Publications by authors named "Peter Liu"

549 Publications

Vagus nerve stimulation does not alter brainstem nuclei morphology in patients with refractory epilepsy.

Epilepsy Behav 2021 Apr 7;118:107940. Epub 2021 Apr 7.

Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, Ontario, Canada; Department of Pathology and Lab Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada. Electronic address:

Objective: To describe morphological characteristics of the brainstem nuclei in response to chronic vagus nerve stimulation (VNS) in patients with refractory epilepsy.

Background: VNS is a treatment option for individuals with medically refractory epilepsy. While treatment with VNS may achieve up to 50% seizure reduction and is protective against sudden unexpected death in epilepsy (SUDEP), its mechanism of action is not fully understood. Long-term structural and cellular changes in response to VNS have rarely been addressed in humans.

Methods: Four autopsy cases with history of chronic epilepsy treated with VNS (VNS+) and 4 age- and sex-matched chronic epilepsy-related death cases without VNS (VNS-) were included. Detailed clinical and postmortem data were obtained. Serial horizontal sections of the brainstem were prepared and stained with hematoxylin, eosin, and luxol fast blue (HE/LFB). Three regions of interest (ROIs) were delineated, including nucleus tractus solitarius (NTS), locus coeruleus (LC), and the rostral pontine group of raphe nuclei (rRN). Immunohistochemistry studies were performed using antibodies to GFAP, NeuN, HLA-DR, and IBA-1. Immunolabeling index was analyzed.

Results: Three of the 4 VNS+ patients and all 4 control (VNS-) patients died of SUDEP. There was no laterality difference in the NeuN, GFAP, HLA-DR and IBA-1 expression in LC and NTS of VNS+ patients. Similarly, there was no difference in the rRN, LC, and NTS between the VNS+ and VNS- groups.

Conclusion: This study represents the first histopathological study of the long-term effects of VNS therapy in the human brain. There was no difference observed in the neuronal cell number, degree of astrocytosis, and neuroinflammation in the main brainstem vagal afferent nuclei after prolonged VNS treatment in patients with refractory epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2021.107940DOI Listing
April 2021

Can Hernia Sac to Abdominal Cavity Volume Ratio Predict Fascial Closure Rate for Large Ventral Hernia? Reliability of the Tanaka Score.

J Am Coll Surg 2021 Apr 5. Epub 2021 Apr 5.

Center for Abdominal Core Health, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH.

Background: The hernia sac to abdominal cavity volume ratio (VR) on abdominal CT was described previously as a way to predict which hernias would be less likely to achieve fascial closure. The aim of this study was to test the reliability of the previously described cutoff ratio in predicting fascial closure in a cohort of patients with large ventral hernias.

Methods: Patients who underwent elective, open incisional hernia repair of 18 cm or larger width at a single center were identified. The primary end point of interest was fascial closure for all patients. Secondary outcomes included operative details and abdominal wall-specific quality-of-life metrics. We used VR as a comparison variable and calculated the test characteristics (ie, sensitivity, specificity, and positive and negative predictive values).

Results: A total of 438 patients were included, of which 337 (77%) had complete fascial closure and 101 (23%) had incomplete fascial closure. The VR cutoff of 25% had a sensitivity of 76% (95% CI, 71% to 80%), specificity of 64% (95% CI, 54% to 74%), positive predictive value of 88% (95% CI, 83% to 91%), and negative predictive value of 45% (95% CI, 36% to 53%). The incomplete fascial closure group had significantly lower quality of life scores at 1 year (83.3 vs 52.5; p = 0.001), 2 years (85 vs 33.3; p = 0.003), and 3 years (86.7 vs 63.3; p = 0.049).

Conclusions: In our study, the VR cutoff of 25% was sensitive for predicting complete fascial closure for patients with ratios below this threshold. Although there is a higher likelihood of incomplete fascial closure when VR is ≥ 25%, this end point cannot be predicted reliably. Additional studies should be done to study this ratio in conjunction with other hernia-related variables to better predict this important surgical end point.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jamcollsurg.2021.03.009DOI Listing
April 2021

Fracture Risks in Patients Treated With Different Oral Anticoagulants: A Systematic Review and Meta-Analysis.

J Am Heart Assoc 2021 Apr 24;10(7):e019618. Epub 2021 Mar 24.

Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan.

Background Evidence on the differences in fracture risk associated with non-vitamin K antagonist oral anticoagulants (NOAC) and warfarin is inconsistent and inconclusive. We conducted a systematic review and meta-analysis to assess the fracture risk associated with NOACs and warfarin. Methods and Results We searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov from inception until May 19, 2020. We included studies presenting measurements (regardless of primary/secondary/tertiary/safety outcomes) for any fracture in both NOAC and warfarin users. Two or more reviewers independently screened relevant articles, extracted data, and performed quality assessments. Data were retrieved to synthesize the pooled relative risk (RR) of fractures associated with NOACs versus warfarin. Random-effects models were used for data synthesis. We included 29 studies (5 cohort studies and 24 randomized controlled trials) with 388 209 patients. Patients treated with NOACs had lower risks of fracture than those treated with warfarin (pooled RR, 0.84; 95% CI, 0.77-0.91; <0.001) with low heterogeneity (=38.9%). NOACs were also associated with significantly lower risks of hip fracture than warfarin (pooled RR, 0.89; 95% CI, 0.81-0.98; =0.023). A nonsignificant trend of lower vertebral fracture risk in NOAC users was also observed (pooled RR, 0.74; 95% CI, 0.54-1.01; =0.061). Subgroup analyses for individual NOACs demonstrated that dabigatran, rivaroxaban, and apixaban were significantly associated with lower fracture risks. Furthermore, the data synthesis results from randomized controlled trials and real-world cohort studies were quite consistent, indicating the robustness of our findings. Conclusions Compared with warfarin, NOACs are associated with lower risks of bone fracture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.019618DOI Listing
April 2021

Night shift schedule alters endogenous regulation of circulating cytokines.

Neurobiol Sleep Circadian Rhythms 2021 May 5;10:100063. Epub 2021 Mar 5.

Sleep and Performance Research Center, Washington State University, Spokane, WA, 99202, USA.

Night shift work is a risk factor for viral infection, suggesting that night shift schedules compromise host defense mechanisms. Prior studies have investigated changes in the temporal profiles of circulating cytokines important for priming and restraining the immune response to infectious challenges from night shift work, but not by way of a 24-h constant routine of continuous wakefulness devoid of behavioral or environmental influences. Hence the true pattern of cytokines, and the combined effect of sleep loss and circadian misalignment on these cytokines remains unknown. Here, 14 healthy young men and women underwent three days of either a simulated night shift or a simulated day shift schedule under dim light in a controlled in-laboratory environment. This was followed by a 24-h constant routine protocol during which venous blood was collected at 3-h intervals. Those who had been in the night shift schedule showed lower mean circulating TNF-α (t = -6.03, p < 0.001), without any significant differences in IL-1β, IL-8 and IL-10, compared with those who had been in the day shift (i.e., control) schedule. Furthermore, circulating IL-6 increased with time awake in both shift work conditions (t = 6.03, p < 0.001), such that temporal changes in IL-6 were markedly shifted relative to circadian clock time in the night shift condition. These results indicate that night shift work compromises host defense by creating cytokine conditions that initially impede anti-viral immunity (lower TNF-α) and may eventually promote autoimmunity (mistimed rise in IL-6).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbscr.2021.100063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970107PMC
May 2021

Contact-free screening for obstructive sleep apnea: comfort, especially in a physically distanced brave new world.

J Clin Sleep Med 2021 Mar 10. Epub 2021 Mar 10.

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center and The Lundquist Institute, Torrance, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5664/jcsm.9238DOI Listing
March 2021

Discovery of a dual pathway aggregation mechanism for a therapeutic constrained peptide.

J Pharm Sci 2021 Feb 27. Epub 2021 Feb 27.

Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.

Constrained peptides (CPs) have emerged as attractive candidates for drug discovery and development. To fully unlock the therapeutic potential of CPs, it is crucial to understand their physical stability and minimize the formation of aggregates that could induce immune responses. Although amyloid like aggregates have been researched extensively, few studies have focused on aggregates from other peptide scaffolds (e.g., CPs). In this work, a streamlined approach to effectively profile the nature and formation pathway of CP aggregates was demonstrated. Aggregates of various sizes were detected and shown to be amorphous. Though no major changes were found in peptide structure upon aggregation, these aggregates appeared to have mixed natures, consisting of primarily non-covalent aggregates with a low level of covalent species. This co-existence phenomenon was also supported by two kinetic pathways observed in time- and temperature-dependent aggregation studies. Furthermore, a stability study with 8 additional peptide variants exhibited good correlation between aggregation propensity and peptide hydrophobicity. Therefore, a dual aggregation pathway was proposed, with the non-covalent aggregates driven by hydrophobic interactions, whereas the covalent ones formed through disulfide scrambling. Overall, the workflow presented here provides a powerful strategy for comprehensive characterization of peptide aggregates and understanding their mechanisms of formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xphs.2020.12.041DOI Listing
February 2021

Lower Risk of Dementia in Patients With Atrial Fibrillation Taking Non-Vitamin K Antagonist Oral Anticoagulants: A Nationwide Population-Based Cohort Study.

J Am Heart Assoc 2021 Feb 15;10(5):e016437. Epub 2021 Feb 15.

Center for Aging and Health Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan.

Background A higher risk of developing dementia is observed in patients with atrial fibrillation (AF). Results are inconsistent regarding the risk of dementia when patients with AF use different anticoagulants. We aimed to investigate the risk of dementia in patients with AF receiving non-vitamin K antagonist oral anticoagulants (NOACs) compared with those receiving warfarin. Methods and Results We conducted a nationwide population-based cohort study of incident cases using the Taiwan National Health Insurance Research Database. We initially enlisted all incident cases of AF and then selected those treated with either NOACs or warfarin for at least 90 days between 2012 and 2016. First-ever diagnosis of dementia was the primary outcome. We performed propensity score matching to minimize the difference between each cohort. We used the Fine and Gray competing risk regression model to calculate the hazard ratio (HR) for dementia. We recruited 12 068 patients with AF (6034 patients in each cohort). The mean follow-up time was 3.27 and 3.08 years in the groups using NOACs and warfarin, respectively. Compared with the HR for the group using warfarin, the HR for dementia was 0.82 (95% CI, 0.73-0.92; =0.0004) in the group using NOACs. Subgroup analysis demonstrated that users of NOAC aged 65 to 74 years, with a high risk of stroke or bleeding were associated with a lower risk of dementia than users of warfarin with similar characteristics. Conclusions Patients with AF using NOACs were associated with a lower risk of dementia than those using warfarin. Further randomized clinical trials are greatly needed to prove these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.016437DOI Listing
February 2021

Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter.

J Hepatol 2021 Jan 29. Epub 2021 Jan 29.

Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. Electronic address:

Background & Aims: Hypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism, yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. We therefore investigated the role of HIFs in regulating HBV replication.

Methods: Using cell culture, animal models, human tissue and pharmacological agents inhibiting the HIF-prolyl hydroxylases, we investigated the impact of hypoxia on the HBV life cycle.

Results: Culturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pre-genomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlights an evolutionary conserved role for HIFs in regulating this virus family.

Conclusions: Identifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF signaling pathway to persist in the low oxygen environment of the liver. Our studies show the importance of considering oxygen availability when studying HBV-host interactions and provide innovative routes to better understand and target chronic HBV infection.

Lay Summary: Viral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen tension. Hepatitis B virus (HBV) replicates in the liver, a naturally hypoxic organ. Hypoxia inducible factors (HIFs) are the major sensors of low oxygen; herein, we identify a new role for these factors in regulating HBV replication, revealing new therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.12.034DOI Listing
January 2021

Integrated photothermal decontamination device for N95 respirators.

Sci Rep 2021 01 19;11(1):1822. Epub 2021 Jan 19.

Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y4W7, Canada.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the COVID-19 global pandemic has infected over 25 million people worldwide and resulted in the death of millions. The COVID-19 pandemic has also resulted in a shortage of personal protective equipment (PPE) in many regions around the world, particularly in middle- and low-income countries. The shortages of PPE, such as N95 respirators, is something that will persist until an effective vaccine is made available. Thus, devices that while being easy to operate can also be rapidly deployed in health centers, and long-term residences without the need for major structural overhaul are instrumental to sustainably use N95 respirators. In this report, we present the design and validation of a decontamination device that combines UV-C & B irradiation with mild-temperature treatment. The device can decontaminate up to 20 masks in a cycle of < 30 min. The decontamination process did not damage or reduce the filtering capacity of the masks. Further, the efficacy of the device to eliminate microbes and viruses from the masks was also evaluated. The photothermal treatment of our device was capable of eradicating > 99.9999% of the bacteria and > 99.99% of the virus tested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-80908-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815715PMC
January 2021

Finite-Time-Prescribed Performance-Based Adaptive Fuzzy Control for Strict-Feedback Nonlinear Systems With Dynamic Uncertainty and Actuator Faults.

IEEE Trans Cybern 2021 Jan 15;PP. Epub 2021 Jan 15.

In this article, finite-time-prescribed performance-based adaptive fuzzy control is considered for a class of strict-feedback systems in the presence of actuator faults and dynamic disturbances. To deal with the difficulties associated with the actuator faults and external disturbance, an adaptive fuzzy fault-tolerant control strategy is introduced. Different from the existing controller design methods, a modified performance function, which is called the finite-time performance function (FTPF), is presented. It is proved that the presented controller can ensure all the signals of the closed-loop system are bounded and the tracking error converges to a predetermined region in finite time. The effectiveness of the presented control scheme is verified through the simulation results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TCYB.2020.3046316DOI Listing
January 2021

High-sensitivity nanophotonic sensors with passive trapping of analyte molecules in hot spots.

Light Sci Appl 2021 Jan 5;10(1). Epub 2021 Jan 5.

Department of Electrical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.

Nanophotonic resonators can confine light to deep-subwavelength volumes with highly enhanced near-field intensity and therefore are widely used for surface-enhanced infrared absorption spectroscopy in various molecular sensing applications. The enhanced signal is mainly contributed by molecules in photonic hot spots, which are regions of a nanophotonic structure with high-field intensity. Therefore, delivery of the majority of, if not all, analyte molecules to hot spots is crucial for fully utilizing the sensing capability of an optical sensor. However, for most optical sensors, simple and straightforward methods of introducing an aqueous analyte to the device, such as applying droplets or spin-coating, cannot achieve targeted delivery of analyte molecules to hot spots. Instead, analyte molecules are usually distributed across the entire device surface, so the majority of the molecules do not experience enhanced field intensity. Here, we present a nanophotonic sensor design with passive molecule trapping functionality. When an analyte solution droplet is introduced to the sensor surface and gradually evaporates, the device structure can effectively trap most precipitated analyte molecules in its hot spots, significantly enhancing the sensor spectral response and sensitivity performance. Specifically, our sensors produce a reflection change of a few percentage points in response to trace amounts of the amino-acid proline or glucose precipitate with a picogram-level mass, which is significantly less than the mass of a molecular monolayer covering the same measurement area. The demonstrated strategy for designing optical sensor structures may also be applied to sensing nano-particles such as exosomes, viruses, and quantum dots.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41377-020-00449-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785746PMC
January 2021

Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.

Nat Commun 2020 12 14;11(1):6387. Epub 2020 Dec 14.

Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.

Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19974-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736581PMC
December 2020

Patient- and Physician-Level Factors Associated With Adherence to C-CHANGE Recommendations in Primary Care Settings in Ontario.

CJC Open 2020 Nov 17;2(6):563-576. Epub 2020 Jul 17.

Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Background: We previously found large variation among family physicians in adherence to the anadian ardiovascular armonization of ational uidelines ndeavour (C-CHANGE). We assessed the role of patient- and physician-level factors in the variation in adherence to recommendations for managing cardiovascular disease risk factors.

Methods: We conducted a retrospective study using multilevel logistic regression analyses with the lectronic edical ecord dministrative data inked atabase (EMRALD) housed at ICES in Ontario. Five quality indicators based on C-CHANGE guidelines were modelled. Effects of clustering and between-group variation, patient-level (sociodemographics, comorbidities) and physician-level characteristics (demographic and practice information) were assessed to determine odds ratios of receiving C-CHANGE recommended care.

Results: In all, 324 Ontario physicians practicing in 41 clinics who provided care to 227,999 adult patients were studied. We found significant variation in quality indicators, with 15% to 39% of the total variation attributable to nonpatient factors. The largest variation was in performing 2-hour plasma glucose testing in prediabetic patients. Patient-level factors most frequently associated with recommendation adherence included sex, age, and multi-comorbidities. Women were more likely than men to have their body mass index measured, and their blood pressure controlled, but less likely to receive antiplatelet medications and liver-enzyme testing if overweight or obese.

Conclusions: The majority of variations in adherence were attributable to patient attributes, but a substantial proportion of unexplained variation was due to differences among physicians and clinics. This finding may signal suboptimal processes or structures and warrant further investigation to improve the quality of primary care management of cardiovascular disease in Ontario.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cjco.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711016PMC
November 2020

Sex-specific temporal trends in ambulatory heart failure incidence, mortality and hospitalisation in Ontario, Canada from 1994 to 2013: a population-based cohort study.

BMJ Open 2020 11 26;10(11):e044126. Epub 2020 Nov 26.

Cardiovasulcar Research Program, ICES (formerly the Institute for Clinical Evaluative Sciences), Toronto, Ontario, Canada.

Objectives: To examine the temporal trends in mortality and heart failure (HF) hospitalisation in ambulatory patients following a new diagnosis of HF.

Design: Retrospective cohort study SETTING: Outpatient PARTICIPANTS: Ontario residents who were diagnosed with HF in an outpatient setting between 1994 and 2013.

Primary And Secondary Outcome Measures: The primary outcome was all-cause mortality within 1 year of diagnosis and the secondary outcome was HF hospitalisation within 1 year. Risks of mortality and hospitalisation were calculated using the Kaplan-Meier method and the relative hazard of death was assessed using multivariable Cox proportional hazard models.

Results: A total of 352 329 patients were studied (50% female). During the study period, there was a greater decline in age standardised 1-year mortality rates (AMR) in men (33%) than in women (19%). Specifically, female AMR at 1 year was 10.4% (95% CI 9.1% to 12.0%) in 1994 and 8.5% (95% CI 7.5% to 9.5%) in 2013, and male AMR at 1 year was 12.3% (95% CI 11.1% to 13.7%) in 1994 and 8.3% (95% CI 7.5% to 9.1%) in 2013. Conversely, age standardised HF hospitalisation rates declined in men (11.4% (95% CI 10.1% to 12.9%) in 1994 and 9.1% (95% CI 8.2% to 10.1%) in 2013) but remained unchanged in women (9.7% (95% CI 8.3% to 11.3%) in 1994 and 9.8% (95% CI 8.6% to 11.0%) in 2013).

Conclusion: Among patients with HF over a 20-year period, there was a greater improvement in the prognosis of men compared with women. Further research should focus on the determinants of this disparity and ways to reduce this gap in outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-044126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692840PMC
November 2020

Expression Associates With Inflammation in Early Atherosclerosis in Humans and Can Be Therapeutically Silenced to Reduce NF-κB Activation and Atherogenesis in Mice.

Circulation 2021 Jan 23;143(2):163-177. Epub 2020 Nov 23.

University of Ottawa Heart Institute, Canada (D.K., M.-A.N., M.G., Z.L., H.W., J.W.K., R.J., A.M., A.R., P.L., K.J.R.).

Background: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. We previously showed that macrophages in the atherogenic plaque undergo RIPK3 (receptor-interacting serine/threonine-protein kinase 3)-MLKL (mixed lineage kinase domain-like protein)-dependent programmed necroptosis in response to sterile ligands such as oxidized low-density lipoprotein and damage-associated molecular patterns and that necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1 (receptor-interacting serine/threonine-protein kinase 1), which acts as a master switch that controls whether the cell undergoes NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells)-dependent inflammation, caspase-dependent apoptosis, or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is driven largely by NF-κB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NF-κB-dependent inflammation in early atherogenic lesions, and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis.

Methods: We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and used loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 antisense oligonucleotides to mice fed a cholesterol-rich (Western) diet for 8 weeks.

Results: We find that RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 antisense oligonucleotides led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, <0.01) and plasma inflammatory cytokines (IL-1α [interleukin 1α], IL-17A [interleukin 17A], <0.05) in comparison with controls. knockdown in macrophages decreased inflammatory genes (NF-κB, TNFα [tumor necrosis factor α], IL-1α) and in vivo lipopolysaccharide- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown of prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of , , and monocyte attachment.

Conclusions: We identify RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038379DOI Listing
January 2021

Cross-Sectional Imaging Evaluation of Vascular Lesions in the Gastrointestinal Tract and Mesentery.

J Comput Assist Tomogr 2020 Nov/Dec;44(6):870-881

Department of Diagnostic Radiology, University of Missouri, Columbia, MO.

Gastrointestinal (GI) tract and mesenteric vascular lesions can have various clinical presentations, of which GI bleeding is the most common. This collection of pathology is highly variable in etiology ranging from occlusive disease to vascular malformations to trauma to neoplasms which makes for a challenging workup and diagnosis. The advent of multiple imaging modalities and endoscopic techniques makes the diagnosis of these lesions more achievable, and familiarity with their various imaging findings can have a significant impact on patient management. In this article, we review the gamut of GI tract and mesenteric vascular lesions and their associated imaging findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RCT.0000000000001107DOI Listing
December 2020

A vortex method of 3D smoke simulation for virtual surgery.

Comput Methods Programs Biomed 2021 Jan 27;198:105813. Epub 2020 Oct 27.

School of Information and Engineering, Nanchang University, Nanchang, China 330031.

Background And Objective: A realistic virtual surgery simulation needs to simulate smoke as electrical cutting causes thermal tissue damage. The vortex particle method of simulating smoke can realistically present the vortex details and motion trajectory of the smoke, but there is high computational cost.

Methods: To address this problem, we propose the 3D Vortex Particles in Cube Algorithm (3D-VPICA). 3D-VPICA can realistically show the visual effect of smoke and reduce the computational cost. In addition, in order to enhance the reality of the smoke, we propose the Auxiliary Particles Algorithm (APA) method to deal with the collision problem of smoke.

Results: The 3D-VPICA can calculate the velocity of the vortex particles speedily with the help of cube grids and with the complexity decreasing from O(N) to O(N) + O(Mlog M). The APA can ensure that boundary conditions are satisfied when the smoke collides with irregular surfaces. Experimental results show that 3D-VPICA is faster than traditional methods of smoke simulation and that APA is successful in simulating smoke colliding with moving objects with irregular surfaces.

Conclusions: The proposed 3D smoke simulation method was applied to a virtual surgery system using a high frequency electric knife. The cutting and coagulate operations were fluent and the smoke flowed with fidelity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmpb.2020.105813DOI Listing
January 2021

Risk of developing diabetes in patients with atrial fibrillation taking non-vitamin K antagonist oral anticoagulants or warfarin: A nationwide cohort study.

Diabetes Obes Metab 2021 Feb 18;23(2):499-507. Epub 2020 Nov 18.

Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.

Aim: To compare the risk of diabetes development in patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin.

Materials And Methods: We conducted a nationwide retrospective cohort study using Taiwan's National Health Insurance Research Database. Adult patients with new onset of AF, treated with NOACs or warfarin between 2012 and 2016, were included. The NOAC cohort was further divided into dabigatran, rivaroxaban and apixaban groups. The primary outcome was incident diabetes requiring treatment with antidiabetic drugs. Fine and Gray subdistribution hazards models were used to estimate the adjusted hazard ratio (aHR). Propensity score matching was performed for each head-to-head comparison.

Results: A total of 10 746 new-onset AF patients were included in our study. During the mean 2.4-year follow-up, NOACs were associated with a lower risk of developing diabetes than warfarin (aHR = 0.80, 95% confidence interval [CI]: 0.68-0.94, P = .007). Subgroup analyses confirmed that dabigatran, rivaroxaban and apixaban each had a reduced diabetes risk. Stratified analyses showed that the lower risk of diabetes associated with NOAC treatment was specific to patients aged 65 years or older (aHR = 0.74, 95% CI: 0.62-0.89, P = .002) and those with good medication adherence (aHR = 0.70, 95% CI: 0.58-0.84, P < .001).

Conclusions: Taking an NOAC was associated with a lower risk of developing diabetes than taking warfarin in patients with AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14243DOI Listing
February 2021

Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis.

Viruses 2020 10 25;12(11). Epub 2020 Oct 25.

Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK.

The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v12111213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693908PMC
October 2020

Time to Reframe Ejection Fraction in Light of New Pathophysiological Insights Into Heart Failure.

J Am Coll Cardiol 2020 10;76(17):1995-1998

University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada; Department of Anesthesiology, Critical Care and Burn Center, Lariboisière-Saint Louis Hospitals, Département Médico-Universitaire Parabol, Assistance Publique des Hôpitaux de Paris Nord, University of Paris, Paris, France; INSERM Unité mixte de Recherche-S 942, Cardiovascular Markers in Stress Conditions, University of Paris, Paris, France. Electronic address: https://twitter.com/BletAlice.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2020.09.012DOI Listing
October 2020

Dimethandrolone Undecanoate, a Novel, Nonaromatizable Androgen, Increases P1NP in Healthy Men Over 28 Days.

J Clin Endocrinol Metab 2021 Jan;106(1):e171-e181

University of Washington, Seattle, Washington.

Context: Dimethandrolone undecanoate (DMAU) is being developed as a male contraceptive. Daily oral administration of DMAU, a potent androgen that is not aromatized, markedly suppresses serum testosterone (T) and estradiol (E2) in healthy men. E2 deficiency can increase bone resorption in men.

Objective: This work aimed to assess changes in bone turnover markers with DMAU administration in a 28-day study.

Design: A randomized, double-blind, placebo-controlled study was conducted.

Setting: This study took place at 2 academic medical centers.

Participants: Healthy men, age 18 to50 years (n = 81), participated.

Intervention: Men received 0, 100, 200, or 400 mg of oral DMAU for 28 days. Serum C-terminal telopeptide of type I collagen (CTX; bone resorption marker) and procollagen type I amino-terminal propeptide (P1NP; bone formation marker) were measured on days 1 and 28.

Main Outcome Measures: Changes in bone turnover markers and serum hormones over the treatment period were measured.

Results: On day 28, median serum T and E2 were markedly suppressed in all treatment groups vs placebo (P < .001 for both). Percentage change (%) in serum P1NP significantly differed across treatment groups (P = .007): Serum P1NP significantly increased in the 200 mg (5%, interquartile range [IQR] -7% to 27%) and 400 mg (22%, IQR -1% to 40%) groups relative to placebo (-8%, IQR -20% to 0%). Change (%) in serum CTX did not differ between groups (P = .09).

Conclusions: DMAU administration for 28 days to healthy men leads to marked suppression of serum T and E2, yet increases P1NP, a serum marker of bone formation. Longer-term studies of the potent androgen DMAU are warranted to determine its impact on bone health in men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765650PMC
January 2021

Innate Immune Nod1/RIP2 Signaling Is Essential for Cardiac Hypertrophy but Requires Mitochondrial Antiviral Signaling Protein for Signal Transductions and Energy Balance.

Circulation 2020 Dec 19;142(23):2240-2258. Epub 2020 Oct 19.

University of Ottawa Heart Institute (H.-B.L., Y.O., G.F., L.Z., G.H.L., D.S., W.L., B.R., K.-H.K., P.P.L.), University of Ottawa, Canada.

Background: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone.

Methods: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1, RIP2, or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice.

Results: Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 and RIP2 mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1 and RIP2 mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions.

Conclusions: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041213DOI Listing
December 2020

Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 10;76(16):1878-1901

Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, New York.

Sarcoidosis is a complex disease with heterogeneous clinical presentations that can affect virtually any organ. Although the lung is typically the most common organ involved, combined pulmonary and cardiac sarcoidosis (CS) account for most of the morbidity and mortality associated with this disease. Pulmonary sarcoidosis can be asymptomatic or result in impairment in quality of life and end-stage, severe, and/or life-threatening disease. The latter outcome is seen almost exclusively in those with fibrotic pulmonary sarcoidosis, which accounts for 10% to 20% of pulmonary sarcoidosis patients. CS is problematic to diagnose and may cause significant morbidity and death from heart failure or ventricular arrhythmias. The diagnosis of CS usually requires surrogate cardiac imaging biomarkers, as endomyocardial biopsy has relatively low yield, even with directed electrophysiological mapping. Treatment of CS is often multifactorial, involving a combination of antigranulomatous therapy and pharmacotherapy for cardiac arrhythmias and/or heart failure in addition to device placement and cardiac transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2020.08.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808240PMC
October 2020

Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort.

J Appl Lab Med 2021 Mar;6(2):344-353

Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Cardiac troponin (cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are increasingly used clinically to evaluate and prognosticate acute myocardial infarction and heart failure, respectively. Pediatric reference intervals and cut-offs have not been established for Roche's Elecsys Troponin T hs (high sensitive) assay. Although pediatric reference intervals exist for NT-proBNP, cut-off values do not exist. In this study, we report reference intervals and 99th percentile cut-offs in a large, healthy Canadian pediatric population using the CALIPER cohort.

Methods: Blood samples from 484 healthy children and adolescents between 0 and <19 years old were recruited from hospital outpatient clinics and community settings. Serum samples were analyzed using Roche's Cobas e411 and evaluated for high-sensitivity cTnT (hs-cTnT) and NT-proBNP concentrations. 95% reference intervals and 99th percentile cut-off values were established.

Results: Three hs-cTnT age partitions were established (0 to <6 months, 6 months to <1 year, and 1 to <19 years) with highest concentrations observed in children under 1 year. Two NT-proBNP age partitions were established (0 to <1 year, and 1 to <19 years), also with higher concentrations in infants under 1 year of age. For each of these age partitions, the 99th percentile cut-off, 95% reference interval, and proportion of detectable concentrations were determined.

Conclusions: This is the first study to examine hs-cTnT and NT-proBNP reference values together in a healthy pediatric cohort without other clinical indications. We present 99th percentile cut-offs, which will allow clinicians to appropriately evaluate cardiovascular disease in children and adolescents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jalm/jfaa090DOI Listing
March 2021

RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice.

Nat Metab 2020 10 28;2(10):1113-1125. Epub 2020 Sep 28.

Cardiometabolic microRNA Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-020-00279-2DOI Listing
October 2020

Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models.

Sci Rep 2020 08 24;10(1):14101. Epub 2020 Aug 24.

Nuffield Department of Medicine Research Building, University of Oxford, Oxford, OX3 7LF, UK.

Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-70865-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445281PMC
August 2020

COVID-19 and the Heart: ACE2 Level and the Company it Keeps Hold the Key.

JACC Basic Transl Sci 2020 Sep 25;5(9):884-887. Epub 2020 Jul 25.

University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381924PMC
September 2020

Structure of the essential inner membrane lipopolysaccharide-PbgA complex.

Nature 2020 08 12;584(7821):479-483. Epub 2020 Aug 12.

Infectious Diseases, Genentech Inc., South San Francisco, CA, USA.

Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2597-xDOI Listing
August 2020