Glomerular crescents are associated with the risk of type 2 diabetic kidney disease progression: a retrospective cohort study.

BACKGROUND: Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease and end-stage kidney disease. Its diverse range of manifestations complicates the treatment approach for patients. Although kidney biopsy is considered the gold standard for diagnosis, it lacks precision in predicting the progression of kidney dysfunction. Herein, we addressed whether the presence of glomerular crescents is linked to the outcomes in patients with biopsy-confirmed type 2 DKD. METHODS: We performed a retrospective evaluation, involving 327 patients diagnosed with biopsy-confirmed DKD in the context of type 2 diabetes, excluding cases with other glomerular diseases, from nine tertiary hospitals. Hazard ratios (HRs) were calculated using a Cox regression model to assess the risk of kidney disease progression, defined as either ≥ 50% decrease in estimated glomerular filtration rates or the development of end-stage kidney disease, based on the presence of glomerular crescents. RESULTS: Out of the 327 patients selected, ten patients had glomerular crescents observed in their biopsied tissues. Over the follow-up period (median of 19 months, with a maximum of 18 years), the crescent group exhibited a higher risk of kidney disease progression than the no crescent group, with an adjusted HR of 2.82 (1.32-6.06) (P = 0.008). The presence of heavy proteinuria was associated with an increased risk of developing glomerular crescents. CONCLUSION: The presence of glomerular crescents is indeed linked to the progression of type 2 DKD. Therefore, it is important to determine whether there is an additional immune-mediated glomerulonephritis requiring immunomodulation, and it may be prudent to monitor the histology and repeat a biopsy.

End-to-End Semi-Supervised Opportunistic Osteoporosis Screening Using Computed Tomography.

Background: Osteoporosis is the most common metabolic bone disease and can cause fragility fractures. Despite this, screening utilization rates for osteoporosis remain low among populations at risk. Automated bone mineral density (BMD) estimation using computed tomography (CT) can help bridge this gap and serve as an alternative screening method to dual-energy X-ray absorptiometry (DXA). Methods: The feasibility of an opportunistic and population agnostic screening method for osteoporosis using abdominal CT scans without bone densitometry phantom-based calibration was investigated in this retrospective study. A total of 268 abdominal CT-DXA pairs and 99 abdominal CT studies without DXA scores were obtained from an oncology specialty clinic in the Republic of Korea. The center axial CT slices from the L1, L2, L3, and L4 lumbar vertebrae were annotated with the CT slice level and spine segmentation labels for each subject. Deep learning models were trained to localize the center axial slice from the CT scan of the torso, segment the vertebral bone, and estimate BMD for the top four lumbar vertebrae. Results: Automated vertebra-level DXA measurements showed a mean absolute error (MAE) of 0.079, Pearson's r of 0.852 (P<0.001), and R2 of 0.714. Subject-level predictions on the held-out test set had a MAE of 0.066, Pearson's r of 0.907 (P<0.001), and R2 of 0.781. Conclusion: CT scans collected during routine examinations without bone densitometry calibration can be used to generate DXA BMD predictions.

Texture-preserving low dose CT image denoising using Pearson divergence.

Objective.The mean squared error (MSE), also known asL2loss, has been widely used as a loss function to optimize image denoising models due to its strong performance as a mean estimator of the Gaussian noise model. Recently, various low-dose computed tomography (LDCT) image denoising methods using deep learning combined with the MSE loss have been developed; however, this approach has been observed to suffer from the regression-to-the-mean problem, leading to over-smoothed edges and degradation of texture in the image.Approach.To overcome this issue, we propose a stochastic function in the loss function to improve the texture of the denoised CT images, rather than relying on complicated networks or feature space losses. The proposed loss function includes the MSE loss to learn the mean distribution and the Pearson divergence loss to learn feature textures. Specifically, the Pearson divergence loss is computed in an image space to measure the distance between two intensity measures of denoised low-dose and normal-dose CT images. The evaluation of the proposed model employs a novel approach of multi-metric quantitative analysis utilizing relative texture feature distance.Results.Our experimental results show that the proposed Pearson divergence loss leads to a significant improvement in texture compared to the conventional MSE loss and generative adversarial network (GAN), both qualitatively and quantitatively.Significance.Achieving consistent texture preservation in LDCT is a challenge in conventional GAN-type methods due to adversarial aspects aimed at minimizing noise while preserving texture. By incorporating the Pearson regularizer in the loss function, we can easily achieve a balance between two conflicting properties. Consistent high-quality CT images can significantly help clinicians in diagnoses and supporting researchers in the development of AI-diagnostic models.

Relationship Between Asymptomatic Hyperuricemia and the Hypertriglyceridemic-Waist Phenotype in Korean Adults: A Cross-Sectional Study.

Purpose: Visceral fat accumulation can negatively affect uric acid metabolism in healthy adults. The hypertriglyceridemic-waist (HTGW) phenotype is a predictor of diabetes and cardiometabolic risk. This study aimed to investigate the association between the HTGW phenotype and asymptomatic hyperuricemia in Korean adults. Patients and Methods: The study included 23,240 adults, aged 20-80 years who underwent comprehensive health examinations at a general hospital in Gyeonggi Province, Korea, from January 2020 to December 2022. The HTGW phenotype was defined as the simultaneous presence of elevated serum triglyceride (TG) levels and increased waist circumference (WC). The diagnostic capability of the HTGW phenotype for hyperuricemia and its association with the condition were assessed using the receiver operating characteristic (ROC) curve and logistic regression analysis. Results: The prevalence of hyperuricemia in the HTGW phenotype was 3.44 times higher than that in the normal TG normal waist (NTNW) phenotype. Compared with those in the NTNW group, the hazard ratios for developing hyperuricemia in the HTGW group were 2.887 (2.566-3.249, P <0.001) for men and 7.341 (5.139-10.487, P <0.001) for women, and these values remained significant after adjusting for potential confounders. The stratified analysis revealed that the HTGW phenotype, coupled with diabetes, had the highest probability of developing asymptomatic hyperuricemia (2.55 times). ROC curve analysis revealed that the area under the curve values of the WC*TG index for hyperuricemia diagnosis were 0.702, 0.627, and 0.685 for all participants, men, and women, respectively. Conclusion: Among Korean adults, the HTGW phenotype was closely related to hyperuricemia in both men and women and showed a particularly strong association in patients with diabetes. It may be used in combination with an indicator that can complement its accuracy for identifying individuals at high risk of hyperuricemia.

Association between heat and hospital admissions in people with disabilities in South Korea: a nationwide, case-crossover study.

BACKGROUND: Despite extensive findings on the hazardous impacts of environmental heat exposure, little is known about the effect on people with disabilities. This study aimed to estimate the association between environmental heat exposure and emergency department admissions for people with disabilities compared with people without disabilities. METHODS: In this nationwide, case-crossover study, we linked data on emergency department admissions (cases) for any cause in the warm season in South Korea from the Korean National Health Insurance Service (NHIS)-National Sample Cohort database (a nationally representative database of 1 million systematically sampled beneficiaries covering all ages) from Jan 1, 2002, to Dec 31, 2019, and short-term daily mean temperature exposure (measured via Google Earth Engine at a 9 km spatial grid, aggregated to district). We defined beneficiaries with disabilities as those who were registered as disabled in the NHIS; disabilities included in our study were physical disability, brain lesion disorders, blindness or vision loss, and deafness or hearing loss. Other types of disability were not included for confidentiality reasons. A time-stratified case-crossover design, in which participants served as their own control, was used with conditional logistic regression to estimate the association between heat and emergency department admissions in people with and without disabilities. FINDINGS: 23 792 emergency department admissions were recorded for 59 527 people with disabilities. Of these 23 792 admissions, 10 234 (43·0%) individuals were female and 13 558 (57·0%) were male. The odds ratio (OR) of emergency department admissions associated with heat (99th temperature percentile vs 75th percentile) was 1·15 (95% CI 1·07-1·24) in people with disabilities and 1·06 (1·04-1·09) in people without disabilities. The annual excess number of emergency department admissions attributable to heat per 100 000 persons-years was 27·81 admissions (95% CI 9·20-45·69) and excess medical costs were US$638 739·47 (95% CI 201 900·12-1 059 641·87) in people with disabilities; these values were more than four times that of the non-disabled population. People with brain lesion disorders, people with severe physical disabilities, female individuals, and those aged 65 years or older showed higher heat risks. The risks of emergency department admissions due to mental disorder (1·89, 95% CI 1·18-3·00) and respiratory diseases (1·34, 1·06-1·70) also showed higher heat risks than for the other two analysed causes of admission (cardiovascular and genitourinary diseases). INTERPRETATION: Heat was associated with increased risk of emergency department admissions for people with and without disabilities, but the risk appeared to be higher for those with disabilities. These results can inform policy makers when establishing action plans for people with disabilities. FUNDING: National Research Foundation of Korea, the South Korean Ministry of Environment, and the South Korean Ministry of Education.

Prenatal exposure to Di(2-ethylhexyl) phthalate and high-fat diet synergistically disrupts gonadal function in male mice†.

Prenatal exposure to Di (2-ethylhexyl) phthalate (DEHP) impairs the reproductive system and causes fertility defects in male offspring. Additionally, high-fat (HF) diet is a risk factor for reproductive disorders in males. In this study, we tested the hypothesis that prenatal exposure to a physiologically relevant dose of DEHP in conjunction with HF diet synergistically impacts reproductive function and fertility in male offspring. Female mice were fed a control or HF diet 7 days prior to mating and until their litters were weaned on postnatal day 21. Pregnant dams were exposed to DEHP or vehicle from gestational day 10.5 until birth. The male offspring's gross phenotype, sperm quality, serum hormonal levels, testicular histopathology, and testicular gene expression pattern were analyzed. Male mice born to dams exposed to DEHP + HF had smaller testes, epididymides, and shorter anogenital distance compared with those exposed to HF or DEHP alone. DEHP + HF mice had lower sperm concentration and motility compared with DEHP mice. Moreover, DEHP + HF mice had more apoptotic germ cells, fewer Leydig cells, and lower serum testosterone levels than DEHP mice. Furthermore, testicular mRNA expression of Dnmt1 and Dnmt3a was two to eight-fold higher than in DEHP mice by qPCR, suggesting that maternal HF diet and prenatal DEHP exposure additively impact gonadal function by altering the degree of DNA methylation in the testis. These results suggest that the combined exposure to DEHP and high-fat synergistically impairs reproductive function in male offspring, greater than exposure to DEHP or HF diet alone.

Natural History of IntraDiscal Vacuum Phenomenon and its role in Advanced Disc Degeneration.

STUDY DESIGN: Observational serial CT analysis of the lumbar spine in a normal-aging population. OBJECTIVE: Assess the natural history of IntraDiscal Vacuum Phenomenon and its role in disc degeneration. Summary of Background Data: The natural history of disc degeneration is well described but our understanding of the end stage of pathogenesis remains incomplete. MRI loses accuracy with advanced degeneration, becoming hyporesonant and indistinct. Cadaveric specimens display adaptive changes in the disc with loss of the hydrostatic capacity of the nucleus, increased intra-discal clefts and end-plate impermeability. IDVP is associated with advanced disc degeneration and CT is the optimal modality to visualise this, yet these insights remain unreported. METHODS: Subjects only included historic CT abdomen scans of those over 60 years of age without acute or relevant spinal pathology, with a diagnosis of at least one level with IDVP on the original CT scan and all of whom had a similar scan >7 years later. A history of clinically significant back pain was also recorded. RESULTS: CT scans included 360 levels in 29 males and 31 females (mean 68.9 years), displaying 82 levels of IDVP, with a second scan included after a mean of 10.3 years, Most levels displayed the same level of severity (persisted, 45) compared to where some progressed (26), regressed (8) and fused (3) (P<0.01). There was also an increased incidence, 37/60 (62%) of developing IDVP at another level. Disc heights were reduced with increased severity of IDVP. A record of back pain was evident in 31/60 subjects, which was not significantly worse in those with worsening severity or additional level involvement over the study period. CONCLUSION: As disc degeneration advances, the associated IDVP persists in most cases, displaying a plateauing of severity over long periods, but rarely with progression to autofusion.

Intradiscal vacuum phenomenon matches lumbar spine degeneration patterns in an ageing population.

PURPOSE: Intra-Discal Vacuum phenomenon (IDVP) is well-recognised, yet poorly visualised and poorly understood radiological finding in disc degeneration, particularly with regard to its role in spinal alignment. CT analysis of the lumbar spine in an aging population aims to identify patterns associated with IDVP including lumbopelvic morphology and associated spinal diagnoses. METHODS: An analysis was performed of an over-60s population sample of 2020 unrelated abdominal CT scans, without acute spinal presentations. Spinal analysis included sagittal lumbopelvic reconstructions to assess for IDVP and pelvic incidence (PI). Subjects with degenerative pathologies, including previous vertebral fractures, auto-fusion, transitional vertebrae, and listhesis, were also selected out and analysed separately. RESULTS: The prevalence of lumbar spine IDVP was 50.3% (955/1898) and increased with age (125 exclusions). This increased in severity towards the lumbosacral junction (L1L2 8.3%, L2L3 10.9%, L3L4 11.5%, L4L5 23.9%, and L5S1 46.3%). A lower PI yielded a higher incidence of IDVP, particularly at L5S1 (p < 0.01). A total of 292 patients had IDVP with additional degenerative pathologies, which were more likely to occur at the level of isthmic spondylolisthesis, adjacent to a previous fracture or suprajacent to a lumbosacral transitional vertebra (p < 0.05). CONCLUSIONS: This study identified the prevalence and severity of IDVP in an aging population. Sagittal patterns that influence the pattern of IVDP, such as pelvic incidence and degenerative pathologies, provide novel insights into the function of aging spines.

A Standardized Education Program on Deceased Organ and Tissue Donation for Premedical and Medial Students in Korea.

Background: As the imbalance in organ demand and supply is getting worse, <1000 patients waiting for organ transplants die each year in South Korea. To enhance positive attitudes to deceased organ-tissue donation through systematic education, we developed an educational program with delivery pathways for premedical and medical students. Methods: Online and offline self-learning educational materials on deceased organ-tissue donation were generated and posted on the Vitallink Academy YouTube site. Thirty-two pre- and 15 posteducation questionnaires were developed using a web-based survey platform, and conducted before and immediately after the education process. The education proceeded in 3 steps: (1) group study sessions on selected topics, (2) poster submissions by each group and the selection of excellent poster by the organizing committee, and (3) excellent poster presentation and questions and answers. Results: A total of 141 students in the first year of premedical classes at the Seoul National University College of Medicine participated in this program. Only 24.2% of responders agreed that anyone who was diagnosed with brain death should donate. The proportion of students with positive attitudes toward organ-tissue donation increased from 74.7% to 97.7% (P < 0.001) with our education. Likewise, interest in deceased organ-tissue donation-related issues increased from 33.3% to 84.9% (P < 0.001). The expressed willingness for organ-tissue donation also increased from 76.8% to 96.5% (P < 0.001). The proportion of accepting brain death as the determination of death increased from 61.6% to 89.5% (P < 0.001). Moreover, 81.4% changed their approach and planned to register with an organ donor card. Conclusions: In this study, significant improvements were observed in knowledge, awareness, and attitude toward organ-tissue donation with our newly developed co-participatory education program for premedical students. Hence, target-specific education can be regarded as a valuable approach to enhancing public awareness of deceased organ-tissue donation.

The Impact of Obesity on Kidney Disease: Observational Cohort Study Analyzing 14,492 Kidney Biopsy Cases.

BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.

Vitamin D and narrowband ultraviolet B phototherapy for chronic kidney disease-associated pruritus.

BACKGROUND: In addition to improving the serum vitamin D balance, narrowband ultraviolet B (NB-UVB) phototherapy can effectively treat chronic kidney disease-associated pruritus (CKD-aP). We investigated the degree of CKD-aP amelioration according to changes in the serum vitamin D level after NB-UVB phototherapy. METHODS: This was a before-after clinical study in patients with refractory CKD-aP on hemodialysis. NB-UVB phototherapy was administered thrice weekly for 12 weeks. The response of CKD-aP to NB-UVB phototherapy was assessed as the change in pruritus intensity over time. A rapid response was defined as a reduction in the visual analog scale (VAS) score of ≥50% within the first 6 weeks of NB-UVB phototherapy. RESULTS: We included 34 patients in this study. Although serum 25-hydroxy vitamin D [25(OH)D] concentrations increased significantly, by a median of 17.4 ng/mL, after the phototherapy course, other serologic parameters did not change. NB-UVB phototherapy reduced the VAS score for pruritus intensity over time significantly more in patients with Δ25(OH)D of >17.4 ng/mL than in patients with Δ25(OH)D of ≤17.4 ng/mL (p = 0.001). Ten patients were rapid responders. Multivariate logistic regression analysis showed that Δ25(OH)D was independently associated with rapid response (odds ratio, 1.29; 95% confidence interval, 1.02-1.63; p = 0.04). CONCLUSION: The effect of NB-UVB phototherapy on patients with CKD-aP correlated with their increase in serum vitamin D levels. Further well-designed clinical and experimental studies are needed to clarify the relationship between NB-UVB phototherapy and serum vitamin D levels in patients with CKD-aP.

Beneficial impacts of residential greenness on sleep deprivation in adults aged 19 or older living in South Korea: A nationwide community health survey in 2011-2018.

BACKGROUND: Evidence of the relationship between greenness and sleep is limited, and, given the worsening sleep insufficiency worldwide, this relationship needs elucidation. In this study, we investigated the association of greenness with sleep deprivation using nationwide survey data. METHODS: This study included 1,727,273 participants in the Korea Community Health Survey who resided in all 229 districts of South Korea from 2011 to 2018. Sleep deprivation variables were defined as strong deprivation or mild deprivation, based on average daily sleep duration of <5 or 5-6 h, respectively. District-specific annual average of satellite-derived enhanced vegetation index (EVI) was used as a green space exposure. A logistic regression with complex survey weights was used to estimate the association between greenness and sleep deprivation, and it was further examined by sex, age group, educational status, income level, and population density. The regression analysis was performed annually, and the annual estimates were pooled by a combined data analysis. RESULTS: A higher level of greenness was associated (odds ratio [95 % confidence interval]) with strong and mild sleep deprivation (0.96 [0.93-0.99] and 0.96 [0.95-0.97]), respectively, and males and the younger age group (<65 years) showed a more prominent association with greenness than in females and the elderly group (65 years or older). In addition, only high-population-density areas showed evident associations of greenness with both strong and mild sleep deprivation. CONCLUSIONS: This large population-based study provides important epidemiological evidence for improving sleep quantity through an increase in greenness exposure and supports policymakers in establishing strategies for urban planning.

Ginsenoside Rg5 promotes muscle regeneration via p38MAPK and Akt/mTOR signaling.

Background: Skeletal muscles play a key role in physical activity and energy metabolism. The loss of skeletal muscle mass can cause problems related to metabolism and physical activity. Studies are being conducted to prevent such diseases by increasing the mass and regeneration capacity of muscles. Ginsenoside Rg5 has been reported to exhibit a broad range of pharmacological activities. However, studies on the effects of Rg5 on muscle differentiation and growth are scarce. Methods: To investigate the effects of Rg5 on myogenesis, C2C12 myoblasts were induced to differentiate with Rg5, followed by immunoblotting, immunostaining, and qRT-PCR for myogenic markers and promyogenic signaling (p38MAPK). Immunoprecipitation confirmed that Rg5 increased the interaction between MyoD and E2A via p38MAPK. To investigate the effects of Rg5 on prevention of muscle mass loss, C2C12 myotubes were treated with dexamethasone to induce muscle atrophy. Immunoblotting, immunostaining, and qRT-PCR were performed for myogenic markers, Akt/mTOR signaling for protein synthesis, and atrophy-related genes (Atrogin-1 and MuRF1). Results: Rg5 promoted C2C12 myoblast differentiation through phosphorylation of p38MAPK and MyoD/E2A heterodimerization. Furthermore, Rg5 stimulated C2C12 myotube hypertrophy via phosphorylation of Akt/mTOR. Phosphorylation of Akt induces FoxO3a phosphorylation, which reduces the expression of Atrogin-1 and MuRF1. Conclusion: This study provides an understanding of how Rg5 promotes myogenesis and hypertrophy and prevents dexamethasone-induced muscle atrophy. The study is the first, to the best of our knowledge, to show that Rg5 promotes muscle regeneration and to suggest that Rg5 can be used for therapeutic intervention of muscle weakness and atrophy, including cancer cachexia.

Consumer Acceptance of Texture-Modified Mackerel Stew Products in Older Adults.

Along with concerns regarding societal aging, the dietary requirements of older adults have become a priority. Older adults in Korea experience difficulties consuming animal protein sources as they age. Therefore, this study aimed to develop a senior-friendly food product using mackerel. Accordingly, carbohydrates and proteins were added to the brine solution before saturated vapor treatment. Calcium lactate and poly-gamma-glutamic acid were added to the sauce, and when compared to four commercial products (GT_R, GT_K, PC_K, and AC_G) in an acceptance test, the product was found to exhibit the highest overall liking score (p < 0.001). Higher flavor-liking and familiarity ratings were found to increase purchase intention, while higher flavor-liking, overall-liking, and familiarity ratings increased recommendation intention. Those in mid-to-late adulthood preferred the GT_R and PC_K samples, whereas the AC_G sample was preferred by those in very late adulthood. AC_G sample analysis suggested that those in the very late adulthood group had a relatively higher acceptance of spiciness. In this study, a calcium-added mackerel stew product was manufactured, meeting the standards for senior-friendly food in Korea. It will serve as a baseline for further research on fish- and mackerel-based foods for older adults, which is in its early stages.

Direct oral anti-Xa anticoagulants versus warfarin in newly diagnosed atrial fibrillation and CKD: the Korean National Health Insurance Data.

Introduction: Despite the benefits of direct oral anti-Xa anticoagulants (DOACs), the risk-benefit profile of DOAC therapy compared to warfarin therapy in patients with non-valvular atrial fibrillation (AF) and chronic kidney disease (CKD), including end-stage renal disease (ESRD), is uncertain. Methods: We conducted a retrospective study using the Korea National Health Insurance Database from 2013 to 2018. We evaluated patients with incident non-valvular AF and CKD. The primary and secondary effectiveness outcomes were ischemic stroke and all-cause mortality. The primary safety outcomes included intracranial hemorrhage, gastrointestinal bleeding, and extracranial or unclassified major bleeding. Results: Among the 1,885 patients evaluated, 970 (51.5%) initiated warfarin therapy, and 915 (48.5%) initiated DOAC therapy. During a mean follow-up period of 23.8 months, there were 293 and 214 cases of ischemic stroke and all-cause death, respectively. Kaplan-Meier survival analysis showed significantly lower all-cause mortality in DOAC users than in warfarin users. In multivariate Cox regression analyses, DOAC therapy had a hazard ratio for all-cause mortality of 0.41 (95% CI, 0.30-0.56; p < 0.001) compared to warfarin therapy. Additionally, DOAC therapy significantly reduced intracranial hemorrhage and gastrointestinal bleeding. Discussion: Our study demonstrates that DOAC therapy has a better risk-benefit profile than warfarin therapy in patients with AF and CKD. Further well-designed clinical trials are needed to clarify the benefits of DOACs in this patient population.

In situ photo-crosslinkable hyaluronic acid-based hydrogel embedded with GHK peptide nanofibers for bioactive wound healing.

A versatile hydrogel was developed for enhancing bioactive wound healing by introducing the amphiphilic GHK peptide (GHK-C16) into a photo-crosslinkable tyramine-modified hyaluronic acid (HA-Ty). GHK-C16 self-assembled into GHK nanofibers (GHK NF) in HA-Ty solution, which underwent in situ gelation after the wound area was filled with precursor solution. Blue light irradiation (460-490 nm), with riboflavin phosphate as a photoinitiator, was used to trigger crosslinking, which enhanced the stability of the highly degradable hyaluronic acid and enabled sustained release of the nanostructured GHK derivatives. The hydrogels provided a microenvironment that promoted the proliferation of dermal fibroblasts and the activation of cytokines, leading to reduced inflammation and increased collagen expression during wound healing. The complexation of Cu2+ into GHK nanofibers resulted in superior wound healing capabilities compared with non-lipidated GHK peptide with a comparable level of growth factor (EGF). Additionally, nanostructured Cu-GHK improved angiogenesis through vascular endothelial growth factor (VEGF) activation, which exerted a synergistic therapeutic effect. Furthermore, in vivo wound healing experiments revealed that the Cu-GHK NF/HA-Ty hydrogel accelerated wound healing through densely packed remodeled collagen in the dermis and promoting the growth of denser fibroblasts. HA-Ty hydrogels incorporating GHK NF also possessed improved mechanical properties and a faster wound healing rate, making them suitable for advanced bioactive wound healing applications. STATEMENT OF SIGNIFICANCE: By combining photo-crosslinkable tyramine-modified hyaluronic acid with self-assembled Cu-GHK-C16 peptide nanofibers (Cu-GHK NF), the Cu-GHK NF/HA-Ty hydrogel offers remarkable advantages over conventional non-structured Cu-GHK for wound healing. It enhances cell proliferation, migration, and collagen remodeling-critical factors in tissue regeneration. The incorporation of GHK nanofibers complexed with copper ions imparts potent anti-inflammatory effects, promoting cytokine activation and angiogenesis during wound healing. The Cu-GHK NF/hydrogel's unique properties, including in situ photo-crosslinking, ensure high customization and potency in tissue regeneration, providing a cost-effective alternative to growth factors. In vivo experiments further validate its efficacy, demonstrating significant wound closure, collagen remodeling, and increased fibroblast density. Overall, the Cu-GHK NF/HA-Ty hydrogel represents an advanced therapeutic option for wound healing applications.

Repopulation of autophagy-deficient stromal cells with autophagy-intact cells after repeated breeding in uterine mesenchyme-specific Atg7 knockout mice.

OBJECTIVE: Autophagy is highly active in ovariectomized mice experiencing hormone deprivation, especially in the uterine mesenchyme. Autophagy is responsible for the turnover of vasoactive factors in the uterus, which was demonstrated in anti-Müllerian hormone receptor type 2 receptor (Amhr2)-Cre-driven autophagy-related gene 7 (Atg7) knockout (Amhr-Cre/Atg7f/f mice). In that study, we uncovered a striking difference in the amount of sequestosome 1 (SQSTM1) accumulation between virgin mice and breeder mice with the same genotype. Herein, we aimed to determine whether repeated breeding changed the composition of mesenchymal cell populations in the uterine stroma. METHODS: All female mice used in this study were of the same genotype. Atg7 was deleted by Amhr2 promoter-driven Cre recombinase in the uterine stroma and myometrium, except for a triangular stromal region on the mesometrial side. Amhr-Cre/Atg7f/f female mice were divided into two groups: virgin mice with no mating history and aged between 11 and 12 months, and breeder mice with at least 6-month breeding cycles with multiple pregnancies and aged around 12 months. The uteri were used for Western blotting and immunofluorescence staining. RESULTS: SQSTM1 accumulation, representing Atg7 deletion and halted autophagy, was much higher in virgin mice than in breeders. Breeders showed reduced accumulation of several vasoconstrictive factors, which are potential autophagy targets, in the uterus, suggesting that the uterine stroma was repopulated with autophagy-intact cells during repeated pregnancies. CONCLUSION: Multiple pregnancies seem to have improved the uterine environment by replacing autophagy-deficient cells with autophagy-intact cells, providing evidence of cell mixing.

Exploration of Potential Breath Biomarkers of Chronic Kidney Disease through Thermal Desorption-Gas Chromatography/Mass Spectrometry.

Breath volatile organic compound (VOC) analysis is a non-invasive tool for assessing health status; the compositional profile of these compounds in the breath of patients with chronic kidney disease is believed to change with decreasing renal function. We aimed to identify breath VOCs for recognizing patients with chronic kidney disease. Using thermal desorption-gas chromatography/mass spectrometry, untargeted analysis of breath markers was performed using breath samples of healthy controls (n = 18) versus non-dialysis (n = 21) and hemodialysis (n = 12) patients with chronic kidney disease in this cross-sectional study. A total of 303 VOCs alongside 12 clinical variables were used to determine the breath VOC profile. Metabolomic analysis revealed that age, systolic blood pressure, and fifty-eight breath VOCs differed significantly between the chronic kidney disease group (non-dialysis + hemodialysis) and healthy controls. Thirty-six VOCs and two clinical variables that showed significant associations with chronic kidney disease in the univariate analysis were further analyzed. Different spectra of breath volatile organic compounds between the control and chronic kidney disease groups were obtained. A multivariate model incorporating age, 2-methyl-pentane, and cyclohexanone showed high performance (accuracy, 86%) in identifying patients with chronic kidney disease with odds ratios of 0.18 (95% CI, 0.07-2.49, p = 0.013); 2.10 (0.94-2.24, p = 0.025); and 2.31 (0.88-2.64, p = 0.008), respectively. Hence, this study showed that renal dysfunction induces a characteristic profile of breath VOCs that can be used as non-invasive potential biomarkers in screening tests for CKD.

Fibroblast growth factor-23 and cardiovascular disease among prevalent hemodialysis patients focusing on residual kidney function.

Background: In patients undergoing incident hemodialysis, increased fibroblast growth factor-23 (FGF-23) levels are associated with the development of cardiovascular disease (CVD), but the influence of residual kidney function (RFK) on this association is unclear. This study aimed to investigate the association between FGF-23 levels, RKF, and CVD in patients undergoing prevalent hemodialysis. Methods: This cross-sectional and longitudinal observational study included 296 patients undergoing maintenance hemodialysis for at least three months who were followed up for a median of 44 months. RKF was defined as 24-h urine output >200 mL, left ventricular (LV) diastolic dysfunction as E/E' >15 on echocardiographic parameters. CVD was defined as hospitalization or emergency room visits due to cardiovascular causes, such as angina, myocardial infarction, or congestive heart failure. Results: The median intact FGF-23 (iFGF-23) level was 423.8 pg/mL (interquartile range, 171-1,443). Patients with an FGF-23 level > 423.8 pg/mL significantly had a lower proportion of RKF (39.2% vs. 60.1%, P < 0.001) and a higher proportion of LV diastolic dysfunction (54. 1% vs. 29.1%, P < 0.001) than those with an iFGF-23 level ≤ 423.8 pg/mL. The odds ratio (OR) for LV diastolic dysfunction was significantly higher in patients with RFK (OR per one-unit increase in the natural log-transformed iFGF-23 levels, 1.80; 95% confidence interval [CI]: 1.11-2.93) than in patients without RKF (OR per one-unit increase in the natural log-transformed iFGF-23 levels: 1.42; 95% CI: 1.01-1.99) in multivariate analysis (p < 0.001). During the follow-up period, 55 patients experienced CVD. The hazard ratio (HR) for CVD development was also significantly higher in patients with RKF (HR per one-unit increase in the natural log-transformed iFGF-23 levels, 2.64; 95% CI: 1.29-5.40) than those without RKF (HR per one-unit increase in the natural log-transformed iFGF-23 levels: 1.44; 95% CI: 1.04-1.99) in multivariate analysis (p = 0.05). Conclusions: Increased iFGF-23 levels were associated with LV diastolic dysfunction and CVD development in patients undergoing prevalent hemodialysis; however, the loss of RKF attenuated the magnitude of these associations. Therefore, in these patients, RKF strongly influenced the detrimental role of iFGF-23 in the development of CVD.

CT-based three-dimensional invasiveness analysis of adenocarcinoma presenting as pure ground-glass nodules.

Background: We invest computed tomography (CT) image differences between non-invasive adenocarcinomas (NIAs) and invasive adenocarcinomas (IAs) presenting as pure ground glass nodules (GGNs). Methods: From 2013 to 2019, 48 pure GGNs were surgically resected in 45 patients. Of these, 40 were pathologically diagnosed as non-small cell lung cancers (NSCLCs). We assessed them using the Synapse Vincent (Fujifilm Co., Ltd., Tokyo, Japan) three-dimensional (3D) analysis system; we drew histograms of the CT densities. We calculated the maximum, minimum, means, and standard deviations of the densities. The proportions of GGNs of high CT density were compared between the two groups. The diagnostic performance was investigated via receiver operating curve (ROC) analysis. Results: Of the 40 pure GGNs, 20 were NIAs (4 adenocarcinomas in situ and 16 minimally IAs) and 20 IAs. Significant correlations were evident between histological invasiveness and the maximum and mean CT densities and the standard deviation. Neither the nodule volume nor the minimum CT density significantly predicted invasiveness. A CT volume density proportion >-300 Hounsfield units optimally predicted the invasiveness of pure GGNs; the cutoff was 5.41% with a sensitivity of 85% and a specificity of 95%. Conclusions: CT density reflected the invasiveness of pure GGNs. A CT volume proportion density >-300 Hounsfield units may significantly predict histological invasiveness.