Publications by authors named "Ken Liu"

128 Publications

Silicon nitride waveguides with directly grown WS for efficient second-harmonic generation.

Nanoscale 2021 Dec 1. Epub 2021 Dec 1.

College of Advanced Interdisciplinary Studies & Hunan Provincial Key Laboratory of Novel Nano-Optoelectronic Information Materials and Devices, National University of Defense Technology, Changsha 410073, P. R. China.

Different functions can be directly realized by silicon (Si) in integrated electronic circuits. Although Si and silicon nitride (SiN) photonics have shown great potential in integrated optoelectronic devices, different functions, such as light generation, transparency for guided light, and light detection, cannot be simultaneously achieved only by Si or SiN. Second-order nonlinearity is another optical property they do not possess due to their centrosymmetric properties. Several kinds of 2D materials emerged recently and were transferred to specified photonic devices aimed at improving their nonlinear performance. However, the transferring methods are time-consuming, unable to achieve large-scale production, and will inevitably cause materials damage and introduce impurities at the interface. Herein, we demonstrate the direct growth of large-area homogeneous monolayer WS a physical vapor deposition method onto SiN waveguides. The WS growth can be controlled mainly along the SiN waveguides and the waveguides show an obvious enhancement of second-harmonic generation with the elongated WS coverage. The direct growth of WS endows SiN integrated photonics with new nonlinear optical properties. As an alternative method of transferring 2D materials, the method we present here is compatible with large-scale integrated photonic fabrication, which lays the foundation for on-chip integrated optical fabrication and applications.
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http://dx.doi.org/10.1039/d1nr06216fDOI Listing
December 2021

Prevalence and outcomes of Clostridioides difficile infection in liver transplant recipients.

Transpl Infect Dis 2021 Nov 11. Epub 2021 Nov 11.

AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.

Background And Aim: Data are limited on whether Clostridioides difficile infection (CDI) in the first year after liver transplantation (LT) is associated with increased mortality. In an Australian setting without hypervirulent strain of C.difficile we investigated the prevalence, risk factors and patient survival associated with CDI in LT METHODS: Consecutive patients who underwent deceased-donor LT from 2007-2017 were studied retrospectively. Prevalence and long-term outcomes of LT recipients with and without CDI were examined in the entire LT cohort. A case-control study was performed to investigate risk-factors associated with CDI.

Results: 649 patients underwent LT, of which 32 (4.9%) were diagnosed with CDI within the first 12 months post-LT. There was no difference in patient survival in the overall LT cohort on Kaplan-Meier analysis when stratified by CDI status (log-rank test p = 0.08). Furthermore, age was the only predictor of mortality on Cox Regression (HR 1.06, 95% CI 1.00 -1.13 p = 0.03). On multivariable logistic regression, rifaximin pre-LT reduced risk (OR 0.22, 95% CI 0.65 - 0.74 p = 0.01) whereas antibiotics pre-LT (OR 7.02, 95% CI 1.26 - 39.01, p = 0.03) and length of hospital stay after LT (OR 1.03, 95% CI 1.01 - 1.06, p = 0.02) were associated with increased risk of CDI.

Conclusions: Within the local setting of our study, CDI within 12 months post-LT is of low severity, associated with pre-LT antibiotic exposure and longer hospital stay but no survival impact after LT. Rifaximin use pre-LT reduced the risk of CDI post-LT. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/tid.13758DOI Listing
November 2021

U-shaped relationship between urea level and hepatic decompensation in chronic liver diseases.

Clin Mol Hepatol 2021 Nov 5. Epub 2021 Nov 5.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.

Background/aims: We aimed to determine the association between urea level and incident cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) in chronic liver disease (CLD) patients.

Methods: The association between blood urea level and liver fibrosis/liver-related events were evaluated on continuous scale with restricted cubic spline curves based on generalized additive model or Cox proportional hazards models. Then the above associations were evaluated by urea level within intervals.

Results: Among 4282 patients who had undergone liver stiffness measurement (LSM) by transient elastography, baseline urea level had a U-shaped association with LSM and hepatic decompensation development after a median follow-up of 5.5 years. Compared to patients with urea of 3.6-9.9 mmol/L, those with urea ≤3.5 mmol/L (adjusted hazard ratio [aHR] 4.15, 95% confidence interval [CI] 1.68-10.24) and ≥10 mmol/L (aHR 5.22, 95% CI 1.86-14.67) had higher risk of hepatic decompensation. Patients with urea ≤3.5 mmol/L also had higher risk of incident cirrhosis (aHR 3.24, 95% CI 1.50-6.98). The association between low urea level and incident cirrhosis and hepatic decompensation was consistently observed in subgroups by age, gender, albumin level and comorbidities. The U-shaped relationship between urea level and LSM was validated in another population screening study (n=917). Likewise, urea ≤3.5 mmol/L was associated with a higher risk of incident cirrhosis in a territory-wide cohort of 12476 patients with nonalcoholic fatty liver disease at a median follow-up of 9.9 years (aHR 1.27, 95% CI 1.03-1.57).

Conclusions: We identified a U-shaped relationship between the urea level and fibrosis/incident cirrhosis/hepatic decompensation in patients with CLD.
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http://dx.doi.org/10.3350/cmh.2021.0188DOI Listing
November 2021

Per- and polyfluoroalkyl substance (PFAS) exposure, maternal metabolomic perturbation, and fetal growth in African American women: A meet-in-the-middle approach.

Environ Int 2021 Nov 1;158:106964. Epub 2021 Nov 1.

Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA. Electronic address:

Background: Prenatal exposures to per- and polyfluoroalkyl substances (PFAS) have been linked to reduced fetal growth. However, the detailed molecular mechanisms remain largely unknown. This study aims to investigate biological pathways and intermediate biomarkers underlying the association between serum PFAS and fetal growth using high-resolution metabolomics in a cohort of pregnant African American women in the Atlanta area, Georgia.

Methods: Serum perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) measurements and untargeted serum metabolomics profiling were conducted in 313 pregnant African American women at 8-14 weeks gestation. Multiple linear regression models were applied to assess the associations of PFAS with birth weight and small-for-gestational age (SGA) birth. A high-resolution metabolomics workflow including metabolome-wide association study, pathway enrichment analysis, and chemical annotation and confirmation with a meet-in-the-middle approach was performed to characterize the biological pathways and intermediate biomarkers of the PFAS-fetal growth relationship.

Results: Each log-unit increase in serum PFNA concentration was significantly associated with higher odds of SGA birth (OR = 1.32, 95% CI 1.07, 1.63); similar but borderline significant associations were found in PFOA (OR = 1.20, 95% CI 0.94, 1.49) with SGA. Among 25,516 metabolic features extracted from the serum samples, we successfully annotated and confirmed 10 overlapping metabolites associated with both PFAS and fetal growth endpoints, including glycine, taurine, uric acid, ferulic acid, 2-hexyl-3-phenyl-2-propenal, unsaturated fatty acid C18:1, androgenic hormone conjugate, parent bile acid, and bile acid-glycine conjugate. Also, we identified 21 overlapping metabolic pathways from pathway enrichment analyses. These overlapping metabolites and pathways were closely related to amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism perturbations.

Conclusion: In this cohort of pregnant African American women, higher serum concentrations of PFOA and PFNA were associated with reduced fetal growth. Perturbations of biological pathways involved in amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism were associated with PFAS exposures and reduced fetal growth, and uric acid was shown to be a potential intermediate biomarker. Our results provide opportunities for future studies to develop early detection and intervention for PFAS-induced fetal growth restriction.
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http://dx.doi.org/10.1016/j.envint.2021.106964DOI Listing
November 2021

Are split liver grafts a suitable option in high-risk liver transplant recipients?

Curr Opin Organ Transplant 2021 12;26(6):675-680

Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital.

Purpose Of Review: To assess the outcomes of split liver transplantation (SLT) in adults and children and evaluate its role in high-risk recipients with a high model for end-stage liver disease (MELD) score, an urgent indication or requiring retransplantation.

Recent Findings: Split liver grafts in general have equivalent long-term survival outcomes to whole grafts despite an increase in biliary complications. Recent success and technical advances have encouraged use of these grafts in high-risk recipients. Split liver grafts can be used successfully in recipients with a high MELD score if there is adequate weight-matching. There are mixed results in urgent indication recipients and for retransplantation such that use in this group of patients remains controversial.

Summary: SLT addresses donor shortages by facilitating the transplant of two recipients from the same donor liver. By using careful donor and recipient selection criteria, SLT can achieve equivalent long-term outcomes to whole grafts. These grafts have been used successfully in recipients with a high MELD score, but should be used selectively in urgent indication recipients and for retransplantation.
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http://dx.doi.org/10.1097/MOT.0000000000000938DOI Listing
December 2021

Lung metabolome of 1,3-butadiene exposed Collaborative Cross mice reflects metabolic phenotype of human lung cancer.

Toxicology 2021 Nov 11;463:152987. Epub 2021 Oct 11.

Department of Environment and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States; The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States. Electronic address:

1,3-Butadiene (BD) exposure is known to cause numerous adverse health effects, including cancer, in animals and humans. BD is metabolized to reactive epoxide intermediates, which are genotoxic, but it is not well know what other effects BD has on cellular metabolism. We examined the effects of exposure to BD on the mouse lung metabolome in the genetically heterogeneous collaborative cross outbred mouse model. Mice were exposed to 3 concentra-tions of BD for 10 days (2, 20, and 200 ppm), and lung tissues were analyzed using high-resolution mass spectrometry-based metabolomics. As compared to controls (0 ppm BD), BD had extensive effects on lung metabolism at all concentrations of exposure, including the lowest concentration of 2 ppm, as reflected by reprogramming of multiple metabolic pathways. Metabolites participating in glycolysis and the tricarboxylic acid cycle were elevated, with 8 out of 10 metabolites demonstrating a 2 to 8-fold increase, including the oncometabolite fumarate. Fatty acid levels, sphingosine, and sphinganine were decreased (2 to 8-fold), and fatty acyl-CoAs were significantly increased (16 to 31-fold), suggesting adjustments in lipid metabolism. Furthermore, metabolites involved in basic amino acid metabolism, steroid hormone metabolism, and nucleic acid metabolism were significantly altered. Overall, these changes mirror the metabolic alterations found in lung cancer cells, suggesting that very low doses of BD induce metabolic adaptations that may prevent or promote adverse health effects such as tumor formation.
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http://dx.doi.org/10.1016/j.tox.2021.152987DOI Listing
November 2021

Evaluating the emotion regulation of positive mood states among people with bipolar disorder using hierarchical clustering.

World J Psychiatry 2021 Sep 19;11(9):619-634. Epub 2021 Sep 19.

Department of Social Work and Social Administration, The University of Hong Kong, Hong Kong, China.

Background: People with bipolar disorder (BD) frequently struggle with the recurrence of affective symptoms. However, the interplay between coping mechanism and positive mood state remains under-researched.

Aim: To explore the associations among behavioral approach system (BAS) sensitivity level, coping, and positive mood states among people with BD.

Methods: Using a cross-sectional study design, 90 participants with BD were presented with four BAS-activating life event scenarios and assessed with regard to their BAS trait sensitivity, coping flexibility, and mood states. A hierarchical clustering method was used to identify different groups with different styles of coping. Multiple hierarchical regression analyses were conducted to examine the mediating and moderating roles of different components of coping on mood states.

Results: A three-cluster solution was found to best fit the present data set. The findings showed that a low mass of coping combined with low BAS sensitivity level protects people with BD from detrimentally accentuating mood states when they encounter BAS-activating life events. Moreover, coping flexibility is demonstrated to mediate and moderate the relationships between BAS sensitivity level and mood states. Specifically, subduing the perceived controllability and reducing the use of behavioral-activation/emotion-amplifying coping strategies could help buffer the effect of positive affect.

Conclusion: The judicious use of coping in emotion regulation for people with BD when encountering BAS-activating life events was indicated. Practical applications and theoretical implications are highlighted.
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http://dx.doi.org/10.5498/wjp.v11.i9.619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474994PMC
September 2021

Efficient coupling between an integrated photonic waveguide and an optical fiber.

Opt Express 2021 Aug;29(17):27396-27403

Because on-chip integration of light sources cannot be realized effectively now, integrated nanophotonic chips must couple external light to the integrated photonic waveguide with high efficiency. Realizing high efficiency coupling requires a low-loss coupling structure. In this paper, the factors allowing high efficiency coupling to be realized are analyzed theoretically and the coupling between a lensed fiber and a tapered silicon nitride (SiN) waveguide is realized experimentally. Because the coupling efficiency of this structure is not ideal in the experiment, a scheme of direct alignment between the lensed fiber and a cantilever waveguide is proposed. Although the scheme offers a very high coupling efficiency in theory, because of the warpage of the waveguide they cannot be directly aligned experimentally. Finally, this paper advances a scheme for the tapered fiber to be directly overlapped onto the SiN/SiO cantilever. It is found that the coupler maintains an ideal coupling efficiency for wavelength from 1530 nm to 1600 nm, laying a foundation for the integration of nano-photonic devices and optical fibers.
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http://dx.doi.org/10.1364/OE.430644DOI Listing
August 2021

Erratum for Quinn et al., "Bridging the Gap between Analytical and Microbial Sciences in Microbiome Research".

mSystems 2021 Oct 5;6(5):e0117121. Epub 2021 Oct 5.

Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.

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http://dx.doi.org/10.1128/mSystems.01171-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547442PMC
October 2021

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

PLoS Pathog 2021 09 24;17(9):e1009941. Epub 2021 Sep 24.

Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1β-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.
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http://dx.doi.org/10.1371/journal.ppat.1009941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494353PMC
September 2021

Liberal Use of Interposition Grafts for Arterial Reconstruction Is Safe and Effective in Adult Split Liver Transplantation.

Transplant Direct 2021 Aug 23;7(8):e735. Epub 2021 Jul 23.

Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Background: Split liver transplantation (SLT) addresses donor shortages by providing 2 partial grafts from a single donor liver. Arterial reconstruction using an interposition graft facilitates the use of split grafts with difficult recipient anatomy. Its use, however, remains controversial because of a reported increased risk of complications.

Methods: A retrospective review of the prospectively maintained Australian National Liver Transplantation Unit database was performed. Donor, recipient, operative, and complications data for adults receiving an SLT between July 2002 and November 2019 were extracted.

Results: Arterial reconstruction required an interposition graft in 46 of 155 patients. Overall graft and patient survival were not significantly different between the groups with 1-, 3-, and 5-y graft survivals of 82%, 77%, and 69% for those with interposition grafts and 86%, 79%, and 77% for those without interposition grafts, respectively ( = 0.499). There were more cut liver bile leaks in the interposition graft group (26% versus 9%,  = 0.004), but otherwise, no significant differences in the rate of biliary complications (39% versus 29%  = 0.200), hepatic artery thrombosis (7% versus 10%,  = 0.545), or hepatic artery stenosis (13% versus 10%,  = 0.518).

Conclusions: Liberal use of interposition grafts for arterial reconstruction in SLT is safe and does not result in increased complications.
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http://dx.doi.org/10.1097/TXD.0000000000001192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440025PMC
August 2021

Immune checkpoint inhibitor-related hepatotoxicity: A review.

World J Gastroenterol 2021 Aug;27(32):5376-5391

AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, NSW, Australia.

The application of immune checkpoint inhibitors (ICI) in advanced cancer has been a major development in the last decade. The indications for ICIs are constantly expanding into new territory across different cancers, disease stages and lines of therapy. With this increased use, adverse events including immune checkpoint inhibitor-related hepatotoxicity (ICH) have emerged as an important clinical problem. This along with the introduction of ICI as first- and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists. The incidence of ICH varies between 1%-20% depending on the number, type and dose of ICI received. Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI, corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity. The majority of patients with ICH recover and some may even safely recommence ICI therapy. Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.
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http://dx.doi.org/10.3748/wjg.v27.i32.5376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409159PMC
August 2021

Large scale enzyme based xenobiotic identification for exposomics.

Nat Commun 2021 09 14;12(1):5418. Epub 2021 Sep 14.

Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, Georgia, USA.

Advances in genomics have revealed many of the genetic underpinnings of human disease, but exposomics methods are currently inadequate to obtain a similar level of understanding of environmental contributions to human disease. Exposomics methods are limited by low abundance of xenobiotic metabolites and lack of authentic standards, which precludes identification using solely mass spectrometry-based criteria. Here, we develop and validate a method for enzymatic generation of xenobiotic metabolites for use with high-resolution mass spectrometry (HRMS) for chemical identification. Generated xenobiotic metabolites were used to confirm identities of respective metabolites in mice and human samples based upon accurate mass, retention time and co-occurrence with related xenobiotic metabolites. The results establish a generally applicable enzyme-based identification (EBI) for mass spectrometry identification of xenobiotic metabolites and could complement existing criteria for chemical identification.
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http://dx.doi.org/10.1038/s41467-021-25698-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440538PMC
September 2021

Bridging the Gap between Analytical and Microbial Sciences in Microbiome Research.

mSystems 2021 Oct 14;6(5):e0058521. Epub 2021 Sep 14.

Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.

Metabolites from the microbiome influence human, animal, and environmental health, but the diversity and functional roles of these compounds have only begun to be elucidated. Comprehensively characterizing these molecules are significant challenges, as it requires expertise in analytical methods, such as mass spectrometry and nuclear magnetic resonance spectroscopy, skills that not many traditional microbiologists or microbial ecologists possess. This creates a gap between microbiome scientists that want to understand the role of microbial metabolites in microbiome systems and the skills required to generate and interpret complex metabolomics data sets. To bridge this gap, microbiome scientists should engage analytical chemists to best understand the underlying chemical principles of the data. Conversely, analytical scientists are encouraged to engage with microbiome scientists to better understand the biological questions being asked with metabolomics and to best communicate its intricacies. Better communication across the chemistry/biology disciplines will further reveal the "dark matter" within microbiomes that maintain healthy humans and environments.
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http://dx.doi.org/10.1128/mSystems.00585-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547465PMC
October 2021

Drug-induced liver injury in Australia, 2009-2020: the increasing proportion of non-paracetamol cases linked with herbal and dietary supplements.

Med J Aust 2021 Sep 17;215(6):261-268. Epub 2021 Jul 17.

AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW.

Objective: To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements.

Design: Retrospective electronic medical record data analysis.

Setting, Participants: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020.

Main Outcome Measures: 90-day transplant-free survival; drugs implicated as causal agents in DILI.

Results: A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36).

Conclusion: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI.
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http://dx.doi.org/10.5694/mja2.51173DOI Listing
September 2021

Ovary unusual colonic lesion.

JGH Open 2021 Jul 2;5(7):834-836. Epub 2021 Jun 2.

AW Morrow Gastroenterology and Liver Centre Royal Prince Alfred Hospital Sydney New South Wales Australia.

We describe an unusual endoscopic finding, caused by a dominant ovarian follicle compressing a low-lying ascending colon just inferior to a patulous retroverted cecum. Endoscopically detected extra-colonic lesions represent a diverse group of pathologies, and it is important the endoscopist has an appreciation of the varied number of benign and malignant causes-including those of gynecological origin.
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http://dx.doi.org/10.1002/jgh3.12584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264229PMC
July 2021

Addressing the challenges of split liver transplantation through technical advances. A systematic review.

Transplant Rev (Orlando) 2021 07 19;35(3):100627. Epub 2021 May 19.

Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, Australia. Electronic address:

Background: Split liver transplantation addresses donor shortages by facilitating the transplant of two recipients using one donor liver. Some still consider these grafts inferior due to prolonged cold ischaemia time and at times difficult vascular reconstruction. Techniques such as in-situ splitting, machine perfusion and interposition grafts may address these challenges and thereby address these concerns. The aim of this review is to assess these technical advances in split liver transplantation, their utility and outcomes.

Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Keywords included 'split liver transplantation', 'arterial reconstruction', and 'machine perfusion'. Data found was synthesised into sections including: methods of splitting, full-left full-right splitting, donor cholangiography, machine perfusion and arterial reconstruction.

Results: A total of 78 articles met inclusion criteria after screening of 151 eligible articles. These were subdivided into the following categories: in-situ (25), ex-vivo (25), full-left full-right splitting (15), donor cholangiography (2), machine perfusion (6), and arterial reconstruction (5). The in-situ splitting technique reduces the cold ischaemia time compared to the ex-vivo technique which may improve graft quality and liver splitting during normothermic machine perfusion is a novel technique with the potential to incorporate the best aspects of both techniques. Interposition grafts are often required during split liver transplantation but have an increased risk of hepatic artery thrombosis.

Conclusion: Advancements in technique have allowed many of the unique challenges of split liver transplantation to be overcome. Overall, this supports the use of split liver transplantation in broader and riskier settings and we advocate for liver transplant surgeons to not hesitate in using these grafts liberally and expanding their recipient selection criteria.
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http://dx.doi.org/10.1016/j.trre.2021.100627DOI Listing
July 2021

Cruciferous vegetables () confer cytoprotective effects in intestines.

Gut Microbes 2021 Jan-Dec;13(1):1-6

Center for the Study of Human Health, Emory University College of Arts and Sciences, Atlanta, Georgia.

Varieties and cultivars of the cruciferous vegetable are widely presumed to elicit positive influences on mammalian health and disease, particularly related to their indole and sulforaphane content. However, there is a considerable gap in knowledge regarding the mechanisms whereby these plant-derived molecules elicit their beneficial effects on the host. In this study, we examined the chemical variation between varieties and evaluated their capacity to both activate Nrf2 in the intestine and elicit cytoprotection. Ten types of edible were purchased and was wild collected. Fresh material was dried, extracted by double maceration and green kale was also subjected to anaerobic fermentation before processing. Untargeted metabolomics was used to perform Principal Component Analysis. Targeted mass spectral analysis determined the presence of six indole species and quantified indole. Extracts were tested for their capacity to activate Nrf2 in the intestine in third instar larvae. Cytoprotective effects were evaluated using a paraquat-induced oxidative stress gut injury model. A "Smurf" assay was used to determine protective capacity against a chemically induced leaky gut. Extracts of Brussels sprouts and broccoli activated Nrf2 and protected against paraquat-induced damage and leaky gut. Lacto-fermented kale showed a cytoprotective effect, increasing survival by 20% over the non-fermented extract, but did not protect against leaky gut. The protective effects observed do not directly correlate with indole content, suggesting involvement of multiple compounds and a synergistic mechanism.
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http://dx.doi.org/10.1080/19490976.2021.1921926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115444PMC
November 2021

Interface engineering of cobalt-sulfide-selenium core-shell nanostructures as bifunctional electrocatalysts toward overall water splitting.

Nanoscale 2021 Apr 1;13(14):6890-6901. Epub 2021 Apr 1.

College of Advanced Interdisciplinary Studies & Hunan Provincial Key Laboratory of Novel Nano-Optoelectronic Information Materials and Devices, National University of Defense Technology, Changsha, 410073, China.

The number of active sites and stability of the structure of electrocatalysts are the key factors in the process of overall water splitting. In this paper, cobalt-sulfide-selenium (Se:CoS) core-shell nanostructures are prepared by a simple two-step method, including hydrothermal reaction and chemical vapor deposition. The resulting product exhibits excellent electrochemical performance, owing to the synergistic effects between CoS and CoSe, as well as the plentiful active sites in the electrode structure. The Se:CoS material shows a more improved hydrogen evolution reaction activity compared to CoS and Co(OH)Cl precursor catalysts, with a low overpotential of only 240 mV achieved at 10 mA cm. Meanwhile, Se:CoS as a bifunctional water splitting catalyst also shows remarkably improved oxygen evolution reaction activity, with a low overpotential of only 1.32 V at 10 mA cm. The above results show that selenide/sulfide materials provide a new research direction for discovering high-performance and cheap electrode materials.
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http://dx.doi.org/10.1039/d1nr00987gDOI Listing
April 2021

Palliative medicine referrals for hepatocellular carcinoma: a national survey of gastroenterologists.

BMJ Support Palliat Care 2021 Mar 18. Epub 2021 Mar 18.

AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

Objectives: Palliative care (PC) service involvement for hepatocellular carcinoma (HCC) patients is suboptimal and little is known about the underlying reasons for this. We aimed to study clinicians' experience and attitudes towards PC in HCC.

Methods: A nationwide survey was conducted of consultants/trainees recruited from the Gastroenterological Society of Australia membership directory. Clinician demographics, experience and attitudes towards PC use for HCC patients were collected.

Results: There were 160 participants. Most attended weekly multidisciplinary team meetings (MDTM, 60%) and had no formal PC training (71%). MDTM with PC attendance was reported by 12%. Rates of PC referral increased incrementally from BCLC 0/A to D patients but were not universal even in advanced (46%) or terminal (87%) stages. Most acknowledged PC patient discussions occurred too late (61%). Those with prior PC training were more likely to refer BCLC 0/A and B patients for early PC. Referral rates for outpatient PC were higher in respondents who attended MDTM with PC present across all BCLC stages. PC service was rated good/very good by 70%/81% for outpatients/inpatients. Barriers to PC referral included clinician-perceived negative patient associations with PC (83%), clinician-perceived patient/caregiver lack of acceptance (81%/77%) and insufficient time (70%).

Conclusions: PC referral for HCC patients is not universal and occurs late even in late-stage disease. Prior PC training and/or PC presence at MDTM positively influences referral practices. Barriers to PC referral are not related to quality of PC services but rather to clinician-perceived patients' negative reactions to or lack of acceptance of PC.
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http://dx.doi.org/10.1136/bmjspcare-2020-002807DOI Listing
March 2021

Beware of Portal Vein Thrombosis After Laparoscopic Sleeve Gastrectomy in Liver Transplant Recipients.

Liver Transpl 2021 07 21;27(7):1066-1067. Epub 2021 Apr 21.

Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

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http://dx.doi.org/10.1002/lt.26049DOI Listing
July 2021

Prevalence and Impact of Fatty Liver Disease in Adult Deceased Liver Transplant Donors: Metabolic-Associated Fatty Liver Disease or Nonalcoholic Fatty Liver Disease?

Liver Transpl 2021 10 15;27(10):1498-1501. Epub 2021 Aug 15.

Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, Australia.

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http://dx.doi.org/10.1002/lt.26023DOI Listing
October 2021

Metabolome-wide association study of flavorant vanillin exposure in bronchial epithelial cells reveals disease-related perturbations in metabolism.

Environ Int 2021 02 21;147:106323. Epub 2020 Dec 21.

Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address:

Electronic cigarettes (e-cig) are an increasingly popular alternative to traditional smoking but have been in use for too short of a period of time to fully understand health risks. Furthermore, associated health risks are difficult to evaluate because of a large range of flavoring agents and their combinations for use with e-cig. Many flavoring agents are generally regarded as safe but have limited studies for effects on lung. Vanillin, an aromatic aldehyde, is one of the most commonly used flavoring agents in e-cig. Vanillin is electrophilic and can be redox active, with chemical properties expected to interact within biologic systems. Because accumulating lung metabolomics studies have identified metabolic disruptions associated with idiopathic pulmonary fibrosis, asthma and acute respiratory distress syndrome, we used human bronchial epithelial cells (BEAS-2B) with high-resolution metabolomics analysis to determine whether these disease-associated pathways are impacted by vanillin over the range used in e-cig. A metabolome-wide association study showed that vanillin perturbed specific energy, amino acid, antioxidant and sphingolipid pathways previously associated with human disease. Analysis of a small publicly available human dataset showed associations with several of the same pathways. Because vanillin is a common and high-abundance flavorant in e-cig, these results show that vanillin has potential to be mechanistically important in lung diseases and warrants in vivo toxicity testing in the context of e-cig use.
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http://dx.doi.org/10.1016/j.envint.2020.106323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856097PMC
February 2021

A metabolomic study of cervical dystonia.

Parkinsonism Relat Disord 2021 01 26;82:98-103. Epub 2020 Nov 26.

Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA; Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA. Electronic address:

Introduction: Cervical dystonia is the most common of the adult-onset focal dystonias. Most cases are idiopathic. The current view is that cervical dystonia may be caused by some combination of genetic and environmental factors. Genetic contributions have been studied extensively, but there are few studies of other factors. We conducted an exploratory metabolomics analysis of cervical dystonia to identify potentially abnormal metabolites or altered biological pathways.

Methods: Plasma samples from 100 cases with idiopathic cervical dystonia and 100 controls were compared using liquid chromatography coupled with mass spectrometry-based metabolomics.

Results: A total of 7346 metabolic features remained after quality control, and up to 289 demonstrated significant differences between cases and controls, depending on statistical criteria chosen. Pathway analysis revealed 9 biological processes to be significantly associated at p < 0.05, 5 pathways were related to carbohydrate metabolism, 3 pathways were related to lipid metabolism.

Conclusion: This is the first large scale metabolomics study for any type of dystonia. The results may provide potential novel insights into the biology of cervical dystonia.
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http://dx.doi.org/10.1016/j.parkreldis.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856090PMC
January 2021

Management of patients with intermediate stage hepatocellular carcinoma.

Ther Adv Med Oncol 2020 5;12:1758835920970840. Epub 2020 Nov 5.

Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China.

Hepatocellular carcinoma (HCC) causes a significant health burden globally and its impact is expected to increase in the coming years. Intermediate stage HCC, as defined by the Barcelona Clinic Liver Cancer (BCLC) system stage B, represents up to 30% of patients at diagnosis and encompasses a broad spectrum of tumor burden. Several attempts have been made to further subclassify this heterogenous group. The current standard of care recommended by BCLC for intermediate stage HCC patients is transarterial chemoembolization (TACE), with modest outcomes reported. While refinements have been made to TACE technique and patient selection, it remains non-curative. In the real-world setting, only 60% of patients with intermediate stage HCC receive TACE, with the remainder deviating to a range of other therapies that have shown promise in select patient subgroups. These include curative treatments (resection, ablation, and liver transplantation), radiotherapy (stereotactic and radioembolization), systemic therapies, and their combination. In this review, we summarize the classifications and current management for patients with intermediate stage HCC as well as highlight recent key developments in this space.
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http://dx.doi.org/10.1177/1758835920970840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649909PMC
November 2020

Current perspectives on the tumor microenvironment in hepatocellular carcinoma.

Hepatol Int 2020 Dec 13;14(6):947-957. Epub 2020 Nov 13.

Centenary Institute, The University of Sydney, Sydney, Locked Bag 6, Newtown, NSW, 2042, Australia.

Hepatocellular carcinoma (HCC) is a heterogeneous inflammation-driven malignancy, which, despite significant advances in management, continues to portend a poor prognosis. Recent advances in basic and translational research have increasingly defined the role of the tumor microenvironment in the development and progression of HCC and facilitated the development of novel molecular targets. The hepatoma microenvironment is characterised by an immunosuppressive milieu of immune cells and tumor vasculature that is both structurally and functionally abnormal. Normalising the tumor microenvironment by adopting a multipronged approach that targets both carcinogenic processes and the immunosuppressive milieu has been supported by pre-clinical and clinical data. In this review, we summarise the current understanding of the hepatoma microenvironment, its influences and dynamic interactions with tumor cells, the vasculature and the gut. Finally, we discuss how manipulating the tumor microenvironment continues to shape the evolving landscape of HCC therapy.
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http://dx.doi.org/10.1007/s12072-020-10104-3DOI Listing
December 2020

Light-induced irreversible structural phase transition in trilayer graphene.

Light Sci Appl 2020 13;9:174. Epub 2020 Oct 13.

Chongqing 2D Materials Institute, Liangjiang New Area, 400714 Chongqing, China.

A crystal structure has a profound influence on the physical properties of the corresponding material. By synthesizing crystals with particular symmetries, one can strongly tune their properties, even for the same chemical configuration (compare graphite and diamond, for instance). Even more interesting opportunities arise when the structural phases of crystals can be changed dynamically through external stimulations. Such abilities, though rare, lead to a number of exciting phenomena, such as phase-change memory effects. In the case of trilayer graphene, there are two common stacking configurations (ABA and ABC) that have distinct electronic band structures and exhibit very different behaviors. Domain walls exist in the trilayer graphene with both stacking orders, showing fascinating new physics such as the quantum valley Hall effect. Extensive efforts have been dedicated to the phase engineering of trilayer graphene. However, the manipulation of domain walls to achieve precise control of local structures and properties remains a considerable challenge. Here, we experimentally demonstrate that we can switch from one structural phase to another by laser irradiation, creating domains of different shapes in trilayer graphene. The ability to control the position and orientation of the domain walls leads to fine control of the local structural phases and properties of graphene, offering a simple but effective approach to create artificial two-dimensional materials with designed atomic structures and electronic and optical properties.
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http://dx.doi.org/10.1038/s41377-020-00412-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553909PMC
October 2020

Metabolomic Associations with Serum Bone Turnover Markers.

Nutrients 2020 Oct 16;12(10). Epub 2020 Oct 16.

Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Bone is a dynamic tissue that is in a constant state of remodeling. Bone turnover markers (BTMs), procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptides of type I collagen (CTX), provide sensitive measures of bone formation and resorption, respectively. This study used ultra-high-resolution metabolomics (HRM) to determine plasma metabolic pathways and targeted metabolites related to the markers of bone resorption and formation in adults. This cross-sectional clinical study included 34 adults (19 females, mean 27.8 years), without reported illnesses, recruited from a US metropolitan area. Serum BTM levels were quantified by an ELISA. Plasma HRM utilized dual-column liquid chromatography and mass spectrometry to identify metabolites and metabolic pathways associated with BTMs. Metabolites significantly associated with P1NP ( < 0.05) were significantly enriched in pathways linked to the TCA cycle, pyruvate metabolism, and metabolism of B vitamins important for energy production (e.g., niacin, thiamin). Other nutrition-related metabolic pathways associated with P1NP were amino acid (proline, arginine, glutamate) and vitamin C metabolism, which are important for collagen formation. Metabolites associated with CTX levels ( < 0.05) were enriched within lipid and fatty acid beta-oxidation metabolic pathways, as well as fat-soluble micronutrient pathways including, vitamin D metabolism, vitamin E metabolism, and bile acid biosynthesis. P1NP and CTX were significantly related to microbiome-related metabolites ( < 0.05). Macronutrient-related pathways including lipid, carbohydrate, and amino acid metabolism, as well as several gut microbiome-derived metabolites were significantly related to BTMs. Future research should compare metabolism BTMs relationships reported here to aging and clinical populations to inform targeted therapeutic interventions.
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http://dx.doi.org/10.3390/nu12103161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602719PMC
October 2020

The VE-Cadherin/β-catenin signalling axis regulates immune cell infiltration into tumours.

Cancer Lett 2021 01 28;496:1-15. Epub 2020 Sep 28.

Centre for the Endothelium, Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney, 2050, Australia. Electronic address:

Vascular normalisation, the process that reverses the structural and functional abnormalities seen in tumour-associated vessels, is also accompanied by changes in leucocyte trafficking. Our previous studies have shown the normalisation effects of the agent CD5-2 which acts to stabilise VE-Cadherin leading to increased penetration of CD8 T cells but decreased infiltration of neutrophils (CD11bGr1) into tumour parenchyma. In the present study, we demonstrate that VE-Cadherin stabilisation through CD5-2 treatment of purified endothelial cells (ECs) results in a similar leucocyte-selective regulation of transmigration, suggesting the existence of an endothelial specific intrinsic mechanism. Further, we show by RNA sequencing (RNA-seq)-based transcriptomic analysis, that treatment of ECs with CD5-2 regulates chemokines known to be involved in leucocyte transmigration, including upregulation of CCL2 and CXCL10 that facilitate CD8 T cell transmigration. Both in vitro and in vivo mechanistic studies revealed that the increased CCL2 expression was dependent on expression of VE-Cadherin and downstream activation of the AKT/GSK3β/β-catenin/TCF4 signalling pathway. CD5-2 treatment also contributed to the reorganisation of the cytoskeleton, inducing reorganisation of stress fibres to circumferential actin, which previously has been described as associated with the stabilisation of the endothelial barrier, and amplification of the transcellular migration of CD8 T cells. Thus, we propose that promotion of endothelial junctional integrity during vascular normalisation not only inhibits vascular leak but also resets the endothelial dependent regulation of immune cell infiltration.
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http://dx.doi.org/10.1016/j.canlet.2020.09.026DOI Listing
January 2021
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