Microfluidic Assessment of Clinical Outcomes in Preterm Newborns

早产儿临床结果的微流控评估

• 批准号: 10164831
• 负责人: Daniel Irimia
• 金额: $ 63.58万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-09 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164831
• 关键词: Acute-Phase Proteins; Address; Adult; Attention; Bioinformatics; Biological Assay; Biological Markers; Biomedical Engineering; Blood; Blood Tests; Blood Volume; Blood specimen; C-reactive protein; Cessation of life; Chemistry; Child; Clinic; Clinical; Clinical Chemistry; Clinical Management; Complement; Complete Blood Count; Coupled; Critical Illness; Defect; Development; Diagnosis; Diagnostic; Diagnostics Research; Electrolytes; Elements; Failure; Frequencies; Gene Expression; Gestational Age; Glucose; Goals; Hospital Costs; Hospitalization; Immune; Immune response; Immune system; Immunity; Immunologics; Immunotherapy; Infant; Infection; Inflammatory; Innate Immune Response; Intervention; Investigation; Knowledge; Lab-On-A-Chips; Laboratory Study; Leukocytes; Life; Measurement; Measures; Methods; Microfluidic Microchips; Microfluidics; Monitor; Morbidity - disease rate; NIH Program Announcements; Natural Immunity; Neonatal; Neonatal Mortality; Newborn Infant; Nucleic Acids; Observational Study; Older Population; Organ failure; Outcome; Patients; Phenotype; Population; Postpartum Period; Predictive Value; Pregnancy; Premature Birth; Premature Infant; Renal function; Resolution; Risk; Sampling; Sepsis; Septicemia; Serum; Signal Pathway; Speed; Stratification; Survivors; Systemic infection; Techniques; Technology; Testing; Time; Training; Very Low Birth Weight Infant; White Blood Cell Count procedure; antimicrobial drug; base; biomedical scientist; clinical diagnostics; clinical outcome assessment; cost; design; high risk; immune function; improved; infant infection; innate immune function; innovation; microfluidic technology; migration; milliliter; mortality; mortality risk; neonatal infection; neonatal sepsis; neonate; neutrophil; novel; novel strategies; patient stratification; peripheral blood; point of care; predict clinical outcome; predictive modeling; premature; preterm newborn; prevent; prognostic; prospective; receptor; septic; sex; temporal measurement; tool; transcriptome; transcriptomics

Sepsis has its greatest impact in the prematurely born (preterm) population. Neonatal sepsis (sepsis within the first month of life) causes over one million deaths worldwide annually, and is one of the most common, difficult and costly problems to diagnose, treat and prevent. The preterm infant can suffer rates of sepsis up to 1000-fold higher than the full-term infant, and bears the brunt of the associated mortality and lifelong sepsis-survivor morbidity. Substantial clinical questions in the management of the potentially infected neonate remain unanswered: 1) Is the infant infected?, 2) Which infants have the greatest risk for a complicated clinical course with infection?, and 3) Why are preterm infants (especially very low birth weight infants) at such high risk of developing infections? The paucity of investigations in the preterm infant can be attributed in large part to very limited blood volume for study (80-100 milliliter total blood volume in a typical 28 week, 1000 gram infant), and prior assumptions that the neonatal host immune response is similar to that seen in older children and adults. We propose that deficiencies in innate immune function of neutrophils (PMN) in neonates are one underlying cause of this decrease in host protective immunity, and their function can be used to predict the development of sepsis and protracted clinical course. We intend to deliver accurate methods to diagnose sepsis, identify prognostic and critical illness stratification markers, and uncover immunological differences with the potential for translational interventions that may improve neonatal infection-related outcomes, all based on a novel microfluidics platform. Specifically, we propose a prospective, observational study of 300 preterm (<30 weeks gestational age) and 60 full-term (>36 weeks) infants in whom we will identify specific deficiencies in PMN function, develop prediction models for sepsis, and ultimately, clinical outcome, based on microfluidics measurements of PMN function and transcriptomics, and classical clinical measures. The project is enabled by several novel, validated, microfluidic technologies that are robust and easy to use with little training. These technologies provide comprehensive measures of the functionality of blood PMN population; a critical cellular component of innate immunity. We will also extract high-quality nucleic acids from microfluidic-sorted PMNs for transcriptomic analyses, and deliver a complete blood count with 5-part differential integrated with clinical chemistry and inflammatory biomarkers. Collectively, these techniques require a total of ~100 microliters (L) of blood, which makes them particularly useful for preterm infants where sample volume is limited, and facilitates serial assessments with unprecedented temporal resolution of key functions of PMNs. These studies, integrated with bioinformatics approaches, will generate new tools for diagnosing sepsis in the newborn and predicting clinical outcomes. Such approaches have the capability to dramatically change the clinical management of the preterm infant, and potentially improve long-term outcomes while reducing hospital costs.

败血症对早产（早产）的影响最大。新生儿败血症（败血症 生命的第一个月）每年在全球造成超过100万人死亡，是最常见，困难的死亡之一 诊断，治疗和预防的昂贵问题。早产婴儿可能会遭受败血症的比例高达1000倍 高于完整的婴儿，并首先是相关的死亡率和终生败血症的生存者 发病率。潜在感染的新生儿的管理中的实质性临床问题仍然存在 未解决：1）婴儿感染了吗？，2）哪些婴儿的临床病程最大 感染？和3）为什么早产儿（尤其是非常低的出生体重婴儿）如此高的风险 发展感染？在早产婴儿中的投资很少，这在很大程度上归因于非常归因于 研究有限的研究（80-100毫升典型的28周的总血量，1000克婴儿）和 先前的假设是新生儿宿主免疫反应与大儿童和成人相似。 我们认为，新生儿中嗜中性粒细胞（PMN）的先天免疫功能的缺陷是一个基础 宿主受保护免疫力下降的原因，它们的功能可用于预测 败血症和旷日持久的临床过程。我们打算提供准确的方法来诊断败血症，识别 预后和重大疾病分层标志物，并发现免疫学差异 可以改善新生儿感染相关结果的翻译干预措施，这都是基于新颖的 微流体平台。具体而言，我们提出了一项前瞻性的观察性研究（<30周） 胎龄）和60个完整期（> 36周）的婴儿，我们将在其中确定PMN的特定缺陷 败血症的功能，开发预测模型以及最终基于微流体的临床结果 PMN功能和转录组学以及经典临床测量的测量。该项目由 几种新颖的，经过验证的微流体技术，它们易于训练，易于使用。这些 技术提供了血液PMN人群功能的全面测量；关键细胞 先天免疫的组成部分。我们还将从微流体分类的PMN中提取高质量的核酸 转录组分析，并通过与临床的5部分差异进行完整的血数 化学和炎症生物标志物。总的来说，这些技术总共需要约100微升（L） 血液，这使得它们对于样本体积有限并促进的早产儿特别有用 序列评估，以空前的PMN关键功能的暂时分辨率。这些研究，整合 通过生物信息学方法，将生成新生儿诊断败血症的新工具，并预测 临床结果。这种方法有能力大幅度改变 早产婴儿，并有可能改善长期结局，同时降低医院成本。

项目成果

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants With Late-Onset Infection.

• DOI: 10.1001/jamanetworkopen.2020.36518
• 发表时间: 2021-02-01
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Fleiss N;Coggins SA;Lewis AN;Zeigler A;Cooksey KE;Walker LA;Husain AN;de Jong BS;Wallman-Stokes A;Alrifai MW;Visser DH;Good M;Sullivan B;Polin RA;Martin CR;Wynn JL
• 通讯作者: Wynn JL

Absence of relationship between serum cortisol and critical illness in premature infants.

• DOI: 10.1136/archdischild-2020-319970
• 发表时间: 2021-07
• 期刊: Archives of disease in childhood. Fetal and neonatal edition
• 作者: Prelipcean I;Wynn JL;Thompson L;Burchfield DJ;James-Woodley L;Chase PB;Barnes CP;Bernier A
• 通讯作者: Bernier A

Maximum vasoactive-inotropic score and mortality in extremely premature, extremely low birth weight infants.

• DOI: 10.1038/s41372-021-01030-9
• 发表时间: 2021-09
• 期刊: Journal of perinatology : official journal of the California Perinatal Association
• 作者: Aziz KB;Lavilla OC;Wynn JL;Lure AC;Gipson D;de la Cruz D
• 通讯作者: de la Cruz D

Multicenter Validation of the Neonatal Sequential Organ Failure Assessment Score for Prognosis in the Neonatal Intensive Care Unit.

• DOI: 10.1016/j.jpeds.2021.05.037
• 发表时间: 2021-09
• 期刊: JOURNAL OF PEDIATRICS
• 影响因子: 5.1
• 作者: Wynn, James L.;Mayampurath, Anoop;Carey, Kyle;Slattery, Susan;Andrews, Bree;Sanchez-Pinto, L. Nelson
• 通讯作者: Sanchez-Pinto, L. Nelson

Contribution of Concurrent Comorbidities to Sepsis-Related Mortality in Preterm Infants ≤32 Weeks of Gestation at an Academic Neonatal Intensive Care Network.

• DOI: 10.1055/a-1675-2899
• 发表时间: 2024-01
• 期刊: American journal of perinatology
• 影响因子: 2