The Benefit of Early and Frequent Antitumor Necrosis Factor-Alpha Trough Level Determination in Very Early-Onset Inflammatory Bowel Disease.

A patient with infantile-onset Crohn's disease had a partial response to corticosteroid therapy that worsened on its tapering, leading to treatment with antitumor necrosis factor-alpha monoclonal antibody therapy. Infliximab rapidly cleared before administration of the third accelerated induction dose with the development of antibodies. Adalimumab was initiated with a good clinical effect but also rapidly cleared, requiring dose intensification to improve drug levels and to maintain a good clinical response. The amount of medication could eventually be decreased. Accelerated induction and maintenance drug monitoring can prevent secondary loss of response in very young children with inflammatory bowel disease.

Plasminogen Activator Inhibitor-1-Positive Platelet-Derived Extracellular Vesicles Predicts MACE and the Proinflammatory SMC Phenotype.

Patients with established coronary artery disease remain at elevated risk of major adverse cardiac events. The goal of this study was to evaluate the utility of plasminogen activator inhibitor-1-positive platelet-derived extracellular vesicles as a biomarker for major adverse cardiac events and to explore potential underlying mechanisms. Our study suggests these extracellular vesicles as a potential biomarker to identify and a therapeutic target to ameliorate neointimal formation of high-risk patients.

Impact of intracoronary assessments on revascularization decisions: A contemporary evaluation.

OBJECTIVES: To investigate the real-world implementation of intracoronary assessment (ICA) techniques and evaluate their impact on clinical decisions regarding the management of coronary artery disease (CAD) in contemporary practice. BACKGROUND: Coronary angiogram is the gold standard used to diagnose vessel stenosis and guide percutaneous coronary intervention (PCI); however, it is limited by its two-dimensional imaging capabilities. ICA techniques like intravascular ultrasound and optical coherence tomography capture the vessel in three-dimensional images. Comparatively, fractional flow reserve provides information on the physiologic significance of coronary stenosis. Both techniques may improve PCI outcomes if they routinely change physician behavior. METHODS: Patients who underwent ICA between August 2015 and March 2020 were included in the study. The primary outcome was the clinical impact of ICA on physician clinical decision making of a stenotic vessel. The secondary outcome was the clinical changes that occurred following ICA. RESULTS: A total of 1135 patients were included in the study. Physiologic assessment (PA) and image assessment (IA) were performed in 61.4% and 38.6% respectively. Management plans were changed in 38.1% and 23.9% of patients who received PA and IA. Over half of the management change resulted in physicians deciding to not intervene on the stenotic vessel. One-year outcome of these decisions showed no significant increase in major adverse cardiac events (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.40-1.15; p = 0.15) or unplanned revascularization (HR, 0.78; 95% CI, 0.35-1.74; p = 0.55) suggesting reliance on PA/IA data did not increase risk. CONCLUSION: Selected ICA alters physician management of CAD in one-third of patients being evaluated for revascularization-typically leading to fewer interventions. All cause death is numerally lower in patients that received a change in management. However, the 1-year outcome of these altered decisions does not appear to be significantly different.

Impact of atrial fibrillation on the risk of major adverse cardiac events following coronary revascularisation.

OBJECTIVE: Atrial fibrillation (AF) remains a highly prevalent arrhythmia with significant burden on morbidity and mortality. The impact of AF in the revascularised population remains incompletely described. Given the high prevalence of AF in the revascularised population, we sought to evaluate the incidence and prognosis in patients with pre-existing and new-onset AF following revascularisation. METHODS: We used the University of Ottawa Heart Institute Revascularisation Registry to identify patients who underwent revascularisation between August 2015 and March 2020, who were prospectively followed for an average of one year. We conducted a retrospective cohort study analysing the association between AF and clinical outcomes. The primary outcome of interest was 1-year major adverse cardiac events (MACE) defined as a composite of death, myocardial infarction, unplanned revascularisation and cerebrovascular accidents. Moreover, secondary outcomes include the individual components of MACE and bleeding. RESULTS: A total of 6704 patients underwent revascularisation and completed 1-year clinical follow-up. Median time to follow-up was 12.8 (IQR 11.2-15.9) months. One-year MACE occurred in 166 (21.8%) and 683 (11.5%) patients in AF and non-AF groups, respectively (adjusted HR, 1.61; 95% CI 1.29 to 2.01; p<0.0001). AF was independently predictive of 1-year mortality, myocardial infarction, unplanned revascularisation, cerebrovascular accident and bleeding. Within 1 year, 299 (4.5%) episodes of new-onset AF was observed. New-onset AF following revascularisation was also associated with 1-year MACE, mortality, myocardial infarction, cerebrovascular accident and unplanned revascularisation. CONCLUSIONS: Preprocedural and new-onset AF following revascularisation remains highly predictive 1-year MACE. AF should be considered in addition to traditional risk factors for adverse outcomes following revascularisation.

Dichotomy in hypoxia-induced mitochondrial fission in placental mesenchymal cells during development and preeclampsia: consequences for trophoblast mitochondrial homeostasis.

Dynamic changes in physiologic oxygen are required for proper placenta development; yet, when low-oxygen levels persist, placental development is halted, culminating in preeclampsia (PE), a serious complication of pregnancy. Considering mitochondria's function is intimately linked to oxygen changes, we investigated the impact of oxygen on mitochondrial dynamics in placental mesenchymal stromal cells (pMSCs) that are vital for proper placental development. Transmission electron microscopy, proximity ligation assays for mitochondrial VDAC1 and endoplasmic reticulum IP3R, and immunoanalyses of p-DRP1 and OPA1, demonstrate that low-oxygen conditions in early 1st trimester and PE promote mitochondrial fission in pMSCs. Increased mitochondrial fission of mesenchymal cells was confirmed in whole PE placental tissue sections. Inhibition of DRP1 oligomerization with MDiVi-1 shows that low oxygen-induced mitochondrial fission is a direct consequence of DRP1 activation, likely via HIF1. Mitophagy, a downstream event prompted by mitochondrial fission, is a prominent outcome in PE, but not 1st trimester pMSCs. We also investigated whether mesenchymal-epithelial interactions affect mitochondrial dynamics of trophoblasts in PE placentae. Exposure of trophoblastic JEG3 cells to exosomes of preeclamptic pMSCs caused heightened mitochondrial fission in the cells via a sphingomyelin-dependent mechanism that was restored by MDiVi-1. Our data uncovered dichotomous regulation of mitochondrial fission and health in human placental mesenchymal cells under physiologic and pathologic hypoxic conditions and its impact on neighboring trophoblast cells.

Implications of Myocardial Infarction on Management and Outcome in Cardiogenic Shock.

Background The randomized DOREMI (Dobutamine Compared to Milrinone) clinical trial evaluated the efficacy and safety of milrinone and dobutamine in patients with cardiogenic shock. Whether the results remain consistent when stratified by acute myocardial infarction remains unknown. In this substudy, we sought to evaluate differences in clinical management and outcomes of acute myocardial infarction complicated by cardiogenic shock (AMICS) versus non-AMICS. Methods and Results Patients in cardiogenic shock (n=192) were randomized 1:1 to dobutamine or milrinone. The primary composite end point in this subgroup analysis was all-cause in-hospital mortality, cardiac arrest, non-fatal myocardial infarction, cerebrovascular accident, the need for mechanical circulatory support, or initiation of renal replacement therapy (RRT) at 30-days. Outcomes were evaluated in patients with (n=65) and without (n=127) AMICS. The primary composite end point was significantly higher in AMICS versus non-AMICS (hazard ratio [HR], 2.21; 95% CI, 1.47-3.30; P=0.0001). The primary end point was driven by increased rates of all-cause mortality, mechanical circulatory support, and RRT. No differences in other secondary outcomes including cardiac arrest or cerebrovascular accident were observed. AMICS remained associated with the primary composite outcome, 30-day mortality, and RRT after adjustment for age, sex, procedural contrast use, multivessel disease, and inotrope type. Conclusions AMI was associated with increased rates of adverse clinical outcomes in cardiogenic shock along with increased rates of mortality and initiation of mechanical circulatory support and RRT. Contrast administration during revascularization likely contributes to increased rates of RRT. Heterogeneity of outcomes in AMICS versus non-AMICS highlights the need to study interventions in specific subgroups of cardiogenic shock. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03207165.

The association between mean arterial pressure and outcomes in patients with cardiogenic shock: insights from the DOREMI trial.

AIMS: Cardiogenic shock (CS) is a state of low cardiac output resulting in end-organ hypoperfusion. Despite high in-hospital mortality rates, little evidence exists regarding the optimal mean arterial pressure (MAP) target in CS. We therefore evaluated the relationship between achieved MAP and clinical outcomes in patients with CS. METHODS AND RESULTS: We performed a post hoc analysis of the CAPITAL DOREMI trial: a randomized, double-blind trial comparing dobutamine to milrinone in patients with CS. We divided patients into a high MAP group (average MAP ≥ 70 mmHg over the 36 h following randomization), and a low MAP group (average MAP < 70 mmHg). Our primary outcome included in-hospital all-cause mortality, resuscitated cardiac arrest, need for cardiac transplantation or mechanical circulatory support, non-fatal myocardial infarction, transient ischaemic attack or stroke, or initiation of renal replacement therapy. In total, 71 (37.0%) patients achieved an average MAP < 70 mmHg, and 121 (63.0%) achieved an average MAP ≥ 70 mmHg. The primary outcome occurred in 48 (67.6%) patients in the low MAP group and 51 (42.2%) patients in the high MAP group [adjusted relative risk (aRR) 0.70; 95% confidence interval (CI) 0.53-0.92; P = 0.01]. All-cause mortality occurred in 41 (57.8%) and 35 (28.9%) patients in the low and high MAP groups, respectively (aRR 0.56; 95% CI 0.40-0.79; P < 0.01). There were no significant differences in any secondary outcomes between each group. CONCLUSIONS: In patients with CS treated with inotrope therapy, low MAP is associated with worse clinical outcomes. Randomized data evaluating optimal MAP targets in CS is needed to guide medical therapy.

JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration.

The mechanisms contributing to excessive fibronectin in preeclampsia, a pregnancy-related disorder, remain unknown. Herein, we investigated the role of JMJD6, an O2- and Fe2+-dependent enzyme, in mediating placental fibronectin processing and function. MALDI-TOF identified fibronectin as a novel target of JMJD6-mediated lysyl hydroxylation, preceding fibronectin glycosylation, deposition, and degradation. In preeclamptic placentae, fibronectin accumulated primarily in lysosomes of the mesenchyme. Using primary placental mesenchymal cells (pMSCs), we found that fibronectin fibril formation and turnover were markedly impeded in preeclamptic pMSCs, partly due to impaired lysosomal degradation. JMJD6 knockdown in control pMSCs recapitulated the preeclamptic FN phenotype. Importantly, preeclamptic pMSCs had less total and labile Fe2+ and Hinokitiol treatment rescued fibronectin assembly and promoted lysosomal degradation. Time-lapse imaging demonstrated that defective ECM deposition by preeclamptic pMSCs impeded HTR-8/SVneo cell migration, which was rescued upon Hinokitiol exposure. Our findings reveal new Fe2+-dependent mechanisms controlling fibronectin homeostasis/function in the placenta that go awry in preeclampsia.

Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.

OBJECTIVE: Autophagy is a physiological self-eating process that can promote cell survival or activate cell death in eukaryotic cells. In skeletal muscle, it is important for maintaining muscle mass and function that is critical to sustain mobility and regulate metabolism. The UV radiation resistance-associated gene (UVRAG) regulates the early stages of autophagy and autophagosome maturation and plays a key role in endosomal trafficking. This study investigated the essential in vivo role of UVRAG in skeletal muscle biology. METHODS: To determine the role of UVRAG in skeletal muscle in vivo, we generated muscle-specific UVRAG knockout mice using the Cre-loxP system driven by Myf6 promoter that is exclusively expressed in skeletal muscle. Myf6-Cre+ UVRAGfl/fl (M-UVRAG-/-) mice were compared to littermate Myf6-Cre+ UVRAG+/+ (M-UVRAG+/+) controls under basal conditions on a normal chow diet. Body composition, muscle function, and mitochondria morphology were assessed in muscles of the WT and KO mice at 24 weeks of age. RESULTS: M-UVRAG-/- mice developed accelerated sarcopenia and impaired muscle function compared to M-UVRAG+/+ littermates at 24 weeks of age. Interestingly, these mice displayed improved glucose tolerance and increased energy expenditure likely related to upregulated Fgf21, a marker of muscle dysfunction. Skeletal muscle of the M-UVRAG-/- mice showed altered mitochondrial morphology with increased mitochondrial fission and EGFR accumulation reflecting defects in endosomal trafficking. To determine whether increased EGFR signaling had a causal role in muscle dysfunction, the mice were treated with an EGFR inhibitor, gefitinib, which partially restored markers of muscle and mitochondrial deregulation. Conversely, constitutively active EGFR transgenic expression in UVRAG-deficient muscle led to further detrimental effects with non-overlapping distinct defects in muscle function, with EGFR activation affecting the muscle fiber type whereas UVRAG deficiency impaired mitochondrial homeostasis. CONCLUSIONS: Our results show that both UVRAG and EGFR signaling are critical for maintaining muscle mass and function with distinct mechanisms in the differentiation pathway.

Increased placental mitochondrial fusion in gestational diabetes mellitus: an adaptive mechanism to optimize feto-placental metabolic homeostasis?

INTRODUCTION: Gestational diabetes mellitus (GDM), a common pregnancy disorder, increases the risk of fetal overgrowth and later metabolic morbidity in the offspring. The placenta likely mediates these sequelae, but the exact mechanisms remain elusive. Mitochondrial dynamics refers to the joining and division of these organelles, in attempts to maintain cellular homeostasis in stress conditions or alterations in oxygen and fuel availability. These remodeling processes are critical to optimize mitochondrial function, and their disturbances characterize diabetes and obesity. METHODS AND RESULTS: Herein we show that placental mitochondrial dynamics are tilted toward fusion in GDM, as evidenced by transmission electron microscopy and changes in the expression of key mechanochemical enzymes such as OPA1 and active phosphorylated DRP1. In vitro experiments using choriocarcinoma JEG-3 cells demonstrated that increased exposure to insulin, which typifies GDM, promotes mitochondrial fusion. As placental ceramide induces mitochondrial fission in pre-eclampsia, we also examined ceramide content in GDM and control placentae and observed a reduction in placental ceramide enrichment in GDM, likely due to an insulin-dependent increase in ceramide-degrading ASAH1 expression. CONCLUSIONS: Placental mitochondrial fusion is enhanced in GDM, possibly as a compensatory response to maternal and fetal metabolic derangements. Alterations in placental insulin exposure and sphingolipid metabolism are among potential contributing factors. Overall, our results suggest that GDM has profound impacts on placental mitochondrial dynamics and metabolism, with plausible implications for the short-term and long-term health of the offspring.