Implanted islets in the anterior chamber of the eye are prone to autoimmune attack in a mouse model of diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disease resulting from the destruction of insulin-producing beta cells. Along with advances in generating replacement beta cells for treating diabetes, there is also increasing demand for non-invasive tools to evaluate the recurrence of autoimmune attack on transplanted tissue. Here, we examined the anterior chamber of the eye as a potential islet transplant site, and also evaluated whether in vivo imaging of the islets transplanted in the eye could enable real-time visualisation of autoimmune processes underway in the pancreas. METHODS: Syngeneic islet equivalents were transplanted into the eye or kidney capsule of streptozotocin-induced diabetic C57BL/6 mice to compare islet dose (25-125 islet equivalents) and function across transplant sites. Autoimmune attack of syngeneic islets was evaluated in the pancreas and eye tissues of NOD and NOD-severe combined immunodeficient (SCID) mice given diabetogenic splenocytes. RESULTS: Islet transplantation in the eye decreased fasting plasma glucose levels and increased weight gain and survival in an islet-dose-dependent manner. Even 50 islets in the eye reduced blood glucose levels, whereas ≥ 200 islets were required in the kidney for a similar effect. Autoimmune destruction of pancreatic islets in the eye mirrored that in the pancreas and could be visualised in real time by non-invasive imaging. CONCLUSIONS/INTERPRETATION: We found that far fewer islets were required to restore normoglycaemia when transplanted into the anterior chamber of the eye vs the kidney capsule. However, our results suggest that islets are not protected against autoimmune attack in the eye, making this a suitable site for visualising autoimmune processes against transplanted tissue.

Predicting sepsis severity at first clinical presentation: The role of endotypes and mechanistic signatures.

BACKGROUND: Inter-individual variability during sepsis limits appropriate triage of patients. Identifying, at first clinical presentation, gene expression signatures that predict subsequent severity will allow clinicians to identify the most at-risk groups of patients and enable appropriate antibiotic use. METHODS: Blood RNA-Seq and clinical data were collected from 348 patients in four emergency rooms (ER) and one intensive-care-unit (ICU), and 44 healthy controls. Gene expression profiles were analyzed using machine learning and data mining to identify clinically relevant gene signatures reflecting disease severity, organ dysfunction, mortality, and specific endotypes/mechanisms. FINDINGS: Gene expression signatures were obtained that predicted severity/organ dysfunction and mortality in both ER and ICU patients with accuracy/AUC of 77-80%. Network analysis revealed these signatures formed a coherent biological program, with specific but overlapping mechanisms/pathways. Given the heterogeneity of sepsis, we asked if patients could be assorted into discrete groups with distinct mechanisms (endotypes) and varying severity. Patients with early sepsis could be stratified into five distinct and novel mechanistic endotypes, named Neutrophilic-Suppressive/NPS, Inflammatory/INF, Innate-Host-Defense/IHD, Interferon/IFN, and Adaptive/ADA, each based on ∼200 unique gene expression differences, and distinct pathways/mechanisms (e.g., IL6/STAT3 in NPS). Endotypes had varying overall severity with two severe (NPS/INF) and one relatively benign (ADA) groupings, consistent with reanalysis of previous endotype studies. A 40 gene-classification tool (accuracy=96%) and several gene-pairs (accuracy=89-97%) accurately predicted endotype status in both ER and ICU validation cohorts. INTERPRETATION: The severity and endotype signatures indicate that distinct immune signatures precede the onset of severe sepsis and lethality, providing a method to triage early sepsis patients.

A Case of Adult-Onset Kawasaki Disease Shock Syndrome Complicated by Coronary Aneurysms.

We present a case of adult-onset Kawasaki disease shock syndrome complicated by coronary aneurysms, in which profound hypotension and reduced left ventricular ejection fraction were treated successfully with intravenous immunoglobulin. The diagnosis of Kawasaki disease shock syndrome should be considered in cases of rapidly developing shock, particularly in young adults with an infectious prodrome, in whom it may be under-recognized. We advocate for early identification to minimize delays in treatment with intravenous immunoglobulin, which reverses left ventricular dysfunction and decreases risk of long-term sequelae such as coronary artery aneurysms.

Nous présentons un cas de syndrome de choc dans la maladie de Kawasaki survenu à l'âge adulte et compliqué par des anévrismes des artères coronaires, chez lequel l'injection d'immunoglobulines par voie intraveineuse a permis de traiter avec succès une hypotension prononcée et une fraction d'éjection ventriculaire gauche réduite. Le diagnostic de syndrome de choc dans la maladie de Kawasaki devrait être envisagé dans les cas de choc évoluant rapidement, en particulier chez les jeunes adultes en phase prodromique d'une infection, chez lesquels cette affection peut passer inaperçue. Nous préconisons un diagnostic précoce afin de réduire au minimum les délais du traitement aux immunoglobulines par voie intraveineuse qui a pour effet d'inverser la dysfonction ventriculaire gauche et de diminuer le risque de séquelles à long terme, comme l'anévrisme des coronaires.

Preventability of 28-Day Hospital Readmissions in General Internal Medicine Patients: A Retrospective Analysis at a Quaternary Hospital.

BACKGROUND: Unplanned hospital readmissions are associated with increased patient mortality and health care costs, yet only a fraction are likely to be preventable. This study's objective was to identify preventable hospital readmissions of general internal medicine patients, and their common causes. METHODS: Patients who were discharged from the general internal medicine teaching service and readmitted to hospital within 28 days for 24 hours or more were recruited to the study; they were identified via the hospital electronic medical record system. Data were gathered via structured review of hospital charts/electronic medical records, along with standardized patient interviews. Unique to our study, a multidisciplinary panel of physicians, nurses, and hospital administrators adjudicated preventability and identified common causes of readmission. RESULTS: Fifty-five hospital readmissions were identified; 53% were adjudicated to be preventable. There was no difference in any variable analyzed between preventable and nonpreventable readmissions. The most common causes of preventable readmissions were inadequate coordination of community services upon discharge, insufficient clinical postdischarge follow-up, and suboptimal end-of-life care. CONCLUSION: This study identified a higher proportion of preventable 28-day hospital readmissions when compared with prior research. Increased involvement of palliative care during initial hospitalization for appropriate conditions and improvements in care after discharge may reduce preventable hospital readmissions.