relevant clinical indicators, factors of assisted reproductive therapy and pregnancy outcome were collected from clinical assisted reproductive technology management system. According to the pregnancy outcome, the subjects with spontaneous reduction were classified as case group (n=686), and those with normal twin birth were classified as control group (n=2 162). The features of subjects in the two groups were compared. Non-conditional logistics regression model was used to analyze the related factors of the occurrence of spontaneous reduction. Results: The age of case group and control group were (30.6±4.3) and (30.2±4.0) years old respectively. After the adjustment of male sterile factor, compared to the subjects with luteinizing hormone level on the day of human chorionic gonadotropin administration (HCG) <1.43 IU/L, OR (95%CI) of the subjects with value at 2.59-5.10 IU/L was1.62 (1.08-2.42).Compared to the subjects with number of transferred embryo as 1, OR (95%CI) of the subjects with value as 3 was 0.23 (0.07-0.74). Compared to the subjects with stage of transferred embryo as cleavage stage, OR (95%CI) of the subjects with blastula stage was 0.42 (0.27-0.67). Conclusion: Luteinizing hormone level on day of HCG, number and stage of embryo transfer are related factors to spontaneous reduction in twin pregnancy following assisted reproductive technology.

[Data management and quality control strategies for population based cohort study].

Large-scale cohort study has unique advantages in the field of etiology research for its large sample size a multi-time point data, but it also brings great difficulty in data management and quality control at the same time. Recently, China has initiated a number of large-scale population cohort studies, posing enormous challenges to the management and quality control of related cohort data. This paper summarizes the existing experience and consensus in the field of cohort study in China from the characteristics of the cohort data, aiming at the types and main forms of the four main sources of questionnaire data, clinical diagnosis and treatment data, biological sample detection data and observation outcome data, from the data storage, circulation and transmission work.The contents and methods of queue data management are comprehensively summarized. Corresponding data quality control strategies are advised in the questionnaire evaluation, data logic verification, survey object sampling and multi-database review, etc. The goal of this review is to provide guidance for the management of data and the formulation of quality control strategies in the cohort study in China.

[Progress in diagnosis and management of syncope in children].

Syncope is a common emergency of children and adolescents, which has serious influence on the quality of life. Neurally-mediated syncope, including postural tachycardia syndrome, vasovagal syncope, orthostatic hypotension and orthostatic hypertension, is the main cause of syncope in children and adolescents. The main manifestations of neurally-mediated syncope are diverse, such as dizziness, headache, chest tightness, chest pain, pale complexion, fatigue, pre-syncope and syncope. Although the clinical manifestations are similar, each subtype of syncope has its hemodynamic feature and optimal treatment option. The diagnosis rate of syncope in children has been greatly improved on account of the development of the diagnostic procedures and methods. In recent years, with the promotion of head-up tilt test and drug-provocated head-up tilt test, the hemodynamic classification of neurally-mediated syncope gets continually refined. In recent years, with the effort of clinicians, an appropriate diagnostic protocol for children with syncope has been established. The initial evaluation consists of history taking, physical examination, standing test and standard electrocardiography. After the initial evaluation, some patients could be diagnosed definitely, such as postural tachycardia syndrome, orthostatic hypotension, and situational syncope. Those with a specific entity causing syncope need selective clinical and laboratory investigations. Patients for whom the cause of syncope remained undetermined should undergo head-up tilt test. The precise pathogenesis of neurally-mediated syncope is not entirely clear. In recent years, studies have shown that neurally-mediated syncope may be related to several factors, including hypovolemia, high catecholamine status, abnormal local vascular tension, decreased skeletal muscle pump activity and abnormal neurohumoral factors. Currently based on the possible pathogenesis, the individualized treatment of neurally-mediated syncope has also been studied in-depth. Generally, the management of neurally-mediated syncope includes non-pharmacological and pharmacological interventions. Patient education is the fundamental part above all. In addition to exercise training, the first-line treatments mainly include oral rehydration salts, beta adrenoreceptor blockers, and alpha adrenoreceptor agonists. By analyzing the patient's physiological indexes and biomarkers before treatment, the efficacy of medication could be well predicted. The individualized treatment will become the main direction in the future researches.

[Co-morbidity of vasovagal syncope and postural tachycardia syndrome with allergic diseases in children].

OBJECTIVE: To explore the clinical characteristics of the co-morbidity of vasovagal syncope (VVS) and postural tachycardia syndrome (POTS) with allergic diseases in children. METHODS: A re-trospective analysis was launched to summarize the clinical data of children with VVS and POTS. They were divided into allergic group and non-allergic group according to the history of allergic diseases. The participants' clinical characteristics were compared between allergic group and non-allergic group using independent sample t test or rank sum test; composition comparisons were completed by Chi-square test. Bi-variate correlation analysis was used to explore the association between eosinophil percentage/count and symptom scores/frequency of syncope episodes. A P value <0.05 was defined as statistically significant. RESULTS: Sixty-seven children complaining of orthostatic intolerance (43 patients diagnosed as VVS and 24 cases diagnosed as POTS) were enrolled. Totally 21 cases (31%) had allergic diseases, including allergic rhinitis, atopic eczema, asthma, as well as food allergy. And allergic rhinitis is the most common co-morbidity. There were no significant differences between the two groups in age, gender ratio, height, body weight and basement blood pressure. Compared with the non-allergic group, the allergic group showed later onset age (year) (11±2 vs. 9±3, P<0.05) of orthostatic intolerance and shorter course of the diseases (month) [8.0 (0.1, 0.1) vs. 24.0 (0.1, 144.0), P<0.05]. The frequency of syncope episodes in the allergic group among VVS children (times per month) [2.50 (0.08, 30.00) vs. 0.25 (0.03, 5.00), P<0.05] was much higher than that in the non-allergic group. Additionally, the eosinophil percentage (%) [3.50 (0.70, 0.59) vs. 1.65 (0.30, 6.20), P<0.001] and eosinophil count (×109) [0.18 (0.05, 0.71) vs. 0.10 (0.02, 0.38), P<0.001] were increased in the allergic group. However, there were no remarkable differences in the results of head-up tilt test in children with VVS or in the maximum change of heart rate during standing test in children with POTS were involved. CONCLUSION: Allergic diseases are common co-morbidities in children with both VVS and POTS. Allergic rhinitis is the most common co-morbidity. Children with co-morbidity of VVS/POTS and allergic diseases had a later onset of symptoms of orthostatic intolerance, and were more likely to be hospitalized for intensive attacks of symptoms during a short period when compared with those without allergic diseases. Children diagnosed as VVS combined with allergic diseases had more frequent episodes of syncope.

[Pulmonary arterial hypertension as leading manifestation of methylmalonic aciduria: clinical characteristics and gene testing in 15 cases].

OBJECTIVE: To deepen our understanding of Methylmalonic aciduria (MMA) associated pulmonary hypertension (PH) by analyzing the characteristics of clinical presentation, pulmonary high resolusion CT(HRCT), treatment response and gene mutation. METHODS: This study includes 15 cases of pediatric patients with MMA associated PH diagnosed and treated in Peking University First Hospital pediatric department between May 2012 and May 2016 with symptoms of PH as their leading presentation. Clinical symptoms and signs were recorded, Routine blood laboratory examinations was done including arterial blood gas analysis. Plasma total homocysteine (Hcy) and brain natriuretic peptide(BNP) level were measured. MMA gene mutation was analyzed. Chest HRCT was done in most of the patients. Standard treatment strategy to MMA and PH was given and follow up study was done, and the related literature was reviewed. Statistical analysis was done. The diagnosis of MMA was made by methylmalonic acid level >100 times the normal value in the urine. The diagnosis of PH was made by pulmonary arterial systolic pressure (PASP)>40 mmHg, which was estimated by the measurement of tricuspid regurgitation velocity through Doppler Echocardiography. RESULTS: (1) Patient characteristics: There were 10 male and 5 female patients diagnosed as MMA associated PH, aged 0.5 to 13.8 years, with an average of (5.0±4.3) years. The age of onset of PH was (3.7±3.5) years, with an early onset type MMA in 5 cases and late-onset type in 10 cases. (2) Clinical presentation: Among the 15 cases of MMA, the first symptoms were associated with PH in 10 cases, so PH and MMA were diagnosed at the same time, and PH was diagnosed 3 to 72 months post MMA presentation in the other 5 cases. The main presentations of PH were techypnea/dyspnea and cyanosis in 11 cases each, weakness and fatigue on exertion in 6 cases, and edema in 4 cases. PH WHO functional classification (WHO FC) was Class II in 4 , Class III in 5 and Class VI in 6 cases, with an average of Class 3.1±0.8. Multi-system involvements were common with the highest frequency in the kidney (14 cases). Macrocytic anemia was present in 8 cases and sub-clinical hypothyroidism in 5 cases, and mild to moderate mental retardation in 4 cases. (3) Laboratory examination: PASP of the 15 patients was from 49 to 135 mmHg, with an average of (90.3±23.9) mmHg. Total blood Hcy level was severely elevated to (121.2±48.2) µmol/L (range: 35.0-221.0 µmol/L), and Hcy >100 µmol/L within 11 cases. Plasma BNP level was also elevated, median 794 ng/L (range: 21.0-4 995.0 ng/L) with 12 cases >300 ng/L. Blood gas analysis showed low arterial blood oxygen saturation between 70% and 94%, with an average of 81.4%±8.4%. (4) Chest HRCT: chest HRCT showed a diffuse ground-glass centrilobular nodular opacities with septal line thickening in the lungs in 9 cases, and with associated mediastinal lymph node enlargement in 1 case, which indicated pulmonary veno-occlusive disease (PVOD), a rare type of pulmonary arterial hypertension (PAH). There was lung infection or edema in 3 cases, and interstitial infiltration and mesh-like feature in other 3 cases, which was inferred to interstitial lung disease. (5) Gene mutation: Genetic testing was done in 10 cases, totally 5 reported disease-causing mutations were found. There were 100% presence of MMACHC c.80A>G mutation in all the 10 patients tested, with the allelic genes of c.609G>A mutation in 6 patients, including a sister and a brother from the same parents. (6) Treatment and follow up: Intramuscular hydroxocobalamin or vitamin B12 was given to all of the patients, together with betaine, levocarnidtine, folinic acid and vitamin B6. According to the severity of PH, single or combined PAH targeted drugs was given to 11 cases. By an average of (20.0±13.5) days of in-hospital treatment in 13 patients (excepting 1 case treated as outpatient), symptoms remarkably resolved, WHO FC reduced to an average of Class 2.4±0.9, PASP dropped to (69.4±21.3) mmHg, and plasma Hcy and BNP level were decreased to (74.9±25.9) µmol/L and (341.6±180.2) ng/L, respectively. The above values all reached statistical significance (P<0.05) compared with each related value before treatment. There were 2 patients who expired during hospitalization despite of treatment. At the end of 3 months' follow up, all of the 13 patients disposed oxygen, and PASP significantly dropped to 38.7±7.9 mmHg, and plasma BNP returned to normal, but plasma Hcy level showed no further decline. At the last follow up of 27.5±19.0 (range: 11-64) months, all the patients' PASP remained normal except for the 13.8-year-old boy with 6 years-long history of MMA and almost 3.6 years' history of PH still having PASP 58 mmHg. CONCLUSION: PH is a severe complication of MMA combined type, especially cblC type, it is more often happens in late-onset type of male patients and can be the first and leading manifestations of MMA. Its clinical symptoms are urgent and severe, characterized by tachypnea/dyspnea and cyanosis, and sometimes right heart failure, hypoxemia is usually present, chest HRCT is often indicative of PVOD, lung edema and interstitial lung disease may occur. Rapid diagnosis and targeted treatment of MMA with appropriate anti-PAH medication can reverse PH and save life. MMACHC gene c.80A>G mutation may be the hot point of MMA cblC type associated PH.

[Hydrogen sulfide in cartilage and its inhibitory effect on matrix metalloproteinase 13 expression in chondrocytes induced by interlukin-1ß].

OBJECTIVE: To investigate whether endogenous hydrogen sulfide (H2S) was involved in the pathogenesis of osteoarthritis (OA) and its underlying mechanism, to detect H2S and its synthases expression in knee cartilage in patients diagnosed with different severity of OA, and to explore the transcription and expression of gene MMP-13 in chondrocytes treated with IL-1ß or H2S. METHODS: Synovial fluids of the in-patients with different severity of OA hospitalized in Peking University First Hospital were collected for measurement of H2S content using methylene blue assay. Articular cartilages of the patients who underwent knee arthroplasty were collected for the cell culture of relatively normal chondrocytes. The chondrocytes were cultured to the P3 generation and H2S molecular probes were used for detection of endogenous H2S generation in the chondrocytes. Immunocytochemistry was used to detect the localization of H2S synthases including cystathionine ß-synthase (CBS), cystathionine-γ-lyase (CSE), and mercaptopyruvate sulfurtransferase (MPST) in OA chondrocytes. Western blot was used to quantify the protein expressions of CSE, MPST, and CBS in cartilage tissues of the patients who were diagnosed with OA and underwent knee arthroplasty. The relatively normal human chondrocytes were cultured to passage 3 and then divided into 4 groups for different treatments: (1)the normal control group, no reagent was added; (2)the IL-1ß group, 5 µg/L of IL-1ß was added; (3)the IL-1ß+H2S group, 200 µmol/L of NaHS was added 30 min before adding 5 µg/L of IL-1ß;(4)the H2S group, 200 µmol/L of NaHS was added. The transcription and expression of gene MMP-13 in chondrocytes of each group were determined with Real-time PCR and Western blot, respectively. And the total NF-κB p65 and phosphorylated NF-κB p65 in chondrocytes were detected with Western blot. RESULTS: The content of H2S in the synovial fluid of degenerative knee was (14.3±3.3) µmol/L. Expressions of endogenous H2S and its synthases including CBS, CSE and MPST were present in the cytoplasm of chondrocytes.CSE protein expression in Grade 3 (defined by outerbridge grading) cartilage tissues was significantly increased as compared with that of Grade 1 cartilage tissues (1.67±0.09 vs. 1.26±0.11, P< 0.05). However, no significant difference of CBS or MPST expression among the different groups was observed. The expression of MMP-13 protein in the IL-1ßgroup was significantly higher than that in the normal chondrocytes (1.87±0.67 vs. 0.22±0.10, P<0.05), and that in the IL-1ß+H2S group was significantly decreased than that in the IL-1ß group (0.55±0.11 vs. 1.87±0.67, P< 0.05), and that in the H2S group had no significant difference compared with that in the normal control group. The transcription of MMP-13 protein in the IL-1ß group was significantly higher than that in the normal chondrocytes (31.40±0.31 vs. 1.00±0.00, P<0.05), and that in the IL-1ß+H2S group was significantly decreased than that in the IL-1ß group (24.41±1.28 vs. 31.40±0.31, P<0.05), and that in the H2S group had no significant difference compared with that in the normal control group. The total NF-κB p65 in the IL-1ß group was significantly higher than that in the normal chondrocytes (2.13±0.08 vs. 0.73±0.08, P< 0.05), and that in the IL-1ß+H2S group was significantly decreased than that in the IL-1ß group (1.24±0.13 vs. 2.13±0.08, P<0.05), and that in the H2S group had no significant difference compared with that in the normal control group. The phosphorylated NF-κB p65 in IL-1ß group was significantly higher than that in the normal chondrocytes (1.30±0.13 vs. 0.19±0.04, P<0.05), and that in IL-1ß+H2S group was significantly decreased than that in the IL-1ß group (0.92±0.26 vs. 1.30±0.13, P<0.05), and that in the H2S group had no significant difference compared with that in the normal control group. CONCLUSION: H2S affected the cartilage degeneration by partly inhibiting the degradation of extracellular matrix.

[DNA damage associated genetic variants contribute to lung cancer susceptibility in a Han Chinese population].

OBJECTIVE: To explore the association between DNA damage-related genetic variants and lung cancer susceptibility in a Han Chinese population. METHODS: This case-control study enrolled patients from the Cancer Hospital of Jiangsu Province and Jiangsu Province Hospital from 2003 to 2009. Controls were randomly selected from individuals who visited the same hospital or a community-based health examination program during the same time period. A 5 ml venous blood sample was obtained from each participant and epidemiological information was collected on a standard questionnaire. Illumina Infinium(®) BeadChip was used for genotyping of 35 DNA damage-related single nucleotide variations (SNVs), which were identified in our previous study. Multivariate and binary logistic regressions were used to calculate the OR and 95%CI for lung cancer risk. HaploReg V4.1 and Regulome DB were used to understand functional annotation on important SNV. RESULTS: The distributions of age (61.06±10.15) vs. (61.32±11.07) years; t=-0.72, P=0.473) and sex (χ(2)=1.81, P=0.179) were similar between cases and controls. However, the case group had a higher frequency of smokers (61.08% vs. 48.54%; χ(2)=50.04, P<0.001) and heavy smokers (42.28% vs. 24.07%; χ(2)=122.32, P<0.001). Among the 34 SNVs that passed quality control, two SNVs were significantly associated with lung cancer risk after adjustments for age, sex and cumulative smoking dose: rs9267576 C>A (CA genotype/CC genotype, OR=1.56, 95% CI: 1.01-2.40) and rs3130683 A>G (AG genotype/AA genotype, OR=1.87, 95%CI: 1.13-3.09). After step-wise logistic regression analysis, only the rs3130683 SNV was retained in the model, indicating that the association between rs9267576 and lung cancer may be due to the effect of rs3130683. Functional annotation indicated that rs3130683 was located in the promoter and enhancer regions, and was an expression quantitative trait loci of HLA. The Cancer Genome Atlas indicated that expression of HLA-C, DQB1, DRB1 and DRB5 in lung cancer tissue was significantly lower than in paired normal tumor-adjacent tissue, with down-regulation of the four respective genes in 81.3%, 88.8%, 90.7% and 90.7% of lung cancer tissues (P-values were 6.68×10(-15), 2.21×10(-13), 2.20×10(-16), 2.58×10(-13), respectively). CONCLUSIONS: The SNV rs3130683 (A>G) was associated with the risk of lung cancer in a Han Chinese population. This SNV may affect the risk of lung cancer by regulating HLA expression.

[Association between prenatal exposure to PM2.5 and fetal growth: a prospective cohort study].

Objective: To investigate the association of exposure to PM2.5 and its constituents during pregnancy and fetal growth and to further identify critical windows of exposure for fetal growth. Methods: We included 4 089 mother-child pairs from the Jiangsu Birth Cohort Study between January 2016 and October 2019. Data of general characteristics, clinical information, daily average PM2.5 exposure, and its constituents during pregnancy were collected. Fetal growth parameters, including head circumference (HC), abdominal circumference (AC), and femur length (FL), were measured by ultrasound after 20 weeks of gestation, and then estimated fetal weight (EFW) was calculated. Generalized linear mixed models were adopted to examine the associations of prenatal exposure to PM2.5 and its constituents with fetal growth. Distributed lag nonlinear models were used to identify critical exposure windows for each outcome. Results: A 10 µg/m3 increase in PM2.5 exposure during pregnancy was associated with a decrease of 0.025 (ß=-0.025, 95%CI: -0.048- -0.001) in HC Z-score, 0.026 (ß=-0.026, 95%CI: -0.049- -0.003) in AC Z-score, and 0.028 (ß=-0.028, 95%CI:-0.052--0.004) in EFW Z-score, along with an increased risk of 8.5% (RR=1.085, 95%CI: 1.010-1.165) and 13.5% (RR=1.135, 95%CI: 1.016-1.268) for undergrowth of HC and EFW, respectively. Regarding PM2.5 constituents, prenatal exposure to black carbon, organic matter, nitrate, sulfate (SO42-) and ammonium consistently correlated with decreased HC Z-score. SO42- exposure was also associated with decreased FL Z-scores. In addition, we found that gestational weeks 2-5 were critical windows for HC, weeks 4-13 and 19-40 for AC, weeks 4-13 and 23-37 for FL, and weeks 4-12 and 20-40 for EFW. Conclusions: Our findings demonstrated that exposure to PM2.5 and its constituents during pregnancy could adversely affect fetal growth and the critical windows for different fetal growth parameters are not completely consistent.

[Quality control and measures of China National Birth Cohort].

Birth cohort is an effective method to explore the relationship between various prepregnant and pregnant exposures and the health of fetuses, infants and young children. It is a long construction period to build a birth cohort and the quality of research may be affected by many factors. This paper reviews the quality assurance and quality control measures in the process of China National Birth Cohort (CNBC), and summarizes the construction experience. We aim to provide experience for related cohort studies, which could improve the quality of cohort studies through removing the impact of related factors. CNBC adopted a series of measures to ensure the quality of research in the top-level design of quality assurance, including screening research center, developing member management system, formulating standard operating procedures and training staff by it. In terms of quality control, it includes real-time, timely and timing quality control for the process of data generation, full-cycle quality control for biological sample collection, processing, storage and comprehensive three-dimensional quality control for staff training, supervision and quantitative assessment.

[Application of cloud-based information platform in China National Birth Cohort].

Birth cohort is an important observational study which can continuously and dynamically collect the exposure changes and health outcomes from gametophyte development to adolescence and even old age. However, because of its complex design and difficult implementation, how to construct birth cohort with high quality and high efficiency is the main difficulty faced by epidemiologists at home and abroad. In 2016, China National Birth Cohort was officially launched. The network and information technology were used to explore, and a set of "cloud-based information platform" was established to support this queue construction, containing 16 units in China. After four years of development, the platform has formed a complete set of programs about the construction of cohort information platform, which including recruitment and follow-up management of participants, real-time data interaction, queue quality control, multi-level authority management and function division. The relevant design framework and functional elements provide the references to the future information construction of large-scale birth cohort and even population-based research in China.

[Profile of China National Birth Cohort].

With the rapid changes in lifestyle, natural and social environment, the reproductive health status of couples in childbearing age continues to decline, and long-term outcomes of the rapidly increasing offspring conceived by assisted reproductive technology (ART) needs to be evaluated urgently. Therefore, the focus of research now needs to be extended from death and severe diseases to full life cycle and full disease spectrum. In order to meet the demand for such research, we launched the China National Birth Cohort (CNBC) study, an ongoing prospective and longitudinal study aiming to recruit 30 000 families underwent ART and 30 000 families with spontaneous pregnancies. Long-term follow-up programs will be conducted for both spouses and their offspring. Data of couples and their offspring, such as environmental exposure, reproductive history, psychological and behavioral status, will be collected during follow-up. Peripheral blood, urine, umbilical blood, follicular fluid, semen were also collected at different follow-up nodes. Based on high-quality data and biological samples, CNBC will play an extremely important supporting role and have a far-reaching impact on maternal and children's health care and reproductive health in China. This paper is exactly a brief introduction to the construction and basic design of CNBC.

[Baseline characteristics of the participants of China National Birth Cohort].

Objective: To explore the effects of environmental, genetic factors as well as the interactions in early life on the short-term and long-term health of offspring and to systematically evaluate the pregnancy outcomes and health of offspring after birth between families with assisted reproductive technology (ART) conception and families with spontaneous conception. Methods: The China National Birth Cohort (CNBC), a multicenter prospective birth cohort study, includes both families with ART conception and families with spontaneous conception. Since 2016, CNBC has recruited families from 24 hospitals located in 12 provinces, municipalities and autonomous regions throughout China. Information and biospecimens were collected before ART treatment, embryo transfer, at early, second, third trimester and delivery, and at 42 days, 6, 12 and 36 months after birth. Results: By June 2020, CNBC had included 27 044 families with ART conception and 29 589 families with spontaneous conception. The majority of the participants are urban residents. Among the families with ART conception, 65.5% of the men and 63.7% of the women had college degrees or higher. The mean age distribution of men and women was (33.83±5.52) and (32.38±4.67) years. 83.2% of women were primiparas, and the prevalence rates of current regular smokers and current alcohol drinkers were 0.8% and 2.1% in women. Among the families with spontaneous conception, 81.5% of the men and 86.5% of the women had college degrees or higher. The mean age distribution of men and women was (32.06±5.09) and (30.40±4.27) years. 67.2% of women were primiparas, and the prevalence rates of current regular smokers and current alcohol drinkers were 0.1% and 2.2% in women. The baseline characteristics were different between the families with ART conception and spontaneous conception in different regions. Conclusion: CNBC provides a powerful and rich resource in studying the impact of genetic, environmental factors and interactions in early life and ART treatment on the health of offspring after birth.

[The Autism Spectrum Disorder Cohort-the sub-cohort of China National Birth Cohort].

Autism spectrum disorder (ASD), a representative disease of children's neurodevelopmental disorders, brings huge pressure and financial burden to families and society. It is of great significance to explore its etiology and pathogenesis. Therefore, we established an ASD Cohort based on the existing China National Birth Cohort (CNBC), which applied parallel design to recruit and follow up families who achieved pregnancy after receiving assisted reproductive technologies (ART) and families with spontaneous conception. The main aims of this study are to compare the incidence of ASD among children born after ART with those born under spontaneous pregnancy, and to evaluate the impact of ART on the neurobehavioral development of offspring. Additionally, with a variety of clinical and behavioral related information collected during pregnancy and at early life of offspring, we are able to investigate the risk factors associated with ASD comprehensively. This article briefly introduces the objectives, contents, preliminary progress, strength and limitations, as well as further prospects of the ASD cohort study, mainly focusing on the overall design and current progress.

[A sub-cohort study design of the maternal and infant microbes in China National Birth Cohort].

The importance of gut microbes to human health has gradually attracted attention. With the use of animal models, it has been revealed that maternal microbes during pregnancy could influence their children's health outcomes through shaping their microbial composition and regulating the development of their metabolic and immune system. However, the physiological mechanism of the human body is more complex and is affected by the interaction of multiple factors. The research results obtained from animal models are often inconsistent with human studies. At present, the influence of maternal intestinal microbes during pregnancy on the microbial colonization in their offspring and on a series of children's health outcomes is still unclear. Establishing a sub-cohort to detect the microbiome of the women across pregnancy and of their offspring, and further to integrate with variety of environmental and behavioral exposures can better provide reliable support for the research on the mechanism of children's health and diseases. This paper briefly introduces the research objectives, content, progress, strength and limitations of the sub-cohort study.