Background and Aims
Type 2 diabetes is an important risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis. Current international guidelines recommend the use of noninvasive ...tests as initial assessments for NAFLD, but the role of noninvasive tests as monitoring tools has not been established. We aimed to study the role of transient elastography as a monitoring tool in patients with type 2 diabetes.
Approach and Results
We recruited patients with type 2 diabetes without viral hepatitis or excessive alcohol intake from a complication screening facility in Hong Kong in 2013‐2014 and repeated the assessments in 2016‐2018. The primary endpoint was an increase of liver stiffness measurement (LSM) to ≥10 kPa. The secondary endpoint was the change in the controlled attenuation parameter (CAP). A total of 611 patients with type 2 diabetes and a valid LSM (mean age, 57.7 ± 10.9 years; 342 men 56.0%) were included in this study (568 also had a valid CAP). Overall, there was moderate correlation between the baseline and follow‐up LSM (r = 0.689, P < 0.001). Among 487 patients with a baseline LSM <10 kPa, 21 (4.3%) had a follow‐up LSM ≥10 kPa. Baseline body mass index, alanine aminotransferase (ALT), and ∆ALT were independent factors associated with LSM increase. Among 124 patients with a baseline LSM ≥10 kPa, 70 (56.5%) had a follow‐up LSM <10 kPa. Among 198 patients with a CAP <248 dB/m at baseline, 103 (52.0%) had a CAP increased to ≥248 dB/m.
Conclusions
The prevalence and incidence of NAFLD in patients with type 2 diabetes are high. Although advanced fibrosis is common in this population, few patients progress to advanced fibrosis in 3 years. Future studies should define the optimal surveillance interval in patients with diabetes.
Recently, a group of hepatologists proposed to rename non-alcoholic fatty liver disease (NAFLD) as metabolic associated fatty liver disease (MAFLD) with modified diagnostic criteria. We aimed to ...study the impact of the new definition on the epidemiology of fatty liver disease.
We randomly selected 1013 adults from the Hong Kong census database for clinical assessment, proton-magnetic resonance spectroscopy, and transient elastography. Five hundred sixty-five subjects without fatty liver at baseline underwent follow-up assessment. MAFLD was diagnosed as intrahepatic triglyceride content (IHTG) ≥5% and the presence of overweight/obesity, diabetes, or two other metabolic risk factors, with and without concomitant liver diseases. The diagnosis of NAFLD required the exclusion of concomitant liver diseases; metabolic factors were not considered.
The population prevalence of MAFLD and NAFLD was 25.9% (95% CI 23.2-28.7%) and 25.7% (95% CI 23.1-28.5%), respectively. Among 277 subjects with IHTG ≥5%, 247 (89.2%) fulfilled both the definitions of MAFLD and NAFLD. Fourteen subjects (5.1%) had IHTG ≥5% but did not meet the metabolic criteria of MAFLD. The incidence of MAFLD was 2.8 per 100 person-years at a median interval of 47 months (range 34-60 months). Among 78 subjects with incident NAFLD, 59 (75.6%) met the criteria of MAFLD; only one of the latter, a regular drinker, had liver stiffness ≥10 kPa.
The new definition of MAFLD does not significantly change the prevalence compared with NAFLD, but it may reduce the incidence by 25%. People with hepatic steatosis but not fulfilling the definition of MAFLD unlikely have significant liver disease.
Several studies reported hematological abnormalities after vaccination against the coronavirus disease 2019 (COVID‐19). We evaluated the association between COVID‐19 vaccines (CoronaVac and BNT162b2) ...and hematological abnormalities. We conducted nested case–control and self‐controlled case series analyses using the data from the Hong Kong Hospital Authority and the Department of Health, HKSAR. Outcomes of interest were thrombocytopenia, leukopenia, and neutropenia. Adjusted odds ratios (aORs), incidence rate ratios (IRRs), and 95% confidence intervals (CIs) were estimated using conditional logistic regression. In total, 1 643 419 people received COVID‐19 vaccination (738 609 CoronaVac; 904 810 BNT162b2). We identified 457 and 422 cases after CoronaVac and BNT162b2 vaccination, respectively. For CoronaVac, the incidence of thrombocytopenia, leukopenia, and neutropenia was 2.51, 1.08, and 0.15 per 10 000 doses. For BNT162b2, the corresponding incidence was 1.39, 1.17, and 0.26 per 10 000 doses. The incidence per 10 000 COVID‐19 cases were 1254, 2341, and 884, respectively. We only observed an increased risk of leukopenia following the second dose of BNT162b2 (aOR 1.58, 95% CI 1.24–2.02; day 0–14, IRR 2.21; 95% CI 1.59–3.08). There was no increased risk of any hematological abnormalities after CoronaVac vaccination. We observed an increased risk of leukopenia shortly after the second dose of BNT162b2. However, the incidence was much lower than the incidence following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections. There was no association between CoronaVac and hematological abnormalities. The benefits of vaccination against COVID‐19 still outweigh the risk of hematological abnormalities.
The systematic control over association mechanisms of self-assembled materials has been demonstrated through the rational design and synthesis of a series of amphiphilic dinuclear ...alkynylplatinum(II) bzimpy (bzimpy = 2,6-bis(N-alkylbenzimidazol-2′-yl)pyridine) complexes containing the shape-persistent oligo(p-phenyleneethynylene)s. Multistage morphological transformations from plates to fibers and to spherical nanostructures under different solvent compositions have been demonstrated. The subtle balances between multiple noncovalent interactions including Pt···Pt, hydrophobic, hydrophilic, and π–π stacking interactions are found to have profound impact on the supramolecular assembly of the system, in which a change in the association mechanism from isodesmic to cooperative and back to isodesmic growth has been observed upon increasing hydrophilicity of the complexes.
Background and Aim
The Baveno VI Consensus recommends repeating examination in patients with high liver stiffness measurement (LSM) by transient elastography to reduce false‐positive diagnosis of ...advanced liver disease. We tested whether repeating transient elastography can increase the overall diagnostic accuracy.
Methods
Ninety‐seven patients with non‐alcoholic fatty liver disease who underwent two FibroScan examinations within 6 months prior to liver biopsy were evaluated. An LSM cut‐off of 7.9 kPa was used to exclude F3‐4 fibrosis.
Results
Seventy‐eight patients had high LSM at baseline, among whom 27 had low LSM on repeated testing; only four had F3 and none had cirrhosis. In contrast, 31 of 51 patients with high LSM at both examinations had F3‐4. Nineteen patients had low LSM at baseline; none of them had F3‐4 regardless of the second LSM results. If we took LSM <7.9 kPa at either examination as sufficient to exclude F3‐4, the negative predictive value remained high at 91%. The positive predictive value for F3‐4 increased from 45% in patients with high LSM at baseline to 61% in those with high LSM at both examinations. Sensitivity analysis using different cut‐offs yielded similar results, with 76% of patients with LSM >12 kPa at both examinations having F3‐4.
Conclusions
Transient elastography is a highly sensitive screening test to exclude F3‐4 fibrosis in non‐alcoholic fatty liver disease patients. One‐third of patients with high LSM may have normal results on repeated examination. By repeating examination in cases with high LSM, one may spare patients from unnecessary liver biopsy.
Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene ...expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.
A series of oligo(ethynylpyridine)-containing alkynylplatinum(II) terpyridine/bzimpy (bzimpy = 2,6-bis(N-alkylbenzimidazol-2′-yl)pyridine) metallofoldamers has been designed and synthesized to ...investigate the potential applications of metallofoldamers imparted by the rich spectroscopic responses of Pt···Pt interactions. Apart from the control of the folding/unfolding processes by solvent compositions and temperatures, this class of metallofoldamers has also been found to exhibit reversible folding/unfolding behaviors mediated by the addition of acids/bases due to the incorporation of the acid-sensitive oligo(ethynylpyridine) derivatives. More importantly, the intramolecular Pt···Pt interaction has been found to play a crucial role in governing the folded state conformation. The conformation of this class of metallofoldamers has been investigated by 2D ROESY NMR, electronic absorption, and emission spectroscopy, which provide further insights into the rational molecular design and multidimensional control of metallofoldamers upon the application of various external stimuli, leading to the preparation of multi-stimuli-responsive materials for potential applications in material sciences.
A new class of bent amphiphilic alkynylplatinum(
ii
) terpyridine complexes was found to adopt different modes of molecular stacking to give diverse nanostructures. In chlorinated solvents, the ...complexes aggregate in the presence of water droplets and assist in the formation of porous networks, while in DMSO solutions, they self-assemble to give fibrous nanostructures. The complexes would adopt a head-to-tail tetragonal stacking arrangement, as revealed by X-ray crystallographic studies, computational studies and powder X-ray diffraction (PXRD) studies. Their self-assembly follows a cooperative growth mechanism in DMSO and an isodesmic growth mechanism in DMSO-H
2
O mixture. The balance between hydrophobic and hydrophilic components of the complex system, in conjunction with the nuclearity and the positioning of the substituents, are found to govern the mode of molecular stacking and the fabrication of precise functional nanostructures. This class of complexes serve as versatile building blocks to construct orderly packed molecular materials and functional materials in a well-controlled manner.
A new class of bent amphiphilic alkynylplatinum(
ii
) terpyridine complexes was found to adopt different modes of molecular stacking to give diverse nanostructures.
The self-assembly of lanthanide (europium or lanthanium) bimetallic triple helicates from two closely related chiral ligands resulted in a very different supramolecular phenomenon. One gave rise to ...significantly diastereoselective formation of a triple helicate, whereas the other led to diastereoselective breaking to generate a mixture of P and M diastereomers in ∼1 : 1.1 ratio. The first X-ray crystal structure of a chiral ligand based lanthanide triple-helicate indicates that successive CH-π interactions were found to maintain the supramolecular helical structure.
Background Recent trials have shown that low‐density lipoprotein cholesterol (LDL‐C) <1.80 mmol/L (<70 mg/dL) is associated with a reduced risk of major adverse cardiovascular events in White ...patients with ischemic stroke with atherosclerosis. However, it remains uncertain whether the findings can be generalized to Asian patients, or that similar LDL‐C targets should be adopted in patients with stroke without significant atherosclerosis. Methods and Results We performed a prospective cohort study and recruited consecutive Chinese patients with ischemic stroke with magnetic resonance angiography of the intra‐ and cervicocranial arteries performed at the University of Hong Kong between 2008 and 2014. Serial postevent LDL‐C measurements were obtained. Risk of major adverse cardiovascular events in patients with mean postevent LDL‐C <1.80 versus ≥1.80 mmol/L, stratified by presence or absence of significant (≥50%) large‐artery disease (LAD) and by ischemic stroke subtypes, were compared. Nine hundred four patients (mean age, 69±12 years; 60% men) were followed up for a mean 6.5±2.4 years (mean, 9±5 LDL‐C readings per patient). Regardless of LAD status, patients with a mean postevent LDL‐C <1.80 mmol/L were associated with a lower risk of major adverse cardiovascular events (with significant LAD: multivariable‐adjusted subdistribution hazard ratio, 0.65; 95% CI, 0.42–0.99; without significant LAD: subdistribution hazard ratio, 0.53; 95% CI, 0.32–0.88) (both P <0.05). Similar findings were noted in patients with ischemic stroke attributable to large‐artery atherosclerosis (subdistribution hazard ratio, 0.48; 95% CI, 0.28–0.84) and in patients with other ischemic stroke subtypes (subdistribution hazard ratio, 0.64; 95% CI, 0.43–0.95) (both P <0.05). Conclusions A mean LDL‐C <1.80 mmol/L was associated with a lower risk of major adverse cardiovascular events in Chinese patients with ischemic stroke with and without significant LAD. Further randomized trials to determine the optimal LDL‐C cutoff in stroke patients without significant atherosclerosis are warranted.
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