Biobehavioral mechanisms underlying symptoms and healing outcomes in older individuals with CVLU

摘要 我们的长期目标是阐明导致症状和疾病的复杂生物行为机制 对患有静脉性小腿溃疡(VLU)的老年人的愈合结果进行靶向治疗 在这一日益增长的受影响个体群体中，解决以患者为中心的结果和治愈结果。 VLU占小腿溃疡的70%-90%，每年影响200万人，包括 近4%的65岁以上的人。到目前为止，基础生物学的发展和持久性 VLU以及老化和多种疾病条件对伤口愈合的影响通常不是很好 明白了。患有慢性VLU(CVLU)的人有很高的症状负担，这与创伤相关 疼痛、抑郁、焦虑、疲劳和认知功能障碍的症状和症状，统称为 “精神神经症状(PNS)。”美国国立卫生研究院指导的症状科学模型 (NIH-SSM)框架，这一应用的中心假设是存在相互关联的分子 促进CVLU发生和持续的免疫激活机制 也导致了PNS的发展、持久性和严重性。拟议研究的具体目标是 为了：(1)在基线上表征患者-宿主因素、系统性因素之间的关联强度 炎症、伤口微环境、伤口面积和症状(PNS和伤口相关)； (2)随时间推移测试相关性和模型：(A)患者-宿主因素和伤口全身炎症 微环境；(B)患者-宿主因素和伤口微环境与全身炎症；(C) 患者-宿主因素、全身炎症和伤口微环境与伤口愈合；(D)患者-宿主 有症状的因素、全身炎症和伤口微环境(PNS和伤口相关)和(E) 患者-宿主因素、全身炎症、伤口微环境和有症状的伤口愈合(PNS 和创伤相关)。为了实现具体目标，我们将纵向检查200名老年人(年龄&>60岁)。 他们正在接受最先进的标准化伤口治疗，每两周一次，持续八周。我们会 全面描述患者-宿主特征(年龄、合并症、性别、种族/民族、体重指数、营养状况、 生活习惯和伤口治疗(压力疗法、清创、抗生素)；全身炎症 激活(C-反应蛋白和细胞因子)；伤口微环境因素(局部炎症[基质 金属蛋白酶(MMPs)、C反应蛋白、细胞因子、生物膜和微型RNA)；症状(PNS [认知功能障碍、疼痛、疲劳和抑郁/焦虑症状]和与创伤有关)；以及创伤 五个时间点的特征和愈合轨迹。这些知识是提供基础的关键 制定有针对性的干预措施，从整体角度解决这一关键的健康问题，并 为预防或扭转CVLU的不良健康后果提供基础，这种情况 对老年人和少数族裔有不同的影响。

ABSTRACT Our long-term goal is to elucidate the complex biobehavioral mechanisms responsible for symptoms and healing outcomes for older adults’ with venous leg ulcers (VLUs) for the development of targeted therapies that address both the patient-oriented outcomes and healing outcomes in this growing group of affected individuals. VLUs, which account for 70–90% of ulcers found in the lower leg, affect 2 million persons annually, including nearly 4% of people over age 65 years. To date, the basic biology underlying the development and persistence of VLUs and the influence of aging and multiple disease conditions on wound healing are generally not well understood. Individuals living with chronic VLU (CVLU) have a high symptom burden of both wound-related symptoms and symptoms of pain, depression, anxiety, fatigue and cognitive dysfunction, collectively labeled as “psychoneurologic symptoms (PNS).” Guided by the National Institutes of Health Symptom Science Model (NIH-SSM) framework, the central hypothesis of this application is that there are interrelated molecular mechanisms by which the immune activation that contributes to the development and persistence of CVLU also leads to the development, persistence and severity of PNS. The specific aims of the proposed study are to: (1) Characterize the strength of the associations at baseline among patient-host factors, systemic inflammation, and wound microenvironment with wound area and symptoms (PNS and wound-related); and, (2) Test associations and models over time for: (a) Patient-host factors and systemic inflammation with wound microenvironment; (b) Patient-host factors and wound microenvironment with systemic inflammation; (c) Patient-host factors, systemic inflammation, and wound microenvironment with wound healing; (d) Patient-host factors, systemic inflammation, and wound microenvironment with symptoms (PNS and wound-related) and (e) Patient-host factors, systemic inflammation, wound microenvironment and wound healing with symptoms (PNS and wound-related). To achieve the specific aims, we will longitudinally examine 200 older adults (age >60) who are receiving state of the art, standardized wound treatment biweekly across eight weeks time. We will fully characterize patient-host characteristics (age, comorbidities, sex, race/ethnicity, BMI, nutritional status, lifestyle habits, and wound treatment [pressure therapy, debridement, antibiotics]); systemic inflammatory activation (C-reactive protein and cytokines); wound microenvironment factors (local inflammation [Matrix metalloproteinase (MMP) enzymes C-reactive protein, cytokines], biofilm, and micro RNAs); symptoms (PNS [cognitive dysfunction, pain, fatigue, and depressive/anxiety symptoms] and wound-related); and wound characteristics and healing trajectory at the five timepoints. This knowledge is critical to provide a foundation for developing targeted interventions to address this critical health problem from a holistic perspective and to provide a basis for preventing or reversing the adverse health outcomes of CVLUs, a condition that differentially affects older and minority individuals.