Pub Date : 2024-03-21DOI: 10.1101/2024.03.19.24304372
Simran DS Maggo, Liam Y North, Aime Ozuna, Dejerianne Ostrow, Yander I Grajeda, Hesamedin Hakimjavadi, Jennifer Cotter, Alexander R Judkins, Pat Levitt, Xiaowu Gai
The mitochondrion is a multifunctional organelle that modulates multiple systems critical for homeostasis during pathophysiological stress. Variation in mitochondrial DNA (mtDNA) copy number (mtDNAcn), a key mitochondrial change associated with chronic stress, is an emerging biomarker for disease pathology and progression. mtDNAcn can be quantified from whole blood samples using qPCR to determine the ratio of nuclear DNA to mtDNA. However, the collection of blood samples in pediatric populations, particularly in infants and young children, can be technically challenging, yield much smaller volume samples, and can be distressing for the patients and their caregivers. Therefore, we have validated a mtDNAcn assay utilizing DNA from simple buccal swabs (Isohelix SK-2S) and report here its performance in specimens from infants (age = <12 months). Utilizing qPCR to amplify ~200bp regions from two mitochondrial (ND1, ND6) and two nuclear (BECN1, NEB) genes, we demonstrated absolute (100%) concordance with results from low-pass whole genome sequencing (lpWGS). We believe that this method overcomes key obstacles to measuring mtDNAcn in pediatric populations and creates the possibility for development of clinical assays to measure mitochondrial change during pathophysiological stress.
{"title":"A method for measuring mitochondrial DNA copy number in pediatric populations.","authors":"Simran DS Maggo, Liam Y North, Aime Ozuna, Dejerianne Ostrow, Yander I Grajeda, Hesamedin Hakimjavadi, Jennifer Cotter, Alexander R Judkins, Pat Levitt, Xiaowu Gai","doi":"10.1101/2024.03.19.24304372","DOIUrl":"https://doi.org/10.1101/2024.03.19.24304372","url":null,"abstract":"The mitochondrion is a multifunctional organelle that modulates multiple systems critical for homeostasis during pathophysiological stress. Variation in mitochondrial DNA (mtDNA) copy number (mtDNAcn), a key mitochondrial change associated with chronic stress, is an emerging biomarker for disease pathology and progression. mtDNAcn can be quantified from whole blood samples using qPCR to determine the ratio of nuclear DNA to mtDNA. However, the collection of blood samples in pediatric populations, particularly in infants and young children, can be technically challenging, yield much smaller volume samples, and can be distressing for the patients and their caregivers. Therefore, we have validated a mtDNAcn assay utilizing DNA from simple buccal swabs (Isohelix SK-2S) and report here its performance in specimens from infants (age = <12 months). Utilizing qPCR to amplify ~200bp regions from two mitochondrial (ND1, ND6) and two nuclear (BECN1, NEB) genes, we demonstrated absolute (100%) concordance with results from low-pass whole genome sequencing (lpWGS). We believe that this method overcomes key obstacles to measuring mtDNAcn in pediatric populations and creates the possibility for development of clinical assays to measure mitochondrial change during pathophysiological stress.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140204722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Neonatal mortality is a significant challenge that affects babies within the first 28 days of life. The issue is particularly challenging for healthcare systems in developing countries, where interventions are required. Although there has been a decline in neonatal mortality worldwide, comprehensive data on the patterns of neonatal mortality and the contributing factors in rural regions of Ethiopia is lacking. Objective: To determine neonatal mortality trends and mortality in rural Ethiopia using 2011-2019 DHS data Methods: Ethiopian demographic health survey (EDHS) program conducted a cross-sectional community-based study in rural Ethiopia in 2011, 2016, and 2019. The study included women who gave birth within the specified timeframe and agreed to participate. Sampling was done through a multistage cluster approach, and STATA version 17 was used to analyze the data. Predictor variables were validated through multiple logistic regression analysis. Weighted estimates were used to derive population-level statistics and a p-value less than 0.05 was considered significant. Results: The study analyzed data from 22,755 women who participated in EDHS surveys between 2011 and 2019. Neonatal mortality rates decreased from 7.5% to 6.03%. Regional variations were observed, with Gambela and Tigrai having the lowest rates, and Dire Dawa and the Somali region having higher rates. Factors like mother's age, wealth index, birth order, neonate's sex, and presence of twins, immediate breastfeeding, and baby's size were associated with neonatal mortality. Conclusion and recommendation: Despite significant advancements that have been made to decrease neonatal mortality, there remain challenges that need to be addressed. Therefore, regional health bureaus should strengthen their strategies to enhance antenatal care (ANC) visits and promote birth delivery at health facilities.
{"title":"Trends and Determinants of Neonatal Mortality in Rural Ethiopia","authors":"Sintayehu Asaye Biya, Dawit Saketa, Dires Birhanu, Tadesse Gudeta, Merga Besho, Masrie Getnet, Gurmesa Tura, Negalign Berhanu, Yibeltal Siraneh, Fira Abamecha, Dessalegn Tamiru","doi":"10.1101/2024.03.18.24304498","DOIUrl":"https://doi.org/10.1101/2024.03.18.24304498","url":null,"abstract":"Background: Neonatal mortality is a significant challenge that affects babies within the first 28 days of life. The issue is particularly challenging for healthcare systems in developing countries, where interventions are required. Although there has been a decline in neonatal mortality worldwide, comprehensive data on the patterns of neonatal mortality and the contributing factors in rural regions of Ethiopia is lacking.\u0000Objective: To determine neonatal mortality trends and mortality in rural Ethiopia using 2011-2019 DHS data\u0000Methods: Ethiopian demographic health survey (EDHS) program conducted a cross-sectional community-based study in rural Ethiopia in 2011, 2016, and 2019. The study included women who gave birth within the specified timeframe and agreed to participate. Sampling was done through a multistage cluster approach, and STATA version 17 was used to analyze the data. Predictor variables were validated through multiple logistic regression analysis. Weighted estimates were used to derive population-level statistics and a p-value less than 0.05 was considered significant.\u0000Results: The study analyzed data from 22,755 women who participated in EDHS surveys between 2011 and 2019. Neonatal mortality rates decreased from 7.5% to 6.03%. Regional variations were observed, with Gambela and Tigrai having the lowest rates, and Dire Dawa and the Somali region having higher rates. Factors like mother's age, wealth index, birth order, neonate's sex, and presence of twins, immediate breastfeeding, and baby's size were associated with neonatal mortality.\u0000Conclusion and recommendation: Despite significant advancements that have been made to decrease neonatal mortality, there remain challenges that need to be addressed. Therefore, regional health bureaus should strengthen their strategies to enhance antenatal care (ANC) visits and promote birth delivery at health facilities.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Background: Respiratory distress syndrome (RDS) is the single most important cause of morbidity and mortality in preterm neonates. Early management of RDS is crucial in determining short- and long-term outcomes and studies have established initial respiratory support (IRS) among other factors as an important determinant. Despite preexisting guidelines and advancements in the management of RDS, IRS failure with noninvasive ventilation is common and is associated with unfavorable outcomes. Objective: This study evaluated the non-invasive initial respiratory support outcomes and associated factors among preterm neonates with respiratory distress syndrome admitted in the newborn unit (NBU) at Moi Teaching and Referral Hospital Eldoret (MTRH), Kenya Methods: Using a prospective observational hospital-based study, preterm neonates ≤ 35weeks admitted at the newborn unit with clinical RDS were followed up for 28 days. The primary outcome was IRS success or failure characterized by not stepping up or stepping up the respiratory support respectively within 72 hours of life and associated maternal and neonatal factors. Descriptive statistics was described using mean ± (SD) for continuous variables and frequencies and percentages for categorical variables. Simple and multinomial regression analysis was performed to evaluate relationship between different IRS methods with outcome variables and a p-value of < 0.05 was considered significant. Results: We enrolled 320 neonates, 172(53.8%) were male with a mean (SD) gestation age of 30.9 (2.95) weeks. The mothers mean age was 27 years, ranging (15-43). 70(22.4%) 95%CI:17.95,27.47] had IRS failure and 243(77.6%) had IRS success. On multivariate analysis IRS success was associated with primiparity (AOR=2.81;95%CI: 1.42, 7.99), birthweight > 1300g (AOR= 5.04;95%CI 1.81, 14.6), low modified Downes score (AOR=26.395%CI 3.37, 230) and normal admission temperatures (AOR=0.32;95%CI 0.12, 0.72) (p= <0.001). Conclusion: Noninvasive ventilation had a high initial respiratory support success. Primiparity, birthweight >1300g, normal admission temperatures and low Downes score were associated with IRS success.
{"title":"Initial respiratory support outcomes and associated factors among preterm neonates with respiratory distress syndrome admitted at Moi Teaching and Referral hospital Eldoret, Kenya","authors":"Joyce Kalekye Ndeto, Winstone Mokaya Nyandiko, Audrey Chepkemoi","doi":"10.1101/2024.03.17.24304436","DOIUrl":"https://doi.org/10.1101/2024.03.17.24304436","url":null,"abstract":"Abstract\u0000Background: Respiratory distress syndrome (RDS) is the single most important cause of morbidity and mortality in preterm neonates. Early management of RDS is crucial in determining short- and long-term outcomes and studies have established initial respiratory support (IRS) among other factors as an important determinant. Despite preexisting guidelines and advancements in the management of RDS, IRS failure with noninvasive ventilation is common and is associated with unfavorable outcomes.\u0000Objective: This study evaluated the non-invasive initial respiratory support outcomes and associated factors among preterm neonates with respiratory distress syndrome admitted in the newborn unit (NBU) at Moi Teaching and Referral Hospital Eldoret (MTRH), Kenya\u0000Methods: Using a prospective observational hospital-based study, preterm neonates ≤ 35weeks admitted at the newborn unit with clinical RDS were followed up for 28 days. The primary outcome was IRS success or failure characterized by not stepping up or stepping up the respiratory support respectively within 72 hours of life and associated maternal and neonatal factors. Descriptive statistics was described using mean ± (SD) for continuous variables and frequencies and percentages for categorical variables. Simple and multinomial regression analysis was performed to evaluate relationship between different IRS methods with outcome variables and a p-value of < 0.05 was considered significant. Results: We enrolled 320 neonates, 172(53.8%) were male with a mean (SD) gestation age of 30.9 (2.95) weeks. The mothers mean age was 27 years, ranging (15-43). 70(22.4%) 95%CI:17.95,27.47] had IRS failure and 243(77.6%) had IRS success. On multivariate analysis IRS success was associated with primiparity (AOR=2.81;95%CI: 1.42, 7.99), birthweight > 1300g (AOR= 5.04;95%CI 1.81, 14.6), low modified Downes score (AOR=26.395%CI 3.37, 230) and normal admission temperatures (AOR=0.32;95%CI 0.12, 0.72) (p= <0.001).\u0000Conclusion: Noninvasive ventilation had a high initial respiratory support success. Primiparity, birthweight >1300g, normal admission temperatures and low Downes score were associated with IRS success.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-19DOI: 10.1101/2024.03.19.24303825
Rui Zhang, Melanie Schwandt, Leah Vines, Nora D. Volkow
Background Adolescents with disrupted rest-activity rhythm (RAR) including shorter sleep duration, later sleep timing and low physical activity levels have higher risk for mental and behavioral problems. However, it remains unclear whether the same associations can be observed for within-subject changes in RAR. Methods Our longitudinal investigation on RAR used Fitbit data from the Adolescent Brain Cognitive Development (ABCD) Study at the 2-year (FL2: aged 10-13 years) and 4-year follow-up (FL4: aged 13-16 years). 963 youths had good-quality Fitbit data at both time points. In this study we examined changes in RAR from FL2 to FL4, their environmental and demographic contributors as well as brain and behavioral correlates. Results From FL2 to FL4, adolescents showed decreases in sleep duration and physical activity as well as delayed sleep timing (Cohens d .44-.75). The contributions of environmental and demographic factors to RAR changes were greatest to sleep timing (explained 10% variance) and least to sleep duration (explained 1% variance). Delays in sleep timing had stronger correlations with behavioral problems including greater impulsivity and poor academic performance than reductions in sleep duration or physical activity. Additionally, the various brain measures differed in their sensitivity to RAR changes. Reductions in sleep duration were associated with decreased functional connectivity between subcortical regions and sensorimotor and cingulo-opercular networks and with enhanced functional connectivity between sensorimotor, visual and auditory networks. Delays in sleep timing were mainly associated with grey matter changes in subcortical regions while reduced physical activity level was mostly associated with decreased integrity of white matter fiber tracts. Conclusions The current findings corroborate the role of sleep and physical activity in adolescents brain neurodevelopment and behavior problems. RAR might serve as biomarkers or treatment targets for monitoring or treating mental and behavioral problems in adolescents.
{"title":"Changes in rest-activity rhythms in adolescents as they age: associations with brain changes and behavior in the ABCD study","authors":"Rui Zhang, Melanie Schwandt, Leah Vines, Nora D. Volkow","doi":"10.1101/2024.03.19.24303825","DOIUrl":"https://doi.org/10.1101/2024.03.19.24303825","url":null,"abstract":"Background\u0000Adolescents with disrupted rest-activity rhythm (RAR) including shorter sleep duration, later sleep timing and low physical activity levels have higher risk for mental and behavioral problems. However, it remains unclear whether the same associations can be observed for within-subject changes in RAR.\u0000Methods\u0000Our longitudinal investigation on RAR used Fitbit data from the Adolescent Brain Cognitive Development (ABCD) Study at the 2-year (FL2: aged 10-13 years) and 4-year follow-up (FL4: aged 13-16 years). 963 youths had good-quality Fitbit data at both time points. In this study we examined changes in RAR from FL2 to FL4, their environmental and demographic contributors as well as brain and behavioral correlates.\u0000Results\u0000From FL2 to FL4, adolescents showed decreases in sleep duration and physical activity as well as delayed sleep timing (Cohens d .44-.75). The contributions of environmental and demographic factors to RAR changes were greatest to sleep timing (explained 10% variance) and least to sleep duration (explained 1% variance). Delays in sleep timing had stronger correlations with behavioral problems including greater impulsivity and poor academic performance than reductions in sleep duration or physical activity. Additionally, the various brain measures differed in their sensitivity to RAR changes. Reductions in sleep duration were associated with decreased functional connectivity between subcortical regions and sensorimotor and cingulo-opercular networks and with enhanced functional connectivity between sensorimotor, visual and auditory networks. Delays in sleep timing were mainly associated with grey matter changes in subcortical regions while reduced physical activity level was mostly associated with decreased integrity of white matter fiber tracts.\u0000Conclusions\u0000The current findings corroborate the role of sleep and physical activity in adolescents brain neurodevelopment and behavior problems. RAR might serve as biomarkers or treatment targets for monitoring or treating mental and behavioral problems in adolescents.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-19DOI: 10.1101/2024.03.15.24304137
Gilad Hamdani, Elaine M. Urbina, Stephen Robert Daniels, Bonita Falkner, Michael A. Ferguson, Joseph T. Flynn, Coral Hanevold, Julie R Ingelfinger, Philip R Khoury, Marc B. Lande, Kevin E. Meyers, Joshua Samuels, Mark Mitsnefes
Background: Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents. Methods: 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75th percentile), mid- (75th-90th percentile) and high-risk (>90th percentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers. Results: 47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers. Conclusion: High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.
背景：青春期高血压与亚临床靶器官损伤（TOI）有关。我们旨在确定在健康青少年中，不同的血压（BP）阈值是否与靶器官损伤标记物数量的增加有关。方法：我们对 244 名参与者（平均年龄为 15.5±1.8 岁，60.1% 为男性）进行了研究。根据收缩压和动态血压（ABP）将参与者分为低危（第75百分位数）、中危（第75-90百分位数）和高危（第90百分位数）组。TOI评估包括左心室质量、收缩和舒张功能以及血管僵硬度。计算了每位参与者的 TOI 指标数量。建立了一个多变量一般线性模型，以评估不同参与者特征与较高 TOI 标志物数量之间的关联。结果显示47.5%的参与者至少有一个TOI标记：31.2%有一个，11.9%有两个，3.7%有三个，0.8%有四个。TOI标记物的数量随血压风险组别而增加：根据门诊血压，低、中、高组别中拥有一个以上TOI的参与者比例分别为6.7%、19.1%和21.8%（P=0.02），而根据ABP，则分别为9.6%、15.8%和32.2%（P<0.001）。在多变量回归分析中，门诊血压百分位数和非卧床 SBP 指数均与 TOI 标记的数量独立相关。当将门诊血压和 ABP 均纳入模型时，只有非卧床 SBP 指数与标记物数量有显著相关性：结论：高 SBP（尤其是通过 ABPM 评估时）与青少年亚临床心血管损伤标记物数量的增加有关。
{"title":"Ambulatory Blood Pressure and Number of Subclinical Target Organ Injury Markers in Youth: The SHIP AHOY Study","authors":"Gilad Hamdani, Elaine M. Urbina, Stephen Robert Daniels, Bonita Falkner, Michael A. Ferguson, Joseph T. Flynn, Coral Hanevold, Julie R Ingelfinger, Philip R Khoury, Marc B. Lande, Kevin E. Meyers, Joshua Samuels, Mark Mitsnefes","doi":"10.1101/2024.03.15.24304137","DOIUrl":"https://doi.org/10.1101/2024.03.15.24304137","url":null,"abstract":"Background: Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents. Methods: 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75th percentile), mid- (75th-90th percentile) and high-risk (>90th percentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers. Results: 47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers.\u0000Conclusion: High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-19DOI: 10.1101/2024.03.12.24304127
Richard A Forshee, Elizabeth R Smith, Zhiruo Wan, Kandace L Amend, Alex Secora, Djeneba Audrey Djibo, Kamran Kazemi, Jennifer Song, Lauren E Parlett, John D Seeger, Nandini Selvam, Cheryl N McMahill-Walraven, Mao Hu, Yoganand Chillarige, Steven A Anderson
Importance The United States Food and Drug Administration noted a potential safety concern for seizure in children aged 2-5 years receiving the ancestral monovalent COVID-19 mRNA vaccines. Objective To evaluate febrile seizure risk following monovalent COVID-19 mRNA vaccination among children aged 2-5 years. Design, Setting, and Participants The primary analysis evaluated children who had a febrile seizure outcome in the 0-1 days following COVID-19 vaccination. A self-controlled case series analysis was performed in three commercial insurance databases to compare the risk of seizure in the risk interval (0-1 days) to a control interval (8-63 days). Exposure Receipt of dose 1 and/or dose 2 of monovalent COVID-19 mRNA vaccinations. Main Outcomes and Measures The primary outcome was febrile seizure (0-1 day risk interval). Analysis A conditional Poisson regression model was used to compare outcome rates in risk and control intervals and estimate incidence rate ratios (IRR) and 95% confidence intervals (CIs). Meta-analyses were used to pool results across databases. Results The primary meta-analysis found a statistically significant increased incidence of febrile seizure, in the 0-1 days following mRNA-1273 vaccination compared to the control interval (IRR: 2.52, 95% CI: 1.35 to 4.69, risk difference (RD)/100,000 doses = 3.22 (95%CI -0.31 to 6.75)). For the BNT162b2 vaccination, the IRR was elevated but not statistically significant (IRR: 1.41, 95%CI: 0.48 to 4.11, RD/100,000 doses = -0.25 (95%CI -2.75 to 2.24). Conclusions and Relevance Among children aged 2-5 years, the analysis showed a small elevated incidence rate ratio of febrile seizures in the 0-1 days following the mRNA-1273 vaccination. Based on the current body of scientific evidence, the safety profile of the monovalent mRNA vaccines remains favorable for use in young children.
{"title":"Evaluation of Febrile Seizure Risk Following Ancestral Monovalent COVID-19 mRNA Vaccination Among U.S. Children Aged 2-5 Years","authors":"Richard A Forshee, Elizabeth R Smith, Zhiruo Wan, Kandace L Amend, Alex Secora, Djeneba Audrey Djibo, Kamran Kazemi, Jennifer Song, Lauren E Parlett, John D Seeger, Nandini Selvam, Cheryl N McMahill-Walraven, Mao Hu, Yoganand Chillarige, Steven A Anderson","doi":"10.1101/2024.03.12.24304127","DOIUrl":"https://doi.org/10.1101/2024.03.12.24304127","url":null,"abstract":"Importance\u0000The United States Food and Drug Administration noted a potential safety concern for seizure in children aged 2-5 years receiving the ancestral monovalent COVID-19 mRNA vaccines.\u0000Objective\u0000To evaluate febrile seizure risk following monovalent COVID-19 mRNA vaccination among children aged 2-5 years. Design, Setting, and Participants\u0000The primary analysis evaluated children who had a febrile seizure outcome in the 0-1 days following COVID-19 vaccination. A self-controlled case series analysis was performed in three commercial insurance databases to compare the risk of seizure in the risk interval (0-1 days) to a control interval (8-63 days).\u0000Exposure\u0000Receipt of dose 1 and/or dose 2 of monovalent COVID-19 mRNA vaccinations.\u0000Main Outcomes and Measures\u0000The primary outcome was febrile seizure (0-1 day risk interval). Analysis\u0000A conditional Poisson regression model was used to compare outcome rates in risk and control intervals and estimate incidence rate ratios (IRR) and 95% confidence intervals (CIs). Meta-analyses were used to pool results across databases.\u0000Results\u0000The primary meta-analysis found a statistically significant increased incidence of febrile seizure, in the 0-1 days following mRNA-1273 vaccination compared to the control interval (IRR: 2.52, 95% CI: 1.35 to 4.69, risk difference (RD)/100,000 doses = 3.22 (95%CI -0.31 to 6.75)). For the BNT162b2 vaccination, the IRR was elevated but not statistically significant (IRR: 1.41, 95%CI: 0.48 to 4.11, RD/100,000 doses = -0.25 (95%CI -2.75 to 2.24). Conclusions and Relevance\u0000Among children aged 2-5 years, the analysis showed a small elevated incidence rate ratio of febrile seizures in the 0-1 days following the mRNA-1273 vaccination. Based on the current body of scientific evidence, the safety profile of the monovalent mRNA vaccines remains favorable for use in young children.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-18DOI: 10.1101/2024.03.10.24303986
Dinberu Oyamo Oromo
Abstract: Background: Diabetic ketoacidosis is a morbid complication of diabetes mellitus, and its occurrence at diagnosis has rarely been studied in Ethiopia, despite the many cases seen in the pediatric population. Objective: To know the prevalence of diabetic ketoacidosis (DKA) among patients with newly diagnosed diabetes mellitus and identify avoidable risk factors. Method: This institution-based retrospective cross-sectional study was conducted from December 25, 2018 to December 25, 2022. Newly diagnosed type1 diabetes mellitus (DM) patients with age < 15 years were included in the study. DKA was diagnosed based on clinical presentation and blood glucose and urine ketone levels. A data collection form was prepared to collect sociodemographic and clinical data. Descriptive, bivariate, and multivariate logistic regression analyses were performed to identify the risk factors. Result: Among the admitted 61 newly diagnosed T1DM pediatric patients, DKA was the first presentation in 37 patients making 60.7% of newly diagnosed T1DM. Mean age at diagnosis was 8 years and females were affected more. Clinical presentation revealed vomiting accompanied by signs of dehydration (32.4%), with polysymptoms (29.7%) being the most common. Infectious morbidity occurred in 26 patients, 21 of whom were in the DKA group. Inadequate knowledge of signs and symptoms of DM adjusted odds ratio (AOR=0.07(0.019-0.0897), absence of a family history of DM (AOR=0.129 (0.019-0.897), and presence of infection prior to diagnosis of DKA (AOR=11.69(1.34-10.1) were potential predictors for the development of DKA among newly diagnosed T1DM patients. Conclusion: A very high number of children present with DKA at the initial diagnosis of diabetes mellitus (DM), which is attributed to inadequate knowledge of the signs and symptoms of DM and the masking effect of concomitant infections in these children. Healthcare professionals should endeavor to suspect and screen children. Continuous awareness creation of DM at the health professional and community levels is encouraged to diagnose diabetes mellitus earlier and to decrease the prevalence of DKA as an initial presentation. Key words: Child, diabetic ketoacidosis, Dilla, prevalence
{"title":"Pediatric diabetic ketoacidosis (PDKA) among newly diagnosed diabetic patients treated at Dilla university hospital, Dilla, Ethiopia: prevalence and predictors","authors":"Dinberu Oyamo Oromo","doi":"10.1101/2024.03.10.24303986","DOIUrl":"https://doi.org/10.1101/2024.03.10.24303986","url":null,"abstract":"Abstract: Background: Diabetic ketoacidosis is a morbid complication of diabetes mellitus, and its occurrence at diagnosis has rarely been studied in Ethiopia, despite the many cases seen in the pediatric population. Objective: To know the prevalence of diabetic ketoacidosis (DKA) among patients with newly diagnosed diabetes mellitus and identify avoidable risk factors. Method: This institution-based retrospective cross-sectional study was conducted from December 25, 2018 to December 25, 2022. Newly diagnosed type1 diabetes mellitus (DM) patients with age < 15 years were included in the study. DKA was diagnosed based on clinical presentation and blood glucose and urine ketone levels. A data collection form was prepared to collect sociodemographic and clinical data. Descriptive, bivariate, and multivariate logistic regression analyses were performed to identify the risk factors. Result: Among the admitted 61 newly diagnosed T1DM pediatric patients, DKA was the first presentation in 37 patients making 60.7% of newly diagnosed T1DM. Mean age at diagnosis was 8 years and females were affected more. Clinical presentation revealed vomiting accompanied by signs of dehydration (32.4%), with polysymptoms (29.7%) being the most common. Infectious morbidity occurred in 26 patients, 21 of whom were in the DKA group. Inadequate knowledge of signs and symptoms of DM adjusted odds ratio (AOR=0.07(0.019-0.0897), absence of a family history of DM (AOR=0.129 (0.019-0.897), and presence of infection prior to diagnosis of DKA (AOR=11.69(1.34-10.1) were potential predictors for the development of DKA among newly diagnosed T1DM patients. Conclusion: A very high number of children present with DKA at the initial diagnosis of diabetes mellitus (DM), which is attributed to inadequate knowledge of the signs and symptoms of DM and the masking effect of concomitant infections in these children. Healthcare professionals should endeavor to suspect and screen children. Continuous awareness creation of DM at the health professional and community levels is encouraged to diagnose diabetes mellitus earlier and to decrease the prevalence of DKA as an initial presentation. Key words: Child, diabetic ketoacidosis, Dilla, prevalence","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140148002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-18DOI: 10.1101/2024.03.17.24304334
Danying Zhu, Guang Li, Lang Yuan, Zeyu Zeng, Na Dong, Chao Wang, Ming Chen, LIjian Xie, Libing Shen, Guohui Ding, Xiaoyan Dong
Here, using single-cell RNA sequencing, we profile peripheral blood mononuclear cells (PBMCs) from three patients with onset asthma and four age-matched healthy controls to investigate the cellular etiology of childhood asthma. We find that very few differentially expressed genes (DEGs) in hematopoietic stem and progenitor cells (HSPCs) are common among three asthma cases, but the common ones are functionally related to S100A gene family. Furthermore, GO analyses show that the heterogeneous DEGs in HSPCs in three asthma cases can be clearly categorized into the biological processes of immunity and immune responses, which indicates that different DEGs converge on a common pathological base. The overall cellular expression profiles demonstrate that pro-inflammatory mediators and immunoglobulin receptors have a high expression level and interferon alpha induced protein has a low expression level in mononuclear macrophages of acute asthma. The cell developmental trajectories in three asthma cases exhibit an abnormal immune cell development pattern compared to the developmental trajectory in health control. T-cell development in acute asthma is especially dysregulated for three cases with three different T-cell branching pattern. We also find that the innate lymphoid cells (ILCs) in three asthma cases have a low expression level in housekeeping genes. Our scRNA-seq analyses for three asthma patients reveal a complex cellular etiology for childhood asthma and provide a new research direction for the comprehensive and systematic study of effector cells and key molecular mechanisms of childhood asthma.
{"title":"Single-cell RNA sequencing unraveled the expression heterogeneity of hematopoietic stem and progenitor cells and immune cell development dysregulation in childhood asthma","authors":"Danying Zhu, Guang Li, Lang Yuan, Zeyu Zeng, Na Dong, Chao Wang, Ming Chen, LIjian Xie, Libing Shen, Guohui Ding, Xiaoyan Dong","doi":"10.1101/2024.03.17.24304334","DOIUrl":"https://doi.org/10.1101/2024.03.17.24304334","url":null,"abstract":"Here, using single-cell RNA sequencing, we profile peripheral blood mononuclear cells (PBMCs) from three patients with onset asthma and four age-matched healthy controls to investigate the cellular etiology of childhood asthma. We find that very few differentially expressed genes (DEGs) in hematopoietic stem and progenitor cells (HSPCs) are common among three asthma cases, but the common ones are functionally related to S100A gene family. Furthermore, GO analyses show that the heterogeneous DEGs in HSPCs in three asthma cases can be clearly categorized into the biological processes of immunity and immune responses, which indicates that different DEGs converge on a common pathological base. The overall cellular expression profiles demonstrate that pro-inflammatory mediators and immunoglobulin receptors have a high expression level and interferon alpha induced protein has a low expression level in mononuclear macrophages of acute asthma. The cell developmental trajectories in three asthma cases exhibit an abnormal immune cell development pattern compared to the developmental trajectory in health control. T-cell development in acute asthma is especially dysregulated for three cases with three different T-cell branching pattern. We also find that the innate lymphoid cells (ILCs) in three asthma cases have a low expression level in housekeeping genes. Our scRNA-seq analyses for three asthma patients reveal a complex cellular etiology for childhood asthma and provide a new research direction for the comprehensive and systematic study of effector cells and key molecular mechanisms of childhood asthma.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1101/2024.03.13.24304198
Amanda Jane Leach, Nicole Wilson, Beth Arrowsmith, Jemima Beissbarth, Kim Mulholland, Mathuram Santosham, Paul John Torzillo, Peter McIntyre, Heidi Smith-Vaughan, Sue A Skull, Victor M Oguoma, Mark D Chatfield, Deborah Lehmann, Christopher G. Brennan-Jones, Michael J. Binks, Paul V Licciardi, Ross Andrews, Tom Snelling, Vicki Krause, Jonathan Carapetis, Anne B Chang, Peter Stanley Morris
Introduction: In remote communities, Australian First Nations children with hearing loss are disproportionately at risk of poor school readiness and performance, compared to those with normal hearing. Our objective was to compare two pneumococcal conjugate vaccine (PCV) formulations and mixed schedules (the PREVIX trials) designed to broaden protection and reduce conductive hearing loss to age 36 months. Methods: In two sequential parallel, open-label, randomised controlled trials, eligible infants were first allocated 1:1:1 at age 28-38 days to standard or mixed PCV primary schedules, then at age 12 months to a booster dose (1:1) of PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S). Here we report secondary hearing outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. Findings: From March 2013 to September 2018, 461 hearing assessments were performed. Prevalence of mild- moderate hearing loss declined in both groups from ~75% at age 12 months to ~53% at 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% and 41% in the +P and +S groups, respectively (difference -19% [95% confidence interval -38, -1], p=0.07) and prevalence of normal hearing was 36% and 16%, respectively (difference 19% [95%CI 2, 37], p=0.05). At subsequent timepoints prevalence of moderate hearing loss remained lower in the +P group at -3% [95% CI -23, 18] at age 24 months, -12% [95%CI -30, 6] at 30 months, and -9% [95%CI -23, 5] at 36 months. Interpretation: This study provides first evidence of the high prevalence and persistence of mild and moderate hearing loss throughout early childhood. A lower prevalence of moderate (disabling) hearing loss in the +P group may have substantial benefits for high-risk children and warrants further investigation.
{"title":"Hearing loss at 6-monthly assessments from age 12 to 36 months: secondary outcomes from randomised controlled trials of novel pneumococcal conjugate vaccine schedules.","authors":"Amanda Jane Leach, Nicole Wilson, Beth Arrowsmith, Jemima Beissbarth, Kim Mulholland, Mathuram Santosham, Paul John Torzillo, Peter McIntyre, Heidi Smith-Vaughan, Sue A Skull, Victor M Oguoma, Mark D Chatfield, Deborah Lehmann, Christopher G. Brennan-Jones, Michael J. Binks, Paul V Licciardi, Ross Andrews, Tom Snelling, Vicki Krause, Jonathan Carapetis, Anne B Chang, Peter Stanley Morris","doi":"10.1101/2024.03.13.24304198","DOIUrl":"https://doi.org/10.1101/2024.03.13.24304198","url":null,"abstract":"Introduction: In remote communities, Australian First Nations children with hearing loss are disproportionately at risk of poor school readiness and performance, compared to those with normal hearing. Our objective was to compare two pneumococcal conjugate vaccine (PCV) formulations and mixed schedules (the PREVIX trials) designed to broaden protection and reduce conductive hearing loss to age 36 months. Methods: In two sequential parallel, open-label, randomised controlled trials, eligible infants were first allocated 1:1:1 at age 28-38 days to standard or mixed PCV primary schedules, then at age 12 months to a booster dose (1:1) of PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S). Here we report secondary hearing outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. Findings: From March 2013 to September 2018, 461 hearing assessments were performed. Prevalence of mild- moderate hearing loss declined in both groups from ~75% at age 12 months to ~53% at 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% and 41% in the +P and +S groups, respectively (difference -19% [95% confidence interval -38, -1], p=0.07) and prevalence of normal hearing was 36% and 16%, respectively (difference 19% [95%CI 2, 37], p=0.05). At subsequent timepoints prevalence of moderate hearing loss remained lower in the +P group at -3% [95% CI -23, 18] at age 24 months, -12% [95%CI -30, 6] at 30 months, and -9% [95%CI -23, 5] at 36 months. Interpretation: This study provides first evidence of the high prevalence and persistence of mild and moderate hearing loss throughout early childhood. A lower prevalence of moderate (disabling) hearing loss in the +P group may have substantial benefits for high-risk children and warrants further investigation.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140148053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1101/2024.03.10.24304003
Marie-Louis Wronski, Ralf Kuja-Halkola, Elin Hedlund, Miriam I. Martini, Paul Lichtenstein, Sebastian Lundstroem, Henrik Larsson, Mark J. Taylor, Nadia Micali, Cynthia M. Bulik, Lisa Dinkler
Background: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder, characterized by limited variety and/or quantity of food intake impacting physical health and psychosocial functioning. Children with ARFID often present with a range of psychiatric and somatic symptoms, and therefore consult various pediatric subspecialties; large-scale studies mapping comorbidities are however lacking. To characterize health care needs of people with ARFID, we systematically investigated ARFID-related mental and somatic conditions in 616 children with ARFID and >30,000 children without ARFID. Methods: In a Swedish twin cohort, we identified the ARFID phenotype in 6-12-year-old children based on parent-reports and register data. From >1,000 diagnostic ICD-codes, we specified mental and somatic conditions within/across ICD-chapters, number of distinct per-person diagnoses, and inpatient treatment days between birth and 18th birthday (90 outcomes). Hazard ratios (HR) and incidence rate ratios (IRR) were calculated. Findings: Relative risks of neurodevelopmental, gastrointestinal, endocrine/metabolic, respiratory, neurological, and allergic disorders were substantially increased in ARFID (e.g., autism HR[CI95%]=9.7[7.5-12.5], intellectual disability 10.3[7.6-13.9], gastroesophageal reflux disease 6.7[4.6-9.9], pituitary conditions 5.6[2.7-11.3], chronic lower respiratory diseases 4.9[2.4-10.1], epilepsy 5.8[4.1-8.2]). ARFID was not associated with elevated risks of autoimmune illnesses and obsessive-compulsive disorder. Children with ARFID had a significantly higher number of distinct mental diagnoses (IRR[CI95%]=4.7[4.0-5.4]) and longer duration of hospitalizations (IRR[CI95%]=5.5[1.7-17.6]) compared with children without ARFID. Children with ARFID were diagnosed earlier with a mental condition than children without ARFID. No sex-specific differences emerged. Interpretation: This study yields the broadest and most detailed evidence of co-existing mental and somatic conditions in the largest sample of children with ARFID to date. Findings suggest a complex pattern of health needs in youth with ARFID, underscoring the critical importance of attention to the illness across all pediatric specialties. Funding: Fredrik and Ingrid Thurings Foundation, Mental Health Foundation.
{"title":"Co-existing mental and somatic conditions in Swedish children with the avoidant restrictive food intake disorder phenotype","authors":"Marie-Louis Wronski, Ralf Kuja-Halkola, Elin Hedlund, Miriam I. Martini, Paul Lichtenstein, Sebastian Lundstroem, Henrik Larsson, Mark J. Taylor, Nadia Micali, Cynthia M. Bulik, Lisa Dinkler","doi":"10.1101/2024.03.10.24304003","DOIUrl":"https://doi.org/10.1101/2024.03.10.24304003","url":null,"abstract":"Background: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder, characterized by limited variety and/or quantity of food intake impacting physical health and psychosocial functioning. Children with ARFID often present with a range of psychiatric and somatic symptoms, and therefore consult various pediatric subspecialties; large-scale studies mapping comorbidities are however lacking. To characterize health care needs of people with ARFID, we systematically investigated ARFID-related mental and somatic conditions in 616 children with ARFID and >30,000 children without ARFID.\u0000Methods: In a Swedish twin cohort, we identified the ARFID phenotype in 6-12-year-old children based on parent-reports and register data. From >1,000 diagnostic ICD-codes, we specified mental and somatic conditions within/across ICD-chapters, number of distinct per-person diagnoses, and inpatient treatment days between birth and 18th birthday (90 outcomes). Hazard ratios (HR) and incidence rate ratios (IRR) were calculated. Findings: Relative risks of neurodevelopmental, gastrointestinal, endocrine/metabolic, respiratory, neurological, and allergic disorders were substantially increased in ARFID (e.g., autism HR[CI95%]=9.7[7.5-12.5], intellectual disability 10.3[7.6-13.9], gastroesophageal reflux disease 6.7[4.6-9.9], pituitary conditions 5.6[2.7-11.3], chronic lower respiratory diseases 4.9[2.4-10.1], epilepsy 5.8[4.1-8.2]). ARFID was not associated with elevated risks of autoimmune illnesses and obsessive-compulsive disorder. Children with ARFID had a significantly higher number of distinct mental diagnoses (IRR[CI95%]=4.7[4.0-5.4]) and longer duration of hospitalizations (IRR[CI95%]=5.5[1.7-17.6]) compared with children without ARFID. Children with ARFID were diagnosed earlier with a mental condition than children without ARFID. No sex-specific differences emerged. Interpretation: This study yields the broadest and most detailed evidence of co-existing mental and somatic conditions in the largest sample of children with ARFID to date. Findings suggest a complex pattern of health needs in youth with ARFID, underscoring the critical importance of attention to the illness across all pediatric specialties.\u0000Funding: Fredrik and Ingrid Thurings Foundation, Mental Health Foundation.","PeriodicalId":501549,"journal":{"name":"medRxiv - Pediatrics","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140147999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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