Fenofibrate to prevent amputation and reduce vascular complications in patients with diabetes: FENO-PREVENT.

BACKGROUND: The potential preventive effect of fenofibrate on lower extremity amputation (LEA) and peripheral arterial disease (PAD) in patients with type 2 diabetes (T2D) is not fully elucidated. METHODS: We selected adult patients ≥ 20 years of age with T2D from the Korean National Health Insurance Service Database (2009-2012). The fenofibrate users were matched in a 1:4 ratio with non-users using propensity scores (PS). The outcome variables were a composite of LEA and PAD and the individual components. The risks of outcomes were implemented as hazard ratio (HR) with 95% confidence intervals (CI). For safety issues, the risks of acute kidney injury, rhabdomyolysis and resulting hospitalization were analyzed. RESULTS: A total of 114,920 patients was included in the analysis with a median follow-up duration of 7.6 years (22,984 and 91,936 patients for the fenofibrate user and non-user groups, respectively). After PS matching, both groups were well balanced. The fenofibrate group was associated with significantly lower risks of composite outcome of LEA and PAD (HR 0.81; 95% CI 0.70-0.94), LEA (HR 0.76; 95% CI 0.60-0.96), and PAD (HR 0.81; 95% CI 0.68-0.96). The risk of acute kidney injury, rhabdomyolysis, or hospitalization for these events showed no significant difference between the two groups. Subgroup analyses revealed consistent benefits across age groups, genders, and baseline lipid profiles. CONCLUSIONS: This nationwide population-based retrospective observational study suggests that fenofibrate can prevent LEA and PAD in patients with T2D who are on statin therapy.

The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice.

Interleukin (IL)-1ß plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE−/−) mice. ApoE−/− mice (8-week male) were treated with saline (control), anakinra 10, 25, and 50 mg/kg, respectively (n = 10 in each group). Mice were fed a standard chow (4 weeks) followed by an atherogenic diet (35kcal% fat, 1.25% cholesterol, 12 weeks). Atheromatous plaques in ApoE−/− mice and the expression of inflammatory genes and signaling pathways in human umbilical vein endothelial cells (HUVECs), rat aortic smooth muscle cells (RAOSMCs), and 3T3-L1 adipocytes were assessed. Anakinra reduced the plaque size of the aortic arch (30.6% and 25.2% at the 25 mg/kg and 50 mg/kg doses, both p < 0.05) and serum triglyceride in ApoE−/− mice and suppressed inflammatory genes (IL-1ß and IL-6) expressions in HUVECs and RAOSMCs (all p < 0.05). In RAOSMCs, anakinra reduced metalloproteinase-9 expression in a dose-dependent manner and inhibited cell migration. Anakinra-treated mice exhibited trends of lower CD68+ macrophage infiltration in visceral fat and monocyte chemoattractant protein-1 expression was reduced in 3T3-L1 adipocytes. Anakinra could be a useful component for complementary treatment with a standard regimen to reduce the residual cardiovascular risk.

Clinical efficacy and plausibility of a smartphone-based integrated online real-time diabetes care system via glucose and diet data management: a pilot study.

BACKGROUND: Smartphones have become novel healthcare tools for patients with diabetes. However, it is uncertain whether the smartphone application support system helps in glycaemic control in patients with type 2 diabetes. AIMS: To evaluate the efficacy and plausibility of smartphone-based integrated online real-time diabetes care. METHODS: Forty patients with type 2 diabetes were randomly assigned to the smartphone-based care (SC) (n = 20) and conventional care (CC) (n = 20) groups for 12 weeks. The SC group was instructed to use smartphone application (Noom Coach) and a glucose meter, and was provided medical supervision based on blood glucose level and food intake information sent to the central database server. The efficacy was evaluated by glycated haemoglobin (A1C ≤ 6.5%). The Summary of Diabetes Self-Care Activities (SDSCA) questionnaire was collected at baseline and at week 12. RESULTS: Seventeen and 18 patients of the SC and CC groups completed the study respectively. In the SC group, more patients achieved target A1C compared with the CC group (47.1% vs 11.1%, P = 0.019). In both group, SDSCA scores excluding the exercise item showed overall improvement (general diet, 1.4 ± 2.0 → 2.6 ± 2.3 vs 0.4 ± 1.1 → 1.8 ± 2.2; specific diet, 4.2 ± 1.7 → 5.4 ± 1.2 vs 3.8 ± 1.6 → 5.1 ± 1.1; blood glucose test, 3.3 ± 2.8 → 4.9 ± 2.3 vs 1.0 ± 2.2 → 4.7 ± 2.3; foot care, 1.5 ± 1.6 → 3.6 ± 2.8 vs 1.4 ± 1.9 → 6.1 ± 1.4; all P < 0.05). There was no difference between both groups other than the aspect of foot care (P = 0.008). CONCLUSIONS: The smartphone-based integrated online real-time diabetes care system through glucose and diet data management showed clinical plausibility in glucose control in real clinical practice.

Effectiveness and safety of empagliflozin-based quadruple therapy compared with insulin glargine-based therapy in patients with inadequately controlled type 2 diabetes: An observational study in clinical practice.

This open-label, prospective study evaluated the effectiveness and safety of empagliflozin as add-on therapy in inadequately controlled type 2 diabetes (T2D) patients (glycated haemoglobin [HbA1c], 7.5-12%) who were already using three other types of orally active antidiabetic agents. A total of 268 T2D patients were enrolled and divided into two groups, empagliflozin (EMPA 25 mg/d, n = 142) or insulin glargine (INS, n = 126), respectively. After the treatment period of 24 weeks, HbA1c and fasting plasma glucose (FPG) were significantly reduced (HbA1c, P = 0.004; FPG, P = 0.008, respectively) in the EMPA group compared to the INS group. Also, EMPA treatment evoked a significant reduction in body weight (P < 0.001) and systolic blood pressure (P = 0.017) compared to the INS group. Hypoglycaemic adverse events were significantly higher in the INS group compared to the EMPA group (P = 0.001). In conclusion, this study demonstrated that a regimen comprising four different orally active antidiabetic agents, including EMPA, was effective and safe as a therapeutic strategy for treating T2D patients for glycaemic control and improvement of other cardiovascular and metabolic indices.

Associations between the HaeIII Single Nucleotide Polymorphism in the SLC2A1 Gene and Diabetic Nephropathy in Korean Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Diabetic nephropathy (DN) is the most serious microvascular complication of diabetes mellitus and is one of the leading causes of end stage renal failure. In previous studies, the contribution of genetic susceptibility to DN showed inconsistent results. In this study, we investigated the association between the solute carrier family 2 facilitated glucose transporter member 1 (SLC2A1) HaeIII polymorphism and DN in Korean patients with type 2 diabetes mellitus (T2DM) according to disease duration. METHODS: A total of 846 patients with T2DM (mean age, 61.3 ± 12.3 years; mean duration of T2DM, 10.3 ± 7.9 years; 55.3% men) who visited the Chungbuk National University Hospital were investigated. The HaeIII polymorphism of the SLC2A1 gene was determined by the real time polymerase chain reaction method. Genotyping results were presented as GG, AG, or AA. A subgroup analysis was performed according to duration of T2DM (≤ 10 years, > 10 years). RESULTS: The AG + AA genotype showed a significantly higher risk of DN compared with the GG genotype in patients with a type 2 DM duration less than 10 years (12.4% vs. 4.2%; P < 0.001). No significant differences were observed in terms of other diabetic complications, including retinopathy, peripheral neuropathy, cardiovascular disease, cerebrovascular disease or peripheral artery disease, according to the genotypes of the SLC2A1 HaeIII polymorphism. CONCLUSION: The SLC2A1 HaeIII polymorphism was associated with DN in Korean patients with T2DM, particularly in the group with a relatively short disease duration.

Association of Adiponectin 45T/G Polymorphism with Diabetic Cardiovascular Complications in Korean Type 2 Diabetes.

BACKGROUND: Adiponectin is an adipokine that regulates lipid and glucose metabolism and has been shown to have anti-inflammatory and anti-atherogenic effects. It also plays an important role in the development of cardiovascular disease (CVD). METHODS: This study evaluated the association between adiponectin 45T/G polymorphism and cardiovascular complication in type 2 diabetes in Koreans. RESULTS: The present study included 758 patients with type 2 diabetes. The distribution of the adiponectin 45T/G polymorphism was 3.56% (n = 27) for GG, 42.35% (n = 321) for TG, and 54.09% (n = 410) for TT in patients with type 2 diabetes. The prevalence of CVD was significantly higher in subjects with the GG + TG genotype compared to those with the TT genotype (17.5% vs. 9.8%, P = 0.002). The G allele was associated with a higher risk of CVD (P = 0.002). CONCLUSION: Our findings suggest that the adiponectin 45T/G polymorphism is associated with diabetic cardiovascular complication in type 2 diabetes.

Sex differences in the prevalence of metabolic syndrome and its components in hypopituitary patients: comparison with an age- and sex-matched nationwide control group.

PURPOSE: Hypopituitary patients have a reduced life expectancy owing to cardiovascular events. We investigated the prevalence of metabolic syndrome in hypopituitary patients for a follow-up period of at least 1 year in comparison with an age- and sex-matched nationwide control group. METHODS: A total of 515 patients with hypopituitarism who visited Seoul National University Hospital between January 2000 and December 2010 were included. Data for an age- and sex-matched control group were obtained from the Korean National Health and Nutrition Examination Surveys (KNHANES) (n = 1545). Metabolic syndrome was defined according to the modified National Cholesterol Education Program (NCEP-ATPIII). RESULTS: The prevalence of metabolic syndrome did not differ significantly between the hypopituitary and control groups for men (34.9 versus 30.3 %), but the risk of metabolic syndrome was higher in hypopituitary women than in controls (39.8 versus 28.5 %). In both sexes, the risks of central obesity and dyslipidemia were higher in the hypopituitary group than in the control group. Men had lower risks of hypertension and hyperglycemia in the hypopituitary group, which attenuated the risk of metabolic syndrome. Age greater than 40 years and obesity (BMI ≥25 kg/m2) contributed to a higher risk of metabolic syndrome. CONCLUSIONS: The metabolic syndrome prevalence was higher in the hypopituitry group than in the control group in Korean women, and this was attributed to an increased risk of central obesity and dyslipidemia. Accordingly, early intervention to reduce metabolic syndrome needed in hypopituitary patients, i.e. women.

The amount of C1q-adiponectin complex is higher in the serum and the complex localizes to perivascular areas of fat tissues and the intimal-medial layer of blood vessels of coronary artery disease patients.

BACKGROUND: The complement component C1q triggers activation of the classical immune pathway and can bind to adiponectin (APN). Recently, some studies have been reported that serum C1q-APN/total APN ratio correlates with atherosclerosis and coronary artery disease (CAD). We assessed the relationships between C1q related variables and the severity of CAD, and investigated the localization of the C1q-APN complex. METHODS: The sample included 153 subjects comprising healthy controls and patients with subclinical or overt CAD. We measured the serum concentrations of C1q, total APN, and high-molecular weight (HMW)-APN, and the amount of C1q-APN complex. We identified the sites of C1q-APN complex deposition in various adipose tissues and blood vessels. RESULTS: Serum concentrations of C1q and HMW-APN and the C1q/HMW-APN ratio were independently associated with the severity of coronary stenosis. The amount of C1q-APN complex was significantly higher in patients with CAD compared with controls. C1q and APN co-localized in perivascular areas of subcutaneous, visceral, and pericardial fat tissues, and the internal mammary artery of patients with severe CAD. CONCLUSIONS: Serum C1q concentration and the C1q/HMW-APN ratio were independent markers of coronary artery stenosis. The amount of C1q-APN complex was significantly greater in serum from CAD patients. C1q and APN co-localized to perivascular areas in adipose tissue and blood vessels. The association between the increased amount of the C1q-APN complex and CAD should be investigated further.

A phase 4 randomized active-controlled clinical study to compare the efficacy and safety of sustained-release pregabalin with immediate-release pregabalin in type 2 diabetic patients with peripheral neuropathic pain.

AIMS: The objective of this study was to demonstrate that sustained-release (SR) pregabalin is non-inferior to immediate-release (IR) pregabalin in attenuating diabetic peripheral neuropathic (DPN) pain along with patient satisfaction and compliance. METHODS: This was an 8-week, randomized, active-controlled, open-label, phase 4 study. Eligible subjects who had been on IR pregabalin for 4 weeks were randomized to 1:1 ratio to either continue with twice-daily IR pregabalin (75 mg), or to switch to once-daily SR pregabalin (150 mg). Primary efficacy endpoint was the change in visual analogue scale (VAS) scores after 8 weeks of treatment compared to baseline in both SR and IR pregabalin groups. RESULTS: Among 130 randomized subjects, 125 patients were included in full analysis set. For the change in VAS pain score, the least squares (LS) mean were -17.95 (SR pregabalin) and -18.74 (IR pregabalin) and the LS mean difference between both groups was 0.79, with the upper limit of the 95 % confidence interval [-5.99, 7.58] below the pre-specified non-inferiority margin of 9.2 mm. CONCLUSIONS: This study demonstrates that the new once-daily SR pregabalin formulation is not different to the twice-daily IR pregabalin in alleviating DPN pain, indicating its potential as a promising treatment for DPN pain with a comparable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05624853.

Clinical impact of coexistent chronic lymphocytic thyroiditis on central lymph node metastasis in low- to intermediate-risk papillary thyroid carcinoma: The MASTER study.

BACKGROUND: The clinicopathological impact of chronic lymphocytic thyroiditis on patients with papillary thyroid carcinoma patients is still controversial. This study aimed to evaluate the clinicopathologic differences and risk factors for central lymph node metastasis based on the presence of coexistent chronic lymphocytic thyroiditis in patients with low- to intermediate-risk papillary thyroid carcinoma. METHODS: The medical records of 1,022 patients with low- to intermediate-risk papillary thyroid carcinoma who underwent lobectomy and central neck dissection between June 2020 and March 2022 were reviewed. Differences in clinicopathological factors were analyzed in patients with papillary thyroid carcinoma with or without chronic lymphocytic thyroiditis. Furthermore, risk factors for central lymph node metastasis in patients with low- to intermediate-risk papillary thyroid carcinoma with or without chronic lymphocytic thyroiditis were evaluated. RESULTS: Among the 1,022 patients with low to intermediate-risk papillary thyroid carcinoma, 102 (10.0%) had coexisting chronic lymphocytic thyroiditis. Female sex (odds ratio = 3.536, P = .001, 95% confidence interval 1.781-8.069), a multifocal tumor (odds ratio = 2.162, P = .001, 95% confidence interval 1.358-3.395), and angiolymphatic invasion (odds ratio = 0.365, P < .001, 95% confidence interval 0.203-0.625) were independent factors associated with patients who had coexisting chronic lymphocytic thyroiditis compared to those without chronic lymphocytic thyroiditis. There were 358 (35%) patients who had central lymph node metastasis. Multivariate analysis showed that younger age (odds ratio = 0.667, P = .013, 95% confidence interval 0.482-0.555), male sex (odds ratio = 0.549, P < .001, 95% confidence interval 0.402-0.751), tumor size >1 cm (odds ratio = 1.454, P = .022, 95% confidence interval 1.053-2.003), extrathyroidal extension (odds ratio = 1.874, P < .001, 95% confidence interval 1.414-2.486), and angiolymphatic invasion (odds ratio = 3.094, P < .001, 95% confidence interval 2.339-4.101) were risk factors for central lymph node metastasis. Angiolymphatic invasion (odds ratio = 11.184, P < .001, 95% confidence interval 3.277-46.199) was identified as the sole independent risk factor for central lymph node metastasis in patients with papillary thyroid carcinoma with coexisting chronic lymphocytic thyroiditis. CONCLUSION: Our data suggest that patients with low to intermediate-risk papillary thyroid carcinoma with coexistent chronic lymphocytic thyroiditis exhibit different clinical features than patients with papillary thyroid carcinoma without chronic lymphocytic thyroiditis. Additionally, the presence of chronic lymphocytic thyroiditis may be considered a potential factor against central lymph node metastasis.

Effect of thyroid-stimulating hormone suppression on quality of life in thyroid lobectomy patients: interim analysis of a multicenter, randomized controlled trial in low- to intermediate-risk thyroid cancer patients (MASTER study).

Purpose: Current clinical practices favor less or no thyroid-stimulating hormone (TSH) suppression for low- to intermediate-risk thyroid cancer patients who receive thyroid lobectomy. The association of TSH suppression on health-related quality of life (HR-QoL) in patients after thyroid lobectomy is not well studied. This study aimed to evaluate the effect of TSH suppression on patient HR-QoL after thyroid lobectomy. Methods: This study included patients enrolled in an ongoing, multicenter, randomized controlled study investigating the effects of TSH suppression. Patients were randomized to either the low-TSH group (TSH target range, 0.3-1.99 µIU/mL) or the high-TSH group (TSH target range, 2.0-7.99 µIU/mL). The HR-QoL, hyperthyroidism symptom, and depression symptom questionnaires performed preoperatively and 2 weeks and 3 months postoperatively were evaluated. Results: Total of 669 patients (low-TSH group, 340; high-TSH group, 329) were included. Although total HR-QoL score changes were not different between the 2 groups, the high-TSH group had a significantly higher score in the physical domain at postoperative 3 months (P = 0.046). The 2 groups did not have significant differences in hyperthyroidism and depression scores. Conclusion: In the short-term postoperative period, the physical HR-QoL scores in thyroid lobectomy patients were better when they did not receive TSH suppression. This study suggests the importance of considering HR-QoL when setting TSH suppression targets in thyroid lobectomy patients.

Feasibility of active surveillance in patients with clinically T1b papillary thyroid carcinoma ≤1.5 cm in preoperative ultrasonography: MASTER study.

Objective: Active surveillance (AS) is generally accepted as an alternative to immediate surgery for papillary thyroid carcinoma (PTC) measuring ≤1.0 cm (cT1a) without risk factors. This study investigated the clinicopathologic characteristics of PTCs measuring ≤2.0 cm without cervical lymph node metastasis (cT1N0) by tumor size group to assess the feasibility of AS for PTCs between 1.0 cm and 1.5 cm (cT1b≤1.5). Design: This study enrolled clinically T1N0 patients with preoperative ultrasonography information (n= 935) from a cohort of 1259 patients who underwent lobectomy and were finally diagnosed with PTC from June 2020 to March 2022. Results: The cT1b≤1.5 group (n = 171; 18.3 %) exhibited more lymphatic invasion and occult central lymph node (LN) metastasis with a higher metastatic LN ratio than the cT1a group (n = 719; 76.9 %). However, among patients aged 55 years or older, there were no significant differences in occult central LN metastasis and metastatic LN ratio between the cT1a, cT1b≤1.5, and cT1b>1.5 groups. Multivariate regression analyses revealed that occult central LN metastasis was associated with age, sex, tumor size, extrathyroidal extension, and lymphatic invasion in patients under 55, while in those aged 55 or older, it was associated only with age and lymphatic invasion. Conclusion: For PTC patients aged 55 years or older with cT1b≤1.5, AS could be a viable option due to the absence of a significant relationship between tumor size and occult central LN.

Long-Term Effectiveness of Quadruple Combination Therapy with Empagliflozin Versus Basal Long-Acting Insulin Therapy in Patients with Type 2 Diabetes: 3-Year Retrospective Observational Study.

INTRODUCTION: Effective blood glucose control remains a constant problem in patients with type 2 diabetes (T2D), even if they are being properly treated with one or more currently available drugs. The present study was designed as a 3-year retrospective observational study to determine whether the use of either empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, or insulin would provide any improvement in the control of the blood glucose levels in patients with T2D who were already being treated with a cocktail of three different oral antidiabetic drugs. METHODS: Adult patients with T2D were enrolled in this study if they exhibited suboptimal glycemic control (HbA1c 7.5-12.0%) despite being continuously treated for at least 3 months with metformin, dipeptidyl-peptidase 4 inhibitor, and glimepiride. Empagliflozin (25 mg/day, n = 154) or basal long-acting insulin (n = 147) was added as a fourth medication to the existing drug regimen. The major outcomes that were monitored in this study included the measurement of HbA1c, fasting plasma glucose (FPG), and general cardiometabolic and blood markers. RESULTS: After the addition of empagliflozin or basal insulin to the existing oral anti-diabetic agent (OAD) regimen, the baseline levels of HbA1c were reduced after month 36 in both the empagliflozin (8.9 ± 1.0% to 7.4 ± 0.8%, P < 0.01) and insulin (9.0 ± 1.4% to 8.0 ± .1.4%, P < 0.05) groups. The HbA1c reduction was higher in the empagliflozin group to the end of the 36-month study period (7.4 ± 0.8% vs. 8.0 ± 1.4%, empagliflozin vs. insulin, P < 0.05). FPG showed a similar trend in the early period but it was not maintained at the end of study. Body weight decreased (P < 0.01) from baseline (70.4 ± 12.3 kg) to month 36 (65.6 ± 11.4 kg) in the empagliflozin group but not the insulin group. At 36 months, the body weight in the empagliflozin group (65.6 ± 11.4 kg) was significantly lower (P < 0.01) than that in the insulin treatment group (70.0 ± 10.9 kg). CONCLUSION: Empagliflozin was shown to perform as well as better than insulin when used as part of a quadruple drug regimen for regulating blood glucose levels in suboptimally controlled patients with T2D. CLINICAL TRIAL NUMBER: NCT05103306 (ClinicalTrials.gov).

Management of Subclinical Hypothyroidism: A Focus on Proven Health Effects in the 2023 Korean Thyroid Association Guidelines.

Subclinical hypothyroidism (SCH) is characterized by elevated thyroid-stimulating hormone (TSH) and normal free thyroxine levels. The Korean Thyroid Association recently issued a guideline for managing SCH, which emphasizes Korean-specific TSH diagnostic criteria and highlights the health benefits of levothyroxine (LT4) treatment. A serum TSH level of 6.8 mIU/L is presented as the reference value for diagnosing SCH. SCH can be classified as mild (TSH 6.8 to 10.0 mIU/L) or severe (TSH >10.0 mIU/L), and patients can be categorized as adults (age <70 years) or elderly (age ≥70 years), depending on the health effects of LT4 treatment. An initial increase in serum TSH levels should be reassessed with a subsequent measurement, including a thyroid peroxidase antibody test, preferably 2 to 3 months after the initial assessment. While LT4 treatment is not generally recommended for mild SCH in adults, it is necessary for severe SCH in patients with underlying coronary artery disease or heart failure and it may be considered for those with concurrent dyslipidemia. Conversely, LT4 treatment is generally not recommended for elderly patients, regardless of SCH severity. For those SCH patients who are prescribed LT4 treatment, the dosage should be personalized, and serum TSH levels should be regularly monitored to maintain the optimal LT4 regimen.

Incidence of Endocrine-Related Dysfunction in Patients Treated with New Immune Checkpoint Inhibitors: A Meta-Analysis and Comprehensive Review.

BACKGRUOUND: This study investigated the incidence of endocrine immune-related adverse events (irAEs) for recently developed immune checkpoint inhibitor (ICI) drugs. METHODS: We collected studies on newly developed ICI drugs using PubMed/Medline, Embase, and Cochrane Library from inception through January 31, 2023. Among ICI drugs, nivolumab, pembrolizumab, and ipilimumab were excluded from the new ICI drugs because many papers on endocrine-related side effects have already been published. RESULTS: A total of 44,595 patients from 177 studies were included in this analysis. The incidence of hypothyroidism was 10.1% (95% confidence interval [CI], 8.9% to 11.4%), thyrotoxicosis was 4.6% (95% CI, 3.8% to 5.7%), hypophysitis was 0.8% (95% CI, 0.5% to 1.1%), adrenal insufficiency was 0.9% (95% CI, 0.7% to 1.1%), and hyperglycemia was 2.3% (95% CI, 1.6% to 3.4%). Hypothyroidism and thyrotoxicosis occurred most frequently with programmed cell death protein-1 (PD-1) inhibitors (13.7% and 7.5%, respectively). The rate of endocrine side effects for the combination of a programmed death-ligand 1 inhibitor (durvalumab) and cytotoxic T lymphocyte-associated antigen 4 inhibitor (tremelimumab) was higher than that of monotherapy. In a meta-analysis, the combination of tremelimumab and durvalumab had a 9- to 10-fold higher risk of pituitary and adrenal-related side effects than durvalumab alone. CONCLUSION: Newly developed PD-1 inhibitors had a high incidence of thyroid-related irAEs, and combined treatment with durvalumab and tremelimumab increased the risk of pituitary- and adrenal-related irAEs. Based on these facts, it is necessary to predict the endocrine side effects corresponding to each ICI drug, diagnose and treat them appropriately, and try to reduce the morbidity and mortality of patients.

Grave-to-cradle: human embryonic lineage tracing from the postmortem body.

Curiosity concerning the process of human creation has been around for a long time. Relevant questions seemed to be resolved with the knowledge of how cells divide after fertilization obtained through in vitro fertilization experiments. However, we still do not know how human life is created at the cellular level. Recently, the value of cadavers as a resource from which to obtain "normal" cells and tissues has been established, and human research using postmortem bodies has attracted growing scientific attention. As the human genome can be analyzed at the level of nucleotides through whole-genome sequencing, individual cells in a postmortem body can be traced back to determine what developmental processes have transpired from fertilization. These retrospective lineage tracing studies have answered several unsolved questions on how humans are created. This review covers the methodologies utilized in lineage tracing research in a historical context and the conceptual basis for reconstructing the division history of cells in a retrospective manner using postzygotic somatic variants in postmortem tissue. We further highlight answers that postmortem research could potentially address and discuss issues that wait to be solved in the future.

Mortality and Severity of Coronavirus Disease 2019 in Patients with Long-Term Glucocorticoid Therapy: A Korean Nationwide Cohort Study.

BACKGRUOUND: The severity of coronavirus disease 2019 (COVID-19) among patients with long-term glucocorticoid treatment (LTGT) has not been established. We aimed to evaluate the association between LTGT and COVID-19 prognosis. METHODS: A Korean nationwide cohort database of COVID-19 patients between January 2019 and September 2021 was used. LTGT was defined as exposure to at least 150 mg of prednisolone (≥5 mg/day and ≥30 days) or equivalent glucocorticoids 180 days before COVID-19 infection. The outcome measurements were mortality, hospitalization, intensive care unit (ICU) admission, length of stay, and mechanical ventilation. RESULTS: Among confirmed patients with COVID-19, the LTGT group (n=12,794) was older and had a higher proportion of comorbidities than the control (n=359,013). The LTGT group showed higher in-hospital, 30-day, and 90-day mortality rates than the control (14.0% vs. 2.3%, 5.9% vs. 1.1%, and 9.9% vs. 1.8%, respectively; all P<0.001). Except for the hospitalization rate, the length of stay, ICU admission, and mechanical ventilation proportions were significantly higher in the LTGT group than in the control (all P<0.001). Overall mortality was higher in the LTGT group than in the control group, and the significance remained in the fully adjusted model (odds ratio [OR], 5.75; 95% confidence interval [CI], 5.31 to 6.23) (adjusted OR, 1.82; 95% CI, 1.67 to 2.00). The LTGT group showed a higher mortality rate than the control within the same comorbidity score category. CONCLUSION: Long-term exposure to glucocorticoids increased the mortality and severity of COVID-19. Prevention and early proactive measures are inevitable in the high-risk LTGT group with many comorbidities.

Potential impact of obesity on the aggressiveness of low- to intermediate-risk papillary thyroid carcinoma: results from a MASTER cohort study.

PURPOSE: Obesity is associated with an increased risk of papillary thyroid carcinoma (PTC). Evidence of the impact of obesity on PTC aggressiveness is scarce. We aimed to evaluate the association between the body mass index (BMI) and the presence of aggressive features of low- to intermediate-risk PTC in a prospective cohort. METHODS: We prospectively enrolled 1,032 patients with low- to intermediate-risk PTC who underwent lobectomy at 22 hospitals in Korea and divided into three groups according to BMI, as follows: normal/underweight ( < 23 kg/m2), overweight (23-24.9 kg/m2), and obese ( ≥ 25 kg/m2). Clinicopathological features of PTC at diagnosis were evaluated. RESULTS: Obese patients had a higher rate of macro-PTC ( > 1 cm) and greater incidence of extra-thyroidal extension (ETE), vascular invasion, and intermediate-risk tumors than those not classified as obese. Increased BMI was positively associated with the incidence of macro-PTC, ETE, vascular invasion, and intermediate-risk category. After adjusting for age, sex, pathological features, metabolic syndrome, thyroid function test, and smoking habits, obesity was a risk factor for ETE (odds ratio [OR] = 1.7, 95% confidence interval [CI]: 1.2-2.5, p = 0.005) and intermediate-risk PTC (OR = 1.7, 95% CI: 1.1-2.5, p = 0.011) in women. The association between obesity and ETE was significant regardless of whether or not women had metabolic syndrome. There was no significant association between obesity and aggressive PTC features in men. CONCLUSION: BMI at the time of thyroid cancer diagnosis may affect the aggressiveness of low- to intermediate-risk PTC, especially in women.

Preliminary Study of Different Treatment Responses between Bevacizumab, Aflibercept and Dexamethasone Implant According to Renal Function in Diabetic Macular Edema Patients.

Background: The purpose of this study was to investigate the association between responses to intravitreal bevacizumab injection and renal function in diabetic macular edema (DME) patients. Methods: A retrospective study of the medical records of 104 treatment-naïve DME patients who received intravitreal bevacizumab injection (IVBI) was conducted. Based on the estimated glomerular filtration rate (eGFR, mL/min/1.73 m2), the participants were classified into three groups. Intergroup comparisons of the best-corrected visual acuity (BCVA) and central subfield retinal thickness (CST) changes were performed after three-monthly consecutive IVBIs. In the groups with decreased renal function, the response to further treatment with a different drug was investigated. Results: A total of 104 participants were included in the study: 60 participants in the preserved renal function group (eGFR ≥ 60), 25 participants in the moderate chronic kidney disease (CKD) group (30 ≤ eGFR < 60), and 19 participants in the severe CKD group (eGFR < 30). After three-monthly consecutive IVBIs, BCVA (p < 0.001) and CST (p < 0.001) were significantly improved only in the preserved renal function group. Following further treatment of patients with decreased renal function, the treatment results were significantly better in those who were switched to aflibercept or dexamethasone implant than in those who were maintained on IVBI. Conclusions: From this preliminary study, we observed that renal function might affect the response to IVBI treatment in patients with DME. In the case of a poor response to initial IVBI treatment for DME in patients with moderate to severe CKD, our study supports switching to the aflibercept or dexamethasone implant.