Chief Scientist Office of the Scottish Government.

SummaryBackgroundParacetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation.MethodsUsing data from two prospective cohort studies, we assessed the potential for biomarkers to stratify patients who overdose with paracetamol. We completed two independent prospective studies: a derivation study (MAPP) in eight UK hospitals and a validation study (BIOPAR) in ten UK hospitals. Patients in both cohorts were adults (≥18 years in England, ≥16 years in Scotland), were diagnosed with paracetamol overdose, and gave written informed consent. Patients who needed intravenous acetylcysteine treatment for paracetamol overdose had circulating biomarkers measured at hospital presentation. The primary endpoint was acute liver injury indicating need for continued acetylcysteine treatment beyond the standard course (alanine aminotransferase [ALT] activity >100 U/L). Receiver operating characteristic (ROC) curves, category-free net reclassification index (cfNRI), and integrated discrimination index (IDI) were applied to assess endpoint prediction.FindingsBetween June 2, 2010, and May 29, 2014, 1187 patients who required acetylcysteine treatment for paracetamol overdose were recruited (985 in the MAPP cohort; 202 in the BIOPAR cohort). In the derivation and validation cohorts, acute liver injury was predicted at hospital presentation by miR-122 (derivation cohort ROC–area under the curve [AUC] 0·97 [95% CI 0·95–0·98]), HMGB1 (0·95 [0·93–0·98]), and full-length K18 (0·95 [0·92–0·97]). Results were similar in the validation cohort (miR-122 AUC 0·97 [95% CI 0·95–0·99], HMGB1 0·98 [0·96–0·99], and full-length K18 0·93 [0·86–0·99]). A combined model of miR-122, HMGB1, and K18 predicted acute liver injury better than ALT alone (cfNRI 1·95 [95% CI 1·87–2·03], p<0·0001 in the MAPP cohort; 1·54 [1·08–2·00], p<0·0001 in the BIOPAR cohort).InterpretationPersonalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification. This prospective study supports their use for hepatic safety assessment of new medicines.FundingEdinburgh and Lothians Health Foundation, UK Medical Research Council.

ObjectivesTo synthesise the published literature on the patient experience of the medical primary–secondary care interface and to determine priorities for future work in this field aimed at improving clinical outcomes.DesignSystematic review and metaethnographic synthesis of primary studies that used qualitative methods to explore patients’ perspectives of the medical primary–secondary care interface.SettingInternational primary–secondary care interface.Data sourcesEMBASE, MEDLINE, CINAHL Plus with Full text, PsycINFO, Psychology and Behavioural Sciences Collection, Health Business Elite, Biomedica Reference Collection: Comprehensive Library, Information Science & Technology Abstracts, eBook Collection, Web of Science Core Collection: Citation Indexes and Social Sciences Citation Index, and grey literature.Eligibility criteria for selecting studiesStudies were eligible for inclusion if they were full research papers employing qualitative methodology to explore patients’ perspectives of the medical primary–secondary care interface.Review methodsThe 7-step metaethnographic approach described by Noblit and Hare, which involves cross-interpretation between studies while preserving the context of the primary data.ResultsThe search identified 690 articles, of which 39 were selected for full-text review. 20 articles were included in the systematic review that encompassed a total of 689 patients from 10 countries. 4 important areas specific to the primary–secondary care interface from the patients’ perspective emerged: barriers to care, communication, coordination, and ‘relationships and personal value’.Conclusions and implications of key findingsPatients should be the focus of any transfer of care between primary and secondary systems. From their perspective, areas for improvement may be classified into four domains that should usefully guide future work aimed at improving quality at this important interface.Trial registration numberPROSPERO CRD42014009486.

Toddler's fracture (TF) occurs in young children after minor trauma. Clinical diagnosis can be challenging and initial radiological evidence may be lacking. The aim of this study was to compare the management and outcomes of clinically diagnosed TF patients with and without initial radiological evidence. A retrospective cohort study of patients aged between 9 and 36 months treated for TF in a Scottish Paediatric Emergency Department was conducted. Patients with a radiologically confirmed TF were more likely to be placed in a cast than those with a presumptive clinical TF diagnosis (92 vs. 47%; P<0.02). Overall cast duration and duration from follow-up to discharge from clinic were similar in both groups. There were no complications with management in or out of cast. The initial presumptive clinical diagnosis of TF may be as significant as that with radiological confirmation. Follow-up imaging is unlikely to affect management if the diagnosis remains clinically clear.

Background Severe COVID‐19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID‐19 disease arise due to dysregulation of the fibrinolytic system. Methods This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID‐19 disease with 24 patients with non‐COVID‐19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor‐1 (PAI‐1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. Results PAI‐1 and its cofactor, vitronectin, are significantly elevated in patients with COVID‐19 disease compared with those with non‐COVID‐19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID‐19 disease relative to healthy controls. PAI‐1 and tissue plasminogen activator (tPA) were associated with more severe COVID‐19 disease severity. Clots formed from COVID‐19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID‐19 disease, while PAI‐1 activity was elevated. Clot lysis time significantly correlated with PAI‐1 levels. Stratification of COVID‐19 samples according to PAI‐1 levels reveals significantly faster lysis when using the PAI‐1 resistant (tPA) variant, tenecteplase, over alteplase lysis. Conclusion This study shows that the suboptimal fibrinolytic response in COVID‐19 disease is directly attributable to elevated levels of PAI‐1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI‐1 and the possibility of using pre‐existing drugs, such as tenecteplase, to treat COVID‐19 disease and potentially other respiratory diseases.