Nan Huang, Hegan Zhang, Zhengping Huang, Xiaoxia Wu, Na Zhang, Yuying Jiang, Chunnuan Chen, Jianlong Zhuang
Background
Causative mutations of PBX1 are associated with congenital abnormalities of the kidney and urinary tract (CAKUT), often accompanied by hearing loss, abnormal ear morphology, or developmental delay. The aim of the present investigation was to introduce a novel variant in the PBX1 gene identified in a Chinese family, leading to recurrent neonatal mortality.
Methods
A pregnant woman (gravida 5, para 0), who had experienced recurrent neonatal deaths, sought genetic etiology diagnosis. Whole exome sequencing (WES) was conducted to identify sequence variants and copy number variants in the fetus presenting with posterior nuchal cystic hygroma and fetal hydrops.
Results
A novel NM_002585.4:c.694G>C(p.D232H) in PBX1 was identified in the fetus through trio whole exome sequencing (WES), revealing a paternal mosaic PBX1 variant in blood at 11.54% (6/52 variants reads). Subsequent parental Sanger sequencing confirmed the variant detected by WES. Ultimately, the variant was classified as likely pathogenic, leading the family to elect pregnancy termination at 17 weeks gestation.
Conclusion
The novel variant in the PBX1 gene appears to be a significant factor contributing to recurrent neonatal deaths in the Chinese family. Such findings expand the spectrum of PBX1 gene variants and provide valuable perinatal guidance for diagnosing fetuses with PBX1 mutations.
{"title":"Whole Exome Sequencing Revealing a Novel PBX1 Gene Variant in a Chinese Family Causing Recurrent Neonatal Death","authors":"Nan Huang, Hegan Zhang, Zhengping Huang, Xiaoxia Wu, Na Zhang, Yuying Jiang, Chunnuan Chen, Jianlong Zhuang","doi":"10.1002/bdr2.2396","DOIUrl":"10.1002/bdr2.2396","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Causative mutations of <i>PBX1</i> are associated with congenital abnormalities of the kidney and urinary tract (CAKUT), often accompanied by hearing loss, abnormal ear morphology, or developmental delay. The aim of the present investigation was to introduce a novel variant in the <i>PBX1</i> gene identified in a Chinese family, leading to recurrent neonatal mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A pregnant woman (gravida 5, para 0), who had experienced recurrent neonatal deaths, sought genetic etiology diagnosis. Whole exome sequencing (WES) was conducted to identify sequence variants and copy number variants in the fetus presenting with posterior nuchal cystic hygroma and fetal hydrops.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A novel NM_002585.4:c.694G>C(p.D232H) in <i>PBX1</i> was identified in the fetus through trio whole exome sequencing (WES), revealing a paternal mosaic <i>PBX1</i> variant in blood at 11.54% (6/52 variants reads). Subsequent parental Sanger sequencing confirmed the variant detected by WES. Ultimately, the variant was classified as likely pathogenic, leading the family to elect pregnancy termination at 17 weeks gestation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The novel variant in the <i>PBX1</i> gene appears to be a significant factor contributing to recurrent neonatal deaths in the Chinese family. Such findings expand the spectrum of <i>PBX1</i> gene variants and provide valuable perinatal guidance for diagnosing fetuses with <i>PBX1</i> mutations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andreas Gado, Philip Hewitt, Peter Ballard, Belen Tornesi, Tobias Hyun Ho Baeurle, Claude Oeuvray, Thomas Spangenberg, Claudia Demarta-Gatsi
Background
When developing new antimalarial drugs, considering their potential use during pregnancy as preventive or curative therapy is crucial. This prevents the parasite from affecting embryonic development and reduces maternal and fetal death risks. Consequently, understanding the exposure and safety of antimalarial drugs during pregnancy is crucial, with well-designed animal studies playing a key role in this assessment.
Methods
As part of the drug development program for cabamiquine, a series of developmental and reproductive toxicity studies were conducted in rats and rabbits. Additionally, the zebrafish embryo model was used to further improve embryo exposure, minimize confounding factors related to maternal toxicity, and assess developmental risks of cabamiquine.
Results
In these studies, although maternal toxicity was observed, there were no cabamiquine-related adverse effects on fertility, embryonic, or fetal development at maternal exposures representing significant multiples (up to five and 10 times higher in rabbit and rats, respectively) than the exposure at the anticipated efficacious human dose. Similarly, no adverse effects were observed on ZF embryonic development, even though cabamiquine concentrations in the embryos were 10-fold higher than nominal concentrations.
Conclusions
The results obtained in a full set of reproductive toxicity studies did not provide evidence of detrimental effects on the conceptuses and progeny at maternally nontoxic doses and exposures, still representing a multiple of the anticipated systemic exposures in women of childbearing potential (WOCBP). Cabamiquine can therefore be considered a suitable therapeutic option for WOCBP and pregnant women living in malaria-endemic regions by significantly reducing maternal and infant malaria death rates.
{"title":"Absence of developmental and reproductive toxicity in rats, rabbits, and zebrafish embryos exposed to antimalarial drug cabamiquine","authors":"Andreas Gado, Philip Hewitt, Peter Ballard, Belen Tornesi, Tobias Hyun Ho Baeurle, Claude Oeuvray, Thomas Spangenberg, Claudia Demarta-Gatsi","doi":"10.1002/bdr2.2389","DOIUrl":"10.1002/bdr2.2389","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>When developing new antimalarial drugs, considering their potential use during pregnancy as preventive or curative therapy is crucial. This prevents the parasite from affecting embryonic development and reduces maternal and fetal death risks. Consequently, understanding the exposure and safety of antimalarial drugs during pregnancy is crucial, with well-designed animal studies playing a key role in this assessment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>As part of the drug development program for cabamiquine, a series of developmental and reproductive toxicity studies were conducted in rats and rabbits. Additionally, the zebrafish embryo model was used to further improve embryo exposure, minimize confounding factors related to maternal toxicity, and assess developmental risks of cabamiquine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In these studies, although maternal toxicity was observed, there were no cabamiquine-related adverse effects on fertility, embryonic, or fetal development at maternal exposures representing significant multiples (up to five and 10 times higher in rabbit and rats, respectively) than the exposure at the anticipated efficacious human dose. Similarly, no adverse effects were observed on ZF embryonic development, even though cabamiquine concentrations in the embryos were 10-fold higher than nominal concentrations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results obtained in a full set of reproductive toxicity studies did not provide evidence of detrimental effects on the conceptuses and progeny at maternally nontoxic doses and exposures, still representing a multiple of the anticipated systemic exposures in women of childbearing potential (WOCBP). Cabamiquine can therefore be considered a suitable therapeutic option for WOCBP and pregnant women living in malaria-endemic regions by significantly reducing maternal and infant malaria death rates.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2389","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joan D. Garey, Per Damkier, Anthony R. Scialli, Shari Lusskin, Stephen R. Braddock, Laurent Chouchana, Brian Cleary, Elizabeth A. Conover, Orna Diav-Citrin, Rachel S. Dragovich, Facundo Garcia-Bournissen, Ken Hodson, Debra Kennedy, Steven H. Lamm, Sharon A. Lavigne, Sarah G. Običan, Alice Panchaud, Kirstie Perrotta, Alfred N. Romeo, Svetlana Shechtman, Corinna Weber-Schoendorfer
On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far-reaching recommendations.
{"title":"Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated","authors":"Joan D. Garey, Per Damkier, Anthony R. Scialli, Shari Lusskin, Stephen R. Braddock, Laurent Chouchana, Brian Cleary, Elizabeth A. Conover, Orna Diav-Citrin, Rachel S. Dragovich, Facundo Garcia-Bournissen, Ken Hodson, Debra Kennedy, Steven H. Lamm, Sharon A. Lavigne, Sarah G. Običan, Alice Panchaud, Kirstie Perrotta, Alfred N. Romeo, Svetlana Shechtman, Corinna Weber-Schoendorfer","doi":"10.1002/bdr2.2392","DOIUrl":"10.1002/bdr2.2392","url":null,"abstract":"<div>\u0000 \u0000 <p>On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far-reaching recommendations.</p>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara B. Stephens, Renata H. Benjamin, Keila N. Lopez, Brett R. Anderson, Angela E. Lin, Charles J. Shumate, Wendy N. Nembhard, Shaine A. Morris, A. J. Agopian
Introduction
Traditional strategies for grouping congenital heart defects (CHDs) using birth defect registry data do not adequately address differences in expected clinical consequences between different combinations of CHDs. We report a lesion-specific classification system for birth defect registry–based outcome studies.
Methods
For Core Cardiac Lesion Outcome Classifications (C-CLOC) groups, common CHDs expected to have reasonable clinical homogeneity were defined. Criteria based on combinations of Centers for Disease and Control-modified British Pediatric Association (BPA) codes were defined for each C-CLOC group. To demonstrate proof of concept and retention of reasonable case counts within C-CLOC groups, Texas Birth Defect Registry data (1999–2017 deliveries) were used to compare case counts and neonatal mortality between traditional vs. C-CLOC classification approaches.
Results
C-CLOC defined 59 CHD groups among 62,262 infants with CHDs. Classifying cases into the single, mutually exclusive C-CLOC group reflecting the highest complexity CHD present reduced case counts among lower complexity lesions (e.g., 86.5% of cases with a common atrium BPA code were reclassified to a higher complexity group for a co-occurring CHD). As expected, C-CLOC groups had retained larger sample sizes (i.e., representing presumably better-powered analytic groups) compared to cases with only one CHD code and no occurring CHDs.
Discussion
This new CHD classification system for investigators using birth defect registry data, C-CLOC, is expected to balance clinical outcome homogeneity in analytic groups while maintaining sufficiently large case counts within categories, thus improving power for CHD-specific outcome association comparisons. Future outcome studies utilizing C-CLOC-based classifications are planned.
{"title":"Enhancing the Classification of Congenital Heart Defects for Outcome Association Studies in Birth Defects Registries","authors":"Sara B. Stephens, Renata H. Benjamin, Keila N. Lopez, Brett R. Anderson, Angela E. Lin, Charles J. Shumate, Wendy N. Nembhard, Shaine A. Morris, A. J. Agopian","doi":"10.1002/bdr2.2393","DOIUrl":"10.1002/bdr2.2393","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Traditional strategies for grouping congenital heart defects (CHDs) using birth defect registry data do not adequately address differences in expected clinical consequences between different combinations of CHDs. We report a lesion-specific classification system for birth defect registry–based outcome studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>For Core Cardiac Lesion Outcome Classifications (C-CLOC) groups, common CHDs expected to have reasonable clinical homogeneity were defined. Criteria based on combinations of Centers for Disease and Control-modified British Pediatric Association (BPA) codes were defined for each C-CLOC group. To demonstrate proof of concept and retention of reasonable case counts within C-CLOC groups, Texas Birth Defect Registry data (1999–2017 deliveries) were used to compare case counts and neonatal mortality between traditional vs. C-CLOC classification approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>C-CLOC defined 59 CHD groups among 62,262 infants with CHDs. Classifying cases into the single, mutually exclusive C-CLOC group reflecting the highest complexity CHD present reduced case counts among lower complexity lesions (e.g., 86.5% of cases with a common atrium BPA code were reclassified to a higher complexity group for a co-occurring CHD). As expected, C-CLOC groups had retained larger sample sizes (i.e., representing presumably better-powered analytic groups) compared to cases with only one CHD code and no occurring CHDs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>This new CHD classification system for investigators using birth defect registry data, C-CLOC, is expected to balance clinical outcome homogeneity in analytic groups while maintaining sufficiently large case counts within categories, thus improving power for CHD-specific outcome association comparisons. Future outcome studies utilizing C-CLOC-based classifications are planned.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reena Das, Mona Duggal, Jorge Rosenthal, Ankita Kankaria, Hari K. Senee, Shameem Jabbar, Manmeet Kaur, Vishal Kumar, Swati Bhardwaj, Neha Singh, Gursharan S. Dhanjal, Akash Kumar, Charles E. Rose, Rita Bhatia, Rachita Gupta, Suresh Dalpath, Krista S. Crider, Mindy Zhang, Christine M. Pfeiffer, Rakesh Gupta, Rajesh Mehta, Neena Raina, Lorraine F. Yeung
Background
Folate and vitamin B12 deficiencies in pregnant women are associated with increased risk for adverse maternal and infant health outcomes, including neural tube defects (NTDs).
Methods
A population-based cross-sectional survey was conducted in two rural areas in Ambala District, Haryana, India in 2017 to assess baseline folate and vitamin B12 status among women of reproductive age (WRA) and predict the prevalence of NTDs. We calculated the prevalence of folate and vitamin B12 deficiency and insufficiency by demographic characteristics among 775 non-pregnant, non-lactating WRA (18–49 years). Using red blood cell (RBC) folate distributions and an established Bayesian model, we predicted NTD prevalence. All analyses were conducted using SAS-callable SUDAAN Version 11.0.4 to account for complex survey design.
Results
Among WRA, 10.1% (95% CI: 7.9, 12.7) and 9.3% (95% CI: 7.4, 11.6) had serum (<7 nmol/L) and RBC folate (<305 nmol/L) deficiency, respectively. The prevalence of RBC folate insufficiency (<748 nmol/L) was 78.3% (95% CI: 75.0, 81.3) and the predicted NTD prevalence was 21.0 (95% uncertainly interval: 16.9, 25.9) per 10,000 live births. Prevalences of vitamin B12 deficiency (<200 pg/mL) and marginal deficiency (≥200 pg/mL and ≤300 pg/mL) were 57.7% (95% CI: 53.9, 61.4) and 23.5% (95% CI: 20.4, 26.9), respectively.
Conclusions
The magnitude of folate insufficiency and vitamin B12 deficiency in this Northern Indian population is a substantial public health concern. The findings from the survey help establish the baseline against which results from future post-fortification surveys can be compared.
{"title":"Folate and Vitamin B12 Status in Women of Reproductive Age in Rural Haryana, India: Estimating Population-Based Prevalence for Neural Tube Defects","authors":"Reena Das, Mona Duggal, Jorge Rosenthal, Ankita Kankaria, Hari K. Senee, Shameem Jabbar, Manmeet Kaur, Vishal Kumar, Swati Bhardwaj, Neha Singh, Gursharan S. Dhanjal, Akash Kumar, Charles E. Rose, Rita Bhatia, Rachita Gupta, Suresh Dalpath, Krista S. Crider, Mindy Zhang, Christine M. Pfeiffer, Rakesh Gupta, Rajesh Mehta, Neena Raina, Lorraine F. Yeung","doi":"10.1002/bdr2.2390","DOIUrl":"10.1002/bdr2.2390","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Folate and vitamin B12 deficiencies in pregnant women are associated with increased risk for adverse maternal and infant health outcomes, including neural tube defects (NTDs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A population-based cross-sectional survey was conducted in two rural areas in Ambala District, Haryana, India in 2017 to assess baseline folate and vitamin B12 status among women of reproductive age (WRA) and predict the prevalence of NTDs. We calculated the prevalence of folate and vitamin B12 deficiency and insufficiency by demographic characteristics among 775 non-pregnant, non-lactating WRA (18–49 years). Using red blood cell (RBC) folate distributions and an established Bayesian model, we predicted NTD prevalence. All analyses were conducted using SAS-callable SUDAAN Version 11.0.4 to account for complex survey design.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among WRA, 10.1% (95% CI: 7.9, 12.7) and 9.3% (95% CI: 7.4, 11.6) had serum (<7 nmol/L) and RBC folate (<305 nmol/L) deficiency, respectively. The prevalence of RBC folate insufficiency (<748 nmol/L) was 78.3% (95% CI: 75.0, 81.3) and the predicted NTD prevalence was 21.0 (95% uncertainly interval: 16.9, 25.9) per 10,000 live births. Prevalences of vitamin B12 deficiency (<200 pg/mL) and marginal deficiency (≥200 pg/mL and ≤300 pg/mL) were 57.7% (95% CI: 53.9, 61.4) and 23.5% (95% CI: 20.4, 26.9), respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The magnitude of folate insufficiency and vitamin B12 deficiency in this Northern Indian population is a substantial public health concern. The findings from the survey help establish the baseline against which results from future post-fortification surveys can be compared.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Erik D. Slawsky, Anne M. Weaver, Thomas J. Luben, Kristen M. Rappazzo
Background
Brownfields consist of abandoned and disused sites, spanning many former purposes. Brownfields represent a heterogenous yet ubiquitous exposure for many Americans, which may contain hazardous wastes and represent urban blight. Neonates and pregnant individuals are often sensitive to subtle environmental exposures. We evaluate if residential exposure to lead (Pb) brownfields is associated with birth defects.
Methods
Using North Carolina birth records from 2003 to 2015, we sampled 169,499 births within 10 km of a Pb brownfield with 3255 cardiovascular, central nervous, or external defects identified. Exposure was classified by binary specification of residing within 3 km of a Pb brownfield. We utilized multivariable logistic regression models adjusted for demographic covariates available from birth records and 2010 Census to estimate odds ratios (OR) and 95% confidence intervals (CI). Effect measure modification was assessed by inclusion of interaction terms and stratification for the potential modifiers of race/ethnicity and diabetes status.
Results
We observed positive associations between cardiovascular birth defects and residential proximity to Pb brownfields, OR (95%CI): 1.15 (1.04, 1.26), with suggestive positive associations for central nervous 1.16 (0.91, 1.47) and external defects 1.19 (0.88, 1.59). We did observe evidence of effect measure modification via likelihood ratio tests (LRT) for race/ethnicity for central nervous and external defect groups (LRT p values 0.08 and 0.02). We did observe modification by diabetes status for the cardiovascular group (LRT p value 0.08).
Conclusions
Our results from this analysis indicate that residential proximity to Pb brownfields is associated with cardiovascular birth defects with suggestive associations for central nervous and external defects. In-depth analyses of individual defects and other contaminants or brownfield site functions may reveal additional novel associations.
{"title":"Lead brownfields and birth defects in North Carolina 2003–2015: A cross-sectional case–control study","authors":"Erik D. Slawsky, Anne M. Weaver, Thomas J. Luben, Kristen M. Rappazzo","doi":"10.1002/bdr2.2367","DOIUrl":"10.1002/bdr2.2367","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Brownfields consist of abandoned and disused sites, spanning many former purposes. Brownfields represent a heterogenous yet ubiquitous exposure for many Americans, which may contain hazardous wastes and represent urban blight. Neonates and pregnant individuals are often sensitive to subtle environmental exposures. We evaluate if residential exposure to lead (Pb) brownfields is associated with birth defects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using North Carolina birth records from 2003 to 2015, we sampled 169,499 births within 10 km of a Pb brownfield with 3255 cardiovascular, central nervous, or external defects identified. Exposure was classified by binary specification of residing within 3 km of a Pb brownfield. We utilized multivariable logistic regression models adjusted for demographic covariates available from birth records and 2010 Census to estimate odds ratios (OR) and 95% confidence intervals (CI). Effect measure modification was assessed by inclusion of interaction terms and stratification for the potential modifiers of race/ethnicity and diabetes status.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed positive associations between cardiovascular birth defects and residential proximity to Pb brownfields, OR (95%CI): 1.15 (1.04, 1.26), with suggestive positive associations for central nervous 1.16 (0.91, 1.47) and external defects 1.19 (0.88, 1.59). We did observe evidence of effect measure modification via likelihood ratio tests (LRT) for race/ethnicity for central nervous and external defect groups (LRT <i>p</i> values 0.08 and 0.02). We did observe modification by diabetes status for the cardiovascular group (LRT <i>p</i> value 0.08).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results from this analysis indicate that residential proximity to Pb brownfields is associated with cardiovascular birth defects with suggestive associations for central nervous and external defects. In-depth analyses of individual defects and other contaminants or brownfield site functions may reveal additional novel associations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emma Kalk, Alexa Heekes, Diane Lavies, Lizel Jacobs, Careni Spencer, Alison Boutall, Ayesha Osman, Chantal Stewart, Mary-Ann Davies, Anika van Niekerk, Karen Fieggen, Andrew Boulle, Ushma Mehta
Background
Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures.
Methods
We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016–2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD.
Results
Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (n = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD.
Conclusions
A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record-keeping could improve CD ascertainment.
背景：南非缺乏有关先天性疾病（CD）的负担和范围的数据，这有损于资源分配，并限制了检测潜在致畸妊娠暴露信号的能力：我们利用西开普省妊娠暴露登记处（PER）的常规电子数据，确定了 2016-2022 年南非西开普省出生时新生儿体表检查发现的先天性疾病的总体和个体患病率。CD通过记录审查得到确认。我们评估了晚期（≤24 个月）诊断和产前诊断的贡献。我们比较了受 CD 影响/未受 CD 影响的孕妇的人口和产科特征：结果：纳入了存活妊娠（妊娠期大于 22 周；出生体重≥ 500 克）的妇女（n = 32,494 人）。在确定的 1106 例潜在 CD 中，56.1% 经文件夹审查得到确认。排除内脏和轻微 CD 后，出生时体表检查发现的主要 CD 患病率为 7.2/1000。如果将检查（16.8%）和超声波检查（6.8%）的漏诊/迟诊计算在内，则发病率为 9.2/1000：8.9/1000 活产和 21.5/1000 死产。PER没有检测到21.5%的出生时可见的主要CD。高龄产妇和糖尿病与 CD 患病率增加有关。感染/未感染艾滋病毒的妇女（或接受抗逆转录病毒治疗的时间，受孕前/后）、高血压或肥胖对 CD 的患病率没有显著影响：基于常规数据的监测系统成功确定了出生时体表检查发现的主要 CD 患病率，其患病率略高于同等研究。根据模型计算的约 2% 的总体患病率很可能被低估了。加强新生儿常规检查和临床记录保存可提高 CD 的确定率。
{"title":"Population-based prevalence of congenital defects in a routine sentinel site-based surveillance system in the Western Cape, South Africa","authors":"Emma Kalk, Alexa Heekes, Diane Lavies, Lizel Jacobs, Careni Spencer, Alison Boutall, Ayesha Osman, Chantal Stewart, Mary-Ann Davies, Anika van Niekerk, Karen Fieggen, Andrew Boulle, Ushma Mehta","doi":"10.1002/bdr2.2388","DOIUrl":"10.1002/bdr2.2388","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016–2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (<i>n</i> = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record-keeping could improve CD ascertainment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
María de la Paz Barboza-Argüello, Adriana Benavides-Lara
Background
Orofacial clefts (OFCs) are among the most common birth defects (BD). In 2008, a series of improvements began in the Costa Rican Birth Defect Register Center (CREC). We aim to explore trends between 1996 and 2021.
Methods
A trend analysis of OFCs from 1996 to 2021 and a descriptive analysis of OFCs from 2010 to 2021 were performed based on data from the CREC, the national BD surveillance system. Prevalence at birth was calculated according to the type: cleft palate (CP), cleft lip with or without CP (CL ± P), and presentation (isolated, multiple non-syndromic, or syndromes). We used joinpoint regression to identify if a significant change in trend occurred; the average annual percent change (AAPC) was determined. Marginal means and prevalence ratios by subperiod (1996–2009 as referent and 2010–2021) were estimated using Poisson regression and compared using Wald's chi-square tests (α ≤.05).
Results
We found a significant AAPC for OFCs prevalence of +1.4: +0.6 for isolated, +2.9 for multiple non-syndromic, and +7.7 for syndromes (p < .05). When comparing the OFC's prevalence of the subperiod 2010–2021 (11.86 per 10,000) with 1996–2009 (9.36 per 10,000) the prevalence ratio was 1.3 (p < .01): 1.1 (p < .05) for isolated, 1.6 (p < .01) for multiple non-syndromic, and 3.3 (p < .01) for syndromes. The prevalence of OFCs from 2010 to 2021 was 9.1 for CL ± P and 2.8 for CP. Seventy-one percent of the OFCs were isolated, 22% multiple non-syndromic, and 7% syndromes.
Conclusion
The trend in OFCs' prevalence is toward increasing, mainly due to improvements in the surveillance system.
{"title":"Orofacial clefts in Costa Rica, 1996–2021: Analysis of surveillance data","authors":"María de la Paz Barboza-Argüello, Adriana Benavides-Lara","doi":"10.1002/bdr2.2387","DOIUrl":"10.1002/bdr2.2387","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Orofacial clefts (OFCs) are among the most common birth defects (BD). In 2008, a series of improvements began in the Costa Rican Birth Defect Register Center (CREC). We aim to explore trends between 1996 and 2021.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A trend analysis of OFCs from 1996 to 2021 and a descriptive analysis of OFCs from 2010 to 2021 were performed based on data from the CREC, the national BD surveillance system. Prevalence at birth was calculated according to the type: cleft palate (CP), cleft lip with or without CP (CL ± P), and presentation (isolated, multiple non-syndromic, or syndromes). We used joinpoint regression to identify if a significant change in trend occurred; the average annual percent change (AAPC) was determined. Marginal means and prevalence ratios by subperiod (1996–2009 as referent and 2010–2021) were estimated using Poisson regression and compared using Wald's chi-square tests (<i>α</i> ≤.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found a significant AAPC for OFCs prevalence of +1.4: +0.6 for isolated, +2.9 for multiple non-syndromic, and +7.7 for syndromes (<i>p</i> < .05). When comparing the OFC's prevalence of the subperiod 2010–2021 (11.86 per 10,000) with 1996–2009 (9.36 per 10,000) the prevalence ratio was 1.3 (<i>p</i> < .01): 1.1 (<i>p</i> < .05) for isolated, 1.6 (<i>p</i> < .01) for multiple non-syndromic, and 3.3 (<i>p</i> < .01) for syndromes. The prevalence of OFCs from 2010 to 2021 was 9.1 for CL ± P and 2.8 for CP. Seventy-one percent of the OFCs were isolated, 22% multiple non-syndromic, and 7% syndromes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The trend in OFCs' prevalence is toward increasing, mainly due to improvements in the surveillance system.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chris Barnett, James Christiansen, Monica Mills, Jordyn Lord, Jared Parrish
Objectives
We assessed reporting misclassification for 12 critical congenital heart defects (CCHDs) identified through administrative diagnosis codes within a passive surveillance system. We measured the effect of misclassification on prevalence estimation. Lastly, we investigated a sample-based review strategy to estimate surveillance misclassification resulting from administrative diagnosis codes for case detection.
Methods
We received 419 reports of CCHDs between 2007 and 2018; 414 were clinically reviewed. We calculated confirmation probabilities to assess misclassification and adjust prevalence estimates. Random samples of reported cases were taken at proportions between 20% and 90% for each condition to assess sample bias. Sampling was repeated 1000 times to measure sample-estimate variability.
Results
Misclassification ranged from a low of 19% (n = 4/21) to a high of 84% (n = 21/25). Unconfirmed prevalence rates ranged between one and six cases per 10,000 live births, with some conditions significantly higher than national estimates. However, confirmed rates were either lower or comparable to national estimates.
Conclusion
Passive birth defect surveillance programs that rely on administrative diagnosis codes for case identification of CCHDs are subject to misclassification that bias prevalence estimates. We showed that a sample-based review could improve the prevalence estimates of 12 cardiovascular conditions relative to their unconfirmed prevalence rates.
{"title":"Measuring misclassification and sample bias in passive surveillance systems: Improving prevalence estimates of critical congenital heart defects in state-based passive surveillance systems","authors":"Chris Barnett, James Christiansen, Monica Mills, Jordyn Lord, Jared Parrish","doi":"10.1002/bdr2.2386","DOIUrl":"10.1002/bdr2.2386","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We assessed reporting misclassification for 12 critical congenital heart defects (CCHDs) identified through administrative diagnosis codes within a passive surveillance system. We measured the effect of misclassification on prevalence estimation. Lastly, we investigated a sample-based review strategy to estimate surveillance misclassification resulting from administrative diagnosis codes for case detection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We received 419 reports of CCHDs between 2007 and 2018; 414 were clinically reviewed. We calculated confirmation probabilities to assess misclassification and adjust prevalence estimates. Random samples of reported cases were taken at proportions between 20% and 90% for each condition to assess sample bias. Sampling was repeated 1000 times to measure sample-estimate variability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Misclassification ranged from a low of 19% (<i>n</i> = 4/21) to a high of 84% (<i>n</i> = 21/25). Unconfirmed prevalence rates ranged between one and six cases per 10,000 live births, with some conditions significantly higher than national estimates. However, confirmed rates were either lower or comparable to national estimates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Passive birth defect surveillance programs that rely on administrative diagnosis codes for case identification of CCHDs are subject to misclassification that bias prevalence estimates. We showed that a sample-based review could improve the prevalence estimates of 12 cardiovascular conditions relative to their unconfirmed prevalence rates.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nandini Mukherjee, Elijah H. Bolin, Amna Qasim, Mohammed S. Orloff, Philip J. Lupo, Wendy N. Nembhard
Background
Prior studies report associations of maternal serum Lamin A, encoded by the LMNA gene, with fetal congenital heart disease (CHD). It is unknown whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites in LMNA impacts the CHD susceptibility.
Methods
We investigated the associations of LMNA DNAm with CHD using publicly available data of CHD cases (n = 197) and controls (n = 134) from the Gene Expression Omnibus repository. Peripheral blood DNAm was measured using Illumina 850 K BeadChip for cases and 450 K BeadChip for controls. We tested 31 LMNA CpGs to identify differences in DNAm between cases and controls using linear regression correcting for multiple testing with false discovery rate (FDR). In a case-only analysis, we tested the variations in LMNA DNAm between CHD subtypes. To identify the consistency of DNAm across tissue types we compared peripheral blood (n = 197) and heart tissue DNAm (n = 20) in CHD cases.
Results
After adjusting for age, sex, and cell types there were significant differences in 17 of the 31 LMNA CpGs between CHD cases and controls (FDR p ≤ .05). We identified lower DNAm of cg09820673 at 3′ UTR for hypoplastic left heart syndrome compared to other CHD subtypes. Three CpGs exhibited uniform DNAm in blood and heart tissues in cases. Eleven CpGs showed changes in the same direction in blood and heart tissues in cases compared to controls.
Conclusion
We identify statistically significant differences in LMNA DNAm between CHD cases and controls. Future studies should investigate the role of maternal LMNA DNAm in CHD development.
{"title":"DNA methylation of the Lamin A/C gene is associated with congenital heart disease","authors":"Nandini Mukherjee, Elijah H. Bolin, Amna Qasim, Mohammed S. Orloff, Philip J. Lupo, Wendy N. Nembhard","doi":"10.1002/bdr2.2381","DOIUrl":"10.1002/bdr2.2381","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Prior studies report associations of maternal serum Lamin A, encoded by the <i>LMNA</i> gene, with fetal congenital heart disease (CHD). It is unknown whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites in <i>LMNA</i> impacts the CHD susceptibility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated the associations of <i>LMNA</i> DNAm with CHD using publicly available data of CHD cases (<i>n</i> = 197) and controls (<i>n</i> = 134) from the Gene Expression Omnibus repository. Peripheral blood DNAm was measured using Illumina 850 K BeadChip for cases and 450 K BeadChip for controls. We tested 31 <i>LMNA</i> CpGs to identify differences in DNAm between cases and controls using linear regression correcting for multiple testing with false discovery rate (FDR). In a case-only analysis, we tested the variations in <i>LMNA</i> DNAm between CHD subtypes. To identify the consistency of DNAm across tissue types we compared peripheral blood (<i>n</i> = 197) and heart tissue DNAm (<i>n</i> = 20) in CHD cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After adjusting for age, sex, and cell types there were significant differences in 17 of the 31 <i>LMNA</i> CpGs between CHD cases and controls (FDR <i>p</i> ≤ .05). We identified lower DNAm of cg09820673 at 3′ UTR for hypoplastic left heart syndrome compared to other CHD subtypes. Three CpGs exhibited uniform DNAm in blood and heart tissues in cases. Eleven CpGs showed changes in the same direction in blood and heart tissues in cases compared to controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We identify statistically significant differences in <i>LMNA</i> DNAm between CHD cases and controls. Future studies should investigate the role of maternal <i>LMNA</i> DNAm in CHD development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"116 7","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2381","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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