Publications by authors named "Jacob George"

671 Publications

NH-MIL-125(Ti) doped CdS/Graphene composite as electro and photo catalyst in basic medium under light irradiation.

Environ Res 2021 Jul 20;200:111719. Epub 2021 Jul 20.

Centre for Nanotechnology Research, Vellore Institute of Technology, Vellore, Tamil Nadu, India. Electronic address:

The development of active electrocatalysts and photocatalysts for hydrogen evolution reaction (HER) and for environmental remediation is a huge challenge. Research is still underway on the development of low-cost catalytic materials with appreciable efficiency for HER. In the present study, a composite of metal organic framework (MOF) with CdS and graphene (NH-MIL-125(Ti)/CdS-graphene) composites were developed with different loadings of graphene material via solvothermal technique. Further the electrocatalytic activity of the synthesized catalysts were investigated for HER and photocatalytic degradation of dye. Results show that the synthesized catalyst with a less amount of graphene was more active. HER results showed a less Tafel slope of 70.8 and 61.9 mVdec with 15.6 mA/cm and 15.46 mA/cm current densities under light on and off conditions. Further the dye degradation activity of the synthesized catalysts was tested with Rhodamine B dye and results showed that the catalyst showed excellent activity for low weight loading of graphene with a degradation efficiency of 95 % and followed pseudo first order kinetic model. Overall results showed that the synthesized composites are promising for HER and photocatalytic applications.
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http://dx.doi.org/10.1016/j.envres.2021.111719DOI Listing
July 2021

NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease.

Liver Int 2021 Jul 16. Epub 2021 Jul 16.

Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", University of Palermo, Palermo, Italy.

Background And Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis.

Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124).

Results: The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62-0.95; P = .01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47-0.83; P = .001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67-0.98; P = .04). The C allele was associated with higher total circulating cholesterol (P = .01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis.

Conclusions: Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR-targeted therapy warrants further investigation.
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http://dx.doi.org/10.1111/liv.15016DOI Listing
July 2021

Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases.

Lancet Gastroenterol Hepatol 2021 Jul 12. Epub 2021 Jul 12.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

With the global epidemics of obesity and associated conditions, including type 2 diabetes, metabolic dysfunction-associated fatty liver disease, chronic kidney disease, hypertension, stroke, cardiovascular disease, osteoporosis, cancer, and cognitive changes, the prevalence of multimorbidity is rapidly increasing worldwide. In this Review, a panel of international experts from across the spectrum of metabolic diseases come together to identify the challenges and provide perspectives on building a framework for a virtual primary care-driven, patient-centred, multidisciplinary model to deliver holistic care for patients with metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. We focus on clinical care and innovative trial design for metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. This work represents a call to action to promote collaboration and partnerships between stakeholders for improving the lives of people with, or at risk of, metabolic dysfunction-associated fatty liver disease and associated metabolic diseases.
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http://dx.doi.org/10.1016/S2468-1253(21)00132-1DOI Listing
July 2021

Wild-type TTR amyloidosis among patients with unexplained heart failure and systolic LV dysfunction.

PLoS One 2021 9;16(7):e0254104. Epub 2021 Jul 9.

The Heart Institute, Kaplan Medical Center, Rehovot, Israel.

Aim: Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) with preserved left ventricular ejection fraction (LVEF), typically presenting as restrictive cardiomyopathy. The potential co-existence of ATTR-CA with systolic heart failure has not been studied. The aim of this study is to describe the prevalence of ATTR-CA and its clinical characteristics in HF patients with reduced LVEF.

Methods: Patients with an unexplained cause of LV systolic dysfunction were screened for ATTR-CA by a 99mTc-PYP planar scintigraphy. Patients in whom presence of ≥ 2 uptake was confirmed by SPECT imaging were included. Their clinical, laboratory and echocardiographic data were collected.

Results: Out of 75 patients (mean age 65±12 years, LVEF 35.8±7.9%) included in this study, 7 (9.3%) patients (mean age 75±6 years, LVEF 32.0±8.3%) had ATTR-CA. Patients with ATTR-CA were more symptomatic at diagnosis (NYHA FC 3-4 (86% vs 35% (p = 0.03)) and had a more severe clinical course evident by recurrent hospitalizations for HF, and a need for intravenous diuretic treatment (p = 0.04 and p<0.01, respectively) at follow-up, compared with patients with no ATTR-CA. Patients with ATTR-CA had similar LVEF but a clear trend for larger LV mass index (157.1±60.6 g/m2 vs. 121.0±39.5 g/m2, p = 0.07) and a larger proportions of ATTR-CA patients had IVS thickness >13 mm (57.1% vs 13.1%, p = 0.02) as compared to HF patients with no ATTR-CA.

Conclusion: In our study, a meaningful percentage of patients with unexplained LV dysfunction had a co-existing ATTR-CA indicating that the clinical heterogeneity of ATTR-CA is much broader than previously thought.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254104PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270434PMC
July 2021

Editorial: metformin for portal hypertension-old dog, new tricks? Authors' reply.

Aliment Pharmacol Ther 2021 Aug;54(3):347

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, Australia.

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http://dx.doi.org/10.1111/apt.16503DOI Listing
August 2021

A Global Survey of Physicians Knowledge About Non-alcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2021 Jul 3. Epub 2021 Jul 3.

Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, Virginia; Inova Medicine, Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia.

Background & Aims: Despite rapidly increasing nonalcoholic fatty liver disease (NAFLD) prevalence, providers' knowledge may be limited. We assessed NAFLD knowledge and associated factors among physicians of different specialties globally.

Methods: NAFLD knowledge surveys containing 54 and 59 questions covering 3 domains (epidemiology/pathogenesis, diagnostics, and treatment) were completed electronically by hepatologists, gastroenterologists (GEs), endocrinologists (ENDOs), and primary care physicians (PCPs) from 40 countries comprising 5 Global Burden of Disease super-regions. Over 24 months, 2202 surveys were completed (488 hepatologists, 758 GEs, 148 ENDOs, and 808 PCPs; 50% high-income Global Burden of Disease super-region, 27% from North Africa and Middle East, 12% Southeast Asia, and 5% South Asian and Latin America).

Results: Hepatologists saw the greatest number of NAFLD patients annually: median 150 (interquartile range, 60-300) vs 100 (interquartile range, 35-200) for GEs, 100 (interquartile range, 30-200) for ENDOs, and 10 (interquartile range, 4-50) for PCPs (all P < .0001). The primary sources of NAFLD knowledge acquisition for hepatologists were international conferences (33% vs 8%-26%) and practice guidelines for others (39%-44%). The Internet was the second most common source of NAFLD knowledge for PCPs (28%). NAFLD knowledge scores were higher for hepatologists than GEs: epidemiology, 62% vs 53%; diagnostics, 80% vs 73%; and treatment, 61% vs 58% (P < .0001), and ENDOs scores were higher than PCPs: epidemiology, 70% vs 60%; diagnostics, 71% vs 64%; and treatment, 79% vs 68% (P < .0001). Being a hepatologist or ENDO was associated with higher knowledge scores than a GE or PCP, respectively (P < .05). Higher NAFLD knowledge scores were associated independently with a greater number of NAFLD patients seen (P < .05).

Conclusions: Despite the growing burden of NAFLD, a significant knowledge gap remains for the identification, diagnosis, and management of NAFLD.
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http://dx.doi.org/10.1016/j.cgh.2021.06.048DOI Listing
July 2021

The prevalence of gestational diabetes mellitus in women diagnosed with non-alcoholic fatty liver disease during pregnancy: A systematic review and meta-analysis.

J Diabetes Complications 2021 Jun 27:107991. Epub 2021 Jun 27.

Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

Aims: To further explore the relationship between non-alcoholic fatty liver disease (NAFLD) and gestational diabetes mellitus (GDM) by determining the prevalence of GDM in women diagnosed with NAFLD antepartum.

Methods: Electronic databases were searched using specific keywords. Original studies of adult women reporting NAFLD (confirmed on imaging) and GDM (confirmed via oral glucose tolerance test) prevalence were included. Studies involving women with pre-gestational pre-diabetes, type 1/type 2 diabetes, chronic liver disease/cirrhosis unrelated to NAFLD were excluded. The prevalence of GDM occurring in women with NAFLD was calculated along with pooled odds ratios and 95% confidence intervals (CI) using the random effects model.

Results: Seven studies (total 2299 participants) were included. The prevalence of GDM in women with NAFLD was 26.0% (95% CI 20.9-31.7%, I = 48%, τ = 0.06). The odds of having GDM were 2.9 times higher in pregnant women diagnosed with NAFLD compared with non-NAFLD women, although a high degree of heterogeneity existed (unadjusted OR 2.9, 95% CI 1.0-8.4, I = 81%, τ = 0.83, p < 0.05).

Conclusion: Our study provides further insight into the prevalence of GDM in pregnant women diagnosed with NAFLD. There is a current lack of well-conducted studies examining this complex association between NAFLD and GDM.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107991DOI Listing
June 2021

COVID-19-Associated Cardiovascular Complications.

Diseases 2021 Jun 29;9(3). Epub 2021 Jun 29.

Division of Molecular & Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.

Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications such as myocardial injury, thromboembolic events, arrhythmia, and heart failure. Multiple mechanisms-some overlapping, notably the role of inflammation and IL-6-potentially underlie these complications. The reported cardiac injury may be a result of direct viral invasion of cardiomyocytes with consequent unopposed effects of angiotensin II, increased metabolic demand, immune activation, or microvascular dysfunction. Thromboembolic events have been widely reported in both the venous and arterial systems that have attracted intense interest in the underlying mechanisms. These could potentially be due to endothelial dysfunction secondary to direct viral invasion or inflammation. Additionally, thromboembolic events may also be a consequence of an attempt by the immune system to contain the infection through immunothrombosis and neutrophil extracellular traps. Cardiac arrhythmias have also been reported with a wide range of implicated contributory factors, ranging from direct viral myocardial injury, as well as other factors, including at-risk individuals with underlying inherited arrhythmia syndromes. Heart failure may also occur as a progression from cardiac injury, precipitation secondary to the initiation or withdrawal of certain drugs, or the accumulation of des-Arg-bradykinin (DABK) with excessive induction of pro-inflammatory G protein coupled receptor B (BK1). The presenting cardiovascular symptoms include chest pain, dyspnoea, and palpitations. There is currently intense interest in vaccine-induced thrombosis and in the treatment of Long COVID since many patients who have survived COVID-19 describe persisting health problems. This review will summarise the proposed physiological mechanisms of COVID-19-associated cardiovascular complications.
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http://dx.doi.org/10.3390/diseases9030047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293160PMC
June 2021

Viral Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Occurrence and Recurrence.

Front Microbiol 2021 14;12:665201. Epub 2021 Jun 14.

Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth leading cause of cancer-related death. The most common risk factor for developing HCC is chronic infection with hepatitis B virus (HBV). Early stages of HBV-related HCC (HBV-HCC) are generally asymptomatic. Moreover, while serum alpha-fetoprotein (AFP) and abdominal ultrasound are widely used to screen for HCC, they have poor sensitivity. Thus, HBV-HCC is frequently diagnosed at an advanced stage, in which there are limited treatment options and high mortality rates. Serum biomarkers with high sensitivity and specificity are crucial for earlier diagnosis of HCC and improving survival rates. As viral-host interactions are key determinants of pathogenesis, viral biomarkers may add greater diagnostic power for HCC than host biomarkers alone. In this review, we summarize recent research on using virus-derived biomarkers for predicting HCC occurrence and recurrence; including circulating viral DNA, RNA transcripts, and viral proteins. Combining these viral biomarkers with AFP and abdominal ultrasound could improve sensitivity and specificity of early diagnosis, increasing the survival of patients with HBV-HCC. In the future, as the mechanisms that drive HBV-HCC to become clearer, new biomarkers may be identified which can further improve early diagnosis of HBV-HCC.
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http://dx.doi.org/10.3389/fmicb.2021.665201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236856PMC
June 2021

Experimental and theoretical spectroscopic (FT-IR, FT-Raman, UV-VIS) analysis, natural bonding orbitals and molecular docking studies on 2-bromo-6-methoxynaphthalene: A potential anti-cancer drug.

Heliyon 2021 Jun 11;7(6):e07213. Epub 2021 Jun 11.

Department of Physics, Madras Christian College, East Tambaram 600059, Tamil Nadu, India.

The vibrational, electronic and charge transfer studies on 2-bromo-6-methoxynaphthalene (2BMN) were done using DFT method with B3LYP/6-311++G(d,p) theory using GAUSSIAN 09W software. Theoretical and experimental investigations on FT-IR and FT Raman were executed on 2BMN. The calculated vibrational wavenumbers were scaled using suitable scaling factors and vibrational assignments were done to all modes of vibrations using Potential Energy Distribution (PED). Frontier Molecular Orbitals were calculated using TD-DFT method and the HOMO-LUMO energy gap was also obtained. Other electronic properties and global parameters for 2BMN were found using the HOMO-LUMO energy values. An energy gap of 4.208 eV shows the stability of the molecule. The reactive sites were predicted using Molecular Electrostatic Potential (MEP), Electron Localization Function (ELF) and Fukui calculations. Hence all electrophilic sites and nucleophilic areas of the molecule were determined. The delocalization of electron density was studied using NBO calculations. The intramolecular transitions and stability of structure were explained using in detail using the former. As the compound satisfies drug-like properties and has a softness value (indicating its less toxic nature), it may be used as a pharmaceutical product. Molecular docking studies were made and the protein-ligand binding properties were discussed. It was found out that title compound exhibits anti-cancer activities. The low binding energy predicts that the compound may be modified as a drug for treating Cancer.
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http://dx.doi.org/10.1016/j.heliyon.2021.e07213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209084PMC
June 2021

Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension.

Aliment Pharmacol Ther 2021 Aug 24;54(3):320-328. Epub 2021 Jun 24.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia.

Background: Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect.

Aims: To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion.

Methods: In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90 minutes after ingestion of 1000-mg metformin (n = 16) or placebo (n = 16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow.

Results: The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time × group interaction, P = 0.008). In patients with baseline HVPG ≥12 mm Hg clinically significant improvements in HVPG (HVPG <12 mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P = 0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O uptake or inflammation markers between groups.

Conclusions: A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.
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http://dx.doi.org/10.1111/apt.16460DOI Listing
August 2021

Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus.

Adv Sci (Weinh) 2021 06 1;8(11):2004168. Epub 2021 May 1.

Storr Liver Centre Westmead Institute for Medical Research Westmead Hospital and University of Sydney Westmead NSW 2145 Australia.

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype- and context-dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.
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http://dx.doi.org/10.1002/advs.202004168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188187PMC
June 2021

MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach.

Hepatol Res 2021 Jun 15. Epub 2021 Jun 15.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Aim: Metabolic associated fatty liver disease (MAFLD) partly overlaps with non-alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups.

Methods: We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub-classified into three groups: NAFLD with no metabolic dysfunction (non-Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod-Alc MAFLD). ASCVD risk was estimated by non-invasive tests, including the Suita score. An event was defined as worsening of these scores from the low-risk to the high-risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE.

Results: In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02-1.15, p = 0.014) and alcohol consumption (20-39 g/day; HR 1.73, 95% CI 1.26-2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non-Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50-0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod-Alc MAFLD group (HR 1.19, 95% CI 0.89-1.58, p = 0.235).

Conclusions: The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption.
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http://dx.doi.org/10.1111/hepr.13685DOI Listing
June 2021

Cytokines: From Clinical Significance to Quantification.

Adv Sci (Weinh) 2021 Aug 10;8(15):e2004433. Epub 2021 Jun 10.

School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, 518172, P. R. China.

Cytokines are critical mediators that oversee and regulate immune and inflammatory responses via complex networks and serve as biomarkers for many diseases. Quantification of cytokines has significant value in both clinical medicine and biology as the levels provide insights into physiological and pathological processes and can be used to aid diagnosis and treatment. Cytokines and their clinical significance are introduced from the perspective of their pro- and anti-inflammatory effects. Factors affecting cytokines quantification in biological fluids, native levels in different body fluids, sample processing and storage conditions, sensitivity to freeze-thaw, and soluble cytokine receptors are discussed. In addition, recent advances in in vitro and in vivo assays, biosensors based on different signal outputs and intracellular to extracellular protein expression are summarized. Various quantification platforms for high-sensitivity and reliable measurement of cytokines in different scenarios are discussed, and commercially available cytokine assays are compared. A discussion of challenges in the development and advancement of technologies for cytokine quantification that aim to achieve real-time multiplex cytokine analysis for point-of-care situations applicable for both biomedical research and clinical practice are discussed.
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http://dx.doi.org/10.1002/advs.202004433DOI Listing
August 2021

Opportunities to enhance linkage to hepatitis C care among hospitalised people with recent drug dependence in New South Wales, Australia: A population-based linkage study.

Clin Infect Dis 2021 Jun 9. Epub 2021 Jun 9.

The Kirby Institute, UNSW Sydney, Sydney, Australia.

Background: People who inject drugs are at greater risk of hepatitis C virus (HCV) infection and hospitalisation, yet admissions are not utilised for HCV treatment initiation. We aimed to assess the extent to which people with HCV notification, including those with evidence of recent drug dependence, are hospitalised while eligible for direct-acting antiviral (DAA) therapy, and treatment uptake according to hospitalisation in the DAA era.

Methods: We conducted a longitudinal, population-based cohort study of people living with HCV in the DAA era (March 2016-December 2018) through analysis of linked databases in New South Wales, Australia. Kaplan Meier estimates were used to report HCV treatment uptake by frequency, length, and cause-specific hospitalisation.

Results: Among 57,467 people, 14,938 (26%) had evidence of recent drug dependence, 50% (n=7,506) of whom were hospitalised while DAA eligible. Incidence of selected cause-specific hospitalisation was highest for mental health-related (15.84 per 100 person-years [PY]), drug-related (15.20 per 100PY), and injection-related infectious disease (9.15 per 100PY) hospitalisations, and lowest for alcohol use disorder (4.58 per 100PY) and liver-related (3.13 per 100PY). 65% (n=4,898) of those hospitalised had been admitted >2 times and 46% (n=3,437) were hospitalised >7 days. By the end of 2018, DAA therapy was lowest for those hospitalised >2 times, for >7 days, and those whose first admission was for injection-related infectious disease, mental health disorders, and drug-related complications.

Conclusions: Among people who have evidence of recent drug dependence, frequent hospitalisation-particularly mental health, drug, and alcohol admissions-presents an opportunity for engagement in HCV care.
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http://dx.doi.org/10.1093/cid/ciab526DOI Listing
June 2021

The protective effect of SARS-CoV-2 antibodies in Scottish healthcare workers.

ERJ Open Res 2021 Apr 7;7(2). Epub 2021 Jun 7.

Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, UK.

Background: Healthcare workers (HCWs) are believed to be at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is not known to what extent the natural production of antibodies to SARS-CoV-2 is protective against re-infection.

Methods: A prospective observational study of HCWs in Scotland (UK) from May to September 2020 was performed. The Siemens SARS-CoV-2 total antibody assay was used to establish seroprevalence in this cohort. Controls, matched for age and sex to the general local population, were studied for comparison. New infections (up to 2 December 2020) post antibody testing were recorded to determine whether the presence of SARS-CoV-2 antibodies protects against re-infection.

Results: A total of 2063 health and social care workers were recruited for this study. At enrolment, 300 HCWs had a positive antibody test (14.5%). 11 out of 231 control sera tested positive (4.8%). HCWs therefore had an increased likelihood of a positive test (OR 3.4, 95% CI 1.85-6.16; p<0.0001). Dentists were most likely to test positive. 97.3% of patients who had previously tested positive for SARS-CoV-2 by reverse transcriptase (RT)-PCR had positive antibodies. 18.7% had an asymptomatic infection. There were 38 new infections with SARS-CoV-2 in HCWs who were previously antibody negative, and one symptomatic RT-PCR-positive re-infection. The presence of antibodies was therefore associated with an 85% reduced risk of re-infection with SARS-CoV-2 (hazard ratio 0.15, 95% CI 0.06-0.35; p=0.026).

Conclusion: HCWs were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all infected individuals developed an antibody response, which was 85% effective in protecting against re-infection with SARS-CoV-2.
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http://dx.doi.org/10.1183/23120541.00080-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164012PMC
April 2021

Endotrophin, a pro-peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma.

Hepat Oncol 2020 Dec 18;8(2):HEP32. Epub 2020 Dec 18.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital & University of Sydney, NSW, Australia.

Aim: Type VI collagen, is emerging as a signaling collagen originating from different types of fibroblasts. A specific fragment of Type VI collagen, the pro-peptide, is also known as the hormone endotrophin. We hypothesized that this fibroblast hormone would be of particular relevance in cancer types with a high amount of fibrosis activity, namely for outcome in hepatocellular carcinoma (HCC) cirrhotic patients.

Patients & Methods: Plasma C6M, PRO-C6 and alphafeto-protein (AFP) were assessed in 309 patients with mixed etiologies (hepatitis C, hepatitis B, alcohol and nonalcoholic fatty liver) diagnosed as cirrhotics, cirrhotics with HCC, noncirrhotics and healthy controls. Progression-free survival and overall survival (OS) data were collected up to 6120 days after diagnosis. The ability of each marker to predict survival was investigated.

Results & Conclusion: The level of endotrophin assessed by PRO-C6 was able to separate healthy controls, noncirrhotics and cirrhotics from HCC (p < 0.05-0.0001). Both endotrophin and C6M provided value in the prediction of OS in cirrhotic patients with HCC. In the multivariate analysis for identifying HCC, in patients with high endotrophin (highest quartile) and that were positive for AFP (≥20 IU/ml), the hazard ratio for predicting OS was increased from 3.7 (p = 0.0006) to 14.4 (p = 0.0001) when comparing with AFP positive as a stand-alone marker. In conclusion, plasma levels for markers of Type VI collagen remodeling were associated with survival in cirrhotic patients with HCC. A combination of AFP with endotrophin improved the prognostic value compared with AFP alone for predicting OS in cirrhotic patients with HCC.
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http://dx.doi.org/10.2217/hep-2020-0030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162185PMC
December 2020

Non-Obese MAFLD Is Associated with Colorectal Adenoma in Health Check Examinees: A Multicenter Retrospective Study.

Int J Mol Sci 2021 May 22;22(11). Epub 2021 May 22.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.

Colorectal adenoma is linked to metabolic dysfunction. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a precise definition and three subtypes, including non-obese MAFLD. We aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to non-alcoholic fatty liver disease (NAFLD) in health check-up examinees. This is a multicenter retrospective study. We enrolled 124 consecutive health check-up examinees who underwent colonoscopy. NAFLD and MAFLD were present in 58 and 63 examinees, respectively. Colorectal adenoma was diagnosed by biopsy. The impact of the MAFLD definition on the prevalence of colorectal adenoma was investigated by logistic regression, decision-tree, and random forest analyses. In logistic regression analysis, MAFLD was identified as the only independent factor associated with the presence of colorectal adenoma (OR 3.191; 95% CI 1.494-7.070; = 0.003). MAFLD was also identified as the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (29 variable importance value). Among the three subtypes of MAFLD, non-obese MAFLD was the sole independent factor associated with the presence of colorectal adenoma (OR 3.351; 95% CI 1.589-7.262; ≤ 0.001). Non-obese MAFLD was also the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (31 variable importance value). MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.
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http://dx.doi.org/10.3390/ijms22115462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196881PMC
May 2021

Rare case of meningitis in a man without risk factors.

BMJ Case Rep 2021 May 28;14(5). Epub 2021 May 28.

Microbiology, Royal Berkshire NHS Foundation Trust, Reading, UK.

meningitis is an uncommon but potentially serious cause of meningitis, which is considered particularly rare in healthy and immunocompetent individuals. We present a case of meningitis in a young, immunocompetent patient which was acquired following a dog bite. We review the literature and propose that underdiagnosis of this condition is likely. To avoid misdiagnosis, and thus improper management, clinicians should ensure that they identify animal exposure in all meningitic patients, and adopt a higher clinical suspicion in the absence of classical risk factors.
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http://dx.doi.org/10.1136/bcr-2021-241686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166629PMC
May 2021

Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolic-associated Fatty Liver Disease.

J Clin Transl Hepatol 2021 Apr 22;9(2):194-202. Epub 2021 Feb 22.

NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background And Aims: In Europeans, variants in the () gene impact liver histology in metabolic-associated fatty liver disease (MAFLD). The impact of these variants in ethnic Chinese is unknown. The aim of this study was to investigate the potential associations in Chinese patients.

Methods: In total, 427 Han Chinese with biopsy-confirmed MAFLD were enrolled. Two single nucleotide polymorphisms in were genotyped: rs72613567 and rs6531975. Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.

Results: In our cohort, the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis [odds ratio (OR): 2.93 (1.20-7.17), =0.019 for the additive model; OR: 3.32 (1.39-7.91), =0.007 for the recessive model], representing an inverse association as compared to the results from European cohorts. In contrast, we observed a protective effect on fibrosis for the minor A allele carriers of the rs6531975 variant [OR: 0.48 (0.24-0.98), =0.043 for the additive model; OR: 0.62 (0.40-0.94), =0.025 for the dominant model]. variants were only associated with fibrosis but no other histological features. Furthermore, rs6531975 modulated the effect of rs738409 on hepatic steatosis.

Conclusions: rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans. These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
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http://dx.doi.org/10.14218/JCTH.2020.00151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111109PMC
April 2021

Neutrophil-to-lymphocyte ratio and outcomes in patients with new-onset or worsening heart failure with reduced and preserved ejection fraction.

ESC Heart Fail 2021 Aug 16;8(4):3168-3179. Epub 2021 May 16.

Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK.

Aims: Inflammation is thought to play a role in heart failure (HF) pathophysiology. Neutrophil-to-lymphocyte ratio (NLR) is a simple, routinely available measure of inflammation. Its relationship with other inflammatory biomarkers and its association with clinical outcomes in addition to other risk markers have not been comprehensively evaluated in HF patients.

Methods: We evaluated patients with worsening or new-onset HF from the BIOlogy Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) study who had available NLR at baseline. The primary outcome was time to all-cause mortality or HF hospitalization. Outcomes were validated in a separate HF population.

Results: 1622 patients were evaluated (including 523 ventricular ejection fraction [LVEF] < 40% and 662 LVEF ≥ 40%). NLR was significantly correlated with biomarkers related to inflammation as well as NT-proBNP. NLR was significantly associated with the primary outcome in patients irrespective of LVEF (hazard ratio [HR] 1.18 per standard deviation increase; 95% confidence interval [CI] 1.11-1.26, P < 0.001). Patients with NLR in the highest tertile had significantly worse outcome than those in the lowest independent of LVEF (<40%: HR 2.75; 95% CI 1.84-4.09, P < 0.001; LVEF ≥ 40%: HR 1.51; 95% CI 1.05-2.16, P = 0.026). When NLR was added to the BIOSTAT-CHF risk score, there were improvements in integrated discrimination index (IDI) and net reclassification index (NRI) for occurrence of the primary outcome (IDI + 0.009; 95% CI 0.00-0.019, P = 0.030; continuous NRI + 0.112, 95% CI 0.012-0.176, P = 0.040). Elevated NLR was similarly associated with adverse outcome in the validation cohort. Decrease in NLR at 6 months was associated with reduced incidence of the primary outcome (HR 0.75; 95% CI 0.57-0.98, P = 0.036).

Conclusions: Elevated NLR is significantly associated with elevated markers of inflammation in HF patients and is associated with worse outcome. Elevated NLR might potentially be useful in identifying high-risk HF patients and may represent a treatment target.
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http://dx.doi.org/10.1002/ehf2.13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318449PMC
August 2021

Transthyretin Cardiac Amyloidosis Scintigraphy Using Planar D-SPECT on Dedicated Cardiac CZT Camera.

J Nucl Cardiol 2021 May 11. Epub 2021 May 11.

Heart Center, Kaplan Medical Center, Pasternak St., 1, Rehovot, 7661041, Israel.

Background: Bone scintigraphy is a main diagnostic tool in suspected ATTR patients. Almost all literature is based on conventional whole body gamma cameras, and there is very sparse data evaluating the use of dedicated cardiac CZT cameras. The aim of this study was to evaluate the utility of bone scintigraphy in suspected transthyretin cardiac amyloidosis (ATTR-CA) patients on a dedicated cardiac CZT camera.

Methods: Seventy-three patients with suspected ATTR-CA underwent planar and SPECT Tc-99 m pyrophosphate scintigraphy using dedicated cardiac CZT camera between May and August 2019.

Results: Planar D-SPECT image quality was mostly good. Six patients were identified as ATTR-CA positive. Inter-observer agreement based on both Perugini score and on planar D-SPECT H/CL ratio was excellent.

Conclusions: ATTR-CA scintigraphy using dedicated cardiac CZT camera was feasible, and yielded planar D-SPECT images with excellent inter-observer agreement.
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http://dx.doi.org/10.1007/s12350-021-02651-5DOI Listing
May 2021

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates.

Arch Dis Child 2021 May 11. Epub 2021 May 11.

Department of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Basel, Switzerland.

Objective: Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates.

Design: Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates.

Setting: Neonatal intensive care unit at McMaster Children's Hospital.

Patients: Neonates with a gestational age ≤28 weeks treated with oral ibuprofen for closure of a PDA.

Methods: Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation.

Main Outcome Measure: Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC >900 mg·hour/L).

Results: Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours' postdose on the first day, a strong correlation between ibuprofen concentrations and AUC was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure.

Conclusion: We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.
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http://dx.doi.org/10.1136/archdischild-2020-321381DOI Listing
May 2021

Core liver homeostatic co-expression networks are preserved but respond to perturbations in an organism- and disease-specific manner.

Cell Syst 2021 May 5;12(5):432-445.e7. Epub 2021 May 5.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia. Electronic address:

Findings about chronic complex diseases are difficult to extrapolate from animal models to humans. We reason that organs may have core network modules that are preserved between species and are predictably altered when homeostasis is disrupted. To test this idea, we perturbed hepatic homeostasis in mice by dietary challenge and compared the liver transcriptome with that in human fatty liver disease and liver cancer. Co-expression module preservation analysis pointed to alterations in immune responses and metabolism (core modules) in both human and mouse datasets. The extent of derailment in core modules was predictive of survival in the cancer genome atlas (TCGA) liver cancer dataset. We identified module eigengene quantitative trait loci (module-eQTL) for these predictive co-expression modules, targeting of which may resolve homeostatic perturbations and improve patient outcomes. The framework presented can be used to understand homeostasis at systems levels in pre-clinical models and in humans. A record of this paper's transparent peer review process is included in the supplemental information.
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http://dx.doi.org/10.1016/j.cels.2021.04.004DOI Listing
May 2021

Residual alterations of cardiac and endothelial function in patients who recovered from Takotsubo cardiomyopathy.

Clin Cardiol 2021 Jun 6;44(6):797-804. Epub 2021 May 6.

The Heart Institute, Kaplan Medical Center, Rehovot, Hebrew University and Hadassah Medical School, Jerusalem, Israel.

Introduction: Takotsubo cardiomyopathy (TCM) is characterized by transient left ventricle dysfunction.

Hypothesis: A residual cardiac and endothelial dysfunction is present in patients who recovered from TCM.

Methods: In this single-center prospective study, patients with prior TCM were included and followed for 6.4 ± 1.6 years. All underwent comprehensive cardiac function assessment, including tissue Doppler imaging (TDI) and 2-dimensional strain (2DS) echocardiography at their first visit. The number of circulating endothelial progenitor cells and levels of proangiogenic vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) were measured. All measurements were compared with healthy controls.

Results: Forty-two women (age 58. ±8.6 years, LVEF 58.1 ± 6.1%) comprised the TCM group. Patients post-TCM had significantly lower early velocities E' (6 (5.0-8.0) vs. 9 (7.0-11.0) cm/s, p = .001) by TDI and higher E/E' ratio (p = .002), lower LV global average longitudinal strain (LGS) (-18.9 ± 3.5% vs. -21.7 ± 2.3%, p = .002) and RV LGS (-20.1 ± 3.9% vs. -23.4 ± 2.8%, p = .003) were evident. There was a trend toward a higher VEGF-R (p = .09) along with decreased VEGF/VEGF-R ratio representing inadequate VEGF production. In-hospital mortality was not reported and only two non-cardiac deaths occurred at long-term follow-up.

Conclusions: Altered TDI and 2DS indices suggest residual biventricular myocardial injury in post-TCM patients with the apparent LV function recovery. Inappropriate production of VEGF and VEGF-R were observed, suggesting a possible underlying endothelial dysfunction in these patients.
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http://dx.doi.org/10.1002/clc.23604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207966PMC
June 2021

Helmet Tremor: A Rare Dystonic Tremor.

Ann Indian Acad Neurol 2021 Jan-Feb;24(1):116. Epub 2020 Oct 8.

Department of Neurology, Govt Medical College, Kottayam, Kerala, India.

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http://dx.doi.org/10.4103/aian.AIAN_158_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061528PMC
October 2020

Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis.

J Inflamm Res 2021 1;14:1257-1270. Epub 2021 Apr 1.

Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia.

Introduction: Interferon lambdas (IFN-λs) are antiviral cytokines that restrict pathogen infection and dissemination at barrier surfaces. Controlled expression of IFN-λs efficiently eliminates acute infections by activating a suite of interferon stimulated genes that inhibit viral propagation and activate local immune cells. Excessive or prolonged production of IFN-λs can however mediate tissue inflammation and disrupt epithelial barriers in both viral and non-viral disease. The mechanism by which IFN-λs drive this disease pathogenesis is poorly understood but may be caused by IFN-λ-mediated amplification of other innate immune signaling pathways.

Methods: Monocyte-derived macrophages were differentiated ± IFN-λ3 and treated with KDO-lipid A, poly I:C or zymosan, representing bacterial, viral or fungal ligands, respectively. Transcriptome and protein expression were quantified by RNA sequencing/PCR and ELISA/bead array, respectively. Bioinformatic analysis was used to define transcription factor profiles and signaling pathways amplified by IFN-λ3. Finally, the SARS-CoV-2 dataset GSE152075 was queried to compare the effects of versus expression in relation to viral load and nasopharyngeal transcriptomes.

Results: IFN-λ3 exacerbated inflammatory and chemotactic responses unique to each microbial ligand, as measured by RNA sequencing and by ELISA/bead array. Functional annotation identified pathways amplified by IFN-λ3, including inflammasome activation. Inflammasome amplification was confirmed in vitro, as measured by caspase 1 activity and IL-1β cleavage. Lastly, SARS-CoV-2 infected nasopharyngeal transcriptomes expressing IFN-λs but not IFN-αs were implicated in myeloid cell-driven pathogenesis including neutrophil degranulation, complement and coagulation cascades.

Discussion: These data suggest that IFN-λs contribute to disease pathology by exacerbating innate immune responses during chronic or severe disease states. IFN-λs may contribute to SARS-CoV-2 disease severity, however further study is required to confirm true causation.
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http://dx.doi.org/10.2147/JIR.S301476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021260PMC
April 2021

Immune-Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Synopsis of Response Rates.

Oncologist 2021 07 21;26(7):e1216-e1225. Epub 2021 Apr 21.

Blacktown Clinical School, Western Sydney University, Sydney, New South Wales, Australia.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I-IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. IMPLICATIONS FOR PRACTICE: Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.
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http://dx.doi.org/10.1002/onco.13776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265367PMC
July 2021

Developing liver organoids from induced pluripotent stem cells (iPSCs): An alternative source of organoid generation for liver cancer research.

Cancer Lett 2021 Jun 23;508:13-17. Epub 2021 Mar 23.

Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia. Electronic address:

Primary liver cancer (PLC) represents a significant proportion of all human cancers and constitutes a substantial health and economic burden to society. Traditional therapeutic approaches such as surgical resection and chemotherapy often fail due to tumour relapse or innate tumour chemoresistance. There is a dearth of efficient treatments for PLC in part due to the poor capacity of current laboratory models to reflect critical features of the native tumour in vivo. The increasing incorporation of organoid systems has led to a resurgence of interest in liver cancer research. Organoid systems show promise as the gold standard for recapitulating tumours in vitro. Further, developments in culturing techniques will improve the various shortcomings of the current systems. Induced pluripotent stem cell (iPSC)-derived liver organoids are a promising alternative to the conventional liver organoid model as it circumvents the need to rely on primary resections which are often scarce. In this concise review, we will discuss novel techniques for organoid culture with a focus on organoid co-cultures and their advantages over traditional organoid systems. A detailed technical protocol for the generation of iPSC-derived liver organoids is provided as an appendix.
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http://dx.doi.org/10.1016/j.canlet.2021.03.017DOI Listing
June 2021

Association and Interaction Between Serum Interleukin-6 Levels and Metabolic Dysfunction-Associated Fatty Liver Disease in Patients With Severe Coronavirus Disease 2019.

Front Endocrinol (Lausanne) 2021 8;12:604100. Epub 2021 Mar 8.

MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Background And Aim: Circulating levels of interleukin (IL)-6, a well-known inflammatory cytokine, are often elevated in coronavirus disease-2019 (COVID-19). Elevated IL-6 levels are also observed in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). Our study aimed to describe the association between circulating IL-6 levels and MAFLD at hospital admission with risk of severe COVID-19.

Methods: A total of 167 patients with laboratory-confirmed COVID-19 from three Chinese hospitals were enrolled. Circulating levels of IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured at admission. All patients were screened for fatty liver by computed tomography. Forty-six patients were diagnosed as MAFLD.

Results: Patients with MAFLD (n = 46) had higher serum IL-6 levels (median 7.1 [interquartile range, 4.3-20.0] vs. 4.8 [2.6-11.6] pg/mL, = 0.030) compared to their counterparts without MAFLD (n = 121). After adjustment for age and sex, patients with MAFLD had a ~2.6-fold higher risk of having severe COVID-19 than those without MAFLD. After adjustment for age, sex and metabolic co-morbidities, increased serum IL-6 levels remained associated with higher risk of severe COVID-19, especially among infected patients with MAFLD (adjusted-odds ratio 1.14, 95% CI 1.05-1.23; = 0.002). There was a significant interaction effect between serum IL-6 levels and MAFLD for risk of severe COVID-19 ( for interaction = 0.008).

Conclusions: Patients with MAFLD and elevated serum IL-6 levels at admission are at higher risk for severe illness from COVID-19.
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http://dx.doi.org/10.3389/fendo.2021.604100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982673PMC
April 2021
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