Direct Oral Anticoagulant Use Early After Cardiac Surgery: A Retrospective Cohort Study.

Background: There is limited literature guiding the prescribing of direct oral anticoagulants (DOACs) early after cardiac surgery as this population has been excluded from landmark randomized controlled trials. This study aims to determine the rate of in-hospital DOAC use compared with warfarin early after cardiac surgery, evaluate factors associated with DOAC use, determine difference in postoperative length of stay, and characterize bleeding events. Methods: A retrospective cohort study was conducted in adult patients with indications for anticoagulation and receiving either a DOAC or warfarin after cardiac surgery during their index hospitalization. Patients were excluded if they had any contraindications to DOAC use. The primary outcome was the proportion of patients discharged on a DOAC compared with warfarin. Results: Of included 210 patients, 30% received DOACs and 70% received warfarin on discharge. The most common DOAC used was apixaban (74.6%), and median postoperative day of initiation was 5 days. Patients receiving DOACs were older (70.8 vs 68.0 years), had less valvular heart disease (38.1% vs 63.9%), were more likely to be on DOACs preoperatively (50.8% vs 31.3%), and were more likely to have undergone coronary artery bypass graft alone (54.0% vs 24.5%) compared with those on warfarin. Postoperative length of stay (7 vs 9 days; P = 0.59) and in-hospital bleeding (1.6% vs 2.0%; P = 1.00) did not differ between DOAC and warfarin groups. Conclusions: At a quaternary referral centre for cardiac surgery, DOACs were used in approximately one-third of patients with an indication for anticoagulation early after cardiac surgery.

Introduction: Il existe peu de documentation sur la prescription des anticoagulants oraux directs (AOC) peu de temps après la chirurgie cardiaque puisque cette population a été exclue des essais cliniques novateurs à répartition aléatoire. La présente étude vise à déterminer le taux d'utilisation des AOC à l'hôpital par rapport au taux d'utilisation de la warfarine peu de temps après la chirurgie cardiaque, à évaluer les facteurs associés à l'utilisation des AOC, à déterminer l'écart de la durée du séjour et à caractériser les événements hémorragiques. Méthodes: Nous avons réalisé une étude de cohorte rétrospective auprès de patients adultes qui avaient des indications d'anticoagulation et qui recevaient des AOC ou de la warfarine après la chirurgie cardiaque durant l'hospitalisation de référence. Les patients étaient exclus s'ils avaient des contre-indications à l'utilisation des AOC. Le critère d'évaluation principal était la proportion de patients sortis de l'hôpital sous AOC par rapport à celle des patients sortis de l'hôpital sous warfarine. Résultats: Parmi les 210 patients inclus, 30 % ont reçu des AOC et 70 % ont reçu de la warfarine à la sortie de l'hôpital. L'AOC le plus fréquemment utilisé était l'apixaban (74,6 %), et le nombre médian de jours après l'intervention chirurgicale du début du traitement était 5 jours. Les patients qui recevaient les AOC étaient plus âgés (70,8 vs 68,0 ans), avaient moins de cardiopathies valvulaires (38,1 % vs 63,9 %), étaient plus susceptibles de recevoir des AOC avant l'opération (50,8 % vs 31,3 %) et étaient plus susceptibles d'avoir seulement subi un pontage aorto-coronarien (54,0 % vs 24,5 %) que ceux sous warfarine. La durée du séjour postopératoire (7 vs 9 jours ; P = 0,59) et les événements hémorragiques à l'hôpital (1,6 % vs 2,0 % ; P = 1,00) ne différaient pas entre les groupes qui recevaient les AOC et les groupes qui recevaient la warfarine. Conclusions: Dans un centre d'aiguillage de soins quaternaires en chirurgie cardiaque, les AOC ont été utilisés chez environ un tiers des patients qui avaient une indication d'anticoagulation peu de temps après la chirurgie cardiaque.

Neurological Pupillary Index (NPi) Measurement Using Pupillometry and Outcomes in Critically Ill Children.

Aim/objective Neurological Pupil Index (NPi), measured by automated pupillometry (AP), allows the objective assessment of pupillary light reflex (PLR). NPi ranges from 0 (non-reactive) to 5 (normal). In this study, we aimed to compare neurologic and functional outcomes in children admitted for neurologic injury with normal (≥3) versus abnormal (<3) NPi measured during their pediatric intensive care unit (PICU) stay. Materials and methods We conducted a retrospective chart review of children between one month and 18 years admitted to our PICU with a diagnosis of neurologic injury between January 2019 and June 2022. We collected demographic, clinical, pupillometer, and outcome data, including mortality, Pediatric Cerebral Performance Category (PCPC), Pediatric Overall Performance Category (POPC), and Functional Status Score (FSS) at admission, at discharge, and at the three to six-month follow-up. We defined abnormal pupil response as any NPi <3 at any point during the PICU stay. Using the student's t-test and chi-square test, we compared the short-term and long-term outcomes of children with abnormal NPi (<3) versus those with normal NPi (≥3). Results There were 49 children who met the inclusion criteria and who had pupillometry data available for analysis. The mean (SD) Glasgow Coma Scale (GCS) in the study cohort was 5.6 (4.3), and 61% had low (<3) NPi during ICU stay. Mortality was significantly higher among patients with an abnormal NPi as compared to those with normal NPi. Children with abnormal NPi exhibited significant worsening of neurologic and functional status (ΔPCPC, ΔPOPC, and ΔFSS) from admission to discharge (mean (SD): 3.55(1.5), 3.45(1.43), 16.75(7.85), p<0.001) as compared to those with normal NPi (mean (SD): 1.45(0.93), 1.73(0.90), 3.55(2.07), p>0.05). The significant difference in neurologic and functional status persisted at the three to six-month follow-up between the two groups - children with abnormal NPi (mean (SD): 2.0(1.41), 2.08(1.38), 6.92(6.83), p<0.01) and children with normal NPi (mean (SD): 0.82(1.01), 0.94(1.03), 1.53(1.70), p>0.05). Conclusion In our retrospective cohort study, children admitted to the PICU for a neuro injury and with abnormal NPi (< 3) have higher mortality, and worse short-term and long-term neurologic and functional outcomes as compared to those with normal NPi (≥ 3) measured during the PICU course. AP provides an objective assessment of PLR and has potential applications for neuro-prognostication. More research needs to be done to elucidate the prognostic value of NPi in pediatrics.

Optimal Therapeutic Drug Monitoring Strategy for IV Aminoglycosides and IV Vancomycin in People with Cystic Fibrosis: A Systematic Review.

Background: Given altered pharmacokinetics in people with cystic fibrosis (pwCF), there is debate regarding optimal strategies for therapeutic drug monitoring (TDM) for aminoglycosides and vancomycin administered intravenously. Objectives: To determine the TDM strategy for IV aminoglycosides and IV vancomycin associated with optimal clinical outcomes in pwCF. Data Sources: Several databases (MEDLINE, Embase, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov ) were searched from inception to November 15, 2020, with searches rerun on February 13, 2023. Study Selection and Data Extraction: Full articles evaluating TDM strategies and clinical outcomes in pwCF receiving IV aminoglycosides or IV vancomycin were included. Data Synthesis: Three studies met the inclusion criteria for IV aminoglycosides, and 1 study met the inclusion criteria for IV vancomycin. Data are presented with descriptive analyses. Conclusions: The available evidence is insufficient to determine an optimal TDM strategy for IV aminoglycoside or IV vancomycin therapy in pwCF.

Contexte: Étant donné que la pharmacocinétique des personnes atteintes de fibrose kystique est altérée, un débat existe concernant les stratégies optimales de suivi thérapeutique des médicaments (STM) pour les aminoglycosides et la vancomycine administrés par voie intraveineuse. Objectif: Déterminer la stratégie de suivi thérapeutique des médicaments pour les aminoglycosides et la vancomycine par voie intraveineuse associée aux résultats cliniques optimaux chez les personnes atteintes de fibrose kystique. Sources des données: Plusieurs bases de données (MEDLINE, Embase, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials et ClinicalTrials.gov ) ont été consultées depuis leur création jusqu'au 15 novembre 2020, avec des recherches répétées le 13 février 2023. Sélection des études et extraction des données: Les articles en texte intégral évaluant les stratégies de suivi thérapeutique des médicaments et les résultats cliniques chez les personnes atteintes de fibrose kystique recevant des aminoglycosides ou de la vancomycine par voie intraveineuse ont été inclus. Synthèse des données: Trois études répondaient aux critères d'inclusion pour les aminoglycosides par voie intraveineuse, et une étude répondait aux critères d'inclusion pour la vancomycine par voie intraveineuse. Les données s'accompagnent d'analyses descriptives. Conclusions: Les éléments probants disponibles sont insuffisants pour déterminer une stratégie optimale de suivi thérapeutique des médicaments pour la thérapie par aminoglycosides par voie intraveineuse ou la vancomycine par voie intraveineuse chez les personnes atteintes de fibrose kystique.

Tissue plasminogen activator challenge thrombelastography is the most accurate assay in predicting the need for massive transfusion in hypotensive trauma patients.

BACKGROUND: Tissue plasminogen activator (tPA) added to thrombelastography (TEG) detects hyperfibrinolysis by measuring clot lysis at 30 min (tPA-challenge-TEG). We hypothesize that tPA-challenge-TEG is a better predictor of massive transfusion (MT) than existing strategies in trauma patients with hypotension. METHODS: Trauma activation patients (TAP, 2014-2020) with 1) systolic blood pressure <90 mmHg (early) or 2) those who arrived normotensive but developed hypotension within 1H postinjury (delayed) were analyzed. MT was defined as >10 RBC U/6H postinjury or death within 6H after ≥1 RBC unit. Area under the receiver operating characteristics curves were used to compare predictive performance. Youden index determined optimal cutoffs. RESULTS: tPA-challenge-TEG was the best predictor of MT in the early hypotension subgroup (N = 212) with positive (PPV) and negative predictive values (NPV) of 75.0%, and 77.6%, respectively. tPA-challenge-TEG was a better predictor of MT than all but TASH (PPV = 65.0%, NPV = 93.3%) in the delayed hypotension group (N = 125). CONCLUSIONS: The tPA-challenge-TEG is the most accurate predictor of MT in trauma patients arriving hypotensive and offers early recognition of MT in patients with delayed hypotension.

SBMLDiagrams: a python package to process and visualize SBML layout and render.

SUMMARY: The systems biology markup language (SBML) is an extensible standard format for exchanging biochemical models. One of the extensions for SBML is the SBML Layout and Render package. This allows modelers to describe a biochemical model as a pathway diagram. However, up to now, there has been little support to help users easily add and retrieve such information from SBML. In this application note, we describe a new Python package called SBMLDiagrams. This package allows a user to add a layout and render information or retrieve it using a straightforward Python API. The package uses skia-python to support the rendering of the diagrams, allowing export to commons formats such as PNG or PDF. AVAILABILITY AND IMPLEMENTATION: SBMLDiagrams is publicly available and licensed under the liberal MIT open-source license. The package is available for all major platforms. The source code has been deposited at GitHub (github.com/sys-bio/SBMLDiagrams). Users can install the package using the standard pip installation mechanism: pip install SBMLDiagrams. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Low viscoelastic clot strength, platelet transfusions, and graft dysfunction are associated with persistent postoperative ascites following liver transplantation.

INTRODUCTION: High output, persistent ascites (PA) is a common complication following liver transplant (LT). Recent work has identified that platelets help maintain endothelial integrity and can decrease leakage in pathological states. We sought to assess the association of PA following LT with platelet count and platelet function. METHODS: Clot strength (MA) is a measure of platelet function and was quantified using thrombelastography (TEG). Total drain output following surgery was recorded in 24-h intervals during the same time frame as TEG. PA was considered >1 L on POD7, as that much output prohibits drain removal. RESULTS: 105 LT recipients with moderate or high volume preoperative ascites were prospectively enrolled. PA occurred in 28%. Platelet transfusions before and after surgery were associated with PA, in addition to POD5 TEG MA and POD5 MELD score. Patients with PA had a longer hospital length of stay and an increased rate of intraabdominal infections. CONCLUSION: Persistent ascites following liver transplant is relatively common and associated with platelet transfusions, low clot strength, and graft dysfunction.

The relationship between stress and disease onset and relapse in multiple sclerosis: A systematic review.

BACKGROUND: The impact of stress in persons with multiple sclerosis (MS) is an area of ongoing inquiry. A limited number of published systematic reviews have reported an association between stress and MS onset. In addition to reviewing more recently published evidence, this review expands upon existing systematic reviews by considering the timing of stress exposure (childhood or adulthood). METHODS: A review of human-subjects literature published in English after 2010 was conducted between April 2020 and May 2020. In total, 6 databases were searched using the terms 'allostatic load', 'multiple sclerosis (MS)', 'chronic stress', and 'stress', and 13 relevant studies were analyzed. Each article was read by at least two of the authors to confirm its relevance. Studies were categorized based on the timing of stress exposure (childhood or adulthood). Study designs included longitudinal cohort, cross-sectional cohort, cross-sectional case-control, and longitudinal case-control studies. The NIH study quality assessment tools and Strengthening The Reporting of OBservational studies in Epidemiology (STROBE) checklist were used to assess study quality. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews were followed. RESULTS: Manuscripts reviewed included 8 studies on MS onset, 2 studies on MS relapse, and 3 studies on MS onset and relapse. In total, 5 studies examined childhood stress, 7 studies examined adulthood stress, and 1 study examined both childhood and adulthood stress in 2 respective cohorts. Studies of varying design consistently reported an association between MS relapse and stress, regardless of the timing of stress exposure. However, the link between stress and MS onset was conflicting for both childhood and adult stress exposures. CONCLUSIONS: This systematic review is the first to report the strong association between stress and MS relapse, and, contradictory to past reports, an inconsistent relationship between stress and MS onset. Notably, the timing of stress (childhood or adulthood) seems to have little effect on the occurrence of either MS onset or relapse, though no study examined both childhood and adult stress within the same participant. Most studies were conducted in small, homogeneous samples using self-reported stress measures, which ultimately limits the generalizability of the findings. Overall, the state of the science remains tentative for all areas examined in this review, necessitating future research.

Fibrinolysis resistance after liver transplant as a predictor of early infection.

BACKGROUND: Infection is a leading cause of morbidity in liver transplant (LT). Considering that the fibrinolytic system is altered in sepsis, we investigated the relationship between fibrinolysis resistance (FR) and post-transplant infection. METHODS: Fibrinolysis was quantified using thrombelastography (TEG) with the addition of tPA to quantify FR. FR was defined as LY30 = 0% and stratified as transient if present on POD1 or POD5 (tFR), persistent (pFR) if present on both, or no FR (nFR) if absent. RESULTS: 180 LT recipients were prospectively enrolled. 52 (29%) recipients developed infection. 72 had tFR; 37 had pFR; and 71 had nFR. Recipients with pFR had significantly greater incidence of infections (51% vs. 26% tFR vs. 20% nFR, p = 0.002). pFR was independently associated with increased odds of post-transplant infection (adjusted OR 3.39, p = 0.009). CONCLUSIONS: Persistent fibrinolysis resistance is associated with increased risk of post-transplant infection.

PNPase and RhlB Interact and Reduce the Cellular Availability of Oxidized RNA in Deinococcus radiodurans.

8-Oxo-7,8-dihydroguanine (8-oxoG) is a major RNA modification caused by oxidative stresses and has been implicated in carcinogenesis, neurodegeneration, and aging. Several RNA-binding proteins have been shown to have a binding preference for 8-oxoG-modified RNA in eukaryotes and protect cells from oxidative stress. To date, polynucleotide phosphorylase (PNPase) is one of the most well-characterized proteins in bacteria that recognize 8-oxoG-modified RNA, but how PNPase cooperates with other proteins to process oxidized RNA is still unclear. Here, we use RNA affinity chromatography and mass spectrometry to search for proteins that preferably bind 8-oxoG-modified RNA in Deinococcus radiodurans, an extremophilic bacterium with extraordinary resistance to oxidative stresses. We identified four proteins that preferably bind to oxidized RNA: PNPase (DR_2063), DEAD box RNA helicase (DR_0335/RhlB), ribosomal protein S1 (DR_1983/RpsA), and transcriptional termination factor (DR_1338/Rho). Among these proteins, PNPase and RhlB exhibit high-affinity binding to 8-oxoG-modified RNA in a dose-independent manner. Deletions of PNPase and RhlB caused increased sensitivity of D. radiodurans to oxidative stress. We further showed that PNPase and RhlB specifically reduce the cellular availability of 8-oxoG-modified RNA but have no effect on oxidized DNA. Importantly, PNPase directly interacts with RhlB in D. radiodurans; however, no additional phenotypic effect was observed for the double deletion of pnp and rhlB compared to the single deletions. Overall, our findings suggest the roles of PNPase and RhlB in targeting 8-oxoG-modified RNAs and thereby constitute an important component of D. radiodurans resistance to oxidative stress. IMPORTANCE Oxidative RNA damage can be caused by oxidative stress, such as hydrogen peroxide, ionizing radiation, and antibiotic treatment. 8-oxo-7,8-dihydroguanine (8-oxoG), a major type of oxidized RNA, is highly mutagenic and participates in a variety of disease occurrences and development. Although several proteins have been identified to recognize 8-oxoG-modified RNA, the knowledge of how RNA oxidative damage is controlled largely remains unclear, especially in nonmodel organisms. In this study, we identified four RNA binding proteins that show higher binding affinity to 8-oxoG-modified RNA compared to unmodified RNA in the extremophilic bacterium Deinococcus radiodurans, which can endure high levels of oxidative stress. Two of the proteins, polynucleotide phosphorylase (PNPase) and DEAD-box RNA helicase (RhlB), interact with each other and reduce the cellular availability of 8-oxoG-modified RNA under oxidative stress. As such, this work contributes to our understanding of how RNA oxidation is influenced by RNA binding proteins in bacteria.

GPR37 modulates progenitor cell dynamics in a mouse model of ischemic stroke.

The generation of neural stem and progenitor cells following injury is critical for the function of the central nervous system, but the molecular mechanisms modulating this response remain largely unknown. We have previously identified the G protein-coupled receptor 37 (GPR37) as a modulator of ischemic damage in a mouse model of stroke. Here we demonstrate that GPR37 functions as a critical negative regulator of progenitor cell dynamics and gliosis following ischemic injury. In the central nervous system, GPR37 is enriched in mature oligodendrocytes, but following injury we have found that its expression is dramatically increased within a population of Sox2-positive progenitor cells. Moreover, the genetic deletion of GPR37 did not alter the number of mature oligodendrocytes following injury but did markedly increase the number of both progenitor cells and injury-induced Olig2-expressing glia. Alterations in the glial environment were further evidenced by the decreased activation of oligodendrocyte precursor cells. These data reveal that GPR37 regulates the response of progenitor cells to ischemic injury and provides new perspectives into the potential for manipulating endogenous progenitor cells following stroke.

Signal Recognition Particle RNA Contributes to Oxidative Stress Response in Deinococcus radiodurans by Modulating Catalase Localization.

The proper functioning of many proteins requires their transport to the correct cellular compartment or their secretion. Signal recognition particle (SRP) is a major protein transport pathway responsible for the co-translational movement of integral membrane proteins as well as periplasmic proteins. Deinococcus radiodurans is a ubiquitous bacterium that expresses a complex phenotype of extreme oxidative stress resistance, which depends on proteins involved in DNA repair, metabolism, gene regulation, and antioxidant defense. These proteins are located extracellularly or subcellularly, but the molecular mechanism of protein localization in D. radiodurans to manage oxidative stress response remains unexplored. In this study, we characterized the SRP complex in D. radiodurans R1 and showed that the knockdown (KD) of the SRP RNA (Qpr6) reduced bacterial survival under hydrogen peroxide and growth under chronic ionizing radiation. Through LC-mass spectrometry (MS/MS) analysis, we detected 162 proteins in the periplasm of wild-type D. radiodurans, of which the transport of 65 of these proteins to the periplasm was significantly reduced in the Qpr6 KD strain. Through Western blotting, we further demonstrated the localization of the catalases in D. radiodurans, DR_1998 (KatE1) and DR_A0259 (KatE2), in both the cytoplasm and periplasm, respectively, and showed that the accumulation of KatE1 and KatE2 in the periplasm was reduced in the SRP-defective strains. Collectively, this study establishes the importance of the SRP pathway in the survival and the transport of antioxidant proteins in D. radiodurans under oxidative stress.

Structural Insight into a Novel Formyltransferase and Evolution to a Nonribosomal Peptide Synthetase Tailoring Domain.

Nonribosomal peptide synthetases (NRPSs) increase the chemical diversity of their products by acquiring tailoring domains. Linear gramicidin synthetase starts with a tailoring formylation (F) domain, which likely originated from a sugar formyltransferase (FT) gene. Here, we present studies on an Anoxybacillus kamchatkensis sugar FT representative of the prehorizontal gene transfer FT. Gene cluster analysis reveals that this FT acts on a UDP-sugar in a novel pathway for synthesis of a 7-formamido derivative of CMP-pseudaminic acid. We recapitulate the pathway up to and including the formylation step in vitro, experimentally demonstrating the role of the FT. We also present X-ray crystal structures of the FT alone and with ligands, which unveil contrasts with other structurally characterized sugar FTs and show close structural similarity with the F domain. The structures reveal insights into the adaptations that were needed to co-opt and evolve a sugar FT into a functional and useful NRPS domain.