RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling.

BACKGROUND: Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD. METHODS: We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3. RESULTS: RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1. CONCLUSIONS: The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.

Surgical outcomes and prognosis of intracorporeal versus extracorporeal esophagojejunostomy after laparoscopic total gastrectomy for gastric cancer: a propensity score-matching study.

This study compared the surgical outcomes and long-term prognosis of intracorporeal and extracorporeal esophagojejunostomy after laparoscopic total gastrectomy (LTG) for gastric cancer patients. In total 228 clinical stage I gastric cancer patients undergoing LTG were enrolled from January 2012 and December 2022. Each case in the totally laparoscopic total gastrectomy (TLTG) group was 1:1 propensity score-matched to control cases in the laparoscopy-assisted total gastrectomy (LATG) group. In total, 95 and 93 LATG and TLTG patients were included after propensity score matching (PSM). Clinicopathological features, surgical outcomes, and survival variables were compared, and risk factors for postoperative complications were analyzed. Patient characteristics were well balanced between the LATG and TLTG groups after PSM. The TLTG group showed less blood loss, decreased frequency of analgesic use, and shorter duration of analgesic use. The TLTG group had significantly lower rates of intestinal obstruction and surgical site infection. Larger tumor size and advanced pTNM stage were independent risk factors for postoperative complications. There was no significant difference in overall survival (OS). Compared with LATG, TLTG was associated with better surgical outcomes and fewer postoperative surgical complications in gastric cancer patients although there was no significant difference in OS.

Malnutrition is associated with mortality in Sjögren's syndrome-associated interstitial lung disease.

The role of nutritional status as a prognostic factor in patients with Sjögren's syndrome-associated interstitial lung disease (SjS-ILD) is currently unclear. This study aimed to predict the prognosis of patients with SjS-ILD through their nutritional status assessment. In this retrospective observational study, nutritional status was evaluated at the time of diagnosis using body mass index (BMI) and nutritional markers such as controlling nutritional status (CONUT), the Glasgow prognostic score (GPS), and prognostic nutrition index (PNI) for all participants. Receiver operating characteristic (ROC) analyses were performed using BMI and each nutritional marker data to compare the area under the ROC curve (AUC) and find the cutoff value using the maximum Youden index. Kaplan-Meier analysis and Cox proportional hazards regression analysis were performed to predict the prognosis of SjS-ILD patients. A total of 112 SjS-ILD patients were enrolled in the study, and 8.9% died during the follow-up period. The median time from diagnosis to follow-up period was 4.2 years. The AUC for PNI was the highest among nutritional markers and BMI, and PNI cutoff value was used to distinguish between the PNI < 47.7 and PNI ≥ 47.7 groups. A statistical difference was observed in the Kaplan-Meier analysis and log-rank test (p = 0.005). In multivariable analyses, PNI < 47.7 (hazard ratio 9.40, 95% confidence interval 1.54-57.21) is associated with increased mortality, suggesting the importance of early nutritional intervention for malnutrition in SjS-ILD patients.

Prognostic Role of CA-125 Elimination Rate Constant (KELIM) in Patients with Advanced Epithelial Ovarian Cancer Who Received PARP Inhibitors.

BACKGROUND: This multicenter retrospective study aimed to investigate the prognostic value of the CA-125 elimination rate constant K (KELIM) in EOC patients who received platinum-based chemotherapy followed by PARP inhibitors, in either upfront or interval treatment settings. METHODS: Between July 2019 and November 2022, we identified stage III-IV EOC patients who underwent primary or interval cytoreductive surgery and received olaparib or niraparib. Individual KELIM values were assessed based on validated kinetics and classified into favorable and unfavorable cohorts. RESULTS: In a study of 252 patients undergoing frontline maintenance therapy with olaparib or niraparib, favorable KELIM (≥1) scores were associated with a higher PFS benefit in the primary cytoreductive surgery (PCS) cohort (hazard ratio (HR) for disease progression or death 3.51, 95% confidence interval (CI); 1.37-8.97, p = 0.009). Additionally, within the interval cytoreductive surgery (ICS) cohort, a favorable KELIM score (≥1) significantly increased the likelihood of achieving complete resection following cytoreductive surgery, with 59.4% in the favorable KELIM group compared to 37.8% in those with unfavorable KELIM. CONCLUSIONS: A favorable KELIM score was associated with improved PFS in patients with advanced EOC undergoing PCS. Furthermore, in the ICS cohort, a favorable KELIM score increased the probability of complete cytoreduction.

Dietary supplementation with Lactium and L-theanine alleviates sleep disturbance in adults: a double-blind, randomized, placebo-controlled clinical study.

Introduction: The use of natural products for the treatment of sleep disturbances is increasing owing to the side effects and limitations of traditional sleep therapy. Moreover, recent studies have shown a significant correlation between sleep quality and gut microbiota composition. This study aimed to assess the impact of LTC-022, a commercially available dietary supplement containing Lactium and L-theanine, on enhancing sleep quality. Methods: Forty participants experiencing sleep discomfort were enrolled in a double-blind randomized controlled trial, wherein they received LTC-022 or a placebo orally for 8 weeks. The effects of treatment on sleep quality were assessed using the Pittsburgh Sleep Quality Index and Insomnia Severity Index. To comprehensively evaluate changes in sleep patterns, various parameters were evaluated, including the time in bed (TIB), total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), wake after sleep onset (WASO) counts, and bedtime. These parameters were derived from daily sleep logs recorded over the 8-week study period, categorized into weekdays and weekends. Stool samples were analyzed for microbiome composition. The V4 region of bacterial 16S rRNA genes was amplified using specific primers (515F and 806R) and targeted for analysis. Microbial diversity, including operational taxonomic units, the Shannon and Chao indices, the Firmicutes/Bacteroidetes (F/B) ratio, and the variety of bacterial taxa, was assessed. Results: No significant differences were observed in sleep quality and insomnia scale characteristics between the two groups. In-depth analysis using sleep diaries showed that WASO counts after 8 weeks and bedtime after 4 weeks showed significant differences between the LTC-022 and control groups. In the LTC-022 group, significant differences were observed in the increase in TST, decrease in SOL, increase in SE, decrease in WASO counts, and earlier bedtime. Microbiome analysis revealed that the abundance of the genera Blautia and Ruminococcus increased in fecal samples from the LTC-022 group. Conclusion: These results suggest that continuous LTC-022 intake has a beneficial effect on maintaining sleep duration and an appropriate bedtime. Additionally, changes in the gut microbiota may be linked to changes in sleep patterns resulting from the consumption of Lactium and L-theanine. Clinical trial registration: https://cris.nih.go.kr/cris/search/detailSearch.do/22841, KCT0007750.

Optimizing angular range in digital breast tomosynthesis: A phantom study investigating lesion detection across varied breast density and thickness.

PURPOSE: To determine the optimal angular range (AR) for digital breast tomosynthesis (DBT) systems that provides highest lesion visibility across various breast densities and thicknesses. METHOD: A modular DBT phantom, consisting of tissue-equivalent adipose and glandular modules, along with a module embedded with test objects (speckles, masses, fibers), was used to create combinations simulating different breast thicknesses, densities, and lesion locations. A prototype DBT system operated at four ARs (AR±7.5°, AR±12.5°, AR±19°, and AR±25°) to acquire 11 projection images for each combination, with separate fixed doses for thin and thick combinations. Three blinded radiologists independently assessed lesion visibility in reconstructed images; assessments were averaged and compared using linear mixed models. RESULTS: Speckle visibility was highest with AR±7.5° or AR±12.5°, decreasing with wider ARs in all density and thickness combinations. The difference between AR±7.5° and AR±12.5° was not statistically significant, except for the tube-side speckles in thin-fatty combinations (5.83 [AR±7.5°] vs. 5.39 [AR±12.5°], P = 0.019). Mass visibility was not affected by AR in thick combinations, while AR±12.5° exhibited the highest mass visibility for both thin-fatty and thin-dense combinations (P = 0.032 and 0.007, respectively). Different ARs provided highest fiber visibility for different combinations; however, AR±12.5° consistently provided highest or comparable visibility. AR±12.5° showed highest overall lesion visibility for all density and thickness combinations. CONCLUSIONS: AR±12.5° exhibited the highest overall lesion visibility across various phantom thicknesses and densities using a projection number of 11.

Relationship between continuous EEG monitoring findings and prognostic factors in patients with status epilepticus.

BACKGROUND AND PURPOSE: Little information is available regarding the use of continuous electroencephalography (cEEG) monitoring findings to predict the prognosis of patients with status epilepticus, which could aid in prognostication. This study investigated the relationship between cEEG monitoring findings and various prognostic indicators in patients with status epilepticus. METHODS: We reviewed the clinical profiles and cEEG monitoring data of 28 patients with status epilepticus over a ten-year period. Patient demographics, etiology, EEG features, duration of hospital stay, number of antiseizure medications, and outcome measures were analyzed. Functional outcomes were assessed using the modified Rankin Scale (mRS), which evaluates the degree of daily living impairment and dependence on others resulting from neurological injury. RESULTS: Patients exhibiting electrographic status epilepticus (ESE) demonstrated significantly longer duration of status epilepticus (77.75 ± 58.25 vs. 39.86 ± 29.81 h, p = 0.024) and total length of hospital stay (13.00 ± 6.14 vs. 8.14 ± 5.66 days, p = 0.038) when compared to those with ictal-interictal continuum (IIC). Individuals who displayed any increase in modified Rankin Scale (mRS) score between their premorbid state and discharge also had significantly longer duration of status epilepticus (74.09 ± 34.94 vs. 51.56 ± 54.25 h, p = 0.041) and total length of hospital stay (15.89 ± 6.05 vs. 8.05 ± 4.80 days, p = 0.004) when compared to those who showed no difference. The most prevalent etiology of status epilepticus in our study was chronic structural brain lesions. CONCLUSIONS: This suggests that ESE may serve as a predictor of prolonged duration of status epilepticus and increased hospitalization among patients with status epilepticus.

Effects of Various Concentrations of Pronase on Flow Cytometric Crossmatching Patients Treated With Rituximab and Donor HLA-Specific Antibodies.

Background: Pronase pretreatment can reduce rituximab (RTX) interference by degrading CD20 in B-cell flow cytometry crossmatch (FCXM) testing. However, it may also reduce the assay sensitivity by degrading HLA molecules. We investigated the effects of various pronase concentrations on RTX interference and the analytical sensitivity of B-cell FCXM testing. Methods: Using 59 patient serum samples and 38 donor lymphocyte samples, we designed 97 recipient-donor pairs and divided them into three groups according to RTX use and the presence of weak-to-moderate donor HLA-specific antibody (DSA) reactions: RTX+/DSA-, RTX+/DSA+, and RTX-/DSA+. FCXM was performed after pretreating lymphocytes with six different pronase concentrations (0, 0.5, 1, 2, 3, and 4 mg/mL). Results: With B-FCXM testing, false-positive results due to RTX in the RTX+/DSA- group markedly decreased with increasing pronase concentrations. The median channel shift values in the RTX+/DSA+ and RTX-/DSA+ groups did not significantly decrease when the pronase concentration was increased from 1 mg/mL to 2 or 3 mg/mL. All eight RTX+/DSA+ cases that were positive at 1 mg/mL pronase but negative at 2 or 3 mg/mL had mean fluorescence intensity (MFI) DSA values of less than 3,000 except for DQ5 (MFI: 5,226). With T-cell FCXM, false-positive results were observed in 2.9% of 315 FCXM tests with pronase pretreatment. Conclusions: Higher concentrations (2 or 3 mg/mL) of pronase effectively eliminated RTX interference but still carried a risk for false negativity for weak DSA reactions in B-cell FCXM. Higher pronase concentrations can be used as an auxiliary method to detect moderate-to-strong DSA reactions in RTX-treated patients.

A study on the formative usability testing for modular powered wheelchair.

The increasing prevalence of mobility impairments underscores the urgent need for accessible and affordable mobility aids. To overcome the mobility limitations of people with disabilities, there is an increasing need for the development of lightweight and portable powered wheelchairs that can be easily loaded. This study aimed to perform an early health technology assessment and a formative usability evaluation on a modular (detachable) powered wheelchair. It aimed to gauge device satisfaction among users, pinpoint areas for improvement, and detect any unforeseen errors to inform future development. Engaging 16 participants, including powered wheelchair users, healthcare professionals, and caregivers, the research evaluated the wheelchair's functionality in various scenarios, emphasizing safety, effectiveness, and convenience. Statistical analyses of task performance and satisfaction surveys highlighted that, while powered wheelchair users successfully completed tasks focusing on driving and power control, healthcare professionals and caregivers encountered difficulties with the wheelchair's assembly and disassembly. Despite general positivity, the surveys indicated mixed satisfaction levels regarding safety, validity, and convenience, with specific issues related to frame durability, seat comfort, and control mechanisms. These findings suggest that refining the wheelchair's design and addressing user concerns could significantly enhance satisfaction and mobility services. Future efforts will include a thorough review of an advanced prototype and further satisfaction assessments.

We believe that our study makes a significant contribution to the literature by addressing a critical gap in the understanding of user-centric design and usability testing for powered wheelchairs.By emphasizing the importance of early assessments and incorporating user feedback into the development process, our research offers practical insights for creating more accessible and user-friendly mobility solutions.This contribution is particularly relevant in the context of advancing assistive technology and improving the quality of life for individuals with disabilities.

Deep learning model using stool pictures for predicting endoscopic mucosal inflammation in patients with ulcerative colitis.

OBJECTIVES: Stool characteristics may change depending on the endoscopic activity of ulcerative colitis (UC). We developed a deep learning model using stool photos of patients with UC (DLSUC) to predict endoscopic mucosal inflammation. METHODS: This was a prospective multicenter study conducted in six tertiary referral hospitals. Patients scheduled to undergo endoscopy for mucosal inflammation monitoring were asked to take photos of their stool using smartphones within 1 week before the day of endoscopy. DLSUC was developed using 2161 stool pictures from 306 patients and tested on 1047 stool images from 126 patients. The ulcerative colitis endoscopic index of severity (UCEIS) was used to define endoscopic activity. The performance of DLSUC in endoscopic activity prediction was compared with that of fecal calprotectin (Fcal). RESULTS: The area under the receiver operating characteristic curve (AUC) of DLSUC for predicting endoscopic activity was 0.801 (95% confidence interval [CI] 0.717-0.873), which was not statistically different from the AUC of Fcal (0.837 [95% CI, 0.767-0.899, DeLong's P=0.458]). When rectal sparing cases (23/126, 18.2%) were excluded, the AUC of DLSUC increased to 0.849 (95% CI, 0.760-0.919). The accuracy, sensitivity, and specificity of DLSUC in predicting endoscopic activity were 0.746, 0.662, and 0.877 in all patients and 0.845, 0.745, and 0.958 in patients without rectal sparing, respectively. Active patients classified by DLSUC were more likely to experience disease relapse during a median 8-month follow-up (log-rank test, P=0.002). CONCLUSIONS: DLSUC demonstrated a good discriminating power similar to that of Fcal in predicting endoscopic activity with improved accuracy in patients without rectal sparing. This study implies that stool photos are a useful monitoring tool for typical UC.

Resource Utilization of Residual Organic Sludge Generated from Bioenergy Facilities Using Hermetia illucens Larvae.

Residual organic sludge generated from bioenergy facilities (BF-rOS) is often disposed instead of recycled, thus contributing to further environmental pollution. This study explored the resource utilization of BF-rOS using Hermetia illucens larvae (BSFL). When BF-rOS was fed to BSFL for two weeks, the dry weight per individual BSFL was approximately 15% of that of BSFL that were fed food waste (FW). However, the dry weight increased by approximately two-fold in BSFL that were fed effective microorganism (EM)-supplemented BF-rOS containing 60% moisture. However, under both conditions, the BSFL did not mature into pupae. In contrast, the highest dry weight per BSFL was observed with the BF-rOS/FW (50%:50%) mixture, regardless of EM supplementation. Furthermore, the highest bioconversion rate was observed when the BSFL were fed the BF-rOS/FW (50%:50%) mixture, and the frass produced by the BSFL contained fertilizer-appropriate components. In addition, the nutritional components of the BSFL exhibited a nutrient profile suitable for animal feed, except for those fed BF-rOS only. In conclusion, this investigation demonstrates that BF-rOS should be recycled for fertilizer production by mixing it with FW as a BSFL feed, which generates the valuable insect biomass as potential nutrition for animal feeding.

Prevention of UVB-Induced Photoaging by an Ethyl Acetate Fraction from Allomyrina dichotoma Larvae and Its Potential Mechanisms in Human Dermal Fibroblasts.

Allomyrina dichotoma larvae (ADL) is an insect type that is used ethnopharmacologically to treat various diseases; however, its use as an antiaging treatment has not been widely studied. Previously, we found that an ethyl acetate (EA) fraction derived from an ADL extract (ADLE) has a high polyphenol content and antioxidant properties. In this study, we identified the underlying molecular mechanism for the protective effect of the EA fraction against UVB-induced photodamage in vitro and ex vivo. UVB treatment increased intracellular reactive oxygen species levels and DNA damage; the latter of which was significantly decreased following cotreatment with the EA fraction. Biological markers of aging, such as p16INK4a, p21WAF1, and senescence-associated ß-gal levels, were induced by UVB treatment but significantly suppressed following EA-fraction treatment. UVB-induced upregulation of matrix metalloproteinase (MMP)-1 and downregulation of COL1A1 were also reversed by EA-fraction treatment in both cells and a 3D skin model, which resulted in increased keratin and collagen deposition. Moreover, EA-fraction treatment inhibited the phosphorylation of MAPKs (p38, ERK, and JNK) and nuclear factor (NF-)-kB and decreased the levels of inflammatory cytokines in UVB-treated cells. The results indicate that an EA fraction from ADLE ameliorates UVB-induced degradation of COL1A1 by inhibiting MMP expression and inactivating the MAPK/NF-κB p65/AP-1 signaling pathway involved in this process.

Cross-sectional associations of gender identity and sexual orientation, with co-occurrence and clustering of health-related behaviours among British adolescents: Millennium cohort study.

PURPOSE: We examined whether gender identity and sexual orientation were associated with seven health-related behaviours, and with co-occurrence and clustering of these behaviours among British adolescents. METHODS: Millennium Cohort Study (age 17 wave) provided data on the exposures, gender identity (male, female, genderqueer) and sexual orientation (heterosexual, bisexual, gay or lesbian, or other), and seven self-reported health-related behaviours (binge drinking, drug use, no consumption of breakfast, no consumption of fruits or vegetables, physical inactivity, poor sleep, and smoking or vaping). Poisson regressions examined associations between the exposures and single behaviours (reporting prevalence ratios (PRs)); and multinomial logistic regressions were used for behavioural cumulative co-occurrence score (reporting PRs). Cluster patterns were identified using Ward's agglomerative hierarchical cluster analysis while associations with cluster membership were performed using logistic regressions (reporting odds ratios (ORs)). RESULTS: Our sample included 6022 adolescents (55.4% female, 1.5% genderqueer, 11.6% non-heterosexual). Adolescents who identified as genderqueer had the highest prevalence of not eating breakfast (PR: 60.5% [95%CI 48.4-71.4]) and poor sleep (68.7% [95%CI 55.6-79.3]). Those who identified as bisexual had a higher PR of co-occurring behaviours (2.46 [95%CI 1.39-4.27]). Among the three clusters identified (1: Multiple risk behaviours; 2: Physical inactivity and binge drinking; 3: Poor diet and physical inactivity), adolescents who identified as genderqueer or other sexual orientation showed the highest prevalence in cluster 3. CONCLUSION: Gender and sexual minority British adolescents showed a higher prevalence of risky health-related behaviours, and higher risk of co-occurring behaviours. Physical inactivity and poor diet behaviours commonly clustered together for these groups.

Validation of the Utility of the Genetically Shared Regions of Chromosomes (GD-ICS) Measuring Method in Identifying Complicated Genetic Relatedness.

BACKGROUND: Relatives share more genomic regions than unrelated individuals, with closer relatives sharing more regions. This concept, paired with the increased availability of high-throughput single nucleotide polymorphism (SNP) genotyping technologies, has made it feasible to measure the shared chromosomal regions between individuals to assess their level of relation to each other. However, such techniques have remained in the conceptual rather than practical stages in terms of applying measures or indices. Recently, we developed an index called "genetic distance-based index of chromosomal sharing (GD-ICS)" utilizing large-scale SNP data from Korean family samples and demonstrated its potential for practical applications in kinship determination. In the current study, we present validation results from various real cases demonstrating the utility of this method in resolving complex familial relationships where information obtained from traditional short tandem repeats (STRs) or lineage markers is inconclusive. METHODS: We obtained large-scale SNP data through microarray analysis from Korean individuals involving 13 kinship cases and calculated GD-ICS values using the method described in our previous study. Based on the GD-ICS reference constructed for Korean families, each disputed kinship was evaluated and validated using a combination of traditional STRs and lineage markers. RESULTS: The cases comprised those A) that were found to be inconclusive using the traditional approach, B) for which it was difficult to apply traditional testing methods, and C) that were more conclusively resolved using the GD-ICS method. This method has overcome the limitations faced by traditional STRs in kinship testing, particularly in a paternity case with STR mutational events and in confirming distant kinship where the individual of interest is unavailable for testing. It has also been demonstrated to be effective in identifying various relationships without specific presumptions and in confirming a lack of genetic relatedness between individuals. CONCLUSION: This method has been proven effective in identifying familial relationships across diverse complex and practical scenarios. It is not only useful when traditional testing methods fail to provide conclusive results, but it also enhances the resolution of challenging kinship cases, which suggests its applicability in various types of practical casework.

Long-Term Use of Oral Corticosteroids and Safety Outcomes for Patients With Atopic Dermatitis.

Importance: The use of oral corticosteroids for prolonged periods may be associated with adverse events (AEs). Nevertheless, the risk of AEs with oral corticosteroids, especially among patients with atopic dermatitis (AD), has not been comprehensively investigated and lacks evidence on duration of treatment. Objective: To assess the association between long-term exposure to oral corticosteroids and AEs among adult patients with AD. Design, Setting, and Participants: This nested case-control study used data from the Health Insurance Review and Assessment Service database of South Korea between January 1, 2012, and October 31, 2021, which included 1 year prior to the cohort entry date of January 1, 2013, for assessing exclusion criteria and baseline characteristics, and 1 year after the study end date of October 31, 2020, to ensure a minimum duration for assessing exposure. Among the population of adults with AD, patients diagnosed with any of 11 AEs were matched with patients who had never received a diagnosis of any of the 11 AEs. Exposure: Long-term use of oral corticosteroids was defined as cumulative supply of more than 30 days or more than 90 days of oral corticosteroid prescription per year. Main Outcomes and Measures: We used multivariable conditional logistic regression analyses to measure the risk of 11 individual outcomes (osteoporosis, fracture, type 2 diabetes, hyperlipidemia, hypertension, myocardial infarction, stroke, heart failure, avascular necrosis, cataract, or glaucoma) as the composite outcome, controlling for potential confounders. We further classified the composite outcome to individual outcomes to evaluate the AE-specific risk. Results: Among 1 025 270 patients with AD between 2013 and 2020, 164 809 cases (mean [SD] age, 39.4 [14.8]; 56.9% women) were matched with 328 303 controls (mean [SD] age, 39.3 [14.7]; 56.9% women) for sex, age, cohort entry date, follow-up duration, and severity of AD, where the balance of most baseline characteristics was achieved. A total of 5533 cases (3.4%) and 10 561 controls (3.2%) were exposed to oral corticosteroids for more than 30 days, while 684 cases (0.4%) and 1153 controls (0.4%) were exposed to oral corticosteroids for more than 90 days. Overall, there was no increased risk of AEs with use of oral corticosteroids for more than 30 days (adjusted odds ratio [AOR], 1.00; 95% CI, 0.97-1.04), whereas the risk was slightly higher with use of oral corticosteroids for more than 90 days (AOR, 1.11; 95% CI, 1.01-1.23). The small elevation in experiencing an AE was observed with each cumulative or consecutive year of ever long-term use. Conclusions and Relevance: This case-control study found a slightly increased risk of AEs associated with use of oral corticosteroids for more than 90 days per year, which warrants future research to fully elucidate the observed findings.

Impact of glycemic control on residual kidney function and technique failure associated with volume overload in diabetic patients on peritoneal dialysis.

Background: It is unclear whether poor glycemic control contributes to residual kidney function (RKF) decline and consequent volume overload in diabetic patients on peritoneal dialysis (PD). Methods: This retrospective analysis included 80 diabetic patients who started PD at a single center. The first 2 years of patient data were collected to investigate the impact of glycemic control on RKF and volume overload in the early stages of PD. We used the time-averaged glycated hemoglobin (HbA1c) levels to estimate glycemic control. RKF loss was measured as the slope of RKF decline and time to anuria. To assess the association between glycemic control and volume overload, we examined technique failure (TF) associated with volume overload (TFVO), defined as TF due to excessive fluid accumulation. Multivariable linear regression and Cox regression analysis were performed to assess how glycemic control affects RKF and TFVO. Results: Over the first 2 years, the mean rate of RKF decline was -3.25 ± 3.94 mL/min/1.73 m2 per year. Multivariable linear regression showed that higher time-averaged HbA1c was associated with a rapid RKF decline (ß = -0.95; 95% confidence interval [CI], -1.66 to -0.24; p = 0.01). In the adjusted Cox regression analysis, higher time-averaged HbA1c increased the risk of progression to anuria (adjusted hazard ratio [HR], 1.97; 95% CI, 1.29-3.00; p = 0.002) and TFVO (adjusted HR, 2.88; 95% CI, 1.41-5.89; p = 0.004). Conclusion: Poor glycemic control is associated with rapid RKF decline and leads to volume overload in diabetic patients on PD.

Exploring the Challenges of Distinguishing Punctate Inner Choroidopathy from Multifocal Choroiditis and Panuveitis.

PURPOSE: This retrospective case series aimed to assess the concordance between clinical diagnoses of punctate inner choroidopathy (PIC) and multifocal choroiditis and panuveitis (MCP) using the 2021 Standardization of Uveitis Nomenclature (SUN) Working Group criteria. METHODS: Using the medical records of the patients, we reevaluated 100 eyes of 75 patients with idiopathic multifocal chorioretinal inflammatory lesions based on SUN criteria and compared the result to the clinical diagnosis. RESULTS: Of 100 eyes, 29 eyes (29%) were diagnosed as PIC and 15 eyes (15%) were diagnosed as MCP using SUN criteria, and 56 (56%) eyes could not be diagnosed as either. Clinically diagnosed PIC eyes were significantly more myopic than the clinically diagnosed MCP eyes (mean spherical equivalent -6.65 ± 4.63 vs. -3.85 ± 2.31, P = 0.01). Sixteen eyes with vitreous inflammation were all clinically diagnosed as MCP, but four (25%) could not be diagnosed as MCP using SUN criteria. CONCLUSIONS: The existing diagnostic criteria showed limitations in capturing all clinical cases of PIC or MCP, and adding or revising criteria on features such as vitreous inflammation or myopia, could be considered to enhance diagnostic accuracy.

Clinical efficacy of multigene panels in the management of congenital hypothyroidism with gland in situ.

Congenital hypothyroidism (CHT) is a diverse condition with various genetic etiologies. This study aimed to investigate the utility of next-generation sequencing (NGS) analysis in guiding treatment decisions and predicting prognosis for CHT patients with gland in situ (GIS). A retrospective analysis was conducted on 33 CHT patients with GIS who underwent NGS analysis at a single institution between 2018 and 2023. Patients were classified as having permanent (PCH), transient congenital hypothyroidism, or ambiguous congenital hypothyroidism (ACH) CHT based on their response to levothyroxine discontinuation at 3 years of age. Among the 33 patients, genetic variants were identified in 26, with the most prevalent variants found in DUOX2 (26.92%), TSHR (30.77%), TG (19.35%), and DUOXA2 (19.23%). Patients with high initial thyroid-stimulating hormone levels (>50 mIU/L) and low free thyroxine levels (<0.89 ng/dL) at diagnosis tended to have compound heterozygous or homozygous variants in DUOX2, DUOXA2, and TG, and were more likely to develop PCH. In contrast, patients with heterozygous variants in these genes often exhibited ACH. TSHR variants were associated with diverse clinical manifestations, ranging from PCH to ACH, and were more common in patients with initial thyroid-stimulating hormone levels <50 mIU/L. The study highlights the potential utility of NGS analysis in predicting the clinical course and guiding treatment decisions for CHT patients with GIS. Genetic analysis may aid in determining the appropriate duration of levothyroxine therapy and monitoring strategies, particularly in cases where traditional clinical indicators are inconclusive.

Risk factors of acute exacerbation and disease progression in young patients with COPD.

OBJECTIVE: We aimed to elucidate the clinical factors associated with acute exacerbation and disease progression in young patients with chronic obstructive pulmonary disease (COPD). METHODS: This retrospective longitudinal observational study included patients with COPD aged between 20 and 50 years with post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC)<0.7. Eligible patients were followed up with ≥2 spirometry examinations at 1 year interval after COPD diagnosis. The primary outcome was moderate-to-severe acute exacerbation in young patients with COPD. Secondary outcomes were early initiation of regular inhalation therapy and accelerated annual post-bronchodilator FEV1 decline. RESULTS: A total of 342 patients were followed up during a median of 64 months. In multivariable analyses, risk factors for moderate-to-severe exacerbation were history of asthma (adjusted HR (aHR)=2.999, 95% CI=[2.074-4.335]), emphysema (aHR=1.951, 95% CI=[1.331-2.960]), blood eosinophil count >300/µL (aHR=1.469, 95% CI=[1.038-2.081]) and low FEV1 (%) (aHR=0.979, 95% CI=[0.970-0.987]). A history of asthma, sputum, blood eosinophil count >300/µL, low FEV1 (%) and low diffusing capacity of the lung for carbon monoxide (DLCO) (%) were identified as clinical factors associated with the early initiation of regular inhalation therapy. The risk factors associated with worsened FEV1 decline were increasing age, female sex, history of pulmonary tuberculosis, sputum, low FEV1 (%) and low DLCO (%). CONCLUSIONS: In young COPD patients, specific high-risk features of acute exacerbation and disease progression need to be identified, including a history of previous respiratory diseases, current respiratory symptoms, blood eosinophil counts, and structural or functional pulmonary impairment.