Birth Defects Research最新文献

{"title":"Functional Evaluation of Neural Tube Defect-Related Missense Mutations Using In Silico Methods","authors":"Burcu Biterge Sut","doi":"10.1002/bdr2.2453","DOIUrl":"https://doi.org/10.1002/bdr2.2453","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Neural tube formation is one of the most important developmental events as it gives rise to the key organs comprising the central nervous system. Failure in the proper closure of the neural tube results in congenital abnormalities, namely neural tube defects (NTDs). Previous studies have identified several single nucleotide variations that are considered risk factors and established a genetic background for the increased incidence of NTDs and factors. This study aims to provide a comprehensive functional analysis of NTD-related missense mutations in terms of their potential effects on pathogenicity, protein stability, and structure using predictive in silico analysis tools.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single nucleotide variations associated with NTD risk were identified by a systematic review of previous studies on Pubmed and ClinVar. Protein stability and pathogenicity scores were predicted using MUpro and PloyPhen2, respectively. Structural alterations were determined via the HOPE server. Predicted expression profiles in the brain were retrieved from the Human Protein Atlas.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our analysis identified 43 NTD-related missense mutations in MTHFR, MTRR, PARD3, PACS1, MED12, VANGL1, VANGL2, FZD6, CELSR1, FUZ, DVL2, and LRP6 genes. We found that all of these genes are predicted to be expressed in different regions of the brain. We showed that single nucleotide variations resulted in decreased protein stability, and the majority of them were found to be damaging. We also report that the amino acid changes introduced by these mutations caused differences in size, charge, and hydrophobicity, which potentially resulted in structural alterations within the protein and affected their contacts with other proteins and ligands.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In conclusion, this study provides a comprehensive analysis of NTD-related missense mutations regarding their potential damaging effects, which might contribute to the pathogenesis of NTDs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404363","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}

{"title":"Choosing Words to Limit Stigma: The Use of Person-First Language in Birth Defects Research","authors":"Jacqueline T. Bascom,&nbsp;A. J. Agopian","doi":"10.1002/bdr2.2449","DOIUrl":"https://doi.org/10.1002/bdr2.2449","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Birth defects are associated with psychosocial stress and stigma, in addition to increased mortality and lifelong disabilities. The language and phrasing used to describe individuals with birth defects in scientific writing can affect attitudes that contribute to stigma. Using a “person-first” writing structure (e.g., “infants with Down syndrome”) instead of “identity-first” language (e.g., “Down syndrome infants”) is intended to promote respect and inclusivity. Our work aims to enhance awareness and advocacy of person-first language among researchers and professionals in birth defects research, with the goal of reducing stigma and adopting language that prioritizes dignity for individuals and their families.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 52 population-based birth defects articles published by the National Birth Defects Prevention Network (NBDPN) between 2002 and 2024, which we expect to exemplify writing practices among U.S. birth defects epidemiologists. We evaluated the use of person-first and identity-first language in population-based birth defects research and advocated for increased consideration of person-first language in the field.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 52 NBDPN articles reviewed, seven (13%) articles used person-first language only, <i>N</i> = 6 (12%) used identity-first language only, 38 (73%) used both, and one (2%) used neither.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We encourage researchers to consider using person-first language when describing individuals with birth defects in epidemiologic studies and in training birth defects epidemiologists, while acknowledging that some communities may also prefer an identity-first framework (e.g., the “Deaf community”).</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389120","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}

{"title":"Maternal Separation Exhibits a Sex Dimorphism in Memory Impairments in Adolescent Rats: Acute Methylphenidate Administration as a Treatment","authors":"Fatemeh Mohtashami Borzadaran,&nbsp;Soheila Rezakhani,&nbsp;Reyhaneh Kamali,&nbsp;Khadijeh Esmaeilpour","doi":"10.1002/bdr2.2441","DOIUrl":"https://doi.org/10.1002/bdr2.2441","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Rodents are highly dependent on maternal care after birth. Disturbing mother and pup interactions leads to detrimental alternations for the rat and the mother. Maternal separation (MS) is an accepted model for investigating disruption of mother and pup relationship. In addition to other detrimental effects, MS is a model known to induce permanent changes in learning and memory. Methylphenidate has been effective in memory enhancement in individuals suffering from memory deficits, attention-deficit hyperactive disorder (ADHD), as well as healthy subjects for better performance in exams.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Material and Methods</h3>\u0000 \u0000 <p>In this research, a 21-day separation for 3 h was implemented, and the effects of MS on spatial and passive avoidance learning, and memory were evaluated in the mid-adolescence period of rats, in both males and females. Also, a drug intervention of a high therapeutic dose of 5 mg per kg was used in a five-day period in different control and MS groups. Morris water maze was utilized for spatial learning and memory analysis, and a shuttle box paradigm was used for passive avoidance learning and memory.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Through our behavioral tests, we have shown that MS can alter spatial learning and memory in males. On the other hand, females are protected from the detrimental effects of MS on spatial learning and memory. Furthermore, passive avoidance learning was not different among groups, be it male or female. However, in the case of memory evaluation in the passive avoidance test, the male did not exhibit a significant difference in step-through latency. However, maternally separated females had poor performance in the memory phase with shorter step-through latencies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Methylphenidate compensated for the deleterious effects of MS on learning and spatial memory for the male group and passive avoidance memory in the female group at the behavioral level.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2441","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362309","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}

{"title":"Exploring Ensemble Learning Techniques for Infant Mortality Prediction: A Technical Analysis of XGBoost Stacking AdaBoost and Bagging Models","authors":"Indu Verma,&nbsp;Sanjeev Kumar Prasad","doi":"10.1002/bdr2.2443","DOIUrl":"https://doi.org/10.1002/bdr2.2443","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Infant mortality remains a critical public health issue, reflecting the overall health and well-being of a population. Accurate prediction of infant mortality is crucial, as it enables healthcare providers to identify at-risk populations and implement targeted interventions. By analyzing factors such as maternal education, prenatal care access, nutrition, and environmental influences, predictions help in designing effective programs aimed at reducing infant deaths.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This research paper aims to predict infant mortality in India by employing ensemble learning techniques, specifically eXtreme gradient boosting (XGBoost), stacking, adaptive boosting, and bagging. The data for the analysis are sourced from national surveys and demographic studies focusing on infant mortality in India. The collected data underwent rigorous preprocessing steps to prepare it for predictive modeling. Each ensemble learning model is applied to predict infant mortality rates based on the preprocessed data. The XGBoost handles complex and non-linear relationships within the data, and the stacking model is used for the accurate and robust predictions. The adaptive boosting model iteratively trains multiple weak learners, which makes the predictive model as stronger. The adaptive boosting technique enhances the performance of weak classifiers while effectively addressing class imbalance issues. Further, the bagging approach is implemented to derive the linear and non-linear relationships of infant mortality. Models were optimized using k-fold cross-validation to fine-tune their hyper parameters. The predictive ability of the ensemble techniques is analyzed by deploying using different performance parameters.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;XGBoost attained superior performance results, with a 98.75% accuracy, 98.56% precision, and 98.24% recall. The adaptive boosting model strengthened weak learners and addressed class imbalance issues, while the bagging method captures linear and non-linear relationships. Ensemble learning models demonstrated effectiveness in predicting infant mortality, with XGBoost excelling in handling complex and non-linear relationships.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The simulation results revealed that ensemble learning models are highly effective in predicting infant mortality rates in India, with significant regional disparities observed. For example, the Northeast region exhibited the highest predicted infant mortality rates, while the South region recorded the lowest. These findings underscore the need for targeted i","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362621","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}

{"title":"Variants in Chromatin Remodeling Genes Are Involved in Patients With Chiari Malformation Type 1","authors":"Ferruccio Romano,&nbsp;Maria Cerminara,&nbsp;Patrizia De Marco,&nbsp;Michele Iacomino,&nbsp;Marco Di Duca,&nbsp;Domenico Tortora,&nbsp;Marco Pavanello,&nbsp;Gianluca Piatelli,&nbsp;Marcello Scala,&nbsp;Federico Zara,&nbsp;Aldamaria Puliti,&nbsp;Valeria Capra","doi":"10.1002/bdr2.2446","DOIUrl":"10.1002/bdr2.2446","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Chiari malformation type 1 (CMI) is defined by the herniation of cerebellar tonsils of 5 mm or more, with possible neurological consequences, including compression of the neural tissue and/or anomalies in cerebral spinal fluid circulation. The etiology of CMI is not fully elucidated, with both genetic and environmental factors being involved. Several genes and pathways involved in bone development are pointed out like genes of the WNT, FGF, and BMP signaling pathways. More recently, the crucial role played by chromatin remodeling genes in the pathogenesis of CMI has increasingly emerged.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this paper, we discuss a familial case of CMI and a single patient, harboring variants in chromatin remodeling genes, identified by whole exome sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The first is a family with three affected members and one sibling with a cerebellar tonsil herniation of &lt; 5 mm. The three CMI patients harbor a heterozygous missense variant in the <i>SETD2</i> gene, whose truncating variants are responsible for Luscan–Lumish syndrome. A second variant in <i>HP1BP3</i>, a gene not previously associated with human pathology, with evidence of skeletal anomalies in mice models, was found in the three patients and also in the girl with a herniation of &lt; 5 mm. The second case is a proband with a de novo variant in <i>KMT2A</i>, associated with Wiedemann–Steiner syndrome, in which anomalies of the craniocervical junction are described.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>We highlight the importance of chromatin remodeling genes in both isolated and syndromic CMI and suggest the potential role of <i>HP1BP3</i> as a possible modifier gene in CMI pathogenesis, even if this association needs to be further clarified.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdr2.2446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188231","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}

{"title":"A Supra-Numerary Limb Grafted Onto a Sacrococcygeal Mass in a Child With Spinal Dysraphism: Case Report, Dysmorphogenesis, and Management Review","authors":"Kaylene Freitas,&nbsp;Leonor Castro,&nbsp;Carla Pilar,&nbsp;Catarina Barreira,&nbsp;Rosete Nogueira,&nbsp;Jenny Gonçalves","doi":"10.1002/bdr2.2447","DOIUrl":"https://doi.org/10.1002/bdr2.2447","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Externally attached supra-numerary body structures are a rare congenital malformation. Dysmorphogenesis remains controversial, hence many different classifications have been proposed over the years. We report a case of a supra-numerary lower limb grafted onto a sacrococcygeal mass in a child with a myelomeningocele. Prevailing theories for its origin are revised as well as prenatal and postnatal management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Case</h3>\u0000 \u0000 <p>The case relates to a female neonate with a third lower limb grafted to a lumbosacral mass found upon birth. Postnatal imaging revealed a lipomyelomeningocele and a supra-numerary limb. Surgical intervention was performed on day seven of life with removal of the supra-numerary limb and correction of the dural defect. Anatomopathologic study revealed mature and dysplastic tissues of the three germlines. The infant was discharged after 16 days to follow-up by a multidisciplinary team. In early follow-up, minor asymmetry in lower limb mobility, peri-anal anesthesia, and bladder incontinence was present. Currently 8 years old, the patient has no motor or sensory dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This case challenges the existing theories for conjoined twinning, as they do not fully explain the co-occurrence of neural tube defects in sacrally fused supra-numerary structures. Whether these malformations are entities of a single disease spectrum or the result of independent dysmorphogenesis is debated. Prenatal diagnosis with sequential investigation of morphogenesis as well as postnatal anatomopathological examination are crucial for a better understanding of complex biologic processes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112119","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}

{"title":"Evaluation of the Clinical and Genetic Characteristics of Primary Ciliary Dyskinesia Patients With Situs Inversus Totalis","authors":"Feyza Ustabas Kahraman,&nbsp;Uzeyir Jafarov,&nbsp;Hakan Yazan,&nbsp;Ismail Yurtsever,&nbsp;Erkan Cakir,&nbsp;Gozde Yesil Sayin","doi":"10.1002/bdr2.2444","DOIUrl":"https://doi.org/10.1002/bdr2.2444","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Situs inversus totalis (SIT) is present in approximately 40%–50% of patients with primary ciliary dyskinesia (PCD). We evaluated the relationships between novel genetic results and the clinical and radiological characteristics of PCD patients with SIT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study included 48 patients diagnosed with PCD and SIT. Demographic and clinical features, disease-related scores (Bhalla, Primary Ciliary Dyskinesia Rule [PICADAR], and American Thoracic Society [ATS]), and genetic analyses were retrospectively assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The median age of patients was 13 (6.5–16) years, and parental consanguinity was observed in 43 (89.58%) patients. Bhalla score was available in 31 patients and “moderate and severe” score was observed in 19 (61.29%) patients. The median PICADAR score was 10 (8–11), and 34 (70.83%) patients had a high (≥ 10) PICADAR score. The ATS score was found to be 4 in 24 (50%) patients and 3 in 20 (43.75%) patients. Genetic data were available in 40 patients and mutations were found in 27 (67.5%) patients. The most common pathogenic variants were DNAH5 in 8 (20%), CCDC103 in 4 (10%), and CCDC39 in 3 (7.5%) patients. Subjects with any genetic variants may be older, have a greater frequency of parental consanguinity, higher Bhalla score, and higher ATS score (<i>p</i> &lt; 0.05). DNAH5 mutation was associated with a lower likelihood of neonatal ICU stay and neonatal respiratory distress-related symptoms (<i>p</i> = 0.036 and 0.015, respectively).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Situs abnormalities may be a warning sign for the early diagnosis of PCD. Early diagnosis of PCD through genetic analysis is important for preventing chronic lung pathologies and predicting prognosis and may improve the quality of life.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112121","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}

{"title":"Risk of Congenital Ocular Anomaly After Prenatal Exposure to Medications: A EUROmediCAT Study","authors":"E.-A. Cifuentes,&nbsp;A. Beau,&nbsp;A. Caillet,&nbsp;F. Frémont,&nbsp;A. J. Neville,&nbsp;E. Ballardini,&nbsp;H. Dolk,&nbsp;M. Loane,&nbsp;E. Garne,&nbsp;B. Khoshnood,&nbsp;N. Lelong,&nbsp;A. Rissmann,&nbsp;M. O'Mahony,&nbsp;A. Pierini,&nbsp;M. Gatt,&nbsp;J. E. H. Bergman,&nbsp;M. R. Krawczynski,&nbsp;A. Latos Bielenska,&nbsp;L.-J. Echevarría González de Garibay,&nbsp;C. Cavero Carbonell,&nbsp;M.-C. Addor,&nbsp;D. Tucker,&nbsp;S. Jordan,&nbsp;E. Den Hond,&nbsp;V. Nelen,&nbsp;I. Barisic,&nbsp;F. Rouget,&nbsp;H. Randrianaivo,&nbsp;J. Hoareau,&nbsp;I. Perthus,&nbsp;M. Courtade-Saïdi,&nbsp;C. Damase-Michel,&nbsp;C. Dubucs","doi":"10.1002/bdr2.2435","DOIUrl":"10.1002/bdr2.2435","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>In Europe, the prevalence of congenital ocular anomaly (COA) is estimated at 3.7 per 10,000 births. While certain COAs have a genetic origin, the cause for most patients remains unknown. The role of medications administered during pregnancy in COA genesis in humans is unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate any association between fetal exposure in the first trimester of pregnancy to medications and the occurrence of COA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a case-malformed-control study using data on 298,351 cases registered as having congenital anomalies (CA) from 19 registries and one healthcare database in 13 European countries. Two analyses were performed: (i) A signal confirmation analysis of signals from the literature, examining associations between COA and specific medications (nitrofurantoin, NSAIDs, opioids, alprazolam, antihypertensives, asthma medications, pyridoxine, and hydroxyethylrutoside). (ii) A signal detection analysis of all medications reported in the database.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 4185 COA cases and 232,718 nongenetic and 38,409 genetic controls. We confirmed the association between prenatal opioid exposure and COA (aROR: 2.66, 95% CI: 1.18, 6.02, and 3.22, 95% CI: 1.35, 7.69, for nongenetic and genetic controls, respectively). Signal detection analysis revealed consistent associations for antiglaucoma preparations and miotics (<i>p</i> &lt; 0.01) related to COA. Other associations included congenital cataracts and lens anomalies with desloratadine, congenital glaucoma with antiepileptics, and eyelid malformations with dermatological hydrocortisone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This pharmacoepidemiological study in Europe analyzing COA following fetal medication exposure confirmed reported signals regarding opioids and COA and identified new associations. Validation in independent datasets is necessary to consolidate these findings.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073839","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}

{"title":"A Generalized Machine Learning Model for Identifying Congenital Heart Defects (CHDs) Using ICD Codes","authors":"Haoming Shi,&nbsp;Wendy M. Book,&nbsp;Lindsey C. Ivey,&nbsp;Fred H. Rodriguez III,&nbsp;Cheryl Raskind-Hood,&nbsp;Karrie F. Downing,&nbsp;Sherry L. Farr,&nbsp;Courtney E. McCracken,&nbsp;Vinita O. Leedom,&nbsp;Susan E. Haynes,&nbsp;Sandra Amouzou,&nbsp;Reza Sameni,&nbsp;Rishikesan Kamaleswaran","doi":"10.1002/bdr2.2440","DOIUrl":"10.1002/bdr2.2440","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p><i>International Classification of Diseases</i> (ICD) codes utilized for congenital heart defect (CHD) case identification in datasets have substantial false-positive (FP) rates. Incorporating machine learning (ML) algorithms following case selection by ICD codes may improve the accuracy of CHD identification, enhancing surveillance efforts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Traditional ML methods were applied to four encounter-level datasets, 2010–2019, for 3334 patients with validated diagnoses and with at least one CHD ICD code identified. A 5-fold cross-validation approach was applied to the dataset to determine the set of overlapping important features best classifying CHD cases. Training and testing combinations were explored to determine the approach yielding the most accurate CHD classification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CHD ICD positive predictive values (PPVs) by site ranged from 53.2% to 84.0%. The ML algorithm achieved a PPV of 95% (1273/1340) for the four-site dataset with a false-negative (FN) rate of 33% (639/1912) by choosing an operating point prioritizing PPV from the PPV–FN rate curve. XGBoost reduced 2105 Clinical Classification Software (CCS) features to 137 that identified those with true-positive (TP) CHD and false-positive FP classification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Applying ML algorithms following case selection by CHD-related ICD codes improved the accuracy of identifying TP true-positive CHD cases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073838","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}

{"title":"Pre- and Postnatal Development Study of Nemolizumab, a Humanized Anti-Interleukin-31 Receptor A Monoclonal Antibody, in Cynomolgus Monkey","authors":"Ryuichi Katagiri,&nbsp;Saori Matsuo,&nbsp;Hisashi Ikegami,&nbsp;Akihisa Kaneko,&nbsp;Akihiro Arima,&nbsp;Shuichi Chiba,&nbsp;Masanori Sasaki","doi":"10.1002/bdr2.2442","DOIUrl":"10.1002/bdr2.2442","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Nemolizumab, a humanized monoclonal antibody against interleukin-31 receptor A (IL-31RA), is used to treat atopic dermatitis and prurigo nodularis. These inflammatory skin diseases affect a wide range of age groups, including pregnant women and children; however, little is known about their biological effects on pre- and postnatal development. Therefore, we report and discuss the results of an enhanced pre- and postnatal development study in cynomolgus monkeys treated with nemolizumab, which also incorporates an assessment of juvenile toxicities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Nemolizumab was subcutaneously administered at doses of 1 or 25 mg/kg to pregnant cynomolgus monkeys once every 2 weeks (biweekly) from Gestation Day 20 until delivery, to investigate the potential toxicities on pre- and postnatal development. Additionally, their offspring were subcutaneously dosed biweekly with 1 or 25 mg/kg from approximately 1 to 7 months after birth to investigate the potential toxicities on juveniles, considering the age of the target patient population. The examination included tests for immune function and nervous system involvement by IL-31, as well as the standard assessments outlined in the ICH S5 guideline to comprehensively assess the safety profile.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>No nemolizumab-related toxicities were observed in both dams and offspring up to 25 mg/kg. Maternal plasma nemolizumab concentrations were well maintained during the gestation period, gradually decreasing after delivery. Plasma concentrations in the offspring, higher than in dams, was maintained until scheduled necropsy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Blocking IL-31 signaling with repeated dosing of nemolizumab did not adversely affect pregnancy, parturition, nursing, or postnatal physical and functional development in cynomolgus monkeys.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045574","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}