Birth Defects Research最新文献_第10页

Sex-dependent alterations of inflammatory factors, oxidative stress, and histopathology of the brain-gut axis in a VPA-induced autistic-like model of rats VPA诱导的大鼠自闭症样模型中炎症因子、氧化应激和脑肠轴组织病理学的改变与性别有关。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-04-02 DOI: 10.1002/bdr2.2310

Zahra Salari, Amirhossein Moslemizadeh, Sara Sheibani Tezerji, Nazanin Sabet, Ali Saeidpour Parizi, Mohammad Khaksari, Vahid Sheibani, Elham Jafari, Sara Shafieipour, Hamideh Bashiri

Introduction

In this study, we aimed to investigate the inflammatory factors, oxidative stress, and histopathological consequences of the brain-gut axis in male and female rats prenatally exposed to VPA.

Methods

Pregnant Wistar rats were randomly divided into two groups. The animals received saline, and valproic acid (VPA) (600 mg/kg, i.p.) on embryonic day 12.5 (E12.5). All offspring were weaned on postnatal day 21, and the experiments were done in male and female rats on day 60. The brain and intestine tissues were extracted to assess histopathology, inflammation, and oxidative stress.

Results

An increase of interleukin-1β (IL-1β) and interleukin-6 (IL-6) and a decrease of interleukin-10 (IL-10) were observed in the two sexes and two tissues of the autistic rats. In the VPA-exposed animals, malondialdehyde (MDA) and protein carbonyl (PC) increased in the brain of both sexes and the intestines of only the males. The total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT) significantly decreased in both tissues of male and female autistic groups. Histopathological evaluation showed that the %apoptosis of the cortex in the autistic male and female groups was more than in controls whereas this parameter in the CA1 and CA3 was significant only in the male rats. In the intestine, histopathologic changes were seen only in the male autistic animals.

Conclusion

The inflammatory and antioxidant factors were in line in the brain-gut axis in male and female rats prenatally exposed to VPA. Histopathological consequences were more significant in the VPA-exposed male animals.

引言本研究旨在探讨产前暴露于 VPA 的雌雄大鼠脑-肠轴的炎症因子、氧化应激和组织病理学后果：方法：将怀孕的 Wistar 大鼠随机分为两组。方法：将妊娠 Wistar 大鼠随机分为两组，一组接受生理盐水，另一组在胚胎 12.5 天（E12.5）接受丙戊酸（VPA）（600 毫克/千克，静脉注射）。所有后代均于出生后第 21 天断奶，实验于第 60 天在雄性和雌性大鼠中进行。提取脑组织和肠组织以评估组织病理学、炎症和氧化应激：结果：在自闭症大鼠的两种性别和两种组织中观察到白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）增加，白细胞介素-10（IL-10）减少。在暴露于 VPA 的动物中，雌雄大鼠大脑中的丙二醛（MDA）和蛋白质羰基（PC）都有所增加，只有雄性大鼠肠道中的丙二醛和蛋白质羰基有所增加。雌雄自闭症组动物两种组织的总抗氧化能力（TAC）、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）均明显下降。组织病理学评估显示，雌雄自闭症组大鼠大脑皮层的凋亡率高于对照组，而只有雄性大鼠的 CA1 和 CA3 的凋亡率明显高于对照组。在肠道中，只有雄性自闭症动物出现了组织病理学变化：结论：产前暴露于 VPA 的雄性和雌性大鼠的脑-肠轴中的炎症和抗氧化因子是一致的。组织病理学后果在暴露于 VPA 的雄性动物中更为显著。

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引用次数: 0

Folate and vitamin B12 status and predicted neural tube defects risk among nonpregnant women of reproductive age from the Malawi National Micronutrient Survey, 2015–2016 2015-2016年马拉维全国微量营养素调查中非怀孕育龄妇女的叶酸和维生素B12状况与预测的神经管缺陷风险。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-25 DOI: 10.1002/bdr2.2329

Yan Ping Qi, Krista S. Crider, Anne M. Williams, Katie Tripp, Carine Mapango, Elizabeth C. Rhodes, Eunice Nyirenda, Felix Phiri, Mindy Zhang, Shameem Jabbar, Christine M. Pfeiffer, Helena Pachón, Sarah Zimmerman, Jennifer L. Williams

Background

Maternal folate and vitamin B₁₂ deficiency can lead to serious adverse pregnancy outcomes. There are no nationally representative estimates on folate and vitamin B₁₂ status among women of reproductive age (WRA) in Malawi.

Objective

We assessed folate and vitamin B₁₂ status among nonpregnant WRA in Malawi and predicted the risk of folate-sensitive neural tube defects (NTDs) were they to become pregnant.

Methods

Using data from the cross-sectional, nationally representative 2015–2016 Malawi Micronutrient Survey, we calculated the proportion of folate and vitamin B₁₂ deficiency and insufficiency by demographic characteristics among 778 nonpregnant WRA (15–49 years). We predicted NTD prevalence using red blood cell (RBC) folate distributions and a published Bayesian model of the association between RBC folate and NTD risk. Analyses accounted for complex survey design.

Results

Among WRA, 8.5% (95% CI: 6.2, 11.6) and 13.3% (10.0, 17.4) had serum (<7 nmol/L) and RBC folate (<305 nmol/L) deficiency, respectively. The proportion of vitamin B₁₂ deficiency (<148 pmol/L) and insufficiency (≤221 pmol/L) was 11.8% (8.6, 16.0) and 40.6% (34.1, 47.4), respectively. RBC folate insufficiency (<748 nmol/L, defined as the concentration associated with the threshold for elevated NTD risk: >8 cases per 10,000 births) was widespread: 81.4% (75.0, 86.4). The predicted NTD risk nationally was 24.7 cases per 10,000 live births. RBC folate insufficiency and higher predicted NTD risk were more common among WRA living in urban areas or with higher education.

Conclusions

These findings highlight the importance of nutritional and NTD surveillance in Malawi and the opportunity for improving folate and vitamin B₁₂ nutrition among Malawian WRA.

背景：孕产妇叶酸和维生素 B12 缺乏可导致严重的不良妊娠结局。关于马拉维育龄妇女（WRA）的叶酸和维生素 B12 状态，目前还没有具有全国代表性的估计数据：我们评估了马拉维未孕育龄妇女的叶酸和维生素 B12 状况，并预测了她们怀孕后患叶酸敏感性神经管缺陷（NTD）的风险：利用具有全国代表性的 2015-2016 年马拉维微量营养素调查的横断面数据，我们按人口特征计算了 778 名未怀孕 WRA（15-49 岁）中叶酸和维生素 B12 缺乏和不足的比例。我们利用红细胞叶酸分布和已发表的红细胞叶酸与 NTD 风险之间关系的贝叶斯模型预测了 NTD 的发病率。分析考虑了复杂的调查设计：在 WRA 中，8.5%（95% CI：6.2, 11.6）和 13.3%（10.0, 17.4）的人血清叶酸缺乏（每 10,000 名新生儿中有 8 例），而在全国范围内，81.4%（75.0, 86.4）的人血清叶酸缺乏（每 10,000 名新生儿中有 8 例）。全国预测的新生儿非畸形风险为每万名活产婴儿 24.7 例。生活在城市地区或受过高等教育的妇女死亡率较高，红细胞叶酸不足和预测的NTD风险也较高：这些发现凸显了马拉维营养和NTD监测的重要性，以及改善马拉维WRA叶酸和维生素B12营养状况的机会。

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引用次数: 0

Genome-wide analysis of spina bifida risk variants in a case–control study from Bangladesh 孟加拉国病例对照研究中脊柱裂风险变异的全基因组分析。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-25 DOI: 10.1002/bdr2.2331

Gwen Tindula, Biju Issac, Sudipta Kumer Mukherjee, Sheikh Muhammad Ekramullah, D. M. Arman, Joynul Islam, Hafiza Sultana Suchanda, Liang Sun, Shira Rockowitz, David C. Christiani, Benjamin C. Warf, Maitreyi Mazumdar

Background

Human studies of genetic risk factors for neural tube defects, severe birth defects associated with long-term health consequences in surviving children, have predominantly been restricted to a subset of candidate genes in specific biological pathways including folate metabolism.

Methods

In this study, we investigated the association of genetic variants spanning the genome with risk of spina bifida (i.e., myelomeningocele and meningocele) in a subset of families enrolled from December 2016 through December 2022 in a case–control study in Bangladesh, a population often underrepresented in genetic studies. Saliva DNA samples were analyzed using the Illumina Global Screening Array. We performed genetic association analyses to compare allele frequencies between 112 case and 121 control children, 272 mothers, and 128 trios.

Results

In the transmission disequilibrium test analyses with trios only, we identified three novel exonic spina bifida risk loci, including rs140199800 (SULT1C2, p = 1.9 × 10⁻⁷), rs45580033 (ASB2, p = 4.2 × 10⁻¹⁰), and rs75426652 (LHPP, p = 7.2 × 10⁻¹⁴), after adjusting for multiple hypothesis testing. Association analyses comparing cases and controls, as well as models that included their mothers, did not identify genome-wide significant variants.

Conclusions

This study identified three novel single nucleotide polymorphisms involved in biological pathways not previously associated with neural tube defects. The study warrants replication in larger groups to validate findings and to inform targeted prevention strategies.

背景：神经管畸形是一种严重的先天缺陷，会对存活儿童的健康造成长期影响，人类对神经管畸形遗传风险因素的研究主要局限于特定生物通路（包括叶酸代谢）中的候选基因：在这项研究中，我们调查了从 2016 年 12 月到 2022 年 12 月在孟加拉国的一项病例对照研究中登记的家庭子集中横跨基因组的遗传变异与脊柱裂（即脊髓膜膨出和脑膜膨出）风险的相关性，孟加拉国的人口在遗传研究中通常代表性不足。唾液 DNA 样本使用 Illumina 全球筛查阵列进行分析。我们进行了遗传关联分析，比较了112名病例儿童和121名对照儿童、272名母亲和128名三人组之间的等位基因频率：结果：经过多重假设检验调整后，我们发现了三个新的外显子脊柱裂风险位点，包括 rs140199800（SULT1C2，p = 1.9 × 10-7）、rs45580033（ASB2，p = 4.2 × 10-10）和 rs75426652（LHPP，p = 7.2 × 10-14）。比较病例和对照的关联分析，以及包括其母亲的模型，均未发现全基因组范围内的显著变异：这项研究发现了三个新的单核苷酸多态性，这些单核苷酸多态性涉及以前与神经管缺陷无关的生物通路。这项研究需要在更大的群体中复制，以验证研究结果，并为有针对性的预防策略提供信息。

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引用次数: 0

Comments on “Maternal–fetal safety evaluation of an aqueous extract of Casearia sylvestris [AECS] leaves in rats” (Nagaoka et al., 2023 [DOI: 10.1002/bdr2.2257]) 关于 "Casearia sylvestris [AECS] 叶子水提取物对大鼠母胎安全性的评价"（Nagaoka 等人，2023 [DOI: 10.1002/bdr2.2257] ）的评论

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-23 DOI: 10.1002/bdr2.2326

L. David Wise, John M. DeSesso

引用次数: 0

Impact of perinatal exposure counseling on patient reported emotional outcomes and decisional empowerment 围产期暴露咨询对患者报告的情绪结果和决定权的影响

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-23 DOI: 10.1002/bdr2.2325

Réka Müller, Madison Lake, Nevena Krstić, Sarah G. Običan, Deborah Cragun

Background

Exposures during pregnancy are common and most pregnant patients utilize at least one medication during pregnancy. The lack of reliable information on medication safety during pregnancy available to providers and patients is a stressor and obstacle to decision-making about medication use in pregnancy. Previous studies showed that exposures in pregnancy are associated with guilt, worry, and decisional conflict. Although prior research has evaluated changes in patient knowledge after teratogen counseling, studies have not examined emotional outcomes or patients' decisional empowerment. This quasi-experimental study measured changes in patients' feelings of guilt, anxiety, and decisional empowerment after receiving exposure counseling from trained teratogen information specialists.

Methods

We administered pre- and post-counseling surveys to patients referred to a perinatal exposure clinic in Tampa, Florida. Validated scales were used to measure anxiety and guilt, and the ‘SURE’ measure was used to assess decisional empowerment. Paired samples t-tests evaluated changes in anxiety and guilt and a McNemar test assessed for changes in empowered decision making.

Results

Among the 34 participants who completed both surveys, anxiety, and guilt scores decreased significantly (p < .001). While only 21% felt informed and empowered to make a decision related to their exposure(s) before counseling, this increased to 85% (p < .001) on the post-survey.

Conclusion

Comprehensive counseling with a trained teratogen information specialist improves patient emotional outcomes as well as feelings of empowerment to make an informed decision regarding medication use in pregnancy. This study highlights that patient-centered teratogen counseling goes beyond simple changes in patient knowledge.

背景怀孕期间接触药物很常见，大多数孕妇在怀孕期间至少会使用一种药物。医疗服务提供者和患者缺乏有关孕期用药安全的可靠信息，这对孕期用药决策造成了压力和障碍。先前的研究表明，孕期暴露与内疚、担忧和决策冲突有关。虽然之前的研究已经评估了患者在接受畸形儿咨询后对相关知识的了解程度，但还没有研究对情感结果或患者的决策能力进行考察。这项准实验研究测量了患者在接受训练有素的畸形儿信息专家提供的暴露咨询后，内疚感、焦虑感和决策能力的变化。方法我们对转诊到佛罗里达州坦帕市一家围产期暴露诊所的患者进行了咨询前和咨询后调查。我们使用经过验证的量表来测量焦虑和内疚感，并使用 "SURE "量表来评估决策能力。配对样本 t 检验评估了焦虑和内疚感的变化，McNemar 检验评估了决策能力的变化。结果在完成这两项调查的 34 名参与者中，焦虑和内疚的得分都有显著下降（p < .001）。在接受咨询前，只有 21% 的人认为自己掌握了相关信息并有能力做出与所接触的疾病有关的决定，而在接受咨询后的调查中，这一比例上升到了 85% (p <.001)。结论由训练有素的畸形源信息专家提供全面的咨询，可改善患者的情绪结果，并增强其就孕期用药做出知情决定的能力。这项研究强调，以患者为中心的畸变咨询不仅仅是简单地改变患者的知识。

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引用次数: 0

Carbon monoxide affects early cardiac development in an avian model 一氧化碳影响鸟类模型的早期心脏发育

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-15 DOI: 10.1002/bdr2.2330

Filipa Rombo Matias, Ian Groves, Joshua Durrans, Mari Herigstad

Introduction

Carbon monoxide (CO) is a toxic gas that can be lethal in large doses and may also cause physiological damage in lower doses. Epidemiological studies suggest that CO in lower doses over time may impact on embryo development, in particular cardiac development, however other studies have not observed this association.

Methods

Here, we exposed chick embryos in ovo to CO at three different concentrations (3, 9, 18 ppm) plus air control (4 protocols in total) for the first 9 days of development, at which point we assessed egg and embryo weight, ankle length, developmental stage, heart weight, ventricular wall thickness, ventricular-septal thickness and atrial wall thickness.

Results

We found that heart weight was reduced for the low and moderate exposures compared to air, that atrial wall and ventricular wall thickness was increased for the moderate and high exposures compared to air and that ventricular septal thickness was increased for low, moderate and high exposures compared to air. Ventricular wall thickness was also significantly positively correlated with absolute CO exposures across all protocols.

Conclusions

This intervention study thus suggests that CO even at very low levels may have a significant impact on cardiac development.

导言：一氧化碳（CO）是一种有毒气体，大剂量时可致死，小剂量时也可能造成生理损害。流行病学研究表明，较低剂量的一氧化碳可能会影响胚胎发育，尤其是心脏发育，但其他研究并未观察到这种关联。方法：在此，我们将小鸡胚胎暴露于三种不同浓度（3、9、18 ppm）的一氧化碳以及空气对照（共 4 个方案）中，持续 9 天，评估卵和胚胎重量、脚踝长度、发育阶段、心脏重量、心室壁厚度、心室-室间隔厚度和心房壁厚度：结果：我们发现，与空气相比，低度和中度暴露的心脏重量减少；与空气相比，中度和高度暴露的心房壁和心室壁厚度增加；与空气相比，低度、中度和高度暴露的室间隔厚度增加。在所有方案中，心室壁厚度与一氧化碳绝对暴露量也呈显著正相关：因此，这项干预研究表明，即使是极低浓度的一氧化碳也会对心脏发育产生重大影响。

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引用次数: 0

Population-based surveillance for birth defects potentially related to Zika virus infection including 3-year mortality and developmental outcomes, and Early Intervention Program service use—New York City, 2016 birth cohort 对可能与寨卡病毒感染有关的出生缺陷进行基于人群的监测，包括 3 年死亡率和发育结果，以及早期干预计划服务的使用情况--纽约市，2016 年出生队列。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-13 DOI: 10.1002/bdr2.2320

Katharine H. McVeigh, Tenzin Tseyang, Mary-Elizabeth Vachon, Aurora Moraes

Background

In response to the 2015–2017 Zika virus outbreak, New York City (NYC) identified and monitored infants with birth defects potentially related to congenital Zika virus.

Methods

Administrative data matches were used to describe the birth characteristics of children born in 2016 meeting screening criteria for birth defects potentially related to congenital Zika virus infection relative to other NYC births and to monitor mortality and Early Intervention Program use through age 2.

Results

Among 120,367 children born in NYC in 2016, 463 met screening criteria and 155 met the Centers for Disease Control and Prevention's case definition for birth defects potentially related to congenital Zika virus infection (1.3 per 1000; 95% confidence interval [CI], 1.1–1.5). Post-neonatal deaths occurred among 7.7% of cases (12) and 5.2% of non-cases (8). Odds of referral to the Early intervention Program among children who met screening criteria were lower among children of mothers who were married (OR, 0.60; 95% CI, 0.37–0.97) and among children not classified as cases whose mothers were born in Latin America and the Caribbean (OR, 0.59; 95% CI, 0.37–1.09).

Discussion

Prevalence of birth defects potentially related to congenital Zika virus infection was similar to that seen in other jurisdictions without local transmission. Birth defects attributable to congenital Zika virus infection may also have been present among screened children who did not meet the case definition.

背景：为应对 2015-2017 年的寨卡病毒疫情，纽约市对可能与先天性寨卡病毒有关的出生缺陷婴儿进行了鉴定和监测：为应对 2015-2017 年的寨卡病毒疫情，纽约市（NYC）发现并监测了出生缺陷可能与先天性寨卡病毒有关的婴儿：方法：利用行政数据匹配来描述 2016 年出生的符合先天性寨卡病毒感染相关出生缺陷筛查标准的儿童与纽约市其他新生儿的出生特征，并监测死亡率和 2 岁前早期干预计划的使用情况：2016年在纽约市出生的120 367名儿童中，有463名符合筛查标准，155名符合美国疾病控制和预防中心对可能与先天性寨卡病毒感染有关的出生缺陷的病例定义（1.3‰；95%置信区间[CI]，1.1-1.5）。产后死亡病例占病例总数的 7.7%（12 例），占非病例总数的 5.2%（8 例）。在符合筛查标准的儿童中，母亲为已婚人士的儿童被转介到早期干预计划的几率较低（OR，0.60；95% CI，0.37-0.97），而母亲出生在拉丁美洲和加勒比海地区的未被归类为病例的儿童被转介到早期干预计划的几率较低（OR，0.59；95% CI，0.37-1.09）：讨论：可能与先天性寨卡病毒感染有关的出生缺陷发生率与其他未发生本地传播的地区相似。先天性寨卡病毒感染导致的出生缺陷也可能出现在不符合病例定义的筛查儿童中。

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引用次数: 0

Expanding the Massachusetts Birth Defects Monitoring Program to include additional pregnancy outcomes: Programmatic efforts and impacts on case ascertainment, 2012–2020 扩大马萨诸塞州出生缺陷监测计划，纳入更多妊娠结果：2012-2020 年计划工作及对病例确定的影响。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-13 DOI: 10.1002/bdr2.2323

Amy Fothergill, Rebecca F. Liberman, Eirini Nestoridi, Cara T. Mai, Lorraine F. Yeung, Cathleen Higgins, Mahsa M. Yazdy

Background

Birth defects affect 1 in 33 infants in the United States and are a leading cause of infant mortality. Birth defects surveillance is crucial for informing public health action. The Massachusetts Birth Defects Monitoring Program (MBDMP) began collecting other pregnancy losses (OPLs) in 2011, including miscarriages (<20 weeks gestation) or elective terminations (any gestational age), in addition to live births and stillbirths (≥20 weeks gestation). We describe programmatic changes for adding OPLs and their impact on prevalence estimates.

Methods

Using population-based, statewide, data from the MBDMP (2012–2020), we assessed prevalence per 10,000 live births and 95% confidence intervals (CIs) with and without OPLs overall and for specific birth defects by time period, maternal age, and race/ethnicity.

Results

Including OPLs required amending a state statute and promulgating regulations, new data sources, and additional data processing, cleaning, and verification. Overall prevalence with OPLs increased from 257.4 (95% CI: 253.5–261.4) to 333.9 (95% CI: 329.4–338.4) per 10,000; increases were observed in all time periods, age, and race/ethnicity groups. After including OPLs, the prevalence increased for neural tube defects [3.2 (2.7–3.6) to 8.3 (7.6–9.0)], and trisomies 13 [0.5 (0.3–0.7) to 4.1 (3.6–4.6)], 18 [1.5 (1.2–1.9) to 8.2 (7.5–8.9)], and 21 [12.3 (11.4–13.2) to 28.9 (27.6–30.2)]. Cardiovascular defects increased slightly, while prevalence of eye/ear, respiratory, and gastrointestinal defects remained similar.

Conclusions

Adding OPLs required substantial programmatic efforts and resulted in more complete case ascertainment, particularly for certain birth defects. More complete case ascertainment will allow for improved research, screening, and resource allocation.

背景：在美国，每 33 个婴儿中就有 1 个患有出生缺陷，这是婴儿死亡的主要原因之一。出生缺陷监测对于为公共卫生行动提供信息至关重要。马萨诸塞州出生缺陷监测计划（MBDMP）于 2011 年开始收集其他妊娠损失（OPL），包括流产（方法：通过马萨诸塞州出生缺陷监测计划（MBDMP）中的数据，对流产进行监测：利用马萨诸塞州出生缺陷监测计划（MBDMP）（2012-2020 年）中基于人口的全州数据，我们评估了每 10,000 例活产的患病率和 95% 的置信区间（CIs），包括有无 OPLs 的总体患病率，以及按时间段、孕产妇年龄和种族/民族划分的特定出生缺陷的患病率：将 OPL 纳入其中需要修改州法规和颁布条例、新的数据来源以及额外的数据处理、清理和验证。有 OPLs 的总体患病率从每 10,000 人中 257.4 例（95% CI：253.5-261.4 例）上升到 333.9 例（95% CI：329.4-338.4 例）；在所有时间段、年龄和种族/民族组中都观察到了患病率的上升。在包括 OPL 后，神经管畸形[3.2（2.7-3.6）升至 8.3（7.6-9.0）]、13[0.5（0.3-0.7）升至 4.1（3.6-4.6）]、18[1.5（1.2-1.9）升至 8.2（7.5-8.9）]和 21[12.3（11.4-13.2）升至 28.9（27.6-30.2）]的患病率均有所上升。心血管缺陷略有增加，而眼/耳、呼吸道和胃肠道缺陷的发病率保持相似：增加 OPLs 需要大量的计划工作，但却能更全面地确定病例，尤其是某些出生缺陷。更全面的病例确定将有助于改进研究、筛查和资源分配。

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引用次数: 0

Construction and analysis of a joint diagnostic model of machine learning for cryptorchidism based on single-cell sequencing 基于单细胞测序的隐睾症机器学习联合诊断模型的构建与分析

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-08 DOI: 10.1002/bdr2.2316

Yuehua Chen, Xiaomeng Zhou, Linghua Ji, Jun Zhao, Hua Xian, Yunzhao Xu, Ziheng Wang, Wenliang Ge

Background

Cryptorchidism is a condition in which one or both of a baby's testicles do not fully descend into the bottom of the scrotum. Newborns with cryptorchidism are at increased risk of developing infertility later in life. The aim of this study was to develop a novel diagnostic model for cryptorchidism and to identify new biomarkers associated with cryptorchidism.

Methods

The study data were obtained from RNA sequencing data of cryptorchid patients from Nantong University Hospital and the Gene Expression Omnibus (GEO) database. Differential expression analysis was used to obtain differentially expressed genes (DEGs) between the control and cryptorchid groups. These DEGs were analyzed for their functions by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment using GSEA software. Random Forest algorithm was used to screen central genes based on these DEGs. Neuralnet software package was used to develop artificial neural network models. Based on clinical data, receiver operating characteristic (ROC) was used to validate the models. Single-cell sequencing analysis was used for the pathogenesis of cryptorchidism.

Results

We obtained a total of 525 important DEGs related to cryptorchidism, which are mainly associated with biological functions such as supramolecular complexes and microtubule cytoskeleton. Random forest approach screening obtained eight hub genes. A neural network based on the hub genes showed a 100% success rate of the model. Finally, single-cell sequencing analysis validated the hub genes.

Conclusion

We developed a novel diagnostic model for cryptorchidism using artificial neural networks and validated its utility as an effective diagnostic tool.

背景介绍隐睾症是指婴儿的一个或两个睾丸没有完全下降到阴囊底部。患有隐睾症的新生儿日后患不育症的风险会增加。这项研究的目的是开发一种新型的隐睾症诊断模型，并确定与隐睾症相关的新生物标志物：研究数据来自南通大学附属医院隐睾患者的 RNA 测序数据和基因表达总库（GEO）数据库。差异表达分析用于获得对照组和隐睾组之间的差异表达基因（DEGs）。利用GSEA软件，通过基因本体（GO）和京都基因组百科全书（KEGG）富集分析这些DEGs的功能。使用随机森林算法根据这些 DEGs 筛选中心基因。使用 Neuralnet 软件包开发人工神经网络模型。根据临床数据，使用接收器操作特征（ROC）来验证模型。单细胞测序分析用于研究隐睾症的发病机制：结果：我们共获得了525个与隐睾症相关的重要DEGs，它们主要与超分子复合物和微管细胞骨架等生物功能有关。随机森林法筛选获得了 8 个枢纽基因。基于枢纽基因的神经网络显示该模型的成功率为100%。最后，单细胞测序分析验证了枢纽基因：我们利用人工神经网络开发了一种新型的隐睾症诊断模型，并验证了其作为有效诊断工具的实用性。

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引用次数: 0

Human split hand/foot variants are not as functional as wildtype human PRDM1 in the rescue of craniofacial defects 人类手足分裂变体在挽救颅面缺陷方面的功能不如野生型人类 PRDM1。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-03-08 DOI: 10.1002/bdr2.2327

Brittany T. Truong, Lomeli C. Shull, Bryan J. Zepeda, Ezra Lencer, Kristin B. Artinger

<div> <section> <h3> Background</h3> <p>Split hand/foot malformation (SHFM) is a congenital limb disorder presenting with limb anomalies, such as missing, hypoplastic, or fused digits, and often craniofacial defects, including a cleft lip/palate, microdontia, micrognathia, or maxillary hypoplasia. We previously identified three novel variants in the transcription factor, <i>PRDM1</i>, that are associated with SHFM phenotypes. One individual also presented with a high arch palate. Studies in vertebrates indicate that PRDM1 is important for development of the skull; however, prior to our study, human variants in <i>PRDM1</i> had not been associated with craniofacial anomalies.</p> </section> <section> <h3> Methods</h3> <p>Using transient mRNA overexpression assays in <i>prdm1a</i><sup><i>−/−</i></sup> mutant zebrafish, we tested whether the <i>PRDM1</i> SHFM variants were functional and could lead to a rescue of the craniofacial defects observed in <i>prdm1a</i><sup><i>−/−</i></sup> mutants. We also mined previously published CUT&RUN and RNA-seq datasets that sorted EGFP-positive cells from a <i>Tg</i>(<i>Mmu</i>:<i>Prx1-EGFP</i>) transgenic line that labels the pectoral fin, pharyngeal arches, and dorsal part of the head to examine Prdm1a binding and the effect of Prdm1a loss on craniofacial genes.</p> </section> <section> <h3> Results</h3> <p>The <i>prdm1a</i><sup><i>−/−</i></sup> mutants exhibit craniofacial defects including a hypoplastic neurocranium, a loss of posterior ceratobranchial arches, a shorter palatoquadrate, and an inverted ceratohyal. Injection of wildtype (WT) <i>hPRDM1</i> in <i>prdm1a</i><sup><i>−/−</i></sup> mutants partially rescues the palatoquadrate phenotype. However, injection of each of the three SHFM variants fails to rescue this skeletal defect. Loss of <i>prdm1a</i> leads to a decreased expression of important craniofacial genes by RNA-seq, including <i>emilin3a</i>, confirmed by hybridization chain reaction expression. Other genes including <i>dlx5a/dlx6a</i>, <i>hand2</i>, <i>sox9b</i>, <i>col2a1a</i>, and <i>hoxb</i> genes are also reduced. Validation by real-time quantitative PCR in the anterior half of zebrafish embryos failed to confirm the expression changes suggesting that the differences are enriched in <i>prx1</i> expressing cells.</p> </section> <section> <h3> Conclusion</h3> <p>These data suggest that the three SHFM variants are likely not functional and may be associated with the craniofacial defects observed in the humans. Finally, they demonstrate how Prdm1a can directly bind and regulate genes involv

背景：手足分裂畸形（SHFM）是一种先天性肢体疾病，表现为肢体异常，如缺失、发育不良或融合的手指，而且通常伴有颅面缺陷，包括唇裂/腭裂、小齿畸形、小颌畸形或上颌骨发育不良。我们之前发现了与 SHFM 表型相关的转录因子 PRDM1 的三个新型变体。其中一人还伴有高腭弓。对脊椎动物的研究表明，PRDM1 对头骨的发育非常重要；然而，在我们的研究之前，人类的 PRDM1 变异与颅面畸形并无关联：方法：通过在prdm1a-/-突变斑马鱼中进行瞬时 mRNA 过表达试验，我们检测了 PRDM1 SHFM 变体是否具有功能性，是否能挽救在prdm1a-/-突变体中观察到的颅面缺陷。我们还挖掘了之前发表的CUT&RUN和RNA-seq数据集，这些数据集从标记胸鳍、咽弓和头背的Tg(Mmu:Prx1-EGFP)转基因品系中分选了EGFP阳性细胞，以研究Prdm1a的结合以及Prdm1a缺失对颅面部基因的影响：结果：prdm1a-/-突变体表现出颅面缺陷，包括神经颅骨发育不良、后颅弓缺失、腭胛骨较短和颅骨倒置。在prdm1a-/-突变体中注射野生型（WT）hPRDM1可部分挽救腭咽表现型。然而，注射三种SHFM变体中的每一种都不能挽救这种骨骼缺陷。通过RNA-seq分析，prdm1a的缺失导致重要的颅面基因（包括emilin3a）表达减少，杂交链反应表达证实了这一点。其他基因，包括 dlx5a/dlx6a、hand2、sox9b、col2a1a 和 hoxb 基因的表达也有所减少。在斑马鱼胚胎前半部分进行的实时定量 PCR 验证未能证实这些表达变化，这表明这些差异主要集中在表达 prx1 的细胞中：这些数据表明，这三种 SHFM 变体可能不具有功能性，而且可能与在人类身上观察到的颅面缺陷有关。最后，它们证明了 Prdm1a 如何直接结合并调控参与颅面发育的基因。

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引用次数: 0