Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate- Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Relationship between Change in Physical Activity and Risk of Metabolic Syndrome: A Prospective Cohort Study.

Background: This study investigates the relationship between changes in physical activity levels and risk of metabolic syndrome. Methods: This study examined 1,686 adults aged 40 to 69 years from a community-based cohort study with complete 1st to 4th follow-up data between 2011 and 2020. Changes in physical activity were evaluated through baseline and follow-up surveys using physical activity questionnaires. Metabolic syndrome was diagnosed according to the International Diabetes Federation criteria. A survival analysis was conducted using a multivariate extended Cox regression model with a significance level set at P<0.05. Results: Participants were divided into groups according to physical activity levels. The newly inactive group (vigorous physical activity ≤150 minutes at first follow-up) had a 36% increase in the hazard ratio (HR) for metabolic syndrome compared with the consistently inactive group (≤150 minutes at both baseline and first follow-up) (HR, 1.36; 95% confidence interval [CI], 1.04 to 1.79). The newly active group (walking ≤420 minutes per week at baseline and >420 minutes per week at first follow-up) had a 25% decrease in the HR for metabolic syndrome compared with the consistently inactive group (walking ≤420 minutes per week at both baseline and first follow-up) (HR, 0.75; 95% CI, 0.57 to 0.98). Conclusion: Changes in physical activity levels are associated with risk of metabolic syndrome. These results provide important insights for future investigations into the link between physical activity changes and disease occurrence.

Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add-on therapy in drug-naïve patients with type 2 diabetes (TRIPLE-AXEL study): A multicentre, randomized, 104-week, open-label, active-controlled trial.

AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.

Effect of Pravastatin on Kidney Function in Patients with Dyslipidemia and Type 2 Diabetes Mellitus: A Multicenter Prospective Observational Study.

INTRODUCTION: Several studies have reported that pravastatin can mitigate the progression of kidney disease, but limited evidence exists regarding its effects on kidney function in Asian patients. This multicenter prospective observational study aimed to assess the effect of pravastatin on kidney function in Korean patients with dyslipidemia and type 2 diabetes mellitus (T2DM) in clinical practice. METHODS: This 48-week prospective multicenter study included 2604 of 2997 eligible patients with dyslipidemia and T2DM who had available estimated glomerular filtration rate (eGFR) measurements. The primary endpoint was eGFR percent change at week 24 from baseline. We also assessed secondary endpoints, which included percent changes in eGFR at weeks 12 and 48 from baseline, as well as changes in eGFR, metabolic profiles (lipid and glycemic levels) at 12, 24, and 48 weeks from baseline, and safety. RESULTS: We noted a significant improvement in eGFR, with mean percent changes of 2.5%, 2.5%, and 3.0% at 12, 24, and 48 weeks, respectively (all adjusted p < 0.05). The eGFR percent changes significantly increased in subgroups with baseline eGFR 30-90 mL/min/1.73 m2, glycated hemoglobin (HbA1c) ≥ 7 at baseline, no hypertension history, T2DM duration > 5 years, or previous statin therapy. Lipid profiles were improved and remained stable throughout the study, and interestingly, fasting glucose and HbA1c were improved at 24 weeks. CONCLUSION: Our findings suggest that pravastatin may have potential benefits for improving eGFR in Korean patients with dyslipidemia and T2DM. This could make it a preferable treatment option for patients with reduced kidney function. TRIAL REGISTRATION NUMBER: NCT05107063 submitted October 27, 2021.

A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

Effect of the incorporation of gallium ions into silver indium sulfide nanocrystals.

Gallium ion incorporation into silver indium gallium sulfide nanocrystals is investigated by various methods, including photoluminescence (PL) and X-ray photoelectron spectroscopy. The ZnS shell-growth enhances a PL quantum yield of up to 16%, with which the quantum dot light-emitting diode was successfully fabricated.

Modulating monocyte-derived macrophage polarization in cerebral ischemic injury with hyperglycemia.

Ischemic stroke (IS), characterized by high mortality rate, occurs owing to diminished or blocked blood flow to the brain. Hyperglycemia (HG) is a major contributor to the risk of IS. HG induces augmented oxidative stress and Blood-Brain Barrier breakdown, which increases the influx of blood-derived myeloid cells into the brain parenchyma. In cerebral ischemia, infiltrating monocytes undergo differentiation into pro-inflammatory or anti-inflammatory macrophages, having a large effect on outcomes of ischemic stroke. In addition, interleukin-4 (IL-4) and interleukin-13 (IL-13) engage in post-ischemia repair by polarizing the infiltrating monocytes into an anti-inflammatory phenotype. In this study, we aimed to determine the effect of phenotypic polarization of monocyte-derived macrophages on the prognosis of IS with HG (HG-IS). We first established a hyperglycemic mouse model using streptozotocin (150 mg/kg) and induced transient middle cerebral artery occlusion. We observed that blood-brain barrier permeability increased in HG-IS mice, as per two-photon live imaging and Evans blue staining. We also confirmed the increased infiltration of monocyte-derived macrophages and the downregulation of anti-inflammatory macrophages related to tissue remodeling after inflammation in HG-IS mice through immunohistochemistry, western blotting, and flow cytometry. We observed phenotypic changes in monocyte-derived macrophages, alleviated infarct volume, and improved motor function in HG-IS mice treated with IL-4 and IL-13. These findings suggest that the modulation of phenotypic changes in monocyte-derived macrophages following IS in hyperglycemic mice may influence ischemic recovery.

In-depth correlation analysis between tear glucose and blood glucose using a wireless smart contact lens.

Tears have emerged as a promising alternative to blood for diagnosing diabetes. Despite increasing attempts to measure tear glucose using smart contact lenses, the controversy surrounding the correlation between tear glucose and blood glucose still limits the clinical usage of tears. Herein, we present an in-depth investigation of the correlation between tear glucose and blood glucose using a wireless and soft smart contact lens for continuous monitoring of tear glucose. This smart contact lens is capable of quantitatively monitoring the tear glucose levels in basal tears excluding the effect of reflex tears which might weaken the relationship with blood glucose. Furthermore, this smart contact lens can provide an unprecedented level of continuous tear glucose data acquisition at sub-minute intervals. These advantages allow the precise estimation of lag time, enabling the establishment of the concept called 'personalized lag time'. This demonstration considers individual differences and is successfully applied to both non-diabetic and diabetic humans, as well as in animal models, resulting in a high correlation.

C-C Bond Cleavage-Induced C- to N-Acyl Transfer for Synthesis of Amides.

A new approach for the preparation of amides was developed using C-C bond cleavage that initiates C- to N-acyl transfer, employing activated ketones as acylation reagents and amine nucleophiles. The reaction was operational under the coupling reagent system that is commonly utilized for peptide bond formations. The method enables practical preparation of amides using linear and cyclic ketone substrates under mild conditions.

A self-powered and supercapacitive microneedle continuous glucose monitoring system with a wide range of glucose detection capabilities.

Continuous detection of sudden changes in blood glucose is essential for individuals with diabetes who have difficulty in maintaining optimal control of their blood glucose levels. Hypoglycemic shock or a hyperglycemic crisis are likely to occurs in patients with diabetes and poses a significant threat to their lives. Currently, commercial continuous glucose monitoring (CGM) has limits in the glucose concentration detection range, which is 40-500 mg/dL, making it difficult to prevent the risk of hyperglycemic shock. In addition, current CGMs are invasive, cause pain and irritation during usage, and expensive. In this research, we overcome these limitations by introducing a novel mechanism to detect glucose concentration using supercapacitors. The developed CGM, which is self-powered and minimally invasive due to the use of microneedles, can detect a wider range of glucose concentrations than commercial sensors. In addition, efficacy and stability were proven through in vitro and in vivo experiments. Thus, this self-powered, microneedle and supercapacitive-type CGM can potentially prevent both hypoglycemic and complications of hyperglycemia without pain and with less power consumption than current commercial sensors.

Clinical and radiological outcomes of non-window-type bioactive glass-ceramic cage in single-level ACDF versus PEEK cage filled with autologous bone.

Bioactive glass-ceramic (BGC) cage is a substitute for polyether ether ketone (PEEK) cages in anterior cervical discectomy and fusion (ACDF). Only a few comparative studies exist using PEEK and non-window-type BGC cages (CaO-SiO2-P2O5-B2O3) in single-level ACDF. This study compared PEEK cages filled with autologous iliac bone grafts and BGC cages regarding clinical safety and effectiveness. A retrospective case series was performed on 40 patients who underwent single-level ACDF between October 2020 and July 2021 by a single orthopedic spine surgeon. The spacers used in each ACDF were a PEEK cage with a void filled with an autologous iliac bone graft and a non-window-type BGC cage in 20 cases. The grafts were compared pre-operatively and post-operatively at 6 weeks and 3, 6, and 12 months. Post-operative complications were investigated in each group. Clinical outcome was measured, including Visual Analog Scale (VAS) scores of neck and arm pains, Japanese Orthopedic Association score (JOA), and Neck Disability Index (NDI). Dynamic lateral radiographs were used to assess the inter-spinous motion (ISM) between the fusion segment and subsidence. The fusion status was evaluated using a computed tomography (CT) scan. Overall, 39 patients (19 and 20 patients in the PEEK and BGC groups, respectively) were recruited. Eighteen (94.7%) and 19 (95.0%) patients in the PEEK and BGC groups, respectively, were fused 12 months post-operatively, as assessed by ISM in dynamic lateral radiograph and bone bridging formation proven in CT scan. The PEEK and BGC groups showed substantial improvement in neck and arm VAS, JOA, and NDI scores. No substantial difference was found in clinical and radiological outcomes between the PEEK and BGC groups. However, the operation time was considerably shorter in the BGC group than in the PEEK group. In conclusion, a non-window-type BCG cage is a feasible substitute for a PEEK cage with an autologous iliac bone graft in single-level ACDF.

Mortality in metabolic dysfunction-associated steatotic liver disease: A nationwide population-based cohort study.

BACKGROUND: A new fatty liver disease nomenclature, steatotic liver disease (SLD) has been proposed; however, there are no data on clinical outcomes. We investigated the impact of SLD with metabolic dysfunction (MD; SLD-MD) on all-cause mortality. METHODS: We evaluated nationally representative participants aged ≥19 years using data from the Korea National Health and Nutrition Examination Survey 2007-2015 and their linked death data through 2019. The presence of fatty liver disease was assessed by liver fat score, fatty liver index and significant liver fibrosis was evaluated by the Fibrosis-4 Index, and fibrosis score. SLD-MD was categorized into three groups: metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic alcoholic liver disease (MetALD); and SLD with other combination etiologies. RESULTS: Among 26734 individuals (11561 men and 15173 women, mean age 48.8 years), 1833 (6.9 %) died during a mean follow-up period of 110.6 ± 33.9 months. Mortality risk was significantly higher in individuals with SLD-MD (hazard ratio [HR] = 1.35) than in those without (P < 0.001). Among the three groups, MASLD (HR = 1.32) and SLD with other combination etiologies (HR = 2.06) independently increased mortality risk (all P < 0.001). When individuals with SLD-MD had significant liver fibrosis or diabetes, mortality risk increased further (HR = 1.68 and 1.85, respectively; all P < 0.001). SLD-MD with both significant liver fibrosis and diabetes showed the highest mortality risk (HR = 2.29, P < 0.001). When applied fatty liver index and fibrosis score, similar results were observed. CONCLUSIONS: SLD-MD is associated with a higher mortality risk. When SLD-MD was combined with significant liver fibrosis or diabetes, the mortality risk became much higher. Treatment strategies to reduce fibrotic burden and improve glycemic control in individuals with MASLD are needed.

Intact ketogenesis predicted reduced risk of moderate-severe metabolic-associated fatty liver disease assessed by liver transient elastography in newly diagnosed type 2 diabetes.

Aim: Hepatic ketogenesis is a key metabolic pathway that regulates energy homeostasis. Some related controversies exist regarding the pathogenesis of metabolic-associated fatty liver disease (MAFLD). We aimed to investigate whether intact ketogenic capacity could reduce the risk of MAFLD based on transient electrography (TE) in patients with newly diagnosed type 2 diabetes (T2D). Methods: A total of 361 subjects with newly diagnosed T2D were recruited and classified into two groups based on the median serum ß-hydroxybutyrate (ßHB) level, referred to as the intact and impaired ketogenesis groups. The glucometabolic relevance of ketogenic capacity and associations of the baseline serum ß-HB and MAFLD assessed with TE were investigated. Results: Compared to the impaired ketogenesis group, the intact ketogenesis group showed better insulin sensitivity, lower serum triglyceride levels, and higher glycated hemoglobin levels. The controlled attenuation parameter (CAP) was lower in the intact ketogenesis group without statistical significance (289.7 ± 52.1 vs. 294.5 ± 43.6; p=0.342) but the prevalence of moderate-severe steatosis defined by CAP ≥260 dB/m was significantly lower in the intact group. Moreover, intact ketogenesis was significantly associated with a lower risk of moderate-severe MAFLD after adjusting for potential confounders (adjusted odds ratio 0.55, 95% confidence interval 0.30-0.98; p=0.044). Conclusion: In drug-naïve, newly diagnosed T2D patients, intact ketogenesis predicted a lower risk of moderate-severe MAFLD assessed by TE.