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Background: We aimed to evaluate whether non-alcoholic fatty liver disease (NAFLD) with or without sarcopenia is associated with progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).Methods: We investigated 852 T2DM patients who underwent abdominal ultrasonography, bioelectrical impedance analysis, and carotid artery ultrasonography at baseline and repeated carotid ultrasonography after 6 to 8 years. NAFLD was confirmed by abdominal ultrasonography, and sarcopenia was defined as a sex-specific skeletal muscle mass index (SMI) value

Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. Methods Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. Results Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. Conclusions/interpretation In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. Data availability RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449). Graphical abstract

Determine whether the twice daily (BID) regimen is superior to the once daily (QD) regimen for managing glycemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD.A double-blinded, randomized, multicenter study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5%HbA1c 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring (CGM) was used to measure the mean amplitude of glycemic excursion (MAGE) and postprandial time in range (TIR) before and after DPP-4 inhibitor treatment to compare glycemic variability.The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (p0.05); -30.4 ± 25.6 mg/dL (p0.001) in the anagliptin group versus -9.5 ± 38.0 mg/dL (p=0.215) in the sitagliptin group. The TIR after dinner increased by 33.0 ± 22.0% (p0.001) in the anagliptin group and by 14.6 ± 28.2% (p=0.014) in the sitagliptin group, with a statistically significant difference (p=0.009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG).The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycemic variability, as indicated by MAGE and TIR but equivalent to the QD regimen in terms of HbA1c and FPG. This article is protected by copyright. All rights reserved.

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and CKD is uncertain, particularly in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with T2DM.Methods: In this longitudinal cohort study of patients with T2DM, 3,188 patients with preserved renal function were followed up for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography, without any other causes of chronic liver disease. Advanced liver fibrosis of NAFLD was defined as a fibrosis-4 index ≥2.67. CKD was defined as an estimated glomerular filtration rate

AimsThe ketogenic pathway is an effective mechanism by which the liver disposes of fatty acids (FAs) to the peripheral tissues. Impaired ketogenesis is presumed to be related to the pathogenesis of metabolic-associated fatty liver disease (MAFLD), but the results of previous studies have been controversial. Therefore, we investigated the association between ketogenic capacity and MAFLD in subjects with type 2 diabetes (T2D).MethodsA total of 435 subjects with newly diagnosed T2D was recruited for the study. They were classified into two groups based on median serum β-hydroxybutyrate (β-HB) level: intact vs. impaired ketogenesis groups. The associations of baseline serum β-HB and MAFLD indices of hepatic steatosis index, NAFLD liver fat score (NLFS), Framingham Steatosis index (FSI), Zhejian University index, and Chinese NAFLD score were investigated.ResultsCompared to the impaired ketogenesis group, the intact ketogenesis group showed better insulin sensitivity, lower serum triglyceride level, and higher low-density lipoprotein-cholesterol and glycated hemoglobin levels. Serum levels of liver enzymes were not different between the two groups. Of the hepatic steatosis indices, NLFS (0.8 vs. 0.9, p=0.045) and FSI (39.4 vs. 47.0: p=0.041) were significantly lower in the intact ketogenesis group. Moreover, intact ketogenesis was significantly associated with lower risk of MAFLD as calculated by FSI after adjusting for potential confounders (adjusted odds ratio 0.48, 95% confidence interval 0.25-0.91, p=0.025).ConclusionsOur study suggests that intact ketogenesis might be associated with decreased risk of MAFLD in T2D.

Objective As delayed diagnosis of diabetes increases the risk of irreversible diabetes complications, detecting undiagnosed diabetes using a prediction model could be useful. Recently, machine learning-based disease prediction models have been used; however, the performance of the machine learning-based prediction model and traditional statistics-based prediction models in predicting undiagnosed diabetes has not been compared. Therefore, we developed a machine learning-based undiagnosed diabetes prediction model and compared its prediction performance with that of a traditional statistics-based prediction model. Methods We used the 2014–2020 Korean National Health and Nutrition Examination Survey (KNHANES) (N = 32,827). The KNHANES 2014–2018 data were used as training and internal validation sets and the 2019–2020 data as external validation sets. The receiver operating characteristic curve area under the curve (AUC) was used to compare the prediction performance of the machine learning-based and the traditional statistics-based prediction models. Results Using sex, age, resting heart rate, and waist circumference as features, the machine learning-based model showed a higher AUC (0.788 vs. 0.740) than that of the traditional statistical-based prediction model. Using sex, age, waist circumference, family history of diabetes, hypertension, alcohol consumption, and smoking status as features, the machine learning-based prediction model showed a higher AUC (0.802 vs. 0.759) than the traditional statistical-based prediction model. The machine learning-based prediction model using features for maximum prediction performance showed a higher AUC (0.819 vs. 0.765) than the traditional statistical-based prediction model. Conclusions machine learning-based prediction models using anthropometric and lifestyle measurements showed good performance in predicting undiagnosed diabetes. The machine learning-based prediction model outperformed the traditional statistics-based prediction models.

The clinical and radiological results before and after surgery were compared and analyzed for patients with multilevel lumbar stenosis who underwent bi-portal endoscopic spine surgery (BESS) and microscopic unilateral laminotomy for bilateral decompression (ULBD). We retrospectively identified 47 and 49 patients who underwent BESS and microscopic ULBD, respectively, who were diagnosed with multi-level lumbar stenosis. Clinical outcomes were evaluated using the visual analog scale score for both back and leg pain, and medication (pregabalin) use and Oswestry Disability Index (ODI) scores for overall treatment outcomes were used pre-operatively and at the final follow-up. Radiological outcomes were evaluated as the percentage of dura expansion volume, and percentage preservation of both facets and both lateral recess angles. The follow-up period of patients was about 17.04 months in the BESS group and about 16.90 months in the microscopic ULBD group. The back and leg visual analog scale (VAS) scores and average pregabalin use decreased more significantly in the BESS group than in the microscopic ULBD group (each p-value 0.0443

This study investigated whether a new sustained-release (SR) pregabalin formulation is noninferior to immediate-release (IR) pregabalin in alleviating peripheral neuropathic pain in Korean patients.This was a randomized, double-blind, active-controlled phase 3 study of patients with diabetic peripheral neuropathy or postherpetic neuralgia from 41 sites in South Korea in 2017-2018. Eligible patients were randomized (1:1) to receive once-daily SR pregabalin or twice-daily IR pregabalin (150 to 600 mg/d) in a double-dummy manner for 12 weeks according to a stratified permuted block randomization scheme. The primary endpoint was the Daily Pain Rating Scale score at the end of treatment, averaged from the last 7 available scores.A total of 319 of 371 (86.0%) randomized patients completed the 12-week treatment (SR pregabalin: n=154; IR pregabalin: n=165; per-protocol set: n=296). The least square mean difference between both groups for the primary endpoint was 0.06 (SE 0.19); (95% confidence interval -0.31 to 0.42), with the lower limit of the confidence interval above the pre-specified margin (-0.78; Pnoninferiority0.0001). Drug-related treatment-emergent adverse events (TEAEs) were comparable between both groups. The incidence of drug-related TEAEs leading to treatment discontinuation was low (SR pregabalin: 2.7%; IR pregabalin: 1.1%). No serious drug-related TEAEs or deaths occurred.The results demonstrate that the new once-daily SR pregabalin formulation is noninferior to twice-daily IR pregabalin in reducing peripheral neuropathic pain and is well tolerated in Korean patients with diabetic peripheral neuropathy or postherpetic neuralgia after 12 weeks of treatment.

In the present study, CuFeO vertical nanocolumnar structured arrays are deposited on fluorine-doped tin oxide substrates by reactive ballistic deposition technique in an oxygen atmosphere by fixing the deposition angle at 85°. Scanning electron microscopy images shows the presence of arrays of individual columns. The photocurrent density of the CuFeO2 annealed at 650 oC for 2 h in argon is determined to be -0.22 mA cm-2 at 0.4 V versus RHE in 1 M NaOH under AM 1.5 G illumination, while the same annealed in air exhibits a photocurrent density value of 0.12 mA cm-2 at 1.23 V versus RHE. Here, the film annealed in an argon atmosphere at 650 °C exhibits a p-type characteristic with cathodic photocurrent, while the same annealed in air depicts an n-type characteristic with anodic photocurrent. The p-type character was induced by the Cu vacancies and the shift in the conductivity from n-type to p-type is induced by phase transition formation of delafossite CuFeO2 from copper modfied FeO. The generation of photocurrent density from p-CuFeO2 is expected to be from the presence of Cu2+/Cu+ redox couple which is evidenced by X-ray photoelectron spectroscopy.

There are inconsistent results on the impacts of controlling blood pressure (BP) on the risk of dementia. We investigated the association between BP and risk of dementia subtypes by antihypertensive treatment and comorbidities. Using the Korean National Health Insurance Service-Health Screening Database from 2009 to 2012, a total of 4 522 447 adults aged 60+ years without a history of dementia were analyzed and followed up for a mean of 5.4 years. Individuals were classified according to their baseline systolic BP (SBP) and diastolic BP; SBP 130 to

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) has rapidly increased worldwide. The aim of this study was to investigate whether there is an independent relationship between regional fat distribution, especially leg fat mass, and the presence of NAFLD using nationally representative data in Korea.Methods: This cross-sectional study analyzed data from 14,502 participants in the Korea National Health and Nutrition Examination Survey 2008 to 2011. Total fat mass, leg fat mass, and appendicular skeletal muscle mass were measured by dual-energy X-ray absorptiometry. Validated NAFLD prediction models and scoring systems for hepatic fibrosis were used.Results: The leg fat to total fat (LF/TF) ratio showed a negative relationship with many factors, including body mass index, waist circumference, blood pressure, fasting blood glucose, and liver enzyme levels. When the LF/TF ratio and indices of hepatic steatosis were stratified by quartiles, the LF/TF ratio showed a negative correlation with the scoring systems that were used. The LF/TF ratio showed better accuracy in predicting NAFLD than total fat mass or leg fat mass alone. After adjusting for various traditional and lifestyle factors, a low LF/TF ratio remained a risk factor for NAFLD. Among NAFLD subjects, the LF/TF ratio showed a negative relationship with hepatic fibrosis.Conclusion: A lower LF/TF ratio was markedly associated with a higher risk of hepatic steatosis and advanced hepatic fibrosis using various predictive models in a Korean population. Therefore, the LF/TF ratio could be a useful anthropometric parameter to predict NAFLD or advanced hepatic fibrosis.

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism.Methods: Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks.Results: The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue.Conclusion: SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.

BackgroundGasserian ganglion radiofreqeucy thermoablation is a good treatment option for the management of pain in trigeminal neuralgia. We report a case in which the patient of trigeminal neuralgia combined with anterior cerebral artery aneurysm was treated successfully by gasserian ganglion thermoablation without any complication.CaseAn 85-year-old female presenting with electric shock like sensation in the gum and molar teeth was diagnosed as trigeminal neuralgia. Carbamazepine medication and trigeminal nerve blockade relieved her pain partially, but severe side effects of carbamazepine occurred. Magnetic resonance angiography of the brain showed saccular aneurysm in inferior aspect of the anterior communicating artery. Gasserian ganglion thermoablation under sedation anesthesia using nicardipine was performed carefully without any rupture of the cerebral aneurysm.ConclusionsGasserian ganglion thermoablation could be performed safely in a patient with cerebral aneurysm without any inadvertent event.

Cardiovascular disease (CVD) is the main cause of mortality in subjects with non-alcoholic fatty liver disease (NAFLD). We investigated the association between CVD risk and metabolic dysfunction associated fatty liver disease (MAFLD) or NAFLD and the influence of significant liver fibrosis on the CVD risk.Subjects who underwent a comprehensive medical check-up were recruited (2014-2019). Significant liver fibrosis was defined using NAFLD fibrosis score, fibrosis-4 index, aspartate aminotransferase to platelet ratio index, or FibroScan-AST score. High probability of atherosclerotic CVD (ASCVD) was defined as ASCVD risk score10%.Of the study population (n=78,762), 27,047 (34.3%) and 24,036 (30.5%) subjects had MAFLD and NAFLD, respectively. A total of 1,084 (4.0%) or 921 (3.8%) subjects had previous CVD history in MAFLD or NAFLD subgroup, respectively. The previous CVD history and high probability of ASCVD were significantly higher in MAFLD or NAFLD subgroup with significant liver fibrosis than in the other groups (all P0.001). In multivariable analysis, MAFLD was independently associated with previous CVD history after adjusting for confounders (adjusted odds ratio [aOR]=1.10, P=0.038), whereas NAFLD was not (all P0.05). MAFLD (aOR=1.40) or NAFLD (aOR=1.22) was independently associated with high probability of ASCVD after full adjustment, respectively (all P0.001). Significant liver fibrosis was independently associated with previous CVD history and high probability of ASCVD after adjustment in MAFLD or NAFLD subgroup, respectively (all P0.05).MAFLD might better identify subjects with CVD risk than NAFLD. Fibrosis assessment might be helpful for detailed prognostication in subjects with MAFLD.

SummarySurvival from COVID-19 depends on the ability of the host to effectively neutralize virions and infected cells, a process largely driven by antibody-mediated immunity. However, with the newly emerging variants that evade Spike-targeting antibodies, re-infections and breakthrough infections are increasingly common. A full characterization of SARS-CoV-2 mechanisms counteracting antibody-mediated immunity is needed. Here, we report that ORF8 is a SARS-CoV-2 factor that controls cellular Spike antigen levels. ORF8 limits the availability of mature Spike by inhibiting host protein synthesis and retaining Spike at the endoplasmic reticulum, reducing cell-surface Spike levels and recognition by anti-SARS-CoV-2 antibodies. With limited Spike availability, ORF8 restricts Spike incorporation during viral assembly, reducing Spike levels in virions. Cell entry of these virions leaves fewer Spike molecules at the cell surface, limiting antibody recognition of infected cells. Our studies propose an ORF8-dependent SARS-CoV-2 strategy that allows immune evasion of infected cells for extended viral production.

Magnetoencephalography (MEG) is a functional neuroimaging technique that noninvasively detects the brain magnetic field from neuronal activations. Conventional MEG measures brain signals using superconducting quantum interference devices (SQUIDs). SQUID-MEG requires a cryogenic environment involving a bulky non-magnetic Dewar flask and the consumption of liquid helium, which restricts the variability of the sensor array and the gap between the cortical sources and sensors. Recently, miniature optically pumped magnetometers (OPMs) have been developed and commercialized. OPMs do not require cryogenic cooling and can be placed within millimeters from the scalp. In the present study, we arranged six OPM sensors on the temporal area to detect auditory-related brain responses in a two-layer magnetically shielded room. We presented the auditory stimuli of 1 kHz pure-tone bursts with 200 ms duration and obtained the M50 and M100 components of auditory-evoked fields. We delivered the periodic stimuli with a 40 Hz repetition rate and observed the gamma-band power changes and inter-trial phase coherence of auditory steady-state responses at 40 Hz. We found that the OPM sensors have a performance comparable to that of conventional SQUID-MEG sensors, and our results suggest the feasibility of using OPM sensors for functional neuroimaging and brain–computer interface applications.

Brown mustard (Brassica juncea (L.) is an important oilseed crop that is mostly used to produce edible oils, industrial oils, modified lipids and biofuels in subtropical nations. Due to its higher level of commercial use, the species has a huge array of varieties/cultivars. The purpose of this study is to evaluate the use of visible near-infrared (Vis-NIR) spectroscopy in combination with multiple chemometric approaches for distinguishing four B. juncea varieties in Korea. The spectra from the leaves of four different growth stages of four B. juncea varieties were measured in the Vis-NIR range of 325–1075 nm with a stepping of 1.5 nm in reflectance mode. For effective discrimination, the spectral data were preprocessed using three distinct approaches, and eight different chemometric analyses were utilized. After the detection of outliers, the samples were split into two groups, one serving as a calibration set and the other as a validation set. When numerous preprocessing and chemometric approaches were applied for discriminating, the combination of standard normal variate and deep learning had the highest classification accuracy in all the growth stages achieved up to 100%. Similarly, few other chemometrics also yielded 100% classification accuracy, namely, support vector machine, generalized linear model, and the random forest. Of all the chemometric preprocessing methods, Savitzky–Golay filter smoothing provided the best and most convincing discrimination. The findings imply that chemometric methods combined with handheld Vis-NIR spectroscopy can be utilized as an efficient tool for differentiating B. juncea varieties in the field in all the growth stages.