The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair.

Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A's recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair.

Nesfatin-1 ameliorates pathological abnormalities in Drosophila hTau model of Alzheimer's disease.

In human Alzheimer's disease (AD), the aggregation of tau protein is considered a significant hallmark, along with amyloid-beta. The formation of neurofibrillary tangles due to aberrant phosphorylation of tau disrupts microtubule stability, leading to neuronal toxicity, dysfunction, and subsequent cell death. Nesfatin-1 is a neuropeptide primarily known for regulating appetite and energy homeostasis. However, the function of Nesfatin-1 in a neuroprotective role has not been investigated. In this study, we aimed to elucidate the effect of Nesfatin-1 on tau pathology using the Drosophila model system. Our findings demonstrate that Nesfatin-1 effectively mitigates the pathological phenotypes observed in Drosophila human Tau overexpression models. Nesfatin-1 overexpression rescued the neurodegenerative phenotypes in the adult fly's eye and bristle. Additionally, Nesfatin-1 improved locomotive behavior, neuromuscular junction formation, and lifespan in the hTau AD model. Moreover, Nesfatin-1 controls tauopathy by reducing the protein level of hTau. Overall, this research highlights the potential therapeutic applications of Nesfatin-1 in ameliorating the pathological features associated with Alzheimer's disease.

Increased risk of dementia after transient global amnesia: a nationwide population-based, longitudinal follow-up study in South Korea.

INTRODUCTION: The long-term cognitive outcomes after transient global amnesia (TGA) have been contradictory in the literature. Our study aimed to longitudinally investigate the association between TGA and incident dementia using long-term data from a nationwide population-based cohort in South Korea. METHODS: The study population was recruited between 2002 and 2020 using the International Classification of Diseases (tenth revision; ICD-10) codes from the Korean National Health Insurance Service database. The cumulative incidence curve was plotted to compare the incidence of dementia between the TGA (ICD-10 code G45.4; n = 10,276) and non-TGA (n = 27,389) groups, determined using 1:3 propensity score matching. Using Cox proportional hazard regression models, we obtained crude and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the incident dementia in patients with TGA compared to non-TGA controls. To examine independent variables determining dementia in the TGA group, logistic regression analysis was performed, and adjusted odds ratios (aORs) and 95% CIs were calculated. RESULTS: The TGA group had a significantly higher cumulative incidence of dementia than the non-TGA group (p <0.001, log-rank test). TGA was significantly associated with incident dementia in the univariate and multivariate Cox models (HR 1.34, 95% CI 1.28-1.39 and aHR 1.40, 95% CI 1.34-1.46, respectively). The adjusted logistic regression for incident dementia in the TGA group showed that age (per 1 year, aOR 1.09, 95% CI 1.09-1.10), female sex (aOR 1.31, 95% CI 1.18-1.45), diabetes (aOR 1.21, 95% CI 1.08-1.35), stroke (aOR 1.30, 95% CI 1.16-1.46), depression (aOR 1.53, 95% CI 1.33-1.76), anxiety (aOR 1.24, 95% CI 1.01-1.39), and rural residence (aOR 1.24, 95% CI 1.10-1.41) were independently associated with incident dementia. CONCLUSION: Our results suggest a longitudinal association of TGA with incident dementia.

Enhancement of second-harmonic generation in a 64° stacked WSe2/WS2heterobilayer with local strain.

Transition metal dichalcogenides (TMDs) are actively studied in various fields of optics and optoelectronics, including nonlinear optics of second-harmonic generation (SHG). By stacking two different TMD materials to form a heterobilyaer, unique optical properties emerge, with stronger SHG at a twist angle of 0° between TMDs and weaker SHG at a twist angle of 60°. In this work, we demonstrate the enhancement of SHG in a heterobilayer consisting of WSe2and WS2monolayers stacked at a twist angle of 64.1°, using a nanoparticle to induce local strain. The interatomic spacing of the heterobilayer is deformed by the nanoparticle, breaking the inversion symmetry, resulting in a substantial increase in the SHG of the heterobilayer at room temperature. The SHG increases depending on the polarization of the pump laser: 15-fold for linear polarization, 9-fold for right-circular polarization, and up to 100-fold for left-circular polarization. In addition, the SHG enhanced in the heterobilayer with local strain satisfies the same chiral selection rule as in the unstrained TMD region, demonstrating that the chiral selection rule of SHG is insensitive to local strain. Our findings will increase the applicability of TMD heterobilayers in nonlinear optoelectronics and valleytronics.

Soluble ANPEP Released From Human Astrocytes as a Positive Regulator of Microglial Activation and Neuroinflammation: Brain Renin-Angiotensin System in Astrocyte-Microglia Crosstalk.

Astrocytes are major supportive glia and immune modulators in the brain; they are highly secretory in nature and interact with other cell types via their secreted proteomes. To understand how astrocytes communicate during neuroinflammation, we profiled the secretome of human astrocytes following stimulation with proinflammatory factors. A total of 149 proteins were significantly upregulated in stimulated astrocytes, and a bioinformatics analysis of the astrocyte secretome revealed that the brain renin-angiotensin system (RAS) is an important mechanism of astrocyte communication. We observed that the levels of soluble form of aminopeptidase N (sANPEP), an RAS component that converts angiotensin (Ang) III to Ang IV in a neuroinflammatory milieu, significantly increased in the astrocyte secretome. To elucidate the role of sANPEP and Ang IV in neuroinflammation, we first evaluated the expression of Ang IV receptors in human glial cells because Ang IV mediates biological effects through its receptors. The expression of angiotensin type 1 receptor was considerably upregulated in activated human microglial cells but not in human astrocytes. Moreover, interleukin-1ß release from human microglial cells was synergistically increased by cotreatment with sANPEP and its substrate, Ang III, suggesting the proinflammatory action of Ang IV generated by sANPEP. In a mouse neuroinflammation model, brain microglial activation and proinflammatory cytokine expression levels were increased by intracerebroventricular injection of sANPEP and attenuated by an enzymatic inhibitor and neutralizing antibody against sANPEP. Collectively, our results indicate that astrocytic sANPEP-induced increase in Ang IV exacerbates neuroinflammation by interacting with microglial proinflammatory receptor angiotensin type 1 receptor, highlighting an important role of indirect crosstalk between astrocytes and microglia through the brain RAS in neuroinflammation.

Tranexamic Acid Can Reduce Early Tendon Adhesions After Rotator Cuff Repair and Is Not Detrimental to Tendon-Bone Healing: A Comparative Animal Model Study.

PURPOSE: To determine the effects of topical tranexamic acid (TXA) administration on tendon adhesions, shoulder range of motion (ROM), and tendon healing in an acute rotator cuff repair rat model. METHODS: A total of 20 Sprague Dawley rats were used. Tendon adhesion, ROM, and biomechanical and histological analysis of tendon-bone healing was conducted at 3 and 6 weeks after surgery. The rats underwent rotator cuff repair surgery on both shoulders and were administered TXA via subacromial injections. The tendon adhesion was evaluated macroscopically and histologically. Biomechanical tendon healing was measured using a universal testing machine, and histological analysis was quantified by H&E, Masson's trichrome, and picrosirius red staining. RESULTS: At 3 weeks after surgery, the adhesion score was significantly lower in the TXA group (2.10 ± 0.32) than in the control group (2.70 ± 0.48) (P = .005), but there was no significant difference between the 2 groups at 6 weeks. Regarding ROM, compared with the control group, the TXA group showed significantly higher external rotation (36.35° ± 4.52° vs 28.42° ± 4.66°, P < .001) and internal rotation (45.35° ± 9.36° vs 38.94° ± 5.23°, P = .013) 3 weeks after surgery. However, at 6 weeks, there were no significant differences in external and internal rotation between the 2 groups. In the biomechanical analysis, no significant differences in gross examination (3 weeks, P = .175, 6 weeks, P = .295), load to failure (3 weeks, P = .117, 6 weeks, P = .295), or ultimate stress (3 weeks, P = .602, 6 weeks, P = .917) were noted between the 2 groups 3 and 6 weeks after surgery. In the histological analysis of tendon healing, no significant differences in the total score (3 weeks, P = .323, 6 weeks, P = .572) were found between the 2 groups 3 and 6 weeks after surgery. CONCLUSIONS: Topical TXA administration showed a beneficial effect in reducing tendon adhesions and improving ROM 3 weeks postoperatively and had no effect at 6 weeks. This suggests that additional intervention with TXA may be useful in achieving long-term improvement in shoulder stiffness. Additionally, TXA may increase tissue ground substance accumulation in the late postoperative period but does not adversely affect tendon-bone interface healing. CLINICAL RELEVANCE: The use of TXA after rotator cuff repair has no effect on tendon-bone interface healing in clinical practice and can improve shoulder stiffness in the early postoperative period. Additional research on the long-term effects is needed.

Current research trends on the effect of diabetes mellitus on rotator cuff tendon healing/tendinopathy.

Rotator cuff tendon tears are a leading cause of shoulder pain. They are challenging to treat, and tendon-bone healing has a high failure rate despite successful surgery. Tendons connect the muscles and bones, which make them important for the body's overall mobility and stability. Metabolic diseases, including diabetes or high blood pressure, can affect the healing process after repair of a damaged tendon. With a global incidence of 9.3%, diabetes is considered as a significant risk factor for rotator cuff tendon healing because it causes structural, inflammatory, and vascular changes in the tendon. However, the mechanisms of how diabetes affects tendon healing remain unknown. Several factors have been suggested, including glycation product accumulation, adipokine dysregulation, increased levels of reactive oxygen species, apoptosis, inflammatory cytokines, imbalanced matrix-metalloproteinase-to-tissue-inhibitor ratio, and impaired angiogenesis and differentiation of the tendon sheath. Despite the effects of diabetes on tendon function and healing, few treatments are available to improve recovery in these patients. This review summarizes the current literature on the pathophysiological changes of the tendon in diabetes and hyperlipidemia. Preclinical and clinical evidence regarding the association between diabetes and tendon healing is presented. Moreover, current approaches to improve tendon healing in patients with diabetes are reviewed.

Graphene-Encapsulated Bifunctional Catalysts with High Activity and Durability for Zn-Air Battery.

Carbon-based electrocatalysts with both high activity and high stability are desirable for use in Zn-air batteries. However, the carbon corrosion reaction (CCR) is a critical obstacle in rechargeable Zn-air batteries. In this study, a cost-effective carbon-based novel material is reported with a high catalytic effect and good durability for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), prepared via a simple graphitization process. In situ growth of graphene is utilized in a 3D-metal-coordinated hydrogel by introducing a catalytic lattice of transition metal alloys. Due to the direct growth of few-layer graphene on the metal alloy decorated 3d-carbon network, greatly reduced CCR is observed in a repetitive OER test. As a result, an efficient bifunctional electrocatalytic performance is achieved with a low ΔE value of 0.63 V and good electrochemical durability for 83 h at a current density of 10 mA cm-2 in an alkaline media. Moreover, graphene-encapsulated transition metal alloys on the nitrogen-doped carbon supporter exhibit an excellent catalytic effect and good durability in a Zn-air battery system. This study suggests a straightforward way to overcome the CCR of carbon-based materials for an electrochemical catalyst with wide application in energy conversion and energy storage devices.

Non-contrast low-dose CT can be used for volumetry of ADPKD.

BACKGROUND: Kidney volume provides important information for the diagnosis and prognosis of autosomal dominant polycystic kidney disease (ADPKD), as well as for the evaluation of the effects of drugs such as tolvaptan. Non-contrast computed tomography (CT) is commonly used for volumetry, and this study examined the correspondence and correlation of kidney volume measured by standard-dose or low-dose CT. METHODS: Axial standard-dose and low-dose CT images with 1-mm slices were obtained from 24 ADPKD patients. The kidney was segmented in the Synapse 3D software and the kidney volume was calculated using stereology. The kidney volume was compared between the two sets of images using R2, Bland-Altman plots, coefficient of variation, and intra-class correlation coefficients (ICCs). RESULTS: The mean age of the 24 patients was 48.4 ± 10.9 years, and 45.8% were men (n = 11). The mean total kidney volume on standard-dose CT was 1501 ± 838.2 mL. The R2 of volume between standard-dose and low-dose CT was 0.995. In the Bland-Altman plot, except for one case with a large kidney volume, the two measurements were consistent, and the coefficient of variation and ICC were also good (0.02, 0.998). The CT radiation dose (dose-length product) was 229 ± 68 mGy·cm for standard-dose CT and 50 ± 19 mGy·cm for low-dose CT. A comparable volume was obtained with 20% of the radiation dose of standard-dose CT. CONCLUSIONS: Standard-dose and low-dose CT showed comparable kidney volume in ADPKD. Therefore, low-dose CT can substitute for ADPKD volumetry while minimizing radiation exposure.

NSMF promotes the replication stress-induced DNA damage response for genome maintenance.

Proper activation of DNA repair pathways in response to DNA replication stress is critical for maintaining genomic integrity. Due to the complex nature of the replication fork (RF), problems at the RF require multiple proteins, some of which remain unidentified, for resolution. In this study, we identified the N-methyl-D-aspartate receptor synaptonuclear signaling and neuronal migration factor (NSMF) as a key replication stress response factor that is important for ataxia telangiectasia and Rad3-related protein (ATR) activation. NSMF localizes rapidly to stalled RFs and acts as a scaffold to modulate replication protein A (RPA) complex formation with cell division cycle 5-like (CDC5L) and ATR/ATR-interacting protein (ATRIP). Depletion of NSMF compromised phosphorylation and ubiquitination of RPA2 and the ATR signaling cascade, resulting in genomic instability at RFs under DNA replication stress. Consistently, NSMF knockout mice exhibited increased genomic instability and hypersensitivity to genotoxic stress. NSMF deficiency in human and mouse cells also caused increased chromosomal instability. Collectively, these findings demonstrate that NSMF regulates the ATR pathway and the replication stress response network for genome maintenance and cell survival.

Types and doses of anti-adhesive agents injected into subacromial space do not have an effect on the clinical and anatomical outcomes after arthroscopic rotator cuff repair.

PURPOSE: Joint stiffness after arthroscopic rotator cuff repair is a major concern for orthopaedic surgeons. Various antiadhesive agents are commonly administered after rotator cuff repair for its prevention. This study aimed to compare the outcomes among patients injected with different types and amounts of anti-adhesive agents after rotator cuff repair. It was hypothesized that the outcomes might differ depending on the use of the anti-adhesive agent and its type and dose. METHODS: A total of 267 patients who underwent arthroscopic rotator cuff repair with or without subacromial injection of anti-adhesive agents were enrolled. The first group (group A; 51 patients) were injected with 3 mL of poloxamer/sodium alginate-based anti-adhesive agent. The second group (group B; 93 patients) were injected with 3 mL of sodium hyaluronate-based anti-adhesive agent. The third group (group C; 82 patients) were injected with 1.5 mL of sodium hyaluronate-based anti-adhesive agent. Finally, the last group (group D; 41 patients) who did not use anti-adhesive agents served as the control. The range of motion (ROM) and pain VAS scores were measured preoperatively and at 5 weeks, 3 months, 6 months, and 1 year postoperatively. Functional outcomes were evaluated using American Shoulder and Elbow Surgeons and Constant scores, whereas cuff integrity was assessed via MRI or ultrasonography at least 6 months postoperatively. RESULTS: All ROM measurements, pain VAS scores, and functional scores were significantly improved regardless of the use, type, and dose of the anti-adhesive agents. In addition shoulder ROM and rotator cuff healing did not significantly differ among the groups (all n.s.). CONCLUSIONS: No significant differences were found in the clinical and anatomical outcomes according to the type and dose of the anti-adhesive agents subacromially injected after rotator cuff repair. LEVEL OF EVIDENCE: III.

Superior capsular reconstruction using hybrid graft for irreparable massive rotator cuff tear.

PURPOSE: To evaluate the clinical and radiological outcomes of arthroscopic superior capsular reconstruction (SCR) using hybrid grafts composed of tensor fascia lata autografts and human dermal allografts. METHODS: This study included 30 patients with chronic irreparable posterosuperior rotator cuff tears (RCTs) who underwent arthroscopic SCR using a hybrid graft composed of tensor fascia lata autograft and human dermal allograft. Clinical outcomes were evaluated using the pain visual analogue scale score, shoulder range of motion, American Shoulder and Elbow Surgeons score, constant score, University of California-Los Angeles score, and simple shoulder test score preoperatively and at least 2 years after surgery. Radiographic analysis included the Hamada classification grade, acromiohumeral distance (AHD), and graft integrity at 2 years after surgery. RESULTS: All patients exhibited significant clinical improvement in all functional outcome measurements, except external rotation (all P < 0.05). The number of patients who exhibited pseudoparalysis decreased from 7 (23.3%) to 2 (6.7%) postoperatively. Complications were not observed. Radiologically, the mean postoperative AHD increased significantly from 6.9 ± 1.6 cm to 8.8 ± 2.1 cm at 2 years postoperatively (P < 0.001). Twenty five out of the 30 (83.3%) patients showed successful graft healing, and all healing failures occurred on the humeral side. The differences between the healed-graft and failed-graft groups were significantly lower graft thickness (P = 0.001) and smaller AHD (P < 0.001) in the failed-graft group. Every functional outcome scores were not statistically different between healed-graft and failed-graft groups. CONCLUSIONS: An arthroscopic SCR technique using a hybrid graft consisting of a tensor fascia lata autograft and human dermal allograft showed satisfactory clinical outcomes in patients with irreparable RCTs. LEVEL OF EVIDENCE: IV.

SARS-CoV-2 Infectivity and Antibody Titer Reduction for 6 Months After Second Dose of BNT162b2 mRNA Vaccine in Health Care Workers: A Prospective Cohort Study.

Several studies reported that severe acute respiratory syndrome coronavirus-2 antibody levels change over 6 months in participants receiving the vaccination. From the enrolled 272 health care workers (HCWs), blood samples were obtained at 2, 16, and 24 weeks after the second vaccination dose. In the 267 noninfected HCWs, the neutralizing antibodies decreased by 23.9%, and the anti-spike/receptor binding domain antibody decreased by 53.8% at 24 weeks. We observed no significant difference in antibody reduction between the sexes; however, in younger individuals, there was higher antibody formation and lower reduction rates of the neutralizing antibody. In 3 HCWs with breakthrough infections, the antibody levels were relatively low just before the coronavirus disease 2019 infection. In conclusion, as antibody titers decrease over time after the second vaccination dose and HCWs with low antibody titers tend to have a high probability of breakthrough infection, an additional dose should be considered after several months. Blood samples were obtained from health care workers at 2, 16, and 24 weeks after a second vaccination dose. Antibody titers decreased over time and the participants with low antibody titers tended to have a high probability of breakthrough infection.

Alverine citrate promotes myogenic differentiation and ameliorates muscle atrophy.

Sarcopenia is the age-related loss of muscle mass and function and no pharmacological medication has been approved for its treatment. We established an atrogin-1/MAFbx promoter assay to find drug candidates that inhibit myotube atrophy. Alverine citrate (AC) was identified using high-throughput screening of an existing drug library. AC is an established medicine for stomach and intestinal spasms. AC treatment increased myotube diameter and inhibited atrophy signals induced by either C26-conditioned medium or dexamethasone in cultured C2C12 myoblasts. AC also enhanced myoblast fusion through the upregulation of fusion-related genes during C2C12 myoblast differentiation. Oral administration of AC improves muscle mass and physical performance in aged mice, as well as hindlimb-disused mice. Taken together, our data suggest that AC may be a novel therapeutic candidate for improving muscle weakness, including sarcopenia.

Restratification of Patients with Intermediate-Risk Papillary Thyroid Carcinoma.

BACKGROUND: Long-term management and follow-up strategies in patients with intermediate-risk papillary thyroid carcinoma (PTC) according to the American Thyroid Association (ATA) are still controversial due to the paucity of data on unique risk factors or a risk stratification system predictive of long-term outcomes. PATIENTS AND METHODS: This study included 649 patients with PTC who underwent an initial surgical treatment. Retrospectively enrolled patients were categorized according to the ATA risk stratification system. Intermediate-risk patients were further categorized into subgroups by the number of ATA intermediate risk factors. The recurrence-free survival (RFS) rates of these subgroups were compared with those of low- and high-risk patient groups. Additionally, the patients were classified according to their response to the initial therapy using the dynamic risk stratification (DRS) system, and the percentages of patients in each category were compared among the subgroups. RESULTS: The median follow-up period was 102 months. Structural recurrence occurred in 9.2% of all enrolled patients (60/649) and in 13.0% of intermediate-risk patients (40/308). Patients with two or more current intermediate risk factors had a poorer RFS than patients with only one risk factor (p < 0.001) and showed a comparable RFS to high-risk patients (p > 0.050). The percentages of patients with an excellent response category for DRS significantly decreased with an increase in the number of intermediate risk factors. CONCLUSION: Subclassification according to the number of intermediate risk factors may be useful to better predict the RFS and the response to initial therapy in patients with intermediate-risk PTC.

Optimal cutoff values of primary tumour size to better predict long-term outcomes in patients with papillary thyroid carcinoma undergoing total thyroidectomy: A preliminary study using restricted cubic spline analysis.

OBJECTIVE: Primary tumour size (PTS) is known to be a significant prognostic factor in patients with papillary thyroid carcinoma (PTC) undergoing thyroidectomy. Although cutoff values of 2 and 4 cm are widely used in surgical extent decision and long-term outcomes predictions, the effectiveness of arbitrary cutoff values in stratifying patients for target outcomes is questionable. This study aimed to determine new optimal cutoffs of PTS. DESIGN, PATIENT AND MEASUREMENTS: Patients (n = 529) with PTC who underwent total thyroidectomy were retrospectively reviewed. After risk factor analysis for structural recurrence, the optimal cutoffs of PTS were automatically calculated using restricted cubic spline analysis and X-tile software. Subgroups were classified based on the newly determined cutoff values. Both the recurrence-free survival (RFS) and the proportion of patients in each response-to-therapy category, using the dynamic risk stratification system (DRS), were compared between the subgroups. RESULTS: PTS was confirmed as an independent risk factor for structural recurrence. The optimal cutoff values were calculated as 1.4 and 3.0 cm. The subgroups stratified using these newly determined cutoffs showed significantly different RFS and DRS based on the response to initial therapy, but the subgroups classified using the cutoffs of 2 and 4 cm did not. CONCLUSIONS: The newly determined cutoff values of PTS may be useful in better stratifying patients with PTC undergoing thyroidectomy for target outcomes and can be considered as a new definition in staging and risk stratification systems.

Body mass index at baseline directly predicts new-onset diabetes and to a lesser extent incident cardio-cerebrovascular events, but has a J-shaped relationship to all-cause mortality.

OBJECTIVE: The prevalence of diabetes mellitus (DM), cardio-cerebrovascular diseases (CCVDs) has increased during recent decades. We aimed to investigate the relationship between body mass index (BMI) and each of several outcomes (DM, CCVDs, or mortality) based on the Korean National Health Insurance Service-Health Screening cohort. METHODS: BMI was categorized as appropriate for Asian populations, into underweight (< 18.5 kg/m2), normal (18.5-< 23 kg/m2), overweight (23-< 25 kg/m2), grade 1 obesity (25-< 30 kg/m2), grade 2 obesity (30-< 35 kg/m2), and grade 3 obesity (≥35 kg/m2). In addition, BMI was further stratified into one unit. Multivariate Cox proportional hazards regression analyses were conducted to examine the association between BMI category and the primary outcomes (DM, CCVDs, or mortality). RESULTS: A total of 311,416 individuals were included. The median follow-up was 12.5 years. Compared to normal BMI, underweight, overweight, and grade 1-3 obese individuals had a higher risk of the primary outcomes (hazard ratio [95% confidence intervals] 1.293 [1.224-1.365], 1.101 [1.073-1.129], 1.320 [1.288-1.353], 1.789 [1.689-1.897], and 2.376 [2.019-2.857], respectively, in men and 1.084 [1.010-1.163], 1.150 [1.116-1.185], 1.385 [1.346-1.425], 1.865 [1.725-2.019], and 2.472 [2.025-3.028], respectively, in women). Setting the reference BMI to 20-< 21 kg/m2 and categorizing into one unit increment, BMI was associated with the primary outcomes in a J-shaped manner in both sexes. The risk of DM increased with higher BMI in both sexes, while all-cause mortality decreased in men with a BMI 21-< 31 kg/m2 and women with BMI 22-< 30 kg/m2. CONCLUSIONS: BMI was associated with all-cause mortality in a J-shaped manner in both sexes, while it was associated with risk of DM in a dose-response relationship. The relationship between BMI and the primary outcomes was J-shaped.

Characteristics of Korean BCR-ABL1-Negative Myeloproliferative Neoplasms Related to the 2016 WHO Criteria Revision.

BACKGROUND: We aimed to identify changes in the diagnosis and subtype classification of Korean patients with BCR-ABL1-negative MPN related to the revision of the WHO classification in 2016. METHODS: We evaluated 76 Korean patients with BCR-ABL1-negative MPN who underwent diagnostic work-ups, including bone marrow (BM) examinations and JAK2 V617F mutation analysis, from January 2013 to June 2018. Additionally, we reclassified the subtype of 43 patients who were diagnosed based on the WHO 2008 classification. RESULTS: From January 2013 to April 2016, 43 patients were diagnosed with BCR-ABL1-negative MPN (12 PV, 17 ET, 14 PMF) according to the 2008 WHO classification, and from May 2016 to June 2018, 33 patients were diagnosed according to the 2016 classification (15 PV, 11 ET, 7 PMF). With the application of 2016 classification, 3 cases of ET were reclassified as pre-PMF, and the proportion of PV increased from 27.9% to 45.5%. There were significant differences in CBC between pre-PMF and overt PMF, between ET and overt-PMF, but no difference between ET and pre-PMF. CONCLUSIONS: The overall characteristics of BCR-ABL1-negative MPN patients were not significantly different from those of previous reports. 'Masked PV', which could not be diagnosed according to the WHO 2008 classification, may have been diagnosed as PV since 2016 due to the increase in the diagnostic value of the BM findings and the lowering of the hemoglobin (Hb) threshold.

Triglyceride glucose index is superior biomarker for predicting type 2 diabetes mellitus in children and adolescents.

The triglyceride-glucose (TyG) index is associated with predicting type 2 diabetes mellitus (T2DM), but its relationship with homeostatic model assessment of insulin resistance (HOMA-IR) in T2DM is not established. We aimed to investigate the role of TyG index for detection of T2DM in children and adolescents and compare it with HOMA-IR. A cross sectional study was performed in 176 overweight or obese children and adolescents with mean age of 11.34 ± 3.24 years. TyG index was calculated as ln (fasting triglyceride (TG) [mg/dL] × fasting glucose [mg/dL]/2). Of a total of 176 subjects, 57 (32%) were diagnosed with T2DM. Significant differences were observed in the TyG index between T2DM and non-T2DM (p < 0.001). The TyG index had a positive correlation with fasting glucose (r = 0.519, p < 0.001), HOMA-IR (r = 0.189, p < 0.017), HbA1c (r = 0.429, p < 0.001), total cholesterol (TC) (r = 0.257, p = 0.001), TG (r = 0.759, p < 0.001), and low-density lipoprotein cholesterol (LDL-C)(r = 0.152, p < 0.001), and a negative correlation with high-density lipoprotein cholesterol (HDL-C)(r = -0.107, p < 0.001) after controlling for sex, age and BMI standard deviation scores (SDS). In multiple regression analyses, 91.8% of the variance in TyG index was explained by age, glucose, HOMA-IR, TG, LDL-C, and HDL-C (p < 0.001). In the receiver operating characteristic (ROC) analysis, the TyG index [area under the curve (AUC) 0.839)] showed a better performance compared to HOMA-IR (AUC 0.645) in identifying patients with T2DM (p < 0.001). In conclusion, the TyG index had significant association with insulin resistance in T2DM and was superior to HOMA-IR in predicting T2DM in children and adolescents.

High cortisol levels are associated with oxidative stress and mortality in maintenance hemodialysis patients.

BACKGROUND: Chronic stimulation of the mineralocorticoid receptor has been suggested as one of the potential causes of cardiovascular events and death in patients with end-stage renal disease. This observational cohort study was performed to demonstrate that serum cortisol might be a predictive marker for patient mortality and to evaluate its association with oxidized low-density lipoprotein (oxLDL) in hemodialysis (HD) patients. METHODS: Patients receiving HD three times a week were screened for enrollment at two institutions. Baseline cortisol levels were measured before each HD session, and the patients were divided into two groups according to the median value of serum cortisol before analysis. The baseline characteristics and laboratory values of the high and low cortisol groups were compared. Serum cortisol, adrenocorticotropic hormone, renin, aldosterone, and oxLDL were measured in 52 patients to evaluate the effect of oxidative stress on serum cortisol levels. RESULTS: A total of 133 HD patients were enrolled in this cohort study. Compared to the patients with low serum cortisol levels, the patients with high serum cortisol levels (baseline cortisol ≥ 10 µg/dL) showed higher rates of cardiovascular disease (59.7% vs. 39.4%, P=0.019) and left ventricular systolic dysfunction (LVSD) (25.9% vs. 8.0%, P=0.016). The patients in the high cortisol group demonstrated higher all-cause mortality than those in the low cortisol group. The serum cortisol level was an independent risk factor for patient mortality (hazard ratio 1.234, 95% confidence interval 1.022-1.49, P=0.029). Among the 52 patients with oxLDL measurements, oxLDL was an independent risk factor for elevated serum cortisol levels (Exp(B) 1.114, P=0.013) and LVSD (Exp(B) 12.308, P=0.045). However, plasma aldosterone levels did not affect serum cortisol levels. CONCLUSIONS: Serum cortisol is a useful predictive marker for all-cause death among patients receiving HD. OxLDL is an independent marker for elevated serum cortisol among HD patients.