Selective deforestation and exposure of African wildlife to bat-borne viruses.

Proposed mechanisms of zoonotic virus spillover often posit that wildlife transmission and amplification precede human outbreaks. Between 2006 and 2012, the palm Raphia farinifera, a rich source of dietary minerals for wildlife, was nearly extirpated from Budongo Forest, Uganda. Since then, chimpanzees, black-and-white colobus, and red duiker were observed feeding on bat guano, a behavior not previously observed. Here we show that guano consumption may be a response to dietary mineral scarcity and may expose wildlife to bat-borne viruses. Videos from 2017-2019 recorded 839 instances of guano consumption by the aforementioned species. Nutritional analysis of the guano revealed high concentrations of sodium, potassium, magnesium and phosphorus. Metagenomic analyses of the guano identified 27 eukaryotic viruses, including a novel betacoronavirus. Our findings illustrate how "upstream" drivers such as socioeconomics and resource extraction can initiate elaborate chains of causation, ultimately increasing virus spillover risk.

Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases.

Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration.

IFPA Joan Hunt Senior Award in Placentology lecture: Extracellular vesicle signalling and pregnancy.

The field of extracellular vesicle (EV) signalling has the potential to transform our understanding of maternal-fetal communication and affords new opportunities for non-invasive prenatal testing and therapeutic intervention. EVs have been implicated in implantation, placentation, maternal adaptation to pregnancy and complications of pregnancy, being detectable in maternal circulation as early as 6 weeks of pregnancy. EVs of differing biogenic origin, composition and bioactivity are released by cells to maintain homoeostasis. Induction of EV signalling is associated with aberrant cellular metabolism and manifests as changes in EV concentrations and/or composition. Characterizing such changes affords opportunity to develop more informative diagnostics and efficacious interventions. To develop accurate and reliable EV-based diagnostics requires: identification of disease-associated biomarkers in specific EV subpopulations; and rapid, reproducible and scalable sample processing. Conventional isolation methods face challenges due to co-isolation of particles with similar physicochemical properties. Methods targeting specific vesicle-surface epitopes and compatible with automated platforms show promise. Effective EV therapeutics require precise targeting, achieved through genetic engineering to release EVs expressing cell-targeting ligands and carrying therapeutic payloads. Unlike cell-based therapies, this approach offers advantages including: low immunogenicity; stability; and long-term storage. Although EV diagnostics and therapeutics in reproductive biology are nascent, available technologies can enhance our understanding of EV signalling between mother and fetus, its role in pregnancies and improve outcomes.

Optimal Conduit Diameter Selection in Coronary Bypass Grafting Using Saphenous Vein.

BACKGROUND: Predictors of long-term saphenous vein graft (SVG) patency following coronary artery bypass grafting (CABG) include harvesting technique, degree of proximal coronary stenosis, and target vessel diameter and runoff. The objective of this study was to evaluate the association between vein graft diameter and long-term survival. METHODS: Patients undergoing primary CABG (2000-2017) at Flinders Medical Centre, Adelaide, Australia, were categorised into three groups according to average SVG diameter (<3.5 mm [small], 3.5-4 mm [medium], >4 mm [large]). Survival data was obtained from the Australian Institute of Health and Welfare National Death Index. To determine the association of SVG diameter with long-term survival we used Kaplan-Meier survival analysis and Cox proportional hazard models adjusted for preoperative variables associated with survival. RESULTS: Vein graft diameter was collected in 3,797 patients. Median follow-up time was 7.6 years (interquartile range, 3.9-11.8) with 1,377 deaths. SVG size >4 mm was associated with lower rates of adjusted survival up to 4 years postoperatively (hazard ratio 1.48; 95% confidence interval 1.05-2.1; p=0.026). CONCLUSIONS: Vein graft diameter >4mm was found to be associated with lower rates of survival following CABG.

Characterization of the bacterial microbiome of non-hematophagous bats and associated ectoparasites from Brazil.

Introduction: Bats, along with their ectoparasites, harbor a wide diversity of symbiotic and potential pathogenic bacteria. Despite the enormous diversity of bats (181 species), few studies aimed to investigate the bacterial microbiome of Brazilian chiropterans and associated ectoparasites. This study aimed to characterize the bacterial microbiome of non-hematophagous bats and associated Streblidae flies and Macronyssidae and Spinturnicidae mites in the state of Mato Grosso do Sul, midwestern Brazil. Methods: Oral and rectal swabs were collected from 30 bats (Artibeus lituratus [n = 13], Artibeus planirostris [n = 9], Eptesicus furinalis [n = 5], Carollia perspicillata [n = 2], and Platyrrhinus lineatus [n = 1]). In addition, a total of 58 mites (15 Macronyssidae and 43 Spinturnicidae) and 48 Streblidae bat flies were collected from the captured bats. After DNA extraction and purification, each sample's bacterial composition was analyzed with metagenomic sequencing. Results: The microbiome composition of both oral and rectal bat swab samples showed that Gammaproteobacteria was the most abundant bacterial class. Spiroplasma, Wolbachia and Bartonella represented the most abundant genera in Streblidae flies. While Wolbachia (Alphaproteobacteria) was the most abundant genus found in Spinturnicidae, Arsenophonus (Gammaproteobacteria) was found in high abundance in Macronyssidae mites. In addition to characterizing the microbiome of each sample at the class and genus taxonomic levels, we identified medically significant bacteria able to infect both animals and humans in oral (Streptococcus and Anaplasma) and rectal swabs (Enterobacter, Klebsiella, Escherichia, Enterococcus, Streptococcus), Macronyssidae (Anaplasma, Bartonella, Ehrlichia) and Spinturnicidae (Anaplasma, Bartonella) mites as well as Streblidae flies (Spiroplasma, Bartonella). Discussion and conclusion: Besides expanding the knowledge on the bacterial microbiome of non-hematophagous bats and Streblidae flies from Brazil, the present work showed, for the first time, the bacterial community of bat-associated Macronyssidae and Spinturnicidae mites.

Genomic Surveillance of Rabies Virus in Georgian Canines.

Rabies is a fatal zoonosis that is considered a re-emerging infectious disease. Although rabies remains endemic in canines throughout much of the world, vaccination programs have essentially eliminated dog rabies in the Americas and much of Europe. However, despite the goal of eliminating dog rabies in the European Union by 2020, sporadic cases of dog rabies still occur in Eastern Europe, including Georgia. To assess the genetic diversity of the strains recently circulating in Georgia, we sequenced seventy-eight RABV-positive samples from the brain tissues of rabid dogs and jackals using Illumina short-read sequencing of total RNA shotgun libraries. Seventy-seven RABV genomes were successfully assembled and annotated, with seventy-four of them reaching the coding-complete status. Phylogenetic analyses of the nucleoprotein (N) and attachment glycoprotein (G) genes placed all the assembled genomes into the Cosmopolitan clade, consistent with the Georgian origin of the samples. An amino acid alignment of the G glycoprotein ectodomain identified twelve different sequences for this domain among the samples. Only one of the ectodomain groups contained a residue change in an antigenic site, an R264H change in the G5 antigenic site. Three isolates were cultured, and these were found to be efficiently neutralized by the human monoclonal antibody A6. Overall, our data show that recently circulating RABV isolates from Georgian canines are predominantly closely related phylogroup I viruses of the Cosmopolitan clade. Current human rabies vaccines should offer protection against infection by Georgian canine RABVs. The genomes have been deposited in GenBank (accessions: OQ603609-OQ603685).

Explainable discovery of disease biomarkers: The case of ovarian cancer to illustrate the best practice in machine learning and Shapley analysis.

OBJECTIVE: Ovarian cancer is a significant health issue with lasting impacts on the community. Despite recent advances in surgical, chemotherapeutic and radiotherapeutic interventions, they have had only marginal impacts due to an inability to identify biomarkers at an early stage. Biomarker discovery is challenging, yet essential for improving drug discovery and clinical care. Machine learning (ML) techniques are invaluable for recognising complex patterns in biomarkers compared to conventional methods, yet they can lack physical insights into diagnosis. eXplainable Artificial Intelligence (XAI) is capable of providing deeper insights into the decision-making of complex ML algorithms increasing their applicability. We aim to introduce best practice for combining ML and XAI techniques for biomarker validation tasks. METHODS: We focused on classification tasks and a game theoretic approach based on Shapley values to build and evaluate models and visualise results. We described the workflow and apply the pipeline in a case study using the CDAS PLCO Ovarian Biomarkers dataset to demonstrate the potential for accuracy and utility. RESULTS: The case study results demonstrate the efficacy of the ML pipeline, its consistency, and advantages compared to conventional statistical approaches. CONCLUSION: The resulting guidelines provide a general framework for practical application of XAI in medical research that can inform clinicians and validate and explain cancer biomarkers.

Genomic Characterization of a Relative of Mumps Virus in Lesser Dawn Bats of Southeast Asia.

The importance of genomic surveillance on emerging diseases continues to be highlighted with the ongoing SARS-CoV-2 pandemic. Here, we present an analysis of a new bat-borne mumps virus (MuV) in a captive colony of lesser dawn bats (Eonycteris spelaea). This report describes an investigation of MuV-specific data originally collected as part of a longitudinal virome study of apparently healthy, captive lesser dawn bats in Southeast Asia (BioProject ID PRJNA561193) which was the first report of a MuV-like virus, named dawn bat paramyxovirus (DbPV), in bats outside of Africa. More in-depth analysis of these original RNA sequences in the current report reveals that the new DbPV genome shares only 86% amino acid identity with the RNA-dependent RNA polymerase of its closest relative, the African bat-borne mumps virus (AbMuV). While there is no obvious immediate cause for concern, it is important to continue investigating and monitoring bat-borne MuVs to determine the risk of human infection.

Correlation of Narrative Evaluations to Clerkship Grades Using Statistical Sentiment Analysis.

Introduction: Narrative evaluations are essential components of medical student assessment. This study evaluated how well narrative clerkship evaluation word choice correlated with an assigned letter grade. Methods: One hundred clerkship evaluations, 50 from family medicine (FM) and 50 from internal medicine (IM), with even distribution of "Honors" and "Near-Honors" among medical students that graduated in 2020 from the Oregon Health and Science University (OHSU) were examined. A textual sentiment analysis, which evaluates positive and negative word choice, was used to determine each evaluation's collective sentiment. An average sentiment score and character count were calculated for Honors and Near-Honors evaluations from both clerkship disciplines. Sentiment word totals were used to form "word clouds" that highlight the most frequent word selections. Results: While sentiment scores positively correlated with the assigned grade, there was no statistically significant difference between the average sentiment scores among Honors and Near Honors graded evaluations within the FM or IM clerkship evaluation sets. There was no significant difference in evaluation character length among the assigned grades. Among FM evaluations, "outstanding" and "excellent" were the two most common sentiment words used in both Honors and Near-Honors. Among IM evaluations, outstanding and excellent were most commonly used in Honors evaluations, while "excellent" and "good" were most common in Near-Honors. Conclusion: This study outlines a novel text analysis method for analyzing narrative evaluation association with assigned grade that other institutions can utilize. Sentiment word choices are not significantly different among Honors and Near Honors clerkship narrative evaluations. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01654-2.

Quantification of the internal mammary artery size in Aboriginal and Torres Strait islanders.

BACKGROUND: Variation in size of the internal mammary artery has been demonstrated in ethnic groups, but not reported in Aboriginal patients. We hypothesised that the left internal mammary artery is smaller in Aboriginal patients compared to non-Aboriginal patients and aimed to determine the impact on survival following coronary artery bypass graft (CABG) surgery. METHODS: Left internal mammary artery size was compared between Aboriginal (n = 345) and non-Aboriginal (n = 1819) in 2343 patients undergoing CABG at Flinders Medical Centre from January 2010 to June 2021. To determine the association with-survival we used Kaplan-Meier survival analysis and Cox proportional hazard models adjusted for preoperative variables. RESULTS: There was a significant difference in left internal mammary artery (LIMA) size-Aboriginal 1.8 ± 0.4 mm; non-Aboriginal 2.1 ± 0.4 mm (P < 0.001)-and left anterior descending (LAD) artery size-Aboriginal 1.7 ± 0.3 mm; non-Aboriginal 1.9 ± 0.3 mm (P < 0.001). Aboriginal patients were more likely to have the LIMA discarded (9.3% vs. 0.4%) and to receive a LAD vein graft (17% versus 3%) (P < 0.001). There was no difference in 30-day mortality or survival <5 years. CONCLUSION: This study supports the hypothesis that the left internal mammary artery is smaller in Aboriginal patients compared to non-Aboriginal patients. Although Aboriginal patients were more likely to receive a venous conduit to the LAD, we observed no difference in survival up to 5 years. This data contrasts with reported outcomes of other ethnic groups.

Transcatheter mitral valve-in-valve: treatment of rheumatic heart disease in young patients.

BACKGROUND: Rheumatic heart disease (RHD) in young people presents a complex management problem. In Australia a significant proportion of those affected are Aboriginal and Torres Strait Islanders. Transcatheter mitral valve-in-valve (TMViV) replacement has emerged as an alternative to redo surgery in high-risk patients with degenerated mitral bioprostheses. The aim of this study is to review outcomes of TMViV replacement in young patients with RHD. METHODS: A single-centre, retrospective review of prospectively collected data on patients undergoing TMViV from December 2017 to June 2021. Primary outcome was major adverse cardiovascular events. Secondary outcome was post-operative trans-thoracic echocardiogram (TTE) results. RESULTS: There were seven patients with a mean age of 33 years and predominantly female (n = 5). Pre-operative comorbidities included diabetes (29%), chronic obstructive pulmonary disease (43%), left ventricular dysfunction (43%) and current smoking status (80%). Post-operative median length of hospital stay was 4 days with no post-operative renal failure, stroke, return to theatre, valve embolization or in hospital mortality. Post-operative TTE showed either nil or trivial central mitral regurgitation, no paravalvular leak and a median gradient of 5 mmHg (IQR 4.5, 7) across the new bioprosthesis; sustained at median follow-up of 22 months. CONCLUSION: Current literature of TMViV replacement is focused on an older population with concurrent comorbidities. This study provides a unique insight into TMViV replacement in a young cohort of patients with complex social and geographical factors which sometimes prohibits the use of a mechanical valve. The prevalence of RHD remains high for Aboriginal and Torres Strait Islanders, planning for future repeat valve operations should be considered from the outset. We consider TMViV as a part of a staged procedural journey for young patients with RHD.

SARS-CoV-2 Infections in Vaccinated and Unvaccinated Populations in Camp Lemonnier, Djibouti, from April 2020 to January 2022.

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the disparity between developed and developing countries for infectious disease surveillance and the sequencing of pathogen genomes. The majority of SARS-CoV-2 sequences published are from Europe, North America, and Asia. Between April 2020 and January 2022, 795 SARS-CoV-2-positive nares swabs from individuals in the U.S. Navy installation Camp Lemonnier, Djibouti, were collected, sequenced, and analyzed. In this study, we described the results of genomic sequencing and analysis for 589 samples, the first published viral sequences for Djibouti, including 196 cases of vaccine breakthrough infections. This study contributes to the knowledge base of circulating SARS-CoV-2 lineages in the under-sampled country of Djibouti, where only 716 total genome sequences are available at time of publication. Our analysis resulted in the detection of circulating variants of concern, mutations of interest in lineages in which those mutations are not common, and emerging spike mutations.

SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures.

BACKGROUND: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. METHODS: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. RESULTS: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. CONCLUSIONS: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.

Extracellular Vesicles and Their Emerging Roles as Cellular Messengers in Endocrinology: An Endocrine Society Scientific Statement.

During the last decade, there has been great interest in elucidating the biological role of extracellular vesicles (EVs), particularly, their hormone-like role in cell-to-cell communication. The field of endocrinology is uniquely placed to provide insight into the functions of EVs, which are secreted from all cells into biological fluids and carry endocrine signals to engage in paracellular and distal interactions. EVs are a heterogeneous population of membrane-bound vesicles of varying size, content, and bioactivity. EVs are specifically packaged with signaling molecules, including lipids, proteins, and nucleic acids, and are released via exocytosis into biofluid compartments. EVs regulate the activity of both proximal and distal target cells, including translational activity, metabolism, growth, and development. As such, EVs signaling represents an integral pathway mediating intercellular communication. Moreover, as the content of EVs is cell-type specific, it is a "fingerprint" of the releasing cell and its metabolic status. Recently, changes in the profile of EV and bioactivity have been described in several endocrine-related conditions including diabetes, obesity, cardiovascular diseases, and cancer. The goal of this statement is to highlight relevant aspects of EV research and their potential role in the field of endocrinology.

Immunological and Genetic Investigation of SARS-CoV-2 Reinfection in an Otherwise Healthy, Young Marine Recruit.

We used epidemiologic and viral genetic information to identify a case of likely reinfection in an otherwise healthy, young Marine recruit enrolled in the prospective, longitudinal COVID-19 Health Action Response for Marines (CHARM) study, and we paired these findings with serological studies. This participant had a positive RT-PCR to SARS-CoV-2 upon routine sampling on study day 7, although he was asymptomatic at that time. He cleared the infection within seven days. On study day 46, he had developed symptoms consistent with COVID-19 and tested positive by RT-PCR for SARS-CoV-2 again. Viral whole genome sequencing was conducted from nares swabs at multiple time points. The day 7 sample was determined to be lineage B.1.340, whereas both the day 46 and day 49 samples were B.1.1. The first positive result for anti-SARS-CoV-2 IgM serology was collected on day 49 and for IgG on day 91. This case appears most consistent with a reinfection event. Our investigation into this case is unique in that we compared sequence data from more than just paired specimens, and we also assayed for immune response after both the initial infection and the later reinfection. These data demonstrate that individuals who have experienced an infection with SARS-CoV-2 may fail to generate effective or long-lasting immunity, similar to endemic human beta coronaviruses.

Proteomics and Nucleotide Profiling as Tools for Biomarker and Drug Target Discovery.

Proteomics has gone through tremendous development during recent decades [...].

Manual Annotation Studio (MAS): a collaborative platform for manual functional annotation of viral and microbial genomes.

BACKGROUND: Functional genome annotation is the process of labelling functional genomic regions with descriptive information. Manual curation can produce higher quality genome annotations than fully automated methods. Manual annotation efforts are time-consuming and complex; however, software can help reduce these drawbacks. RESULTS: We created Manual Annotation Studio (MAS) to improve the efficiency of the process of manual functional annotation prokaryotic and viral genomes. MAS allows users to upload unannotated genomes, provides an interface to edit and upload annotations, tracks annotation history and progress, and saves data to a relational database. MAS provides users with pertinent information through a simple point and click interface to execute and visualize results for multiple homology search tools (blastp, rpsblast, and HHsearch) against multiple databases (Swiss-Prot, nr, CDD, PDB, and an internally generated database). MAS was designed to accept connections over the local area network (LAN) of a lab or organization so multiple users can access it simultaneously. MAS can take advantage of high-performance computing (HPC) clusters by interfacing with SGE or SLURM and data can be exported from MAS in a variety of formats (FASTA, GenBank, GFF, and excel). CONCLUSIONS: MAS streamlines and provides structure to manual functional annotation projects. MAS enhances the ability of users to generate, interpret, and compare results from multiple tools. The structure that MAS provides can improve project organization and reduce annotation errors. MAS is ideal for team-based annotation projects because it facilitates collaboration.

Ovarian-Cancer-Associated Extracellular Vesicles: Microenvironmental Regulation and Potential Clinical Applications.

Ovarian cancer (OC) is one of the most diagnosed gynecological cancers in women. Due to the lack of effective early stage screening, women are more often diagnosed at an advanced stage; therefore, it is associated with poor patient outcomes. There are a lack of tools to identify patients at the highest risk of developing this cancer. Moreover, early detection strategies, therapeutic approaches, and real-time monitoring of responses to treatment to improve survival and quality of life are also inadequate. Tumor development and progression are dependent upon cell-to-cell communication, allowing cancer cells to re-program cells not only within the surrounding tumor microenvironment, but also at distant sites. Recent studies established that extracellular vesicles (EVs) mediate bi-directional communication between normal and cancerous cells. EVs are highly stable membrane vesicles that are released from a wide range of cells, including healthy and cancer cells. They contain tissue-specific signaling molecules (e.g., proteins and miRNA) and, once released, regulate target cell phenotypes, inducing a pro-tumorigenic and immunosuppressive phenotype to contribute to tumor growth and metastasis as well as proximal and distal cell function. Thus, EVs are a "fingerprint" of their cell of origin and reflect the metabolic status. Additionally, via the capacity to evade the immune system and remain stable over long periods in circulation, EVs can be potent therapeutic agents. This review examines the potential role of EVs in the different aspects of the tumor microenvironment in OC, as well as their application in diagnosis, delivery of therapeutic agents, and disease monitoring.

Del Nido cardioplegia in adult cardiac surgery: analysis of myocardial protection and post-operative high-sensitivity Troponin T.

BACKGROUND: del Nido cardioplegia has been adopted for use in adult cardiac surgery, despite a lack of robust randomised evidence supporting equivalence or superiority to conventional hyperkalaemic blood cardioplegia. We investigated the clinical surrogates of myocardial protection, and performed an extensive analysis of post-operative high-sensitivity Troponin T (hs-TnT) values in a general adult cardiac surgery population receiving del Nido, in comparison to a historical hyperkalaemic blood cohort. METHOD: 171 consecutive patients of a single surgeon from between November 2018 and June 2020 received del Nido, and were compared to a historical cohort of 326 patients between January 2016 and November 2018 who received hyperkalaemic blood cardioplegia. Clinical markers of myocardial protection were compared, as were hs-TnT values at 6, 12, 24, and 72-h post-operatively. Equivalence between groups was determined using the two one-sided tests procedure. RESULTS: There was no difference between the groups in the incidence of post-operative low cardiac output state, inotropic support, or myocardial infarction. Del Nido patients had less defibrillation requirement, and more spontaneous resumption of normal sinus rhythm. High-sensitivity Troponin T values were similar at all time-points including in a coronary artery bypass graft subgroup, and in those patients with elevated pre-operative hs-TnT. CONCLUSION: In a broad cohort of adult cardiac surgery patients, including those undergoing coronary artery bypass surgery and those with recent myocardial infarction, del Nido provides equivalent myocardial protection and clinical outcomes when compared to hyperkalemic blood cardioplegia. Post-operative high-sensitivity Troponin T values were also equivalent between the groups.

Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9-15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. METHODS: Discovery: A retrospective, case-control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. RESULTS: A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. CONCLUSIONS: During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.