Case Report: A novel RRM2B variant in a Chinese infant with mitochondrial DNA depletion syndrome and collective analyses of RRM2B variants for disease etiology.

Background: There are few reports of infantile mitochondrial DNA depletion syndrome (MDDS) caused by variants in RRM2B and the correlation between genotype and phenotype has rarely been analyzed in detail. This study investigated an infantile patient with MDDS, from clinical characteristics to genetic causes. Methods: Routine physical examinations, laboratory assays, which included gas chromatography-mass spectrometry of blood and urine, and MRI scans were performed to obtain an exact diagnosis. Whole-exome sequencing was used to pinpoint the abnormal gene and bioinformatic analyses were performed on the identified variant. Results: The case presented with progressive neurologic deterioration, failure to thrive, respiratory distress and lactic acidosis. Sequencing revealed that the patient had a homozygous novel missense variant, c.155T>C (p.Ile52Thr), in exon 2 of the RRM2B gene. Multiple lines of bioinformatic evidence suggested that this was a likely detrimental variant. In addition, reported RRM2B variants were compiled from the relevant literature to analyze disease etiology. We found a distinctive distribution of genotypes across disease manifestations of different severity. Pathogenic alleles of RRM2B were significantly enriched in MDDS cases. Conclusion: The novel variant is a likely genetic cause of MDDS. It expands our understanding of the pathogenic variant spectrum and the contribution of the RRM2B gene to the disease spectrum of MDDS.

Visual Cognitive Assessment Test: Utility of the brief cognitive battery for early screening of cognitive impairment in Chongqing, China.

OBJECTIVES: Early detection of cognitive impairment is essential for timely intervention. Currently, most widely used cognitive screening tests are influenced by language and cultural differences; therefore, there is a need for the development of a language-neutral, visual-based cognitive assessment tool. The Visual Cognitive Assessment Test (VCAT), a 30-point test that assesses memory, executive function, visuospatial function, attention, and language, has demonstrated its utility in a multilingual population. In this study, we evaluated the reliability, validity, and diagnostic performance of the VCAT for screening early cognitive impairment in Chongqing, China METHODS: A total of 134 individuals (49 healthy controls (HCs), 52 with mild cognitive impairment (MCI), and 33 with mild dementia) completed the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), VCAT, and domain-specific neuropsychological assessments. The diagnostic performances of MMSE, MoCA, and VCAT were evaluated using the area under the curve (AUC), sensitivity, and specificity. Construct validity of the VCAT was assessed with well-established domain-specific cognitive assessments. Reliability was measured using Cronbach's alpha. RESULTS: The VCAT and its subdomains demonstrated both good construct validity and internal consistency (α = 0.577). The performance of VCAT was comparable to that of MoCA and MMSE in differentiating mild dementia from nondemented groups (AUC: 0.940 vs. 0.902 and 0.977, respectively; p = .098 and .053) and in distinguishing cognitive impairment (CI) from HC (AUC: 0.929 vs. 0.899 and 0.891, respectively; p = .239 and .161), adjusted for education level. The optimal score range for VCAT in determining dementia, MCI, and HC was 0-14, 15-19, and 20-30, respectively. CONCLUSION: The VCAT proves to be a reliable screening test for early cognitive impairment within our cohort. Being both language and cultural neutral, the VCAT has the potential to be utilized among a wider population within China.

A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing.

Background: Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is a rare mitochondrial disease caused by mutations in the GTPBP3 gene. The rare incidence of the disease and the high clinical heterogeneity pose challenges in making a precise diagnosis. Investigations into the rare COXPD23 patients are of pathophysiological and etiological value. In this study, we investigated the genotype-phenotype relationship in a COXPD23 patient from a Manchu family, with GTPBP3 mutations. Methods: Routine physical examinations, laboratory assays and imaging analyses were performed. The metabolic profiles of amino acids in blood, acylcarnitine in blood and organic acids in urine were used to determine the presence of inherited metabolic diseases. Genetic variations in the family were investigated using whole-exome sequencing and Sanger sequencing. Splicing disruption by a mutation was predicted and verified using a minigene assay. Results: The patient presented with severe lactic acidosis, neurological symptoms, multiple symmetrical lesions in the brain and serious mitochondrial energy metabolism disturbances. The c.689A > C (p.Q230P) and c.809-1_809delinsA compound heterozygous mutations were detected in GTPBP3. The novel c.809-1_809delinsA mutation was located at the splicing site of exon 7 and intron 6 and multiple tools predicted that it would disrupt the normal splicing. The minigene assay proved that the novel mutation resulted in two aberrant transcripts that created premature termination codons. Conclusions: The clinical manifestations, brain imaging change, mitochondrial metabolism disturbances and the detection and validation of the GTPBP3 mutations expand the profile of COXPD23 and the pathogenic mutation spectrum. Our study improves the understanding of the pathophysiology and etiology of COXPD23.

Epidemiology and Clinical Characteristics of Pediatric Sepsis in PICUs in Southwest China: A Prospective Multicenter Study.

OBJECTIVES: To describe the epidemiological characteristics of pediatric sepsis in Southwest China PICUs. DESIGN: A prospective, multicenter, and observational study. SETTING: Twelve PICUs in Southwest China. PATIENTS: The patients admitted to the PICU from April 1, 2022, to March 31, 2023. The age ranged from 28 days to 18 years. All patients met the criteria of severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 31 PICUs invited to participate, 12 PICUs (capacity of 292 beds) enrolled patients in the study. During the study period, 11,238 children were admitted to the participating PICUs, 367 (3.3%) of whom met the diagnosis of severe sepsis or septic shock. The most prevalent sites of infection were the respiratory system (55%) and the digestive system (15%). The primary treatments administered to these patients included antibiotics (100%), albumin (61.3%), invasive mechanical ventilation (58.7%), glucocorticoids (55.6%), blood products (51%), gammaglobulin (51%), and vasoactive medications (46.6%). Sepsis-related mortality in the PICU was 11.2% (41/367). Nearly half of the sepsis deaths occurred within the first 3 days of PICU admission (22/41, 53.7%). The mortality rate of septic shock (32/167, 19.2%) was significantly higher than that of severe sepsis (9/200, 4.5%; p < 0.001). The outcomes of a multivariate logistic regression analysis suggested that a higher pediatric Sequential Organ Failure Assessment score, and the use of invasive mechanical ventilation and vasoactive medications were independently associated with PICU mortality in children with sepsis. CONCLUSIONS: This report updates the epidemiological data of pediatric sepsis in PICUs in Southwest China. Sepsis is still a life-threatening disease in children.

A Network Meta-Analysis of Randomized Clinical Trials to Assess the Efficacy and Safety of Antiviral Agents for Immunocompetent Patients with Herpes Zoster-Associated Pain.

BACKGROUND: The most refractory symptom of herpes zoster (HZ) is pain. Approximately 90% of people who have HZ suffer from pain. Early use of antiviral medications has been found to reduce pain across all stages of the disease. Although many antiviral agents via oral or intravenous administration were recommended by clinical practice, the best approach to prevent HZ-associated pain remains uncertain. OBJECTIVES: The purpose of this study was to compare the efficacy and adverse events of various antiviral agents used for the treatment of HZ-associated pain through a network meta-analysis. STUDY DESIGN: A systematic review and meta-analysis. SETTING: The Cochrane Register of Controlled Trials, Embase, and PubMed were searched from inception to Feb 2020. METHODS: Randomized clinical trials evaluating antiviral agents currently available for treating HZ-associated pain were included. We extracted data in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and conducted network meta-analyses with random-effects models. The primary outcome was the presence of acute pain at the end of anti-virus treatment, and the secondary outcomes included the presence of pain at 28-30 days after the onset of the acute herpetic rash, the presence of postherpetic neuralgia (PHN), and any other adverse events. RESULTS: A total of 17 randomized control trials with 5,579 participants were included in this study. According to the results of the network meta-analysis, for the treatment of acute pain, there was no significant difference between oral acyclovir and intravenous acyclovir. Furthermore, oral famciclovir was the most effective treatment concerning both the odds ratio (OR) (superior to placebo OR = 0.25; 95% CI: 0.13~0.48) and the surface under the cumulative ranking curve (SUCRA) values of 0.84 for the treatment of acute pain among all the oral antiviral agents. For the presence of pain at 28-30 days, no significant difference was observed in efficacy between all antiviral treatments and placebo concerning the OR; however, oral valaciclovir ranked first (SUCRA values of 0.96). For the presence of NPH, oral famciclovir was determined to be the most effective (SUCRA values of 0.77) treatment with an efficacy of 0.42 (95% CI: 0.18~0.99) versus placebo. For adverse events, there was no significant difference between oral antivirals and placebo; however, intravenous acyclovir ranked last with a score of OR 4.31 (95% CI: 1.26~14.75) versus placebo. LIMITATIONS: The distribution of severity of pain was different in various studies; then, the lack of availability of individual data prevented us from analyzing the effects of the risk factors. CONCLUSIONS: For the treatment of acute pain and PHN, oral famciclovir was the most effective treatment among all the oral antiviral agents. For alleviating pain after 28-30 days, oral valaciclovir appeared to be the most effective among all antiviral agents. Additionally, all oral antiviral agents were well tolerated. CLINICAL TRIAL REGISTRATION INFORMATION: PROSPERO under the identification CRD42020212834.

Clinical and genetic characterization of pediatric patients with Wilson's disease from Yunnan province where ethnic minorities gather.

Background: Wilson's disease (WD) is an autosomal recessive disease that is caused by mutations in the ATP7B (a copper-transporting P-type ATPase) gene. The disease has a low prevalence and is characterized by a copper metabolism disorder. However, various characteristics of the disease are determined by race and geographic region. We aimed to discover novel ATP7B mutations in pediatric patients with WD from Yunnan province, where there is a high proportion of ethnic minorities. We also performed a comprehensive analysis of ATP7B mutations in the different ethnic groups found in Southwest China. Methods: We recruited 45 patients who had been clinically diagnosed with WD, from 44 unrelated families. Routine clinical examinations and laboratory evaluations were performed and details of age, gender, ethnic group and symptoms at onset were collected. Direct sequencing of the ATP7B gene was performed in 39 of the 45 patients and their families. Results: In this study, participants came from seven different ethnic groups in China: Han, Bai, Dai, Zhuang, Yi, Hui and Jingpo. Three out of ten patients from ethnic minorities presented with elevated transaminases, when compared to the majority of the Han patients. Forty distinct mutations (28 missense, six splicing, three non-sense, two frameshift and one mutation of uncertain significance) were identified in the 39 patients with WD. Four of the mutations were novel and the most frequent mutation was c.2333G > T (p.R778L, allelic frequency: 15.38%). Using the phenotype-genotype correlation analysis, patients from ethnic minorities were shown to be more likely to have homozygous mutations (p = 0.035) than Han patients. The patients who carried the c.2310C > G mutation had lower serum ceruloplasmin levels (p = 0.012). In patients with heterozygous mutations, c.3809A > G was significantly associated with ethnic minorities (p = 0.042). The frequency of a protein-truncating variant (PTV) in Han patients was 34.38% (11/32), while we did not find PTV in patients from ethnic minorities. Conclusion: This study revealed genetic defects in 39 pediatric patients with WD from Yunnan province. Four novel mutations were identified and have enriched the WD database. We characterized the genotypes and phenotypes in different minorities, which will enhance the current knowledge on the population genetics of WD in China.

Primary empty sella: The risk factors and associations with the cerebral small vessel diseases-An observational study.

OBJECTIVE: To investigate the risk factors of primary empty sella (PES) and its associations with cerebral small vessel diseases (CSVD). METHODS: A total of 132 consecutive patients were recruited from Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University from December 2018 to January 2020, including 69 cases of PES, and age, gender-matched 63 subjects without PES. Demographics and clinical characteristics were recorded. Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH), which are image markers for CSVD, were assessed. Univariate logistic regression models and multivariate logistic regression models were performed to predict the independent risk factors of PES. RESULTS: There was a significant difference in baseline characteristics in terms of hypertension (p < 0.001) and pregnancy (p = 0.019) between PES and the control group; among markers of CSVD, whole WMH (p = 0.030) and periventricular hyperintensities (PVH) (p = 0.027) were significantly different; however, no significant differences concerning deep WMH, total PVS, basilar ganglia-PVS and centrum semiovale-PVS (p > 0.05). After adjusting relevant potential confounders, multivariate logistic regression revealed hypertension (OR=3.158, 95 %CI: 1.452∼6.865, p = 0.004) and pregnancy (OR=2.236, 95 %CI: 1.036-4.826, p = 0.040) were independent risk factors for PES. CONCLUSION: Hypertension and pregnancy are independent risk factors of PES. There is a possible correlation between PES and WMH, especially PVH, however, further studies are required to confirm these findings.

Effects of site, cerebral perfusion and degree of cerebral artery stenosis on cognitive function.

OBJECTIVE: To investigate the effects of site, cerebral perfusion and degree of cerebral artery stenosis (CAS) on cognitive function. METHODS: A total of 57 patients with CAS and 53 controls from January 2019 to December 2019 were included. The former group was further divided into different subgroups according to the site, cerebral perfusion and degree of CAS. A series of neuropsychological tests were performed to evaluate the cognitive domains (such as memory, executive function, psychomotor speed, etc.). Rank sum test, t test, Chi-square test and analysis of variance were used for data analysis. Spearman correlation analysis was used to examine the relationship between the site, cerebral perfusion and degree of CAS and all tests' scores. RESULTS: For patients with CAS who have decreased cerebral perfusion, their global cognitive function, memory, psychomotor speed, executive function and frontal lobe function were significantly impaired (all P < 0.05). There was a significant decrease in global cognitive function, psychomotor speed, memory, executive function and frontal lobe function in patients with anterior circulation stenosis (all P < 0.05). Moderate and severe CAS impaired subjects' global cognitive function, memory, psychomotor speed, executive function and frontal lobe function (all P < 0.05). There was a correlation between the site, cerebral perfusion, the degree of CAS and cognitive function. CONCLUSION: Global cognitive function, memory, psychomotor speed, frontal lobe function and executive function are impaired in patients with CAS, especially in those with anterior circulatory stenosis, moderate to severe stenosis and low cerebral perfusion.See Video Abstract, http://links.lww.com/WNR/A613.

Epidemiology of Pediatric Severe Sepsis in Main PICU Centers in Southwest China.

OBJECTIVES: To estimate the prevalence, management, and outcomes of pediatric severe sepsis in the main PICUs in Southwest China. DESIGN: A prospective, observational, and multicenter study. SETTING: Eight PICUs in Southwest China with 19 (13-24) beds and 1,322 (1,066-1,452) annual admissions each. PATIENTS: A total of 10,598 patients (29 d to 18 yr old) were consecutively admitted between September 1, 2016, and August 31, 2017. All patients were screened and evaluated for severe sepsis or septic shock. Of them, 10,353 patients were excluded due to incomplete data or not meeting the consensus criteria for severe sepsis or septic shock; 245 patients were included with complete data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Finally, 245 patients who were diagnosed with severe sepsis or septic shock were included in the study, with an incidence rate of 2.3%. Of them, 64.0% of the enrolled patients were male with 80.8% being less than 5 years old and 60.8% being from rural areas. The respiratory system was the most common organ system in which dysfunction was observed (76.7%) as well as the most frequently infected site (37.6%). The primary therapies were antibiotics (99.0%), immunoglobulin (88.3%), mechanical ventilation (78.4%), vasoactive infusions (59.6%), and corticosteroids (46.1%). Among the 188 patients who had respiratory dysfunction, 173(92%) required mechanical ventilation and 39 (20.7%) met the criteria for pediatric acute respiratory distress syndrome. Seven of the patients with pediatric acute respiratory distress syndrome died (7/39, 17.9%). The median durations for mechanical ventilation and vasoactive medications were 123.5 hours (35.25-226.00 hr) and 2 days (1-5 d), respectively. Eighty-six percent of patients had multiple organ dysfunction syndrome at the point at which severe sepsis was recognized, and 31% had underlying conditions. The hospital mortality rate was 18.8%. CONCLUSIONS: This report is the first to present the prevalence, treatment, and outcomes of pediatric severe sepsis in the main PICU centers in Southwest China. The mortality rate remains high; therefore, improved clinical management and implementation of large-scale clinical trials are necessary to improve early diagnoses and treatment.

A New Model for Birth Weight Prediction Using 2- and 3-Dimensional Ultrasonography by Principal Component Analysis: A Chinese Population Study.

OBJECTIVES: To establish a new model for birth weight prediction using 2- and 3-dimensional ultrasonography (US) by principal component analysis (PCA). METHODS: Two- and 3-dimensional US was prospectively performed in women with normal singleton pregnancies within 7 days before delivery (37-41 weeks' gestation). The participants were divided into a development group (n = 600) and a validation group (n = 597). Principal component analysis and stepwise linear regression analysis were used to develop a new prediction model. The new model's accuracy in predicting fetal birth weight was confirmed by the validation group through comparisons with previously published formulas. RESULTS: A total of 1197 cases were recruited in this study. All interclass and intraclass correlation coefficients of US measurements were greater than 0.75. Two principal components (PCs) were considered primary in determining estimated fetal birth weight, which were derived from 9 US measurements. Stepwise linear regression analysis showed a positive association between birth weight and PC1 and PC2. In the development group, our model had a small mean percentage error (mean ± SD, 3.661% ± 3.161%). At least a 47.558% decrease in the mean percentage error and a 57.421% decrease in the standard deviation of the new model compared with previously published formulas were noted. The results were similar to those in the validation group, and the new model covered 100% of birth weights within 10% of actual birth weights. CONCLUSIONS: The birth weight prediction model based on 2- and 3-dimensional US by PCA could help improve the precision of estimated fetal birth weight.

[Correlation analysis of fetal middle cerebral artery peak systolic velocity, cardiothoracic ratio and crown-rump length in early pregnancy].

OBJECTIVE: To explore the pattern of variations in middle cerebral artery peak systolic velocity (MCA PSV) and cardiothoracic ratio (CTR) during early pregnancy, establish their reference ranges and explore their correlation with the crown-rump length (CRL). METHODS: A total of 522 pregnant women with normal findings in antenatal examinations underwent routine color Doppler ultrasound examination to collect the data of MCA PSV, CTR and CRL. The reference ranges of MCA PSV and CTR for different CRL levels were established, and the correlation of MCA PSV and CTR with CRL was analyzed. RESULTS: During the first trimester, MCA PSV and CRL showed a moderate positive correlation with a correlation coefficient of 0.426 (P<0.001), while CTR and CRL showed no significant correlation (0.168, P<0.001). The reference range of MCA PSV was 14.35 (14.08-14.62) cm/s and that of CTR was 0.34 (0.33-0.34) during early pregnancy. CONCLUSION: Color Doppler ultrasound is a safe and feasible modality to assess fetal MCA PSV and CTR for detecting fetal growth abnormalities in early pregnancy. The established reference ranges of MCA PSV and CTR offer a clinical theoretical basis for detecting α-thalassemia in early pregnancy.