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.

脓毒症对早产儿（早产儿）的影响最大。新生儿败血症（新生儿败血症） 出生后第一个月）每年在全世界造成100多万人死亡，是最常见、最困难的疾病之一。 诊断、治疗和预防的成本高昂的问题。早产儿的败血症发病率可高达1000倍 高于足月婴儿，并承担了相关的死亡率和终身败血症幸存者的冲击 发病率在潜在感染的新生儿的管理中仍然存在大量的临床问题 答：（1）婴儿是否被感染？2)哪些婴儿最有可能出现复杂的临床病程 感染？3）为什么早产儿（特别是极低出生体重的婴儿）有如此高的风险， 发展成感染吗对早产儿的研究很少，这在很大程度上归因于 用于研究的血容量有限（典型的28周、1000克婴儿的总血容量为80-100毫升），以及 先前的假设是新生儿宿主免疫应答与在年龄较大的儿童和成人中观察到的相似。 我们认为，新生儿中性粒细胞（PMN）先天免疫功能的缺陷是一个潜在的 这种减少的原因，在宿主保护性免疫，和他们的功能可以用来预测发展， 败血症和延长的临床病程。我们打算提供准确的方法来诊断脓毒症， 预后和危重病分层标志物，并揭示免疫学差异， 可能改善新生儿感染相关结局的转化干预措施，所有这些都基于一种新的 微流体平台具体来说，我们提议对300名早产儿（<30周）进行一项前瞻性、观察性研究 胎龄）和60名足月（>36周）婴儿，我们将在这些婴儿中确定PMN的特定缺陷。 功能，开发脓毒症的预测模型，并最终，基于微流体的临床结果， PMN功能和转录组学的测量，以及经典的临床测量。该项目是由 几种新颖的、经过验证的微流体技术，这些技术强大且易于使用，几乎不需要培训。这些 技术提供了血液PMN群体功能的全面措施;关键的细胞 先天免疫的组成部分。我们还将从微流控分选的中性粒细胞中提取高质量的核酸， 转录组学分析，并提供全血细胞计数与5部分分类结合临床 化学和炎症生物标志物。总的来说，这些技术需要总共约100微升（μ L）的 血液，这使得它们特别适用于样本量有限的早产儿， 系列评估对中性粒细胞的关键功能具有前所未有的时间分辨率。这些研究，综合 与生物信息学方法，将产生新的工具，诊断败血症的新生儿和预测 临床结果。这种方法有能力大大改变临床管理的 早产儿，并可能改善长期结果，同时降低住院费用。

项目成果

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.

在极早，极低的出生体重婴儿中，最大的血管活性 - 触发性评分和死亡率。

• 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

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

对早产儿的新生儿顺序器官衰竭评估和死亡感染的死亡风险的评估。

• 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

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