Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION).

BACKGRUOUND: This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin. METHODS: In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks. RESULTS: The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was -0.66% (0.07) with a 95% confidence interval of -0.80% to -0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted. CONCLUSION: Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.

Adult-Onset Type 1 Diabetes Development Following COVID-19 mRNA Vaccination.

During the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccination-induced hyperglycemia and related complications have been reported. However, there have been few reports of type 1 diabetes triggered by COVID-19 vaccines in subjects without diabetes. Here, we report the case of a 56-year-old female patient who developed hyperglycemia after the second dose of COVID-19 mRNA-based vaccination without a prior history of diabetes. She visited our hospital with uncontrolled hyperglycemia despite administration of oral hyperglycemic agents. Her initial glycated hemoglobin level was high (11.0%), and fasting serum C-peptide level was normal. The fasting serum C-peptide level decreased to 0.269 ng/mL 5 days after admission, and the anti-glutamic acid decarboxylase antibody was positive. The patient was discharged in stable condition with insulin treatment. To our knowledge, this is the first case of the development of type 1 diabetes without diabetic ketoacidosis after mRNA-based COVID-19 vaccination, and is the oldest case of type 1 diabetes development under such circumstances.

Effect of Blood Pressure on Cardiovascular Diseases at 10-Year Follow-Up.

The American College of Cardiology/American Heart Association (ACC/AHA) recently published a Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. However, the data in other ethnic groups are not well known. We evaluated the prevalence and associated cardiovascular prognosis of Korean subjects with newly reclassified hypertension based on the 2017ACC/AHA guideline. We analyzed data from the Korean Health and Genome Study (n = 10,038). Supine blood pressure (BP) was measured thrice following a standardized protocol and averaged. There was a significant linear relation between BP profiles and cardiovascular disease (CVD)/mortality. Hazard ratio for CVD increased above a systolic BP of 120mm Hg. Systolic BP ≥130mm Hg was significantly associated with increased risk of CVD, coronary heart disease, stroke, CVD death, and total deaths. There was a similar significant linear relation with diastolic BP categories between CVD risk and death. BP is associated with an increased risk of CVD or all-cause mortalities. Moreover, the new BP categories of the 2017ACC/AHA guideline could be applicable for predicting CVD and death in Korean population.

Relationship between serum bilirubin levels and cardiovascular disease.

We tested the hypothesis that higher levels of bilirubin, a bile pigment with antioxidant properties, are associated with a decreased risk of cardiovascular disease (CVD). This study analyzed data from the Korean Health and Genome Study to examine the association between serum total bilirubin (TB) on CVD and CVD death. Serum TB was measured in a total of 8,844 subjects (4,196 males and 4,648 females) and evaluated for the development of new onset CVD from 2001 to 2012 (mean 8.1 years of follow-up). During the follow-up period, 689 cases of incident CVD (7.8%) were identified, and the prevalence of metabolic syndrome (MetS) at baseline was 26.1%. The prevalence of MetS decreased across bilirubin tertile categories. In addition to MetS itself, individual components of MetS significantly decreased with increased bilirubin tertiles. Moreover, the incidence of CVD decreased across bilirubin tertile categories. The hazard ratios (HRs) for developing coronary heart disease (CHD, HR 0.769, 95% CI 0.655-1.000) and CVD death (HR 0.513, 95% CI 0.267-0.985) was significantly lower in the highest tertile group (> 0.63 mg/dL) in comparison to the lowest tertile group (< 0.44 mg/dL) after adjusting for all confounding variables. In the present longitudinal study, a significant negative relationship was demonstrated between baseline bilirubin levels and incident CHD and CVD death.

Influence of Job-seeking Stress on Perimenstrual Symptoms of Female College Students in Health and Non-health related Majors: Mediating Effects of Stress Coping Styles.

PURPOSE: To determine effects of job-seeking stress on perimenstrual symptoms of female college students with health and non-health related majors and mediating effects of stress coping styles. METHODS: Data were collected from 189 female college students who were juniors or seniors. This study was conducted using questionnaires on job-seeking stress, perimenstrual symptoms, and stress coping styles. Data analysis included descriptive statistics, Pearson correlation analysis, and multiple regression analysis using SPSS, version 23.0. Mediation analysis was performed according to the Baron and Kenny method and Sobel test. RESULTS: Job-seeking stress was significantly and positively correlated with perimenstrual symptoms in non-health college students. Passive stress coping styles demonstrated a complete mediating effect on the relationship between job-seeking stress and perimenstrual symptoms of those with non-health related majors (ß=0.31, p=.002). Such effect was significant (Sobel test; Z=2.06, p=.039). CONCLUSION: Effects of job-seeking stress on perimenstrual symptoms were mediated by passive stress coping styles of non-health related major students. Based on findings of this study, effective stress cope strategies should be developed considering characteristics of majors to manage perimenstrual symptoms of female college students with high job-seeking stress.

Multicompartment Vesicles Formation by Emulsification-Induced Assembly of Poly(ethylene oxide)-block-poly(ε-caprolactone) and Their Dual-Loading Capability.

Emulsification-induced assembly is employed to allow structural diversity in nanoaggregates of a biocompatible amphiphilic polymer, poly(ethylene oxide)-block-poly(ε-caprolactone). Onion-like vesicles are efficiently produced by tuning the interfacial instability of the oil-in-water emulsion. The increase in the polymer concentration and use of the organic solvents with a low interfacial tension between water and the oil phase lead to a strong tendency of emulsion droplets to generate the onion-like vesicles. The vesicular networks and fibers are also obtained by controlling the concentration and type of the surfactant, respectively. Interestingly, the onion-like vesicles composed of alternating walls and water channels and the vesicular networks originated from a string of vesicles show dual-loading ability for hydrophobic and hydrophilic dyes but slightly different loading capacities. This result indicates that the development of a methodology to fabricate well-defined, unique nanostructures, such as multivesicular and multilamellar nanostructures, and subsequent elucidation of their structure-property relationships can provide useful guidance in the design of novel biomedical materials.

Serum calcium changes and risk of type 2 diabetes mellitus in Asian population.

AIMS: We examined the association between changes in serum calcium levels with the incidence of type 2 diabetes mellitus (T2DM) in apparently healthy South Korean subjects. METHODS: A retrospective longitudinal analysis was conducted with subjects who had participated in comprehensive health check-ups at least four times over a 7-year period (between 2006 and 2012). In total, 23,121 subjects were categorized into tertiles based on changes in their albumin-adjusted serum calcium levels. Multivariate Cox regression models were fitted to assess the association between changes in serum calcium levels during follow-up and the relative risk of diabetes incidence. RESULTS: After a median follow-up of 57.4months, 1,929 (8.3%) new cases of T2DM occurred. Simple linear regression analysis showed serum calcium level changes correlated positively with changes in HbA1c and fasting plasma glucose (FPG) levels (B=5.72, p<0.001 for FPG; B=0.13, p<0.001 for HbA1c). An increase in albumin-adjusted serum calcium levels during follow-up was related to an increased risk of T2DM. After adjustment for potential confounders, the risk of T2DM was 1.6 times greater for subjects whose albumin-adjusted serum calcium levels were in the highest change tertile during follow-up than for subjects whose levels were in the lowest tertile (HR 1.65, 95% CI 1.44-1.88, P<0.001). CONCLUSIONS: The elevation of albumin-adjusted serum calcium levels was associated with an increased risk of T2DM, independent of baseline glycemic status.

Glucocorticoid-Induced Diabetes Mellitus: An Important but Overlooked Problem.

Glucocorticoids are widely used as potent anti-inflammatory and immunosuppressive drugs to treat a wide range of diseases. However, they are also associated with a number of side effects, including new-onset hyperglycemia in patients without a history of diabetes mellitus (DM) or severely uncontrolled hyperglycemia in patients with known DM. Glucocorticoid-induced diabetes mellitus (GIDM) is a common and potentially harmful problem in clinical practice, affecting almost all medical specialties, but is often difficult to detect in clinical settings. However, scientific evidence is lacking regarding the effects of GIDM, as well as strategies for prevention and treatment. Similarly to nonsteroid-related DM, the principles of early detection and risk factor modification apply. Screening for GIDM should be considered in all patients treated with medium to high doses of glucocorticoids. Challenges in the management of GIDM stem from wide fluctuations in postprandial hyperglycemia and the lack of clearly defined treatment protocols. Together with lifestyle measures, hypoglycemic drugs with insulin-sensitizing effects are indicated. However, insulin therapy is often unavoidable, to the point that insulin can be considered the drug of choice. The treatment of GIDM should take into account the degree and pattern of hyperglycemia, as well as the type, dose, and schedule of glucocorticoid used. Moreover, it is essential to instruct the patient and/or the patient's family about how to perform the necessary adjustments. Prospective studies are needed to answer the remaining questions regarding GIDM.

On-chip electrochemical immunoassay platform for specific protein biomarker estimation in undiluted serum using off-surface membrane matrix.

The manuscript presents a new biosensor platform using bioreceptors modified porous 2-dimensional (2D) membrane based off-surface matrix for on-chip electrochemical immunoassay. Antibody based bioreceptors modified 2D matrix of porous polycarbonate (PC) membrane with densely packed 20µm holes as off-surface matrix was incorporated in very close proximity of the sensor surface and integrated with fluidic system for reagent flow and incubation chamber. Covalent attachment of antibodies on 2D PC membrane based off-matrix was achieved using 4-fluoro-3-nitro-azidobenzene (FNAB) cross-linker. Anti-TNF-α/FNAB/PC membrane was integrated over array of micro fingers of gold based sensor chip using double side tape spacer and StartingBlock phosphate buffer saline- Tween-20; (PBS-T20) blocking buffer was utilized to minimize nonspecific binding. Differential pulse voltammetric studies of Anti-Tnf-α/FNAB/PC-Au for protein biomarker (TNF-α) detection and estimation in undiluted serum indicated that the immunosensor system can detect TNF-α linearly in 100pg/ml to 100ng/ml range with insignificant interference from other cytokines and serum proteins. Further, immunosensor exhibited high sensitivity of 194nA/(ng/ml) and 240nA/(ng/ml), respectively for single and double membrane based system. Thus, use of 2D membrane based off surface matrix may present the new platform to sensitively measure biomarkers electrochemically to pg/ml range with insignificant nonspecific binding and false signal in undiluted serum.

Off surface matrix based on-chip electrochemical biosensor platform for protein biomarker detection in undiluted serum.

The manuscript describes a concept of using off surface matrix modified with capturing biomolecule for on-chip electrochemical biosensing. 3D matrix made by laser engraving of polymethyl methacrylate (PMMA) sheet as off surface matrix was integrated in very close vicinity of the electrode surface. Laser engraving and holes in PMMA along with spacing from surface provide fluidic channel and incubation chamber. Covalent binding of capturing biomolecule (anti-TNF-α antibody) on off-surface matrix was achieved via azide group activity of 4-fluoro-3-nitro-azidobenzene (FNAB), which act as cross-linker and further covalently binds to anti-TNF-α antibody via thermal reaction. Anti-TNF-α/FNAB/PMMA matrix was then integrated over comb structured gold electrode array based sensor chip. Separate surface modification followed by integration of sensor helped to prevent the sensor chip surface from fouling during functionalization. Nonspecific binding was prevented using starting block T20 (PBS). Results for estimating protein biomarker (TNF-α) in undiluted serum using Anti-TNF-α/FNAB/PMMA/Au reveal that system can detect TNF-α in 100pg/ml to 100ng/ml range with high sensitivity of 119nA/(ng/ml), with negligible interference from serum proteins and other cytokines. Thus, use of off surface matrix may provide the opportunity to electrochemically sense biomarkers sensitively to ng/ml range with negligible nonspecific binding and false signal in undiluted serum.

An isothermal, label-free, and rapid one-step RNA amplification/detection assay for diagnosis of respiratory viral infections.

Recently, RNA viral infections caused by respiratory viruses, such as influenza, parainfluenza, respiratory syncytial virus, coronavirus, and Middle East respiratory syndrome-coronavirus (MERS-CoV), and Zika virus, are a major public health threats in the world. Although myriads of diagnostic methods based on RNA amplification have been developed in the last decades, they continue to lack speed, sensitivity, and specificity for clinical use. A rapid and accurate diagnostic method is needed for appropriate control, including isolation and treatment of the patients. Here, we report an isothermal, label-free, one-step RNA amplification and detection system, termed as iROAD, for the diagnosis of respiratory diseases. It couples a one-step isothermal RNA amplification method and a bio-optical sensor for simultaneous viral RNA amplification/detection in a label-free and real-time manner. The iROAD assay offers a one-step viral RNA amplification/detection example to rapid analysis (<20min). The detection limit of iROAD assay was found to be 10-times more sensitive than that of real-time reverse transcription-PCR method. We confirmed the clinical utility of the iROAD assay by detecting viral RNAs obtained from 63 human respiratory samples. We envision that the iROAD assay will be useful and potentially adaptable for better diagnosis of emerging infectious diseases including respiratory diseases.

Experimental demonstration of highly sensitive optical sensor based on grating-assisted light coupling between strip and slot waveguides.

An optical sensor based on grating-assisted light coupling between a strip waveguide and a slot waveguide is demonstrated (the sensor was proposed and analyzed in [Opt. Express21, 5897-5909 (2013)]. The wavelength at which the light is strongly coupled between two waveguides is used to the measure the external medium's refractive index. The sensor was fabricated with silicon nitride waveguides and obvious grating induced band-rejection and band-pass characteristics were observed. The measured sensitivity of the fabricated sensor was -756.1 nm/RIU. Furthermore, by covering the strip waveguide with the silicon dioxide cladding, the sensitivity was measured to be as large as -1970 nm/RIU, which was 2.6 times enhanced. The experimental results agreed well with the calculated sensitivity values.

Two-stage sample-to-answer system based on nucleic acid amplification approach for detection of malaria parasites.

Rapid, early, and accurate diagnosis of malaria is essential for effective disease management and surveillance, and can reduce morbidity and mortality associated with the disease. Although significant advances have been achieved for the diagnosis of malaria, these technologies are still far from ideal, being time consuming, complex and poorly sensitive as well as requiring separate assays for sample processing and detection. Therefore, the development of a fast and sensitive method that can integrate sample processing with detection of malarial infection is desirable. Here, we report a two-stage sample-to-answer system based on nucleic acid amplification approach for detection of malaria parasites. It combines the Dimethyl adipimidate (DMA)/Thin film Sample processing (DTS) technique as a first stage and the Mach-Zehnder Interferometer-Isothermal solid-phase DNA Amplification (MZI-IDA) sensing technique as a second stage. The system can extract DNA from malarial parasites using DTS technique in a closed system, not only reducing sample loss and contamination, but also facilitating the multiplexed malarial DNA detection using the fast and accurate MZI-IDA technique. Here, we demonstrated that this system can deliver results within 60min (including sample processing, amplification and detection) with high sensitivity (<1 parasite µL(-1)) in a label-free and real-time manner. The developed system would be of great potential for better diagnosis of malaria in low-resource settings.

[Effects of an Individual Breast-feeding Promotion Program for Married Immigrant Women].

PURPOSE: This study was designed to evaluate the effects of an individual breast-feeding promotion program to address breast-feeding knowledge, attitude, method and rate of practice for married immigrant women. METHODS: A non-equivalent control group quasi-experimental design was used (experimental group=16, control group=17). The intervention consisted of 3 phases: (1) Within 2 hours of delivery - individual breast-feeding training through video/verbal/practical training education and demonstration (2) After 1~2 days - group training using video, model doll, and breast models (3) After 7 days - family visit, counseling, retraining and reinforcement training. The data were analyzed using non-parametric tests with the SPSS program. RESULTS: Married immigrant women who participated in the individual breast-feeding program scored high in knowledge, attitude, method and rate of practice compared to the control group. CONCLUSION: The results indicate that the individual breast-feeding program is very effective in increasing breast-feeding knowledge, attitude, method and rate of practicing breast feeding for married immigrant women. So, nurses are encouraged to aggressively utilize individual breast-feeding programs to help married immigrant women, who are exposed to vulnerability due to various situations.

Self-powered switch-controlled nucleic acid extraction system.

Over the past few decades, lab-on-a-chip (LOC) technologies have played a great role in revolutionizing the way in vitro medical diagnostics are conducted and transforming bulky and expensive laboratory instruments and labour-intensive tests into easy to use, cost-effective miniaturized systems with faster analysis time, which can be used for near-patient or point-of-care (POC) tests. Fluidic pumps and valves are among the key components for LOC systems; however, they often require on-line electrical power or batteries and make the whole system bulky and complex, therefore limiting its application to POC testing especially in low-resource setting. This is particularly problematic for molecular diagnostics where multi-step sample processing (e.g. lysing, washing, elution) is necessary. In this work, we have developed a self-powered switch-controlled nucleic acid extraction system (SSNES). The main components of SSNES are a powerless vacuum actuator using two disposable syringes and a switchgear made of PMMA blocks and an O-ring. In the vacuum actuator, an opened syringe and a blocked syringe are bound together and act as a working syringe and an actuating syringe, respectively. The negative pressure in the opened syringe is generated by a restoring force of the compressed air inside the blocked syringe and utilized as the vacuum source. The Venus symbol shape of the switchgear provides multiple functions including being a reagent reservoir, a push-button for the vacuum actuator, and an on-off valve. The SSNES consists of three sets of vacuum actuators, switchgears and microfluidic components. The entire system can be easily fabricated and is fully disposable. We have successfully demonstrated DNA extraction from a urine sample using a dimethyl adipimidate (DMA)-based extraction method and the performance of the DNA extraction has been confirmed by genetic (HRAS) analysis of DNA biomarkers from the extracted DNAs using the SSNES. Therefore, the SSNES can be widely used as a powerless and disposable system for DNA extraction and the syringe-based vacuum actuator would be easily utilized for diverse applications with various microchannels as a powerless fluidic pump.

Glucose-Dependent Insulinotropic Peptide Level Is Associated with the Development of Type 2 Diabetes Mellitus.

BACKGROUND: Incretin hormone levels as a predictor of type 2 diabetes mellitus have not been fully investigated. Therefore, we measured incretin hormone levels to examine the relationship between circulating incretin hormones, diabetes, and future diabetes development in this study. METHODS: A nested case-control study was conducted in a Korean cohort. The study included the following two groups: the control group (n=149), the incident diabetes group (n=65). Fasting total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic peptide (GIP) levels were measured and compared between these groups. RESULTS: Fasting total GIP levels were higher in the incident diabetes group than in the control group (32.64±22.68 pmol/L vs. 25.54±18.37 pmol/L, P=0.034). There was no statistically significant difference in fasting total GLP-1 levels between groups (1.14±1.43 pmol/L vs. 1.39±2.13 pmol/L, P=0.199). In multivariate analysis, fasting total GIP levels were associated with an increased risk of diabetes (odds ratio, 1.005; P=0.012) independent of other risk factors. CONCLUSION: Fasting total GIP levels may be a risk factor for the development of type 2 diabetes mellitus. This association persisted even after adjusting for other metabolic parameters such as elevated fasting glucose, hemoglobin A1c, and obesity in the pre-diabetic period.

Dimethyl adipimidate/Thin film Sample processing (DTS); A simple, low-cost, and versatile nucleic acid extraction assay for downstream analysis.

Sample processing, especially that involving nucleic acid extraction, is a prerequisite step for the isolation of high quantities of relatively pure DNA for downstream analyses in many life science and biomedical engineering studies. However, existing methods still have major problems, including labor-intensive time-consuming methods and high costs, as well as requirements for a centrifuge and the complex fabrication of filters and membranes. Here, we first report a versatile Dimethyl adipimidate/Thin film based Sample processing (DTS) procedure without the limitations of existing methods. This procedure is useful for the extraction of DNA from a variety of sources, including 6 eukaryotic cells, 6 bacteria cells, and 2 body fluids in a single step. Specifically, the DTS procedure does not require a centrifuge and has improved time efficiency (30 min), affordability, and sensitivity in downstream analysis. We validated the DTS procedure for the extraction of DNA from human body fluids, as well as confirmed that the quality and quantity of the extracted DNA were sufficient to allow robust detection of genetic and epigenetic biomarkers in downstream analysis.

A rapid MZI-IDA sensor system for EGFR mutation testing in non-small cell lung cancer (NSCLC).

Epidermal growth factor receptor (EGFR) is a non-small-cell lung cancer biomarker, based on which several near-patient-testing methods have been developed and applied to predict treatment response on individual patients. Existing methods for detection of EGFR mutation are costly, labor-intensive and time-consuming. In this paper, we report a novel EGFR mutation testing system, which is based on Mach-Zehnder Interferometer (MZI) sensor and isothermal solid-phase DNA amplification (IDA) technique, called MZI-IDA sensor system. The system can deliver results within 30 min and shows high sensitivity to detect trace amounts of genomic DNA (<1 copy). In addition, the system is able to detect a L858R mutation in a 99:1 mixture of wild-type and mutant cells. In a pilot clinical study, the system is compared with conventional methods (PCR and direct sequencing) by using tissue biopsy samples from NSCLC patients. The MZI-IDA sensor system is proved to be capable of fast and accurate detection of the L858R mutation of EGFR gene in clinical samples. This may greatly help the clinicians develop an appropriate treatment plan.

LoMA-B: a simple and versatile lab-on-a-chip system based on single-channel bisulfite conversion for DNA methylation analysis.

Miniaturized lab-on-a-chip (LOC) systems have been developed for genetic and epigenetic analyses in clinical applications because of advantages such as reduced sample size and reagent consumption, rapid processing speed, simplicity, and enhanced sensitivity. Despite tremendous efforts made towards developing LOC systems for use in the clinical setting, the development of LOC systems to analyze DNA methylation, which is an emerging epigenetic marker causing the abnormal silencing of genes including tumor suppressor genes, is still challenging because of the gold standard methods involving a bisulfite conversion step. Existing bisulfite conversion-based techniques are not suitable for clinical use due to their long processing time, labor intensiveness, and the purification steps involved. Here, we present a lab-on-a-chip system for DNA methylation analysis based on bisulfite conversion (LoMA-B), which couples a sample pre-processing module for on-chip bisulfite conversion and a label-free, real-time detection module for rapid analysis of DNA methylation status using an isothermal DNA amplification/detection technique. The methylation status of the RARß gene in human genomic DNA extracted from MCF-7 cells was analyzed by the LoMA-B system within 80 min (except 16 h for sensor preparation) compared to conventional MS-PCR within 24 h. Furthermore, the LoMA-B system is highly sensitive and can detect as little as 1% methylated DNA in a methylated/unmethylated cell mixture. Therefore, the LoMA-B system is an efficient diagnostic tool for the simple, versatile, and quantitative evaluation of DNA methylation patterns for clinical applications.