Non-syndromic oral cleft (NSOC), a common birth defect, remains to be a critical public health problem in China. In the context of adjustment of childbearing policy for two times in China and the increase of pregnancy at older childbearing age, NSOC risk prediction will provide evidence for high-risk population identification and prenatal counseling. Genome-wide association study and second generation sequencing have identified multiple loci associated with NSOC, facilitating the development of genetic risk prediction of NSOC. Despite the marked progress, risk prediction models of NSOC still faces multiple challenges. This paper summarizes the recent progress in research of NSOC risk prediction models based on the results of extensive literature retrieval to provide some insights for the model development regarding research design, variable selection, model-build strategy and evaluation methods.
Humans ; Cleft Palate/genetics* ; Cleft Lip/genetics* ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Risk Factors ; Polymorphism, Single Nucleotide

Objective: To analyze the clinical characteristics, treatment and prognosis of Hashimoto's encephalopathy presenting with isolated cerebellar ataxia in children. Methods: A retrospective analysis was performed on the clinical features, laboratory tests, neuroelectrophysiological examination, imaging, treatment and outcomes of 13 patients with Hashimoto's encephalopathy presenting with isolated cerebellar ataxia, who were admitted to the Department of Pediatric Neurology of Guangzhou Women and Children's Medical Center from January 2016 to May 2021. Results: Among the 13 cases, 6 were males and 7 were females. The onset age was 2.6 (2.0,3.3) years, 9 children had precursor infection or vaccination before the first course of disease. All the 13 children had gait abnormalities or unsteady sitting, 10 had intentional tremor, 6 had dysarthria, 3 had body tremor, 2 had nystagmus, 3 had fatigue, 3 had hypotonia, 2 had vomiting and 1 had irritability. Thyroglobulin antibody (TgAb) was 500.0 (298.9,587.2) kU/L and thyroid peroxidase antibody (TPOAb) was 621.9 (449.6,869.4) kU/L in 13 cases. Autoantibodies were positive in 9 cases, and cerebrospinal fluid leukocytosis was seen in 4 cases. Regarding electroencephalography result, 4 cases had background slowing and 1 case had occasional sharp waves. Among the 3 patients who had relapses, 1 had cerebellar atrophy shown on cranial magnetic resonance imaging (MRI) during the recurrence. All the patients received intravenous immunoglobulin (IVIG) and intensive methylprednisolone therapy during the first onset, followed by the disappearance of the symptoms, 1 patient had repeated episodes which was decreased after immunosuppressive treatment with Rituximab.Followed up for 25.0 (22.5,33.3) months after the last episode, 12 achieved complete remission and 1 had a wide base gait. Conclusions: Trunk ataxia is the common symptom of Hashimoto's encephalopathy presenting with isolated cerebellar ataxia in children.Children with cerebellar ataxia should be tested for TgAb and TPOAb to detect Hashimoto's encephalopathy, avoiding missed diagnosis and treatment delays; IVIG and intensive steroid therapy is effective, and immunosuppressive therapy for patients with multiple relapses could reduce the recurrence.
Autoantibodies ; Cerebellar Ataxia ; Child ; Encephalitis ; Female ; Hashimoto Disease ; Humans ; Male ; Retrospective Studies

Next-generation sequencing has revolutionized family-based association tests for rare variants. As the lower power of genome wide association study for detecting casual rare variants, methods aggregating effects of multiple variants have been proposed, such as burden tests and variance component tests. This paper summarizes the methods of rare variants association test that can be applied for family data, introduces their principles, characteristics and applicable conditions and discusses the shortcomings and the improvement of the present methods.
Computer Simulation ; Family Relations ; Genetic Association Studies ; Genetic Variation ; Genome-Wide Association Study/methods* ; Humans

OBJECTIVE: To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design. METHODS: Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database. RESULTS: A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes. CONCLUSION Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.
Asians ; Case-Control Studies ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Mutation ; Parents ; Polymorphism, Single Nucleotide ; Whole Exome Sequencing

OBJECTIVE: To study the clinical features and recurrence factors of myelin oligodendrocyte glycoprotein (MOG) antibody disease in children and the effect of recurrence prevention regimens. METHODS: A retrospective analysis was performed on the medical data of 41 children with MOG antibody disease who were hospitalized in the Department of Pediatric Neurology, Xiangya Hospital of Central South University, from December 2014 to September 2020. According to the presence or absence of recurrence, they were divided into a monophasic course group ( RESULTS: For these 41 children, acute disseminated encephalomyelitis was the most common initial manifestation and was observed in 23 children (56%). Of the 41 children, 22 (54%) experienced recurrence, with 57 recurrence events in total, among which optic neuritis was the most common event (17/57, 30%). The proportion of children in the recurrence group who were treated with corticosteroids for less than 3 months in the acute phase was higher than that in the monophasic course group (64% CONCLUSIONS More than half of the children with MOG antibody disease may experience recurrence. Most children with recurrence are treated with corticosteroids for less than 3 months in the acute phase. Rituximab and azathioprine may reduce the risk of recurrence.
Autoantibodies ; Child ; Humans ; Myelin-Oligodendrocyte Glycoprotein ; Optic Neuritis ; Recurrence ; Retrospective Studies

ObjectiveTo explore the clinical and genetic characteristics， treatment and prognosis of children with dopa-responsive dystonia due to tyrosine hydroxylase deficiency （THD）. MethodThe clinical data of 6 children with dopa-responsive dystonia due to THD， who were admitted to the Department of Neurology of Guangzhou Women and Children’s Medical Center from June 2017 to Nov 2020， were retrospectively analyzed. ResultsThese 6 children （4 boys and 2 girls）， who came from four different families， suffered from dystonia. The median age of onset was 11.5 months （range from 3 months to 4 years）. Compound heterozygous TH gene mutations were found in six patients. Seven different mutations were identified in the TH gene including five known mutations： c.698G>A（p.R233H）， c.1145T>C（p.I382T）， c.739G>A（p.G247S）， c.1481C>T（p.T494M）， c.880G>C（p.G294） and two novel mutations： c.1279A>G（p.Y427H） and c.1128_1138del（p.Q377GfsTer12）. The patients took different doses of Madopa， ranging from 2 to 15 mg/（kg·d） in maintenance. All the patients responded well to Madopa but Case 4 was left with scoliosis. ConclusionsTHD can cause a broad range of clinical symptoms and severity. Early identification and initiation of levodopa therapy significantly improved the prognosis. We here identified two novel heterozygous variant in TH（c.1279A>G and c.1128_1138del）. Our study expands the spectrum of genotype of THD in China， providing new insights into the molecular mechanism of THD. Genetic testing can make a definite diagnosis.

Objective:To evaluate the efficacy of artificial intelligence assisted pulmonary nodule diagnosis system in detection pulmonary nodule and predicting the malignant probability of pulmonary nodule.Methods:A retrospectively analyze the clinical data of 199 patients with lung nodules in the Thoracic Surgery Department of Lanzhou University Second Hospital from May 2016 to July 2020. The preoperative chest CT was imported into the artificial intelligence system to record the detected lung nodules, to measure nodal diameter and density classification and malignant probability prediction value of each nodule. The detection rate of pulmonary nodules by artificial intelligence system was calculated, and the sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of artificial intelligence system in the differential diagnosis of benign and malignant pulmonary nodules were calculated and compared with manual film reading. and the sensitivity and specificity in the differential diagnosis of benign and malignant pulmonary nodules under the condition of different size and density of pulmonary nodules.Results:A total of 204 pulmonary nodules were pathologically diagnosed by surgical resection, and the detection rate of pulmonary nodules by artificial intelligence system was 100%. The artificial intelligence system can distinguish benign and malignant pulmonary nodules with a sensitivity of 95.83%(95% CI: 0.8967-0.9883), specificity 25.00%(95% CI: 0.1717-0.3425), and a positive likelihood ratio of 1.27(95% CI: 1.14-1.44), negative likelihood ratio 0.17(95% CI: 0.06-0.46), Manual reading for the differentiation of benign and malignant pulmonary nodules has a sensitivity of 87.36%(95% CI: 0.7850-0.9352), specificity 72.17%(95% CI: 0.6214-0.8079), and a positive likelihood ratio of 3.14(95% CI: 2.26-4.37), the negative likelihood ratio is 0.18(95% CI: 0.10-0.31). 5mm≤diameter of pulmonary nodule<10 mm, sensitivity 100%(95% CI: 0.6637-1.0000), specificity 50.00%(95% CI: 0.01258-0.98740), 10 mm≤diameter of pulmonary nodule <20 mm, sensitivity 94.29%(95% CI: 0.8084-0.9930), specificity 29.83%(95% CI: 0.1843-0.4340), 20 mm≤ diameter of pulmonary nodule ≤30 mm, sensitivity 96.15%(95% CI: 0.8679-0.9953), specificity 18.37%(95% CI: 0.0876-0.9953), sensitivity of subsolid lung nodules: 100%(95% CI: 0.9051-1.0000), specificity 20.00%(95% CI: 0.0051-0.7164), solid lung nodule sensitivity 93.22%(95% CI: 0.8354-0.9812), specificity 25.24%(95% CI: 0.1720-0.3476). Conclusion:The artificial intelligence assistant diagnosis system of pulmonary nodules has a strong performance in the detection of pulmonary nodules, but it can not meet the clinical requirements in the differentiation of benign and malignant pulmonary nodules. At present, the artificial intelligence system can be used as an auxiliary tool for doctors to detect pulmonary nodules and assist in the diagnosis of benign and malignant pulmonary nodules.

OBJECTIVE: To investigate the effects of Da-Cheng-Qi Decoction (DCQD, ) combined with Lactobacillus acidophilus (LA) on the recovery of gastrointestinal (GI) function in traumatic brain-injured (TBI) mice. METHODS: A total of 150 male C57BL/6 mice were randomly divided into sham-injury, normal saline (NS), DCQD (0.4 mL/day), LA (⩾1 × 10 cfu/day LA), DCQD+LA (LA administration at the same dosage after 4 h of feeding DCQD), and ½ DCQD+LA groups (LA administration at the same dosage after 4 h of feeding ½ DCQD dose) by a random number table, 5-8 mice in each group. The sever TBI model was constructed according to Feeney's enhanced gravitational forces of free falling. On days 1, 3, and 7 post-TBI, plasma diamine oxidase (DAO) and D-lactic acid levels were assessed by enzyme-linked immunosorbent assay (ELISA). Occludin expression in the intestinal epithelium was assessed by Western blot analysis. Transmission electron microscopy (TEM) was used to observe the morphological changes in the network structure of interstitial cells of Cajal (ICC) and change of enteric nervous system-ICC-smooth muscle cell (ENS-ICC-SMC). Immunofluorescence staining was used to detect changes in the network structure of the ICC. RESULTS: Compared with the NS group, occludin expression in the DCQD+LA group significantly increased on Day 1, 3, and 7 post-TBI (P<0.05 or P<0.01). The concentration of DAO significantly decreased in the LA, DCQD, and DCQD+LA groups on Day 3 and 7, whilst the D-lactate concentrations in the LA and ½ DCQD+LA groups decreased on Day 1 and 3 post-injury (P<0.05 or P<0.01). The NS group experienced a great damage on the ENS-ICC-SMC network morphology and ICC network structure, and all treatment groups had some improvements, among which the DCQD+LA group presented relatively intact network morphology. CONCLUSIONS DCQD combined with LA treatment could effectively repair the intestinal mucosal barrier and improve GI motility in mice after TBI. The combination of DCQD and LA was more effective than their respective monotherapies.

Objective    To explore the mechanism of DDX46 regulation of esophageal squamous cell carcinoma. Methods    Picture signals of fluorescence in gene array were scanned and differential expression of gene in two groups (a DDX46-shRNA-LV group and a control-LV group) were compared by GCOSvL.4 software. These differential expressed genes were analyzed by bioinformatics methods finally, and validated by quantitative real time polymerase chain reaction (qRT-PCR) analysis. Results    According to the screening criteria of fold change ≥2 and P<0.05, 1 006 genes were differentially expressed after DDX46 knockdown, including 362 up-regulated and 644 down-regulated genes. Bioinformatics analysis and gene co-expression network building identified that these differentially expressed genes were mainly involved in cell cycle, proliferation, apoptosis, adhesion, energy metabolism, immune response, etc. Phosphatidylinositol 3-kinase (PI3K) was the key molecule in the network. The results of RT-qPCR were completely consistent with the results of gene microarra. Conclusion    Bioinformatics can effectively exploit the microarray data of esophageal squamous cell carcinoma after DDX46 knockdown, which provides a valuable clue for further exploration of DDX46 tumorigenesis mechanism and helps to find potential drug therapy.

【Objective】 To evaluate the cerebral hemodynamic changes due to interictal epileptic discharges(IEDs) and explore the associated neuroelectrophysiological factors and cognition deficits on electrical status epilepticus during sleep(ESES) through real-time transcranial Doppler ultrasound-video-electroencephalogram(TCD-vEEG) . 【Methods】 Eighteen ESES patients from August, 2017 to March, 2019 were recruited to undergo TCD-vEEG. The trend curve of mean cerebral blood flow velocity(MCBFV) was generated and analyzed. The spike wave index(SWI) and various TCD parameters during non-rapid eye movement(NREM) sleep were measured. The patients were divided into three clinical level groups based on seizures, their cognitive functions and the Activity of Daily Living Scale. According to the patterns of EEG during pre-ESES, the patients were also separately grouped to three groups: bilateral synchronous epileptogenic foci(BSEF), bilateral asynchronous epileptogenic foci(BAEF) and multiple epileptogenic foci(MEF). The patients were also separated into near-ESES and asymmetric ESES groups based on EEG patterns during ESES. We then performed Fisher's precise test, an analysis of variance(ANOVA) and Student's t-test, to determine that those parameters significantly varied according to clinical level and/or EEG pattern through SPSS 17.0. 【Results】 SWI was(85.22±10.33) % on average; MCBFV oscillations during deep sleep was(17.98±7.27) % on average(t = 7.579, P < 0.01); the mean of MCBFV(MCBFVm) was(92.81±21.53) cm/s on average(t = 6.464, P < 0.01); all increased significantly more than those of healthy children. SWI(F = 3.996, P < 0.05) revealed a statistically significant difference among three clinical level groups. ESES pattern had no obvious relation with the SWI, but Near-ESES influenced MCBFV oscillations during deep sleep significantly more(t = 2.885, P = 0.011) . 【Conclusions】 There are obvious cerebral hemodynamic changes during NREM in ESES, and IEDs frequency are the important factors of cognitive impairment due to ESES. ESES pattern is closely related to MCBFV oscillations during deep sleep.