Weight change in patients with new-onset type 2 diabetes mellitus and its association with remission: Comprehensive real-world data.

AIMS: We aimed to investigate weight change in patients with new-onset type 2 diabetes mellitus and the association of weight loss on diabetes remission in Korean adults. MATERIALS AND METHODS: We used the health examination database of the Korean National Health Insurance Service. Patients diagnosed with type 2 diabetes mellitus from 2009 to 2012 were enrolled and followed to 2017. The baseline body weight was measured at the health examination closest to the time the patient was enrolled, and the change was calculated by examining the weight measured at the subsequent examination within 2 years. Remission was defined as fasting blood glucose less than 126 mg/dl at two or more consecutive health examinations after stopping medication. RESULTS: In total, 114, 874 patients with new-onset type 2 diabetes mellitus were analysed. Of these, 23 156 (20.2%) lost more than 5% of their body weight, and 2429 (2.1%) achieved remission. The adjusted odds ratio for remission in the weight loss group was 2.56 (95% confidence interval 2.35-2.79) compared with the group with stable body weight. Sensitivity analysis according to the degree of weight change showed that the greater weight loss, the higher the likelihood of remission. In the subgroup analysis, the effects of weight loss on remission were significantly greater in subgroups of age <65 years, male sex and body mass index >25. CONCLUSION: Weight loss within the first 2 years of treating type 2 diabetes mellitus was associated with diabetes remission. Physicians should pay more attention to weight management in new-onset type 2 diabetes mellitus, particularly for young and obese individuals.

Repeated detection of non-alcoholic fatty liver disease increases the incidence risk of type 2 diabetes in young adults.

AIM: This study aimed to investigate the effects of repeated detection of non-alcoholic fatty liver disease (NAFLD) on the incidence risk of type 2 diabetes in young adults. MATERIALS AND METHODS: In this nationwide population-based observational study using data from the Korean National Health Insurance Service, approximately 1 125 015 young adults aged 20-39 years who underwent health screening four times between 2009 and 2013 were included. NAFLD was defined as a fatty liver index (FLI) of ≥60. Repeated detection of NAFLD scores was defined as the number of times the participants met the criteria for NAFLD (0-4). To account for the degree of repeated detection of NAFLD, weighted repeated NAFLD scores were scaled as a sum by assigning points (0 points for FLI <30, 1 point for 30 ≤ FLI < 60, and 2 points for FLI ≥60) ranging from 0 to 8 points. RESULTS: The multivariable-adjusted hazard ratios of type 2 diabetes associated with repeated detection of NAFLD scores of 1, 2, 3 and 4 were 2.74 (95% confidence interval 2.57-2.921), 3.45 (3.221-3.694), 4.588 (4.303-4.892) and 6.126 (5.77-6.504), respectively. The incidence risk of type 2 diabetes increased significantly with repeated detection of the NAFLD score. In the analysis of the weighted repeated NAFLD score, the hazard ratios for the incidence of type 2 diabetes showed a significant continuous positive linear association with increasing scores. CONCLUSIONS: Repeated detection of NAFLD influenced the incidence risk of type 2 diabetes in young adults, and a higher degree of repeated detection of NAFLD was independently associated with the risk of type 2 diabetes in young adults.

Cardiorenal outcomes and mortality after sodium-glucose cotransporter-2 inhibitor initiation in type 2 diabetes patients with percutaneous coronary intervention history.

AIMS: To evaluate the effects of initiating sodium-glucose cotransporter-2 (SGLT2) inhibitors on cardiorenal outcomes and mortality compared to dipeptidyl peptidase-4 (DPP-4) inhibitors as active comparators in patients diagnosed with type 2 diabetes with a history of percutaneous coronary intervention (PCI). MATERIALS AND METHODS: We used an active-comparator, new-user design and nationwide data from the National Health Insurance Service in South Korea from 2014 to 2019. Of the 56 392 patients who underwent PCI, 4610 new SGLT2 inhibitor users were paired 1:1 with DPP-4 inhibitor users for analysis using propensity-score matching. RESULTS: During 13 708.59 person-years of follow-up, the initiation of SGLT2 inhibitors, compared with the initiation of DPP-4 inhibitors, was associated with a significantly lower risk of composite repeat revascularization, myocardial infarction, stroke, heart failure (HF), all-cause death and end-stage renal disease (ESRD). The beneficial effects of SGLT2 inhibitor use were consistent with the components of stroke, HF, all-cause death and ESRD. In the cohort that included health examination data, including anthropometric and metabolic factors, new use of SGLT2 inhibitors was associated with a significantly lower risk of HF (hazard ratio [HR] 0.574, 95% confidence interval [CI] 0.36-0.915), all-cause death (HR 0.731, 95% CI 0.567-0.942), and ESRD (HR 0.076, 95% CI 0.018-0.319). The effects of SGLT2 inhibitor use were consistent regardless of the timing of the previous PCI. CONCLUSIONS: The initiation of SGLT2 inhibitors in patients with type 2 diabetes and a history of PCI was significantly associated with a reduced risk of cardiorenal consequences and mortality, irrespective of time since the last PCI.

A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Higher body mass index increases the risk of shoulder adhesive capsulitis in young adults: A nationwide cohort study.

BACKGROUND: The impact of overweight on the incidence of shoulder adhesive capsulitis (AC) has not been clearly proven. This study aimed to investigate the association between overweight and AC by age using a large-scale nationwide population-based cohort in Korea. METHODS: We analyzed clinical data from 3,517,066 individuals older than 20 years who had undergone a National Health Insurance Service health checkup in 2009. Patients who visited a hospital or private clinic to treat shoulder pain at least three times in one year and were assigned a diagnostic code for AC (ICD-10 code M75.00) were identified using claims data during a median follow-up duration of 8.3 years. Hazard ratios (HRs) and 95% confidence intervals for AC were calculated using the Cox proportional hazards model. RESULTS: The adjusted HR for AC in the < 40 year group started to increase in overweight status and was associated with the severity of obesity (body mass index (BMI) < 18.5; 0.654 (0.613-0.697), < 23; 1, < 25; 1.272 (1.231-1.315), < 30; 1.322 (1.281-1.364), ≥ 30; 1.332 (1.253-1.416)). But in the 40-64 year group and the ≥65 year group, there was no significant increasing trend of HR for AC according to BMI level. We conducted a subgroup analysis based on the BMI 23 for defining overweight and presence of comorbidities including diabetes and hyperlipidemia. The adjusted HR for AC was highest with overweight and comorbidities of diabetes and hyperlipidemia (diabetes; 1.528 (1.508-1.549), hyperlipidemia; 1.212 (1.199-1.226)). CONCLUSIONS: In the young age group (20-40 years), a higher BMI level increased the HR for AC. Overweight along with diabetes or hyperlipidemia significantly increased the risk of AC.

Alcohol-induced increase in BMP levels promotes fatty liver disease in male prediabetic stage Otsuka Long-Evans Tokushima Fatty rats.

Alcohol consumption exacerbates liver abnormalities in animal models, but whether it increases the severity of liver disease in early diabetic or prediabetic rats is unclear. To investigate the molecular mechanisms underlying alcohol-induced liver steatosis or hepatitis, we used a prediabetic animal model. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Fatty (LETO) rats were pair-fed with an ethanol-containing liquid diet for 6 weeks. Compared with controls, OLETF and LETO rats displayed more pronounced liver steatosis and higher plasma levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SPGT), indicating liver injury. Ethanol-fed LETO (Pd-L-E) rats showed mild liver steatosis and no inflammation compared with ethanol-fed OLETF (Pd-O-E) rats. Although precursor and active SREBP-1 levels in the liver of ethanol-fed OLETF rats significantly increased compared with control diet-fed OLETF rats (Pd-O-C), those of Pd-L-E rats did not. Bone morphogenetic protein (BMP) and TGF-ß1 balance in Pd-O-E rats was significantly altered because BMP signaling was upregulated by inducing BMP2, BMP4, BMP7, BMP9, Smad1, and Smad4, whereas TGF-ß1, Smad3, and Erk were downregulated. Activation of TGF-ß/Smad signaling inhibited BMP2 and BMP9 expression and increased epithelial-mesenchymal transition (EMT) marker levels (Hepcidin, Snail, and Twist) in the liver of LETO rats. Livers of ethanol-fed OLETF rats showed increased levels of vimentin, FSP-1, α-SMA, MMP1, MMP13, and collagen III compared with rats of other groups, whereas EMT marker levels did not change. Thus, BMP exerted anti- and/or pro-fibrotic effects in ethanol-fed rats. Therefore, BMP and TGF-ß, two key members of the TGF-ß superfamily, play important but diverse roles in liver steatosis in young LETO and OLETF rats.

Bone mineral density and lipid profiles in older adults: a nationwide cross-sectional study.

It has been hypothesized that lipid profiles are associated with bone mineral density (BMD), but previous results have been controversial. In this study, serum triglycerides showed a significant inverse association with BMD, and the relationship is thought to correlate with vitamin D status among older adults. INTRODUCTION: The purpose of this study was to investigate the relationship between lipid profiles and bone mineral density (BMD) in older adults using data from the Korean National Health and Nutrition Examination Survey (KNHANES). METHODS: We enrolled men older than 50 years and postmenopausal women who participated in the KNHANES 2008-2011. Subjects with liver cirrhosis, thyroid disease, or renal dysfunction and those receiving treatment for hyperlipidemia or osteoporosis were excluded. RESULTS: A total of 4323 subjects (2286 men and 2037 women) was analyzed. The prevalence of osteoporosis was 8.7% in men older than 50 years and 38.4% in postmenopausal women. Osteopenia and osteoporosis groups were generally older and tended to have a lower body mass index compared to the normal group (p for trend < 0.001). The correlation between each lipid profile and BMD was analyzed in the linear model adjusted for age and body mass index. Total cholesterol and high-density lipoprotein cholesterol showed a negative correlation with BMD in the total population, but there was no significant correlation when analyzed separately for men and women. Triglycerides had a negative association with whole-body BMD in both men and women (p < 0.05). The adjusted odds ratio of logarithmic triglyceride level for osteoporosis was 2.50 (95% confidence interval 1.13-5.51) in women older than 65 years. CONCLUSION: Serum triglycerides showed a significant inverse association with BMD, and the relationship is thought to correlate with vitamin D status among older adults.

Association between regular physical activity and lower incidence of colorectal cancer in patients with diabetes mellitus: a nationwide cohort study.

AIM: The aim of this work was to investigate the association between changes in physical activity (PA) status and the development of colorectal cancer (CRC) in patients with diabetes. METHOD: This nationwide population study included 1 439 152 patients with diabetes who underwent a health screening provided by the Korean National Health Insurance Service between January 2009 and December 2012 and a follow-up screening after 2 years. Based on changes in PA status, participants were categorized into four groups: remained inactive, remained active, active-to-inactive and inactive-to-active. RESULTS: During the median follow-up period of 5.2 years, 38 244 new cases of CRC were diagnosed. Compared with the remained inactive group, among the three other groups, the remained active group had the lowest risk of CRC [adjusted hazard ratio (aHR) 0.93; 95% CI 0.90-0.96], followed by the inactive-to-active group (aHR 0.97; 95% CI 0.94-1.00) and active-to-inactive group (aHR 0.99; 95% CI 0.96-1.02), after adjusting for confounding variables (p = 0.0007). This reduction in cancer incidence in the remained active group was observed for both rectal cancer (aHR 0.87, 95% CI 0.79-0.95) and colon cancer (aHR 0.93, 95% CI 0.90-0.97), irrespective of sex. In terms of the intensity and amount of PA, moderate intensity PA was the most effective, and a positive correlation was found between the amount of PA and the reduction in CRC incidence. CONCLUSION: Regular PA was independently associated with a decreased risk of CRC in patients with diabetes. The intensity and amount of physical activity both play a role in reducing the risk.

Fast volumetric imaging with line-scan confocal microscopy by electrically tunable lens at resonant frequency.

In microscopic imaging of biological tissues, particularly real-time visualization of neuronal activities, rapid acquisition of volumetric images poses a prominent challenge. Typically, two-dimensional (2D) microscopy can be devised into an imaging system with 3D capability using any varifocal lens. Despite the conceptual simplicity, such an upgrade yet requires additional, complicated device components and usually suffers from a reduced acquisition rate, which is critical to properly document rapid neurophysiological dynamics. In this study, we implemented an electrically tunable lens (ETL) in the line-scan confocal microscopy (LSCM), enabling the volumetric acquisition at the rate of 20 frames per second with a maximum volume of interest of 315 × 315 × 80 µm3. The axial extent of point-spread-function (PSF) was 17.6 ± 1.6 µm and 90.4 ± 2.1 µm with the ETL operating in either stationary or resonant mode, respectively, revealing significant depth axial penetration by the resonant mode ETL microscopy. We further demonstrated the utilities of the ETL system by volume imaging of both cleared mouse brain ex vivo samples and in vivo brains. The current study showed a successful application of resonant ETL for constructing a high-performance 3D axially scanning LSCM (asLSCM) system. Such advances in rapid volumetric imaging would significantly enhance our understanding of various dynamic biological processes.

Development of Intraoperative Near-Infrared Fluorescence Imaging System Using a Dual-CMOS Single Camera.

We developed a single-camera-based near-infrared (NIR) fluorescence imaging device using indocyanine green (ICG) NIR fluorescence contrast agents for image-induced surgery. In general, a fluorescent imaging system that simultaneously provides color and NIR images uses two cameras, which is disadvantageous because it increases the imaging head of the system. Recently, a single-camera-based NIR optical imaging device with quantum efficiency partially extended to the NIR region was developed to overcome this drawback. The system used RGB_NIR filters for camera sensors to provide color and NIR images simultaneously; however, the sensitivity and resolution of the infrared images are reduced by 1/4, and the exposure time and gain cannot be set individually when acquiring color and NIR images. Thus, to overcome these shortcomings, this study developed a compact fluorescent imaging system that uses a single camera with two complementary metal-oxide semiconductor (CMOS) image sensors. Sensitivity and signal-to-background ratio were measured according to the concentrations of ICG solution, exposure time, and camera gain to evaluate the performance of the imaging system. Consequently, the clinical applicability of the system was confirmed through the toxicity analysis of the light source and in vivo testing.

Comparative study on resolution enhancements in fluorescence-structured illumination Fresnel incoherent correlation holography.

Fresnel incoherent correlation holography (FINCH) is a new approach for incoherent holography, which also has enhancement in the transverse resolution. Structured illumination microscopy (SIM) is another promising super-resolution technique. SI-FINCH, the combination of SIM and FINCH, has been demonstrated lately for scattering objects. In this study, we extended the application of SI-FINCH toward fluorescent microscopy. We have built a versatile multimodal microscopy system that can obtain images of four different imaging schemes: conventional fluorescence microscopy, FINCH, SIM, and SI-FINCH. Resolution enhancements were demonstrated by comparing the point spread functions (PSFs) of the four different imaging systems by using fluorescence beads of 1-µm diameter.

Renal outcomes and all-cause death associated with sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL 3 Korea).

AIMS: To investigate the effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors on the risk of progression to end-stage renal disease (ESRD) and all-cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort. MATERIALS AND METHODS: Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all-cause death. RESULTS: There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 ± 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 ± 27.4 mL/min/1.73m2 , and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all-cause deaths during follow-up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all-cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m2 and those with eGFR < 60 mL/min/1.73m2 , and a lower risk of all-cause death was associated with SGLT2 inhibitors versus oGLDs in patients with eGFR ≥90 and 60 to 90 mL/min/1.73m2 . CONCLUSION: In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all-cause death.

Effects of DA-9801 on the inflammation and apoptosis induced by angiotensin II in human dermal microvascular endothelial cells.

DA-9801, a plant-based drug used for the treatment of diabetic neuropathy, is known to improve angiotensin II (Ang II)-induced vascular endothelial cell dysfunction. However, the underlying mechanism is not fully understood. We aimed to determine whether the protective effect of DA-9801 against Ang II-induced endothelial cell dysfunction was mediated via inhibition of endothelial cell inflammation and apoptosis. Ang II-induced oxidative stress was attenuated by pretreatment of human dermal microvascular endothelial cells (HDMECs) with DA-9801. This prevented the Ang II-induced upregulation of NAD(P)H oxidase (the NOX4 and p22phox subunits) and reactive oxygen species. Further, pretreatment of HDMECs with DA-9801 ameliorated Ang II-mediated nuclear factor kappa B activity via prevention of the upregulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. It also decreased the Ang II-stimulated increase in inducible nitric oxide synthase (NOS) and decreased endothelial NOS protein expression. DA-9801 decreased Ang II-induced upregulation of intercellular adhesion molecule 1, vascular adhesion molecule, and E-selectin in HDMECs. Moreover, TUNEL and annexin V-FITC fluorescence staining for apoptosis and the activities of caspases 9, 7, and 3 decreased in HDMECs pretreated with DA-9801, indicating that the drug enhanced anti-apoptotic pathways. Thus, DA-9801 modulated Ang II-induced endothelial cell dysfunction via inflammatory and apoptotic pathways.

Exposure-weighted scoring for metabolic syndrome and the risk of myocardial infarction and stroke: a nationwide population-based study.

BACKGROUND: Metabolic syndrome (MetS) status changes over time, but few studies have investigated the relationship between the extent or duration of exposure to MetS and the risk of cardiovascular disease (CVD). We investigated the cumulative effects of MetS and its components on the risk of myocardial infarction (MI) and stroke. METHODS: From the Korean National Health Insurance database, 2,644,851 people who received annual health examinations from 2010 to 2013 were recruited. Exposure-weighted scores for MetS during this 4-year period were calculated in two ways: cumulative number of MetS diagnoses (MetS exposure score, range: 0-4) and the composite of its five components (MetS component exposure score, range: 0-20). The multivariable Cox proportional-hazards model was used to assess CVD risk according to the exposure-weighted scores for MetS. RESULTS: MetS was identified at least once in 37.6% and persistent MetS in 8.2% of subjects. During the follow-up (median, 4.4 years), 10,522 cases of MI (0.4%) and 10,524 cases of stoke (0.4%) occurred. The risk of MI and stroke increased gradually with increasing exposure scores of MetS and its components (each P for trend < 0.0001). The hazard ratio [(HR) (95% CI)] of MI and stroke were 5.27 (4.20-6.62) and 3.90 (3.09-4.93), respectively, in those with a score of 20 compared with those with a MetS component exposure score of 0. People fulfilling only two MetS components out of 20 already had 22% increased risk of MI, and those with three MetS components had 24% increased risk of stroke. These associations were consistent in the subgroup and sensitivity analyses. CONCLUSIONS: A dose-response relationship between the cumulative exposure to metabolic disturbances and incident MI or stroke was evident. Even minimal exposure to MetS components was sufficient to increase the risk of CVD significantly, highlighting the importance of intensive risk management for the prevention of CVD.

Efficacy and safety of evogliptin treatment in patients with type 2 diabetes: A multicentre, active-controlled, randomized, double-blind study with open-label extension (the EVERGREEN study).

AIM: To investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes. MATERIALS AND METHODS: In this 12-week, multicentre, randomized, double-blind, active-controlled, and 12-week open-label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%-10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92). RESULTS: After 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was -0.85% and -0.75%, respectively. The between-group difference was -0.10% (95% CI: -0.32 to 0.11), showing non-inferiority based on a non-inferiority margin of 0.4%. The change in MAGE was -24.6 mg/dL in the evogliptin group and -16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by -0.94%, with HbA1c values of <7.0% in 80.2% of the patients. The incidence and types of adverse events were comparable between the two groups for 24 weeks. CONCLUSION: In this study, the glucose-lowering efficacy of evogliptin was non-inferior to linagliptin. It was maintained at week 24 with a 0.94% reduction in HbA1c. Evogliptin therapy improved glycaemic variability without causing any serious adverse events in patients with type 2 diabetes.

Compact wide-angle capsule endoscopic lens design.

Capsule endoscopes require a high-quality imaging system in terms of the wide field of view (FOV), image brightness, and resolution to provide accurate diagnostic information. However, because of the wide-angle lens design, the first element of the lens inevitably becomes larger in diameter, making it difficult to reduce the overall size of the lens. In this study, the compact wide-angle lens for a capsule endoscope is reported. The proposed system allows the first element to be compact in diameter and increases image quality by utilizing all aspheric surfaces for optical aberration control. The specification of the proposed capsule endoscope lens shows the wide FOV of 160 deg, F-number 2.8, and total track length of 5 mm. In the overall FOV, relative illumination is still over 60%. To achieve a high image quality in the proposed system, the modulation transfer function is over 30% at 180 lp/mm for a${1920} \times {1080}$1920×1080 1/6 inch CMOS image sensor in a pixel size of 1.4 µm.

WHO implementation workshop on guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 25-26 June 2019.

The first global workshop on implementation of the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products adopted by the WHO Expert Committee in 2018 was held in June 2019. The workshop participants recognized that the principles based on sound science and the potential for risk, as described in the WHO Guidelines on post-approval changes, which constitute the global standard for product life-cycle management are providing clarity and helping national regulatory authorities in establishing guidance while improving time-lines for an efficient regulation of products. Consequently, the regulatory situation for post-approval changes and guideline implementation is changing but there is a disparity between different countries. While the guidelines are gradually being implemented in some countries and also being considered in other countries, the need for regional workshops and further training on post-approval changes was a common theme reiterated by many participants. Given the complexities relating to post-approval changes in different regions/countries, there was a clear understanding among all participants that an efficient approach for product life-cycle management at a national level is needed to ensure faster availability of high standard, safe and efficacious medicines to patients as per the World Health Assembly Resolution 67.21.

Simple Shading Correction Method for Brightfield Whole Slide Imaging.

Whole slide imaging (WSI) refers to the process of creating a high-resolution digital image of a whole slide. Since digital images are typically produced by stitching image sequences acquired from different fields of view, the visual quality of the images can be degraded owing to shading distortion, which produces black plaid patterns on the images. A shading correction method for brightfield WSI is presented, which is simple but robust not only against typical image artifacts caused by specks of dust and bubbles, but also against fixed-pattern noise, or spatial variations in pixel values under uniform illumination. The proposed method comprises primarily of two steps. The first step constructs candidates of a shading distortion model from a stack of input image sequences. The second step selects the optimal model from the candidates. The proposed method was compared experimentally with two previous state-of-the-art methods, regularized energy minimization (CIDRE) and background and shading correction (BaSiC) and showed better correction scores, as smooth operations and constraints were not imposed when estimating the shading distortion. The correction scores, averaged over 40 image collections, were as follows: proposed method, 0.39 ± 0.099; CIDRE method, 0.67 ± 0.047; BaSiC method, 0.55 ± 0.038. Based on the quantitative evaluations, we can confirm that the proposed method can correct not only shading distortion, but also fixed-pattern noise, compared with the two previous state-of-the-art methods.

Associations of Variability in Blood Pressure, Glucose and Cholesterol Concentrations, and Body Mass Index With Mortality and Cardiovascular Outcomes in the General Population.

BACKGROUND: Variability in metabolic parameters, such as fasting blood glucose and cholesterol concentrations, blood pressure, and body weight can affect health outcomes. We investigated whether variability in these metabolic parameters has additive effects on the risk of mortality and cardiovascular outcomes in the general population. METHODS: Using nationally representative data from the Korean National Health Insurance System, 6 748 773 people who were free of diabetes mellitus, hypertension, and dyslipidemia and who underwent ≥3 health examinations from 2005 to 2012 were followed to the end of 2015. Variability in fasting blood glucose and total cholesterol concentrations, systolic blood pressure, and body mass index was measured using the coefficient of variation, SD, variability independent of the mean, and average real variability. High variability was defined as the highest quartile of variability. Participants were classified numerically according to the number of high-variability parameters (eg, a score of 4 indicated high variability in all 4 metabolic parameters). Cox proportional hazards models adjusting for age, sex, smoking, alcohol, regular exercise, income, and baseline levels of fasting blood glucose, systolic blood pressure, total cholesterol, and body mass index were used. RESULTS: There were 54 785 deaths (0.8%), 22 498 cases of stroke (0.3%), and 21 452 myocardial infarctions (0.3%) during a median follow-up of 5.5 years. High variability in each metabolic parameter was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Furthermore, the risk of outcomes increased significantly with the number of high-variability metabolic parameters. In the multivariable-adjusted model comparing a score of 0 versus 4, the hazard ratios (95% CIs) were 2.27 (2.13-2.42) for all-cause mortality, 1.43 (1.25-1.64) for myocardial infarction, and 1.41 (1.25-1.60) for stroke. Similar results were obtained when modeling the variability using the SD, variability independent of the mean, and average real variability, and in various sensitivity analyses. CONCLUSIONS: High variability of fasting blood glucose and total cholesterol levels, systolic blood pressure, and body mass index was an independent predictor of mortality and cardiovascular events. There was a graded association between the number of high-variability parameters and cardiovascular outcomes.

Long-term insulin treatment leads to a change in myosin heavy chain fiber distribution in OLETF rat skeletal muscle.

The objective of this study was to investigate molecular and physiological changes in response to long-term insulin glargine treatment in the skeletal muscle of OLETF rats. Male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats aged 24 weeks were randomly allocated to either treatment with insulin for 24 weeks or no treatment, resulting in three groups. Insulin glargine treatment in OLETF rats (OLETF-G) for 24 weeks resulted in changes in blood glucose levels in intraperitoneal glucose tolerance tests compared with age-matched, untreated OLETF rats (OLETF-C), and the area under the curve was significantly decreased for OLETF-G rats compared with OLETF-C rats (P < 0.05). The protein levels of MHC isoforms were altered in gastrocnemius muscle of OLETF rats, and the proportions of myosin heavy chain type I and II fibers were lower and higher, respectively, in OLETF-G compared with OLETF-C rats. Activation of myokines (IL-6, IL-15, FNDC5, and myostatin) in gastrocnemius muscle was significantly inhibited in OLETF-G compared with OLETF-C rats ( P < 0.05). MyoD and myogenin levels were decreased, while IGF-I and GLUT4 levels were increased, in the skeletal muscle of OLETF-G rats ( P < 0.05). Insulin glargine treatment significantly increased the phosphorylation levels of AMPK, SIRT1, and PGC-1α. Together, our results suggested that changes in the distribution of fiber types by insulin glargine could result in downregulation of myokines and muscle regulatory proteins. The effects were likely associated with activation of the AMPK/SIRT1/PGC-1α signaling pathway. Changes in these proteins may at least partly explain the effect of insulin in skeletal muscle of diabetes mellitus.