Developing a molecular tool to stratify the acute joint presentation: facilitating early diagnosis of septic arthritis.

关键词：脓毒症，生物标记物，关节炎，诊断摘要：非创伤性急性关节肿胀，跛行的儿童或因疼痛而不愿负重/移动关节的儿童是急诊科常见的表现。关键的诊断区别是感染性关节炎和非感染性原因的炎症，如痛风和一过性滑膜炎。然而，区分感染性和非感染性关节炎是一项诊断挑战，因为临床体征和症状可能很微妙，两组之间有相当大的重叠，筛查实验室/影像检查和滑液/血液培养相对不敏感。以前的工作已经证明，细菌及其毒素对骨和软骨等关节组织具有高度破坏性，因此延误诊断和开始治疗，通常需要静脉注射抗生素和关节冲洗相结合，可能会产生严重的临床后果。然而，化脓性关节炎只占急性关节表现的一小部分，然而几乎所有这类患者都入院，接受潜在的侵入性手术，并普遍接受抗感染治疗，在扩大抗生素耐药性、过度使用和费用的背景下，他们都有随之而来的风险。因此，对急性关节表现进行快速、准确的临床分层是非常可取的。这可以通过鉴定感染性关节炎特有的新的血液、滑液和尿液生物标志物来实现。此外，对于那些经微生物确诊的化脓性关节炎患者，对分离细菌的基因组测序可能会识别与结构或系统预后不良相关的独特分子特征，这些特征最终可能被利用来开发新的抗菌治疗方法，以改善此类患者的临床结果。因此，这项研究建议利用已建立的代谢组、蛋白质组和转录组技术以及先进的生物信息学方法来分析疑似化脓性关节炎患者的血液、滑液和尿样。这项研究招募的患者的样本将在常规调查和治疗(关节抽吸/手术冲洗)中收集，因此不会有患者仅为研究目的而接受侵入性程序。将对从常规滑液和血液培养中分离出的所有细菌进行基因组测序。此外，学生还将提供细胞培养和体外感染模型开发方面的实践培训，以提高培训的技能和广度。

Keywords: Sepsis, biomarker, arthritis, diagnosisAbstract:Atraumatic acute joint swelling, a limping child or a child unwilling to weight-bear/move a joint due to pain are common presentations to the Emergency Department. The key diagnostic differential is between septic arthritis, which is defined as inflammation of a joint secondary to bacterial infection, and non-infectious causes of inflammation e.g. gout and transient synovitis. However, distinguishing between infectious and non-infectious arthritis represents a diagnostic challenge as clinical signs and symptoms may be subtle with considerable overlap between the two groups and screening laboratory/imaging studies and synovial fluid/blood cultures are relatively insensitive. Previous work has demonstrated that bacteria and their toxins are highly destructive to joint tissues such as bone and cartilage and therefore a delay in diagnosis and initiation of treatment, which typically involves a combination of intravenous antibiotics coupled with joint irrigation, may have severe clinical consequences. Septic arthritis however comprises only a minority of acute joint presentations, yet almost all such patients are admitted to hospital, undergo potentially invasive procedures and universally receive anti-infective therapeutics, with their attendant risks in the context of expanding antibiotic resistance, overuse and expense. The rapid and accurate clinical stratification of the acute joint presentation would thus be extremely desirable. This may be achieved through the identification of novel blood, synovial fluid and urinary biomarkers unique to infectious arthritis. In addition, for those patients with microbiologically confirmed septic arthritis, genome sequencing of isolated bacteria may identify unique molecular signatures associated with poor structural or systemic prognosis, which could be utilised ultimately to develop novel antimicrobial treatments to improve clinical outcome in such patients. This studentship therefore proposes to analyse blood, synovial fluid and urine samples of patients presenting with suspected septic arthritis utilising established metabolomic, proteomic and transcriptomic techniques coupled with advanced bioinformatic approaches for dataset analysis. Samples from patients recruited to this study will be collected during routine investigations and treatments (joint aspiration/surgical washout) and thus no patients will undergo invasive procedures solely for the purpose of the study. Genome sequencing will be conducted on all bacteria isolated from routine synovial fluid and blood cultures. In addition the studentship will provide hands on training in cell culture and ex vivo infection model development to enhance the skill set and breadth of training on offer.