Microfluidic Assessment of Clinical Outcomes in Preterm Newborns

早产儿临床结果的微流控评估

基本信息

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
项目类别：
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

项目摘要

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.

新生儿败血症（新生儿败血症）生命第一个月）每年在全世界造成超过一百万人死亡，是最常见、最困难的疾病之一诊断、治疗和预防的费用高昂，早产儿患败血症的几率高达 1000 倍。高于足月婴儿，并首当其冲地受到相关死亡率和终身脓毒症幸存者的影响潜在感染新生儿的治疗仍存在重大临床问题。未回答：1）婴儿是否被感染？，2）哪些婴儿出现复杂临床病程的风险最大以及 3) 为什么早产儿（特别是出生体重极低的婴儿）感染的风险如此之高缺乏对早产儿的研究很大程度上可归因于非常严重的问题。用于研究的有限血量（典型 28 周、1000 克婴儿的总血量为 80-100 毫升），以及先前的假设是，新生儿宿主的免疫反应与年龄较大的儿童和成人的免疫反应相似。我们认为新生儿中性粒细胞（PMN）先天免疫功能的缺陷是潜在的原因之一。宿主保护性免疫力下降的原因，其功能可用于预测我们打算提供准确的方法来诊断、识别脓毒症。预后和危重疾病分层标志物，并揭示免疫学差异与潜在的可能改善新生儿感染相关结局的转化干预措施，全部基于一种新的具体来说，我们提出了一项针对 300 名早产儿（<30 周）的前瞻性观察性研究。孕龄）和 60 名足月（>36 周）婴儿，我们将在其中识别 PMN 的具体缺陷功能，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通过以下方式实现的。几种新颖的、经过验证的微流体技术，功能强大且易于使用，只需很少的培训。技术提供了血液中 PMN 群体功能的全面测量；我们还将从微流控分选的 PMN 中提取高质量的核酸。转录组分析，并提供与临床相结合的五部分差异全血细胞计数总的来说，这些技术总共需要约 100 微升 (μL) 的液体。血液，这使得它们对于样本量有限的早产儿特别有用，并且有助于对 PMN 关键功能进行了前所未有的时间分辨率的连续评估，整合了这些研究。通过生物信息学方法，将产生用于诊断新生儿败血症和预测的新工具此类方法能够显着改变临床管理。早产儿，并可能改善长期结果，同时降低医院费用。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
影响因子：
0
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.