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Abstract The presence of Arbuscular Mycorrhizal Fungi (AMF) in vascular land plant roots is one of the most ancient of symbioses supporting nitrogen and phosphorus exchange for photosynthetically derived carbon. Here we provide a multi-scale modeling approach to predict AMF colonization of a worldwide crop from a Recombinant Inbred Line (RIL) population derived from Sorghum bicolor and S. propinquum. The high-throughput phenotyping methods of fungal structures here rely on a Mask Region-based Convolutional Neural Network (Mask R-CNN) in computer vision for pixel-wise fungal structure segmentations and mixed linear models to explore the relations of AMF colonization, root niche, and fungal structure allocation. Models proposed capture over 95% of the variation in AMF colonization as a function of root niche and relative abundance of fungal structures in each plant. Arbuscule allocation is a significant predictor of AMF colonization among sibling plants. Arbuscules and extraradical hyphae implicated in nutrient exchange predict highest AMF colonization in the top root section. Our work demonstrates that deep learning can be used by the community for the high-throughput phenotyping of AMF in plant roots. Mixed linear modeling provides a framework for testing hypotheses about AMF colonization phenotypes as a function of root niche and fungal structure allocations.

The negative environmental and social impacts of food waste accumulation can be mitigated by utilizing bio-refineries’ approach where food waste is revalorized into high-value products, such as prodigiosin (PG), using microbial bioprocesses. The diverse biological activities of PG position it as a promising compound, but its high production cost and promiscuous bioactivity hinder its wide application. Metal ions can modulate the electronic properties of organic molecules, leading to novel mechanisms of action and increased target potency, while metal complex formation can improve the stability, solubility and bioavailability of the parent compound. The objectives of this study were optimizing PG production through bacterial fermentation using food waste, allowing good quantities of the pure natural product for further synthesizing and evaluating copper(II) and zinc(II) complexes with it. Their antimicrobial and anticancer activities were assessed, and their binding affinity toward biologically important molecules, bovine serum albumin (BSA) and DNA was investigated by fluorescence emission spectroscopy and molecular docking. The yield of 83.1 mg/L of pure PG was obtained when processed meat waste at 18 g/L was utilized as the sole fermentation substrate. The obtained complexes CuPG and ZnPG showed high binding affinity towards target site III of BSA, and molecular docking simulations highlighted the affinity of the compounds for DNA minor grooves.

Abstract Long‐term patient and graft survival has been achieved in organ transplantation but at the expense of toxic side effects that are associated with long‐term use of nonspecific immunosuppressive drugs. Discovering new regulators of dendritic cells is the key for development of an ideal treatment to prevent immune rejection. We hypothesized that knockdown of circMAP2K2 induces immunosuppressive DCs and that treatment with circMAP2K2 silenced‐DCs can prevent alloimmune rejection. DCs were cultured and transfected with siRNA for circMAP2K2. circMAP2K2 levels were measured by qRT‐PCR. DC's maturation and immune function were assessed by flow cytometry and mixed lymphocyte reactions. The function of circMAP2K2 was illustrated by a series of RIP and IP. The therapeutics of engineered DCs was tested in a mouse heart transplantation model. We found that circMAP2K2 was highly expressed in mature DCs. Knockdown of circMAP2K2 reduced expression of MHCII, CD40 and CD80, attenuated the ability of DCs to activate allogeneic naïve T cells, and enhanced CD4+CD25+FOXP3+ regulatory T cells (Treg). circMAP2K2‐induced immunosuppressive DCs by interacting with SENP3. Treatment with circMAP2K2‐knockdown DCs attenuated alloimmune rejection and prolonged allograft survival in a murine heart transplantation model. The immune suppression induced in vivo was donor‐antigen specific. In conclusion, knockdown of circMAP2K2 can induce immunosuppressive DCs which are able to inhibit overactive immune response, highlighting a new promising therapeutic approach for immune disorder diseases.

Abstract A consensus species tree is reconstructed from 11 gene trees for human, bat, and pangolin beta coronaviruses from samples taken early in the pandemic (prior to April 1, 2020). Using coalescent theory, the shallow (short branches relative to the hosts) consensus species tree provides evidence of recent gene flow events between bat and pangolin beta coronaviruses predating the zoonotic transfer to humans. The consensus species tree was also used to reconstruct the ancestral sequence of human SARS-CoV-2, which was 2 nucleotides different from the Wuhan sequence. The time to most recent common ancestor was estimated to be Dec 8, 2019 with a bat origin. Some human, bat, and pangolin coronavirus lineages found in China are phylogenetically distinct, a rare example of a class II phylogeography pattern (Avise et al. in Ann Rev Eco Syst 18:489–422, 1987). The consensus species tree is a product of evolutionary factors, providing evidence of repeated zoonotic transfers between bat and pangolin as a reservoir for future zoonotic transfers to humans.

Length of stay (LOS) is a significant contributor to overall patient outcomes for patients undergoing liver transplantation. This study documents a quality improvement project aiming to reduce the median post-transplant LOS for liver transplant patients. We instituted five Plan–Do–Study–Act cycles with the goal of reducing LOS by 3 days from a baseline median of 18.4 days over 1 year. Balancing measures such as readmission rates ensured any decrease in stay was not associated with significantly increased patient complications. Over the 28-month intervention period and 24-month follow-up period, there were 193 patients discharged from hospital with a median LOS of 9 days. The changes appreciated during quality improvement interventions carried over to sustained improvements, with no significant variability in LOS postintervention. Discharge within 10 days increased from 18.4% to 60% over the study period, with intensive care unit stay decreasing from a median of 3.4–1.9 days. Thus, the development of a multidisciplinary care pathway, with patient engagement, led to improved and sustained discharge rates with no significant differences in readmission rates.

Key Points: Question: Does tranexamic acid reduce red blood cell transfusion within 7 days of liver resection? Findings: In this randomized clinical trial, red blood cell transfusion within 7 days of surgery occurred in 16.3% of participants receiving tranexamic acid and 14.5% receiving placebo. Participants receiving tranexamic acid experienced significantly more complications perioperatively compared with placebo (odds ratio, 1.28; 95% CI, 1.02-1.60; P =.03). Meaning: Among patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications. Importance: Tranexamic acid reduces bleeding and blood transfusion in many types of surgery, but its effect in patients undergoing liver resection for a cancer-related indication remains unclear. Objective: To determine whether tranexamic acid reduces red blood cell transfusion within 7 days of liver resection. Design, Setting, and Participants: Multicenter randomized clinical trial of tranexamic acid vs placebo conducted from December 1, 2014, to November 8, 2022, at 10 hepatopancreaticobiliary sites in Canada and 1 site in the United States, with 90-day follow-up. Participants, clinicians, and data collectors were blinded to allocation. A volunteer sample of 1384 patients undergoing liver resection for a cancer-related indication met eligibility criteria and consented to randomization. Interventions: Tranexamic acid (1-g bolus followed by 1-g infusion over 8 hours; n = 619) or matching placebo (n = 626) beginning at induction of anesthesia. Main Outcomes and Measures: The primary outcome was receipt of red blood cell transfusion within 7 days of surgery. Results: The primary analysis included 1245 participants (mean age, 63.2 years; 39.8% female; 56.1% with a diagnosis of colorectal liver metastases). Perioperative characteristics were similar between groups. Red blood cell transfusion occurred in 16.3% of participants (n = 101) in the tranexamic acid group and 14.5% (n = 91) in the placebo group (odds ratio, 1.15 [95% CI, 0.84-1.56]; P =.38; absolute difference, 2% [95% CI, −2% to 6%]). Measured intraoperative blood loss (tranexamic acid, 817.3 mL; placebo, 836.7 mL; P =.75) and total estimated blood loss over 7 days (tranexamic acid, 1504.0 mL; placebo, 1551.2 mL; P =.38) were similar between groups. Participants receiving tranexamic acid experienced significantly more complications compared with placebo (odds ratio, 1.28 [95% CI, 1.02-1.60]; P =.03), with no significant difference in venous thromboembolism (odds ratio, 1.68 [95% CI, 0.95-3.07]; P =.08). Conclusions and Relevance: Among patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications. Trial Registration: ClinicalTrials.gov Identifier: NCT02261415 This randomized clinical trial assesses the effect of tranexamic acid vs placebo on the need for blood transfusion among patients undergoing cancer-related liver resection. [ABSTRACT FROM AUTHOR]

Abstract Background Transplantation offers the best survival for patients with end stage organ disease. Transplant of hepatitis C virus (HCV) nucleic acid test (NAT) positive organs into negative recipients is a novel strategy that can expand the donor pool. We aim to evaluate our centre’s experience. Methods We preformed a retrospective review of anti-HCV NAT positive and negative organs into negative recipients transplanted over 27 months. Primary outcome was the success rate of eradication of HCV post-transplant. Secondary outcomes were rate of transmission of HCV, treatment adverse events, and graft failure. Results 33 anti-HCV positive organs were transplanted into negative recipients. 22 (66.7%) were NAT positive. Median recipients age was 49 years (interquartile range [IQR] 44.5–62.0) with the majority being males (57.6%). NAT positive organ transplantations included 16 kidneys, 3 livers, 1 kidney-pancreas, 1 liver-kidney, and 1 heart. The most common HCV genotype was 1a (59.1%). The median time to initiating therapy was 41.5 days. SVR12 was 100% in patients who finished therapy. There were no adverse events with therapy and no graft failure. Conclusions Anti-HCV NAT positive organ transplantation into negative recipients is safe with excellent eradication rates and no significant adverse events or graft failure. This would expand donor pool to close the gap between supply and demand.

Abstract Background & Aims Cancer metastasis into distant organs is an evolutionarily selective process. A better understanding of the driving forces endowing proliferative plasticity of tumor seeds in distant soils is required to develop and adapt better treatment systems for this lethal stage of the disease. To this end, we aimed to utilize transcript expression profiling features to predict the site-specific metastases of primary tumors and second, to identify the determinants of tissue specific progression. Methods We used statistical machine learning for transcript feature selection to optimize classification and built tree-based classifiers to predict tissue specific sites of metastatic progression. Results We developed a novel machine learning architecture that analyzes 33 types of RNA transcriptome profiles from The Cancer Genome Atlas (TCGA) database. Our classifier identifies the tumor type, derives synthetic instances of primary tumors metastasizing to distant organs and classifies the site-specific metastases in 16 types of cancers metastasizing to 12 locations. Conclusions We have demonstrated that site specific metastatic progression is predictable using transcriptomic profiling data from primary tumors and that the overrepresented biological processes in tumors metastasizing to congruent distant loci are highly overlapping. These results indicate site-specific progression was organotropic and core features of biological signaling pathways are identifiable that may describe proliferative plasticity in distant soils.

Introduction The process of controlled organ donation after circulatory determination of death (cDCDD) results in ischaemic injury to organs and leads to poorer outcomes in organ recipients. Although not yet used in Canada, normothermic regional perfusion (NRP) is a perfusion technology used postmortem with cDCDD donors to selectively restore perfusion of oxygenated blood to target organs in situ, reversing ischaemic injury and improving organ viability and post-transplant outcomes. However, NRP poses significant ethical challenges. To preserve trust in deceased donation, these ethical challenges must be addressed to the satisfaction of Canadian stakeholders before NRP’s implementation. This study will identify ethical issues pertaining to NRP and explore perspectives of NRP among key stakeholders. By developing an explanatory framework delineating how stakeholder perceptions of NRP’s ethical implications impact trust in Canada’s donation and transplantation systems, this study will inform the development of responsible policy on NRP’s use in Canada.Methods and analysis This study includes two workstreams. Workstream 1 is a scoping review of medical and bioethical literature to identify ethical issues stemming from NRP. We will apply a common search string across Medline, PubMed (other than Medline) and Embase to identify relevant articles. We will identify grey literature through Google searches, websites of organ donation organisations and consultation with our research network. No date limits will be applied. All peer-reviewed publications, commentaries, editorials or documents that engage with ethical issues in NRP (or conceptual and empirical issues as they relate to these ethical issues) will be included. News articles, conference abstracts and publications not in English will be excluded. Workstream 2 consists of interviews with healthcare providers, institutional stakeholders, organ recipients and deceased donors’ family members (n=24–36), as well as focus groups with healthcare providers involved in deceased donation and transplantation (n=20–32). Constructivist grounded theory methodology will guide data collection and analysis in workstream 2.Ethics and dissemination This study was approved by Western University’s research ethics committee (Western REM; ID: 120001). All participants will be asked to provide written informed consent to participate. Findings will be shared with Canadian organ donation and transplantation organisations, presented at national conferences and published in medical journals.

Abstract Background Liver transplantation (LT) remains the curative treatment for symptomatic Polycystic Liver Disease (PCLD) patients and is associated with excellent survival rates. The aim of the study is to review the Ontario experience in LT for PCLD. Methods A retrospective study was performed from pre-existing LT databases from the LT Units at Toronto General Hospital and London Health Sciences Center, which are the two LT programs in Ontario, Canada. This database contains demographic, clinical parameters and follow-up of all patients transplanted for PCLD. Data was extracted for patients who underwent LT between January 2000–April 2017 and included follow up until December 31st, 2018. Results A total of 3560 patients underwent LT, of whom 51 (1.4%) had PCLD and met inclusion criteria. 43 (84%) of these patients were female. The median physiologic Model for End Stage Liver Disease (MELD-Na) score at time of referral was 13 (IQR = 7–22), however all patients required MELD-Na exception points to receive LT. The median age of transplant was 62 years (IQR = 59–64) for male vs. 52 (IQR = 45–56) for female patients. 33 (65%) of our cohort had PCLD while 9 (17.5%) had ADPKD and 9 (17.5%) had both diseases. 39 (76%) had LT due to symptoms of mass effect, while 8 (16%) had portal hypertensive complications. After a median follow-up of 6.3 (IQR = 2.9–12.5) years, the probability of survival was 96% (95% CI: 90%, 100%). Log-rank test, comparing survival analysis between males and females did not show a statistically significant difference (p = 0.26). Conclusion Most patients underwent LT for PCLD due to symptoms of mass effect with women being more likely than men to undergo LT. LT for PCLD had excellent long-term survival.

The negative environmental and social impacts of food waste accumulation can be mitigated by utilizing bio-refineries' approach where food waste is revalorized into high-value products, such as prodigiosin (PG), using microbial bioprocesses. The diverse biological activities of PG position it as a promising compound, but its high production cost and promiscuous bioactivity hinder its wide application. Metal ions can modulate the electronic properties of organic molecules, leading to novel mechanisms of action and increased target potency, while metal complex formation can improve the stability, solubility and bioavailability of the parent compound. The objectives of this study were optimizing PG production through bacterial fermentation using food waste, allowing good quantities of the pure natural product for further synthesizing and evaluating copper(II) and zinc(II) complexes with it. Their antimicrobial and anticancer activities were assessed, and their binding affinity toward biologically important molecules, bovine serum albumin (BSA) and DNA was investigated by fluorescence emission spectroscopy and molecular docking. The yield of 83.1 mg/L of pure PG was obtained when processed meat waste at 18 g/L was utilized as the sole fermentation substrate. The obtained complexes CuPG and ZnPG showed high binding affinity towards target site III of BSA, and molecular docking simulations highlighted the affinity of the compounds for DNA minor grooves. [ABSTRACT FROM AUTHOR]

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.

ObjectiveEfforts to improve patient safety are challenged by the lack of universally agreed upon terms. The International Classification for Patient Safety (ICPS) was developed by the World Health Organization for this purpose. This study aimed to test the applicability of the ICPS to a surgical population.DesignA web-based safety debriefing was sent to clinicians involved in surgical care of abdominal organ transplant patients. A multidisciplinary team of patient safety experts, surgeons and researchers used the data to develop a system of classification based on the ICPS. Disagreements were reconciled via consensus, and a codebook was developed for future use by researchers.ResultsA total of 320 debriefing responses were used for the initial review and codebook development. In total, the 320 debriefing responses contained 227 patient safety incidents (range: 0-7 per debriefing) and 156 contributing factors/hazards (0-5 per response). The most common severity classification was 'reportable circumstance,' followed by 'near miss.' The most common incident types were 'resources/organizational management,' followed by 'medical device/equipment.' Several aspects of surgical care were encompassed by more than one classification, including operating room scheduling, delays in care, trainee-related incidents, interruptions and handoffs.ConclusionsThis study demonstrates that a framework for patient safety can be applied to facilitate the organization and analysis of surgical safety data. Several unique aspects of surgical care require consideration, and by using a standardized framework for describing concepts, research findings can be compared and disseminated across surgical specialties. The codebook is intended for use as a framework for other specialties and institutions.

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Polyurethanes (PUs) are an exceedingly heterogeneous group of plastic polymers, widely used in a variety of industries from construction to medical implants. In the past decades, we have witnessed the accumulation of PU waste and its detrimental environmental impacts. PUs have been identified as one of the most toxic polymers leaching hazardous compounds derived both from the polymer itself and the additives used in production. Further environmental impact assessment, identification and characterization of substances derived from PU materials and establishing efficient degradation strategies are crucial. Thus, a selection of eight synthetic model compounds which represent partial PU hydrolysis products were synthesized and characterized both in terms of toxicity and suitability to be used as substrates for the identification of novel biocatalysts for PU biodegradation. Overall, the compounds exhibited low in vitro cytotoxicity against a healthy human fibroblast cell line and virtually no toxic effect on the nematode Caenorhabditis elegans up to 500 µg mL−1, and two of the substrates showed moderate aquatic ecotoxicity with EC50 values 53 µg mL−1 and 45 µg mL−1, respectively, on Aliivibrio fischeri. The compounds were successfully applied to study the mechanism of ester and urethane bond cleaving preference of known plastic-degrading enzymes and were used to single out a novel PU-degrading biocatalyst, Amycolatopsis mediterranei ISP5501, among 220 microbial strains. A. mediterranei ISP5501 can also degrade commercially available polyether and polyester PU materials, reducing the average molecular number of the polymer up to 13.5%. This study uncovered a biocatalyst capable of degrading different types of PUs and identified potential enzymes responsible as a key step in developing biotechnological process for PU waste treatment options.