Colorado APS Clinical Center

科罗拉多有着悠久的异质性相关ARDS、肺炎和脓毒症（APS）的历史 research.在《柳叶刀》首次描述急性呼吸窘迫综合征（ARDS）后，科罗拉多 研究人员随后确定肺炎和败血症为与增加的 易患ARDS。从那时起，科罗拉多的调查人员（包括许多关键人员对这一点 提案）报道了关于ARDS、肺炎和败血症异质性的开创性发现 包括确定a）酒精使用障碍（AUD）作为增加的第一共病病症， 对ARDS的易感性，B）AUDs对脓毒症死亡率的有害影响，c）以及性别、种族和民族 ARDS和脓毒症流行病学的差异。与此同时，科罗拉多的调查人员一直在解开 APS的基本机制集中在宿主炎症反应的异质性上。作为较高 部分患者开始存活APS，我们扩大了我们的研究，以检查生存率，重点是 神经肌肉功能障碍这些研究已经导致了诊断弱点的增强方法， 提高我们对APS幸存者恢复的神经肌肉轨迹的理解。我们建议 开展两个临床中心特定的科学项目，展示我们研究的广度和深度， 涵盖急性APS严重程度及其在幸存者中的恢复轨迹。急性项目将确定不同的 急性呼吸衰竭APS参与者肺和血液中存在的单核细胞内型 使用批量RNA测序。该恢复项目将确定是否神经肌肉内型，主要基于 单个时间点的神经传导研究可以识别不同的和临床相关的恢复轨迹。 我们还将探讨AUDs如何影响APS异质性的交叉主题。建立在强大的 和持久的研究基础，我们有研究基础设施，以实现所有概述的目标， 准备成为国家APS联盟的有力贡献者。作为一个原始的和不可分割的成员， ARDS和PETAL网络（连续28年），我们的多学科和协作 研究小组在进行高质量的NIH资助的前瞻性队列研究方面经验丰富。2021年 科罗拉多研究小组招募了554名APS参与者参加临床和转化研究。这 数量远远超过APS联盟每年240名APS患者的要求。我们也有广泛的 专门知识 学术 农村 招募历史上代表性不足的社区（拉丁裔，黑人和土著）， 和社区医院。对于这个建议，我们还将从经常被忽视的参与者中招募 社区，确保他们在APS联盟的代表。总之，科罗拉多APS中心 计划超出我们的入组义务;保持方案合规性、数据 收购和监管职责;积极为指导委员会和其他APS做出贡献 委员会;最重要的是推进科学，并有助于改善APS患者的护理。

Colorado has a long and storied history of heterogeneity-related ARDS, pneumonia, and sepsis (APS) research. After the initial Lancet description of the acute respiratory distress syndrome (ARDS), Colorado investigators subsequently identified pneumonia and sepsis as diagnoses associated with an increased susceptibility for ARDS. Since that time, Colorado investigators (including many key personnel on this proposal) have reported seminal discoveries regarding heterogeneity of ARDS, pneumonia, and sepsis including identification of a) alcohol use disorders (AUDs) as the first co-morbid conditions that increase susceptibility to ARDS, b) AUDs deleterious impact on sepsis mortality, c) and sex, racial, and ethnic differences in ARDS and sepsis epidemiology. Simultaneously, Colorado investigators have been unraveling the basic mechanisms of APS focusing on heterogeneity in the host inflammatory response. As a higher proportion of patients began to survive APS, we expanded our research to examine survivorship focusing on neuromuscular dysfunction. These studies have resulted in enhanced ways to diagnose weakness and improve our understanding of the neuromuscular trajectory of recovery in APS survivors. We propose to conduct two clinical center-specific scientific projects demonstrating the breadth and depth of our research that spans acute APS severity and its recovery trajectory in survivors. The acute project will identify distinct mononuclear cell endotypes present in the lungs and blood of APS participants with acute respiratory failure using bulk RNA seq. The recovery project will establish whether neuromuscular endotypes, based primarily on a single time-point nerve conduction study, can identify distinct and clinically relevant trajectories of recovery. We will also explore the cross-cutting theme of how AUDs impact APS heterogeneity. Building upon a strong and persistent research foundation, we have the research infrastructure to achieve all the outlined goals and are poised to be a strong contributor to the national APS consortium. As an original and integral member of the ARDS and then PETAL Network (for over 28 consecutive years), our multi-disciplinary and collaborative research group is experienced in conducting high quality NIH-funded prospective cohort research. In 2021, the Colorado research group enrolled 554 APS participants into clinical and translational research studies. This number far exceeds the APS consortium requirement of 240 APS patients per year. We also have extensive expertise academic rural recruiting historically underrepresented communities (Latinx, Black, and Indigenous) from both and community hospitals. For this proposal, we will also enroll participants from the often overlooked community, ensuring their representation in the APS consortium.In summary, the Colorado APS Center plans to exceed our enrollment obligations; maintain excellence in the quality of protocol compliance, data acquisition, and regulatory responsibilities; actively contribute to the steering committee and other APS committees; and most importantly advance science and contribute to improving the care of APS patients.