Cyclosporine A Does Not Mitigate Liver Ischemia/Reperfusion Injury in an Ex Vivo Porcine Model of Donation After Circulatory Death.

BACKGROUND Ischemia/reperfusion injury (IRI) is an inherent problem in organ transplantation, owing to the obligate period of ischemia that organs must endure. Cyclosporine A (CsA), though better know as an immunosuppressant, has been shown to mitigate warm IRI in a variety of organ types, including the liver. However, there is little evidence for CsA in preventing hepatic IRI in the transplant setting. MATERIAL AND METHODS In the present study, we tested the effect of CsA on hepatic IRI in a large-animal ex vivo model of donation after circulatory death (DCD). Porcine donors were pre-treated with either normal saline control or 20 mg/kg of CsA. Animals were subject to either 45 or 60 minutes of warm ischemia before hepatectomy, followed by 2 or 4 hours of cold storage prior to reperfusion on an ex vivo circuit. Over the course of a 12-hour perfusion, perfusion parameters were recorded and perfusate samples and biopsies were taken at regular intervals. RESULTS Peak perfusate lactate dehydrogenase was significantly decreased in the lower-ischemia group treated with CsA compared to the untreated group (4220 U/L [3515-5815] vs 11 305 [10 100-11 674]; P=0.023). However, no difference was seen between controls and CsA-treated groups on other parameters in perfusate alanine or asparagine aminotransferase (P=0.912, 0.455, respectively). Correspondingly, we found no difference on midpoint histological injury score (P=0.271). CONCLUSIONS We found minimal evidence that CsA is protective against hepatic IRI in our DCD model.

Microbiology sampling in non-cystic fibrosis bronchiectasis cases from northern Alberta.

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease resulting in chronic cough, thick sputum, and lower airway microbial colonization, akin to patients with cystic fibrosis (CF). NCFB is a common, yet under recognized entity which inflicts significant morbidity and mortality particularly to older individuals, with a rising prevalence in the developed world. Given that sputum cultures are a non-invasive method to characterize the lower airway microbiota in NCFB patients, for which pathogenic organisms are associated with worsened outcomes, we sought to characterize the microbiological pattern and clinical outcomes associated with sputum culture in a cohort of NCFB patients from Western Canada. A total of 20 subjects were prospectively recruited from various bronchiectasis clinics across the Greater Edmonton area. A retrospective chart review and a symptoms questionnaire was performed, gathering information not limited to symptoms, comorbidities, exacerbations, hospitalizations, sputum production, and sputum culture results over the prior 5 years. Subjects reported frequent hospitalization alongside a significant burden of symptoms. A large majority of sputum cultures grew pathogenic organisms such as Haemophilus influenzae and Pseudomonas aeruginosa. We also note the considerable waste and inefficiency associated with sputum cultures, outlining areas for which this important diagnostic modality can be improved. Accurate characterization of the airway microbiota alongside efficient delivery of health services are key to ensuring the proper treatment of individuals with NCFB, given their high disease burden and frequent hospitalization.

Comparing the Denver criteria sets for blunt trauma: a retrospective study of cases in Edmonton, Alberta.

OBJECTIVE: To determine whether a more conservative Denver criterion set could reduce unnecessary CT angiography (CTA) studies when screening for blunt cerebrovascular injury (BCVI) following blunt trauma. METHODS: Following ethics approval, a retrospective chart review of 447 consecutive patients undergoing emergency CTA at two large teaching hospitals was conducted to determine the presence of risk factors for each Denver criterion set. Imaging studies of adults conducted between January 2016 and June 2020 containing sufficient clinical information for accurate classification were included in the study. Specificity, sensitivity, and predictive values were calculated. A two-sided Fisher exact test was used to evaluate the association between each iteration of the Denver criteria and the presence of BCVI. RESULTS: The specificities of the Original, Modified, and Expanded Denver criteria were 43.58%, 34.32%, and 24.85%, respectively. Positive-predictive values (PPV) followed a different trend, with respective values of 2.77%, 3.06%, and 2.78%. Sensitivity and negative-predictive values (NPV) were found to be 100% for each criterion set. Being positive for a criterion set, and the presence of BCVI, was statistically significant for the original Denver criteria (p = 0.021, n = 443), but not the modified (p = 0.100, n = 345) or expanded Denver criteria (p = 0.202, n = 333). CONCLUSION: Use of the modified and expanded Denver criteria leads to the overuse of cerebrovascular imaging on patients suffering blunt force trauma. ADVANCES IN KNOWLEDGE: The original Denver criteria may more appropriately identify subjects for further evaluation with CTA than the current standard, while retaining diagnostic efficacy for BCVI.

Reconstructing signaling pathways using regular language constrained paths.

MOTIVATION: High-quality curation of the proteins and interactions in signaling pathways is slow and painstaking. As a result, many experimentally detected interactions are not annotated to any pathways. A natural question that arises is whether or not it is possible to automatically leverage existing pathway annotations to identify new interactions for inclusion in a given pathway. RESULTS: We present RegLinker, an algorithm that achieves this purpose by computing multiple short paths from pathway receptors to transcription factors within a background interaction network. The key idea underlying RegLinker is the use of regular language constraints to control the number of non-pathway interactions that are present in the computed paths. We systematically evaluate RegLinker and five alternative approaches against a comprehensive set of 15 signaling pathways and demonstrate that RegLinker recovers withheld pathway proteins and interactions with the best precision and recall. We used RegLinker to propose new extensions to the pathways. We discuss the literature that supports the inclusion of these proteins in the pathways. These results show the broad potential of automated analysis to attenuate difficulties of traditional manual inquiry. AVAILABILITY AND IMPLEMENTATION: https://github.com/Murali-group/RegLinker. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.