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Abstract Gene therapy is a promising method for treating inherited diseases by directly delivering the correct genetic material into patient cells. However, the limited packaging capacity of vectors poses a challenge. Minimizing promoter size is a viable strategy among various approaches to address this issue. This study aims to optimize the bovine myostatin (MSTN) promoter, enhancing its utility in gene therapy applications. We identified the primary driver of activity as the proximal regulatory region. Isolated from the native promoter and termed M243, this 243-bp sequence was assessed for its potential as a ubiquitous promoter. In a variety of cell types, including bovine embryos and embryonic stem cells, the M243 promoter showed consistent expression, highlighting its suitability for applications requiring compact promoters. The isolation of a highly conserved, compact 243-bp sequence serving as a promoter suggests a solution for overcoming the size constraints of AAV vectors, suggesting potential contributions to the field of gene therapy.

Abstract This retrospective study evaluated the association between preoperative topical glaucoma medication containing preservatives and long-term trabeculectomy outcomes in 309 eyes from 201 patients with primary open-angle glaucoma, followed for over 10 years. The Glaucoma Medication Intensity Index (GMII) was calculated to quantify the cumulative preoperative exposure to these medications. Kaplan–Meier analysis revealed cumulative success rates of 89.3%, 59.2%, and 46% at 1, 10, and 20 years postoperatively. At 20 years, the success group had a significantly lower GMII (3.28 vs. 8.74, p = 0.004). A GMII threshold of ≥ 4.35 was associated with poorer long-term intraocular pressure (IOP) control and shorter surgical success duration. Cox regression analysis identified advanced age at surgery, higher GMII, and subsequent cataract surgery as significant risk factors for trabeculectomy failure. These findings underscore the adverse impact of prolonged preoperative use of glaucoma medications on long-term surgical outcomes, highlighting GMII as a valuable predictor for guiding preoperative management strategies.

Abstract Phase-field simulations were performed on the polar vortex array structure appearing in the SrTiO3/PbTiO3/SrTiO3 heterostructure to investigate the Kittel law relationship (w ∝ d 1/2) between the vortex array period (w) and the PbTiO3 ferroelectric layer thickness (d). Quasi-two-dimensional simulation results show that the equilibrium period can be determined from the relationship between the size of the simulation box and the total free energy density and that the obtained period obeys the Kittel law. However, three-dimensional simulation results show that the polar vortex arrays are not homogeneous in the direction perpendicular to the vortex plane. In the pure vortex state, no obvious correlation exists between the simulation size and energy because of the dislocations caused by the vortex period mismatch. However, in the mixed state with ferroelectric a 1/a 2, the vortex domains exhibit equilibrium periods that satisfy the Kittel law relationship because of the confinement effect caused by phase separation. Further study of the confined vortex domains in these mixed states and the vortex domains of finite size due to mismatched dislocations are expected to enable domain engineering of higher domain densities.

Abstract Although several studies showed a correlation between weight perception and depression, the association between weight perception and perceived stress is unclear. This study explored this association using the Korea National Health and Nutrition Examination Survey with 37,022 participants. Participants were grouped based on how they perceived their body versus real body mass index (BMI) and waist circumference: accurate, underperception, or overperception. Stress was assessed through a questionnaire. The logistic regression analysis was performed, and odds ratio (OR) with 95% confidence intervals (CIs) was presented. The results showed a correlation between overperception and higher perceived stress. This correlation was especially apparent in women with significant OR and 95% CIs of 1.15 (1.07–1.23) for BMI and 1.15 (1.07–1.23) for waist circumference. In the subgroup analysis according to the real obese status, all misperceptions were associated with higher perceived stress in normal participants. In comparison, underperception showed a correlation with lower perceived stress in obese participants. The results suggest weight perception as a potential marker for many stress-related diseases and an important factor in treating mental disorders. Further research is needed to understand the relationship between stress and weight perception.

Abstract Due to the development of magnetic resonance (MR) imaging processing technology, image-based identification of endolymphatic hydrops (EH) has played an important role in understanding inner ear illnesses, such as Meniere’s disease or fluctuating sensorineural hearing loss. We segmented the inner ear, consisting of the cochlea, vestibule, and semicircular canals, using a 3D-based deep neural network model for accurate and automated EH volume ratio calculations. We built a dataset of MR cisternography (MRC) and HYDROPS-Mi2 stacks labeled with the segmentation of the perilymph fluid space and endolymph fluid space of the inner ear to devise a 3D segmentation deep neural network model. End-to-end learning was used to segment the perilymph fluid and the endolymph fluid spaces simultaneously using aligned pair data of the MRC and HYDROPS-Mi2 stacks. Consequently, the segmentation performance of the total fluid space and endolymph fluid space had Dice similarity coefficients of 0.9574 and 0.9186, respectively. In addition, the EH volume ratio calculated by experienced otologists and the EH volume ratio value predicted by the proposed deep learning model showed high agreement according to the interclass correlation coefficient (ICC) and Bland–Altman plot analysis.

Abstract This paper proposes a new method for predicting the stage of osteoporosis by estimating bone-density parameters using an ultrasonic-bone densitometer. Using the developed ultrasonic bone densitometer, the ultrasonic signal passing through the phalanx of the finger was measured, and the measured signal was preprocessed to generate input data for parameter estimation. The Nakagami probability-density function was used for modeling this data, and optimal bone-density parameters were estimated using an optimization problem – to predict the stage of osteoporosis. The proposed method was verified through in vitro and in vivo experiments. In phantom experiments, cubes with different materials (ABS plastic, PLA plastic, Nylon) were used, and each cube had a different density through internal density so that it could mimic bones. The experiments were conducted using them and the results were compared. The experimental results confirmed that there was a correlation between the density and estimated parameters for all three materials. In the in vivo experiment, the osteoporosis stages were classified as normal, osteopenia, and osteoporosis, and the bone-density parameters were estimated for the participants of each group. Thus, a basis for predicting the stage of osteoporosis was created, and data from new participants were collected and verified as test data. As a result, normal and abnormal groups (osteopenia and osteoporosis) were predicted.

Abstract This study aimed to investigate the association between non-traditional lipid profiles and the risk of 1-year vascular events in patients who were already using statins before stroke and had admission LDL-C

Abstract It is uncertain whether the prognostic power of white matter hyperintensity (WMH) on post-stroke outcomes is modulated as a function of initial neurological severity, a critical determinant of outcome after stroke. This multi-center MRI study tested if higher WMH quintiles were associated with 3-month poor functional outcome (modified Rankin Scale ≥ 3) for mild versus moderate-to-severe ischemic stroke. Mild and moderate-to-severe stroke were defined as admission National Institute of Health Stroke Scale scores of 1–4 and ≥ 5, respectively. Mean age of the enrolled patients (n = 8918) was 67.2 ± 12.6 years and 60.1% male. The association between WMH quintiles and poor functional outcome was modified by stroke severity (p-for-interaction = 0.008). In mild stroke (n = 4994), WMH quintiles associated with the 3-month outcome in a dose-dependent manner for the 2nd to 5th quintile versus the 1st quintile, with adjusted-odds-ratios (aOR [95% confidence interval]) being 1.29 [0.96–1.73], 1.37 [1.02–1.82], 1.60 [1.19–2.13], and 1.89 [1.41–2.53], respectively. In moderate-to-severe stroke (n = 3924), however, there seemed to be a threshold effect: only the highest versus the lowest WMH quintile was significantly associated with poor functional outcome (aOR 1.69 [1.29–2.21]). WMH burden aggravates 3-month functional outcome after mild stroke, but has a lesser modulatory effect for moderate-to-severe stroke, likely due to saturation effects.

Abstract This study assessed survival for lung cancer patients meeting criteria for the National Lung Cancer Screening Program in Korea launched in 2019 and updated guideline reported by the US Preventive Service Task Force (USPSTF). We assessed all-cause mortality based on the Korean Lung Cancer Registry (KLCR), including lung cancer patients diagnosed in 2014–2016. We compared survival among lung cancer patients eligible for extended USPSTF criteria (age 50–80 years and ≥ 20 pack-years) and those meeting current criteria (age 54–74 years and ≥ 30 pack-years, current or within the past 15 years). The nearest neighbour propensity-score matching was performed to generate a matched set. Kaplan–Meier curves were generated to compare survival among groups; differences in survival were analyzed using the stratified log-rank test. The mortality risk was estimated based on a Cox proportional hazards regression model and the robust standard error was calculated. Of 8110 patients, 37.4% and 24.3% met the extended USPSTF eligibility criteria and National Lung Cancer Screening Program (NLCSP) criteria, respectively. Overall mortality risk was not significantly different between the extended younger age group and the NLCSP group (hazard ratio [HR] [95% confidence interval (CI)]: 0.78 [0.59–1.02]). The extended older age group had a significantly higher mortality risk (HR [95% CI]: 1.41 [1.26–1.58]). Mortality risk was not significantly different between patients who smoked 20–29 pack-years and those who smoked ≥ 30 pack-years (HR [95% CI]: 0.90 [0.79–1.03]). Lung cancer patients aged 50–53 years and those with a 20–29 pack-years smoking history exhibited similar mortality risk to individuals meeting current criteria, while patients aged 75–80 years were at a higher risk of death. Although we verified similar or higher mortality risks in extended subgroups, a careful assessment of the benefits and harms of the screening tests is necessary when contemplating the extension of criteria.

Abstract The relationship between obstructive sleep apnea (OSA) and chronic rhinosinusitis (CRS) has not yet been fully elucidated. Therefore, the objective of this study was to evaluate the connection between OSA risk and CRS by investigating associations between the STOP-Bang questionnaire and presence of CRS in a nationwide, population-based study. This is a cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNHANES). We evaluated 10,081 subjects who completed both the STOP-Bang and CRS-related questionnaires. Among the total subjects, 390 (3.9%) were CRS patients. The median STOP-Bang score was 3.0 [2.0; 4.0] in CRS patients, compared to 2.0 [1.0; 3.0] in subjects without CRS. In a low-risk group according to the STOP-Bang questionnaire, 3.1% of subjects were CRS patients. However, a gradual increase was observed among different risk groups. In the higher risk group, CRS patients accounted for 5.3% (P

Abstract Neural consequences of social disparities are not yet rigorously investigated. How socioeconomic conditions influence children’s connectome development remains unknown. This paper endeavors to gauge how precisely the connectome structure of the brain can predict an individual’s social environment, thereby inversely assessing how social influences are engraved in the neural development of the Adolescent brain. Utilizing Adolescent Brain and Cognition Development (ABCD) data (9099 children residing in the United States), we found that social conditions both at the household and neighborhood levels are significantly associated with specific neural connections. Solely with brain connectome data, we train a linear support vector machine (SVM) to predict socio-economic conditions of those adolescents. The classification performance generally improves when the thresholds of the advantageous and disadvantageous environments compartmentalize the extreme cases. Among the tested thresholds, the 20th and 80th percentile thresholds using the dual combination of household income and neighborhood education yielded the highest Area Under the Precision-Recall Curve (AUPRC) of 0.8224. We identified 8 significant connections that critically contribute to predicting social environments in the parietal lobe and frontal lobe. Insights into social factors that contribute to early brain connectome development is critical to mitigate the disadvantages of children growing up in unfavorable neighborhoods.

Abstract Advances in next-generation sequencing technologies have led to elucidation of sensorineural hearing loss genetics and associated clinical impacts. However, studies on the functional pathogenicity of variants of uncertain significance (VUS), despite their close association with clinical phenotypes, are lacking. Here we identified compound heterozygous variants in ESRRB transcription factor gene linked to DFNB35, specifically a novel splicing variant (NM_004452.4(ESRRB): c.397 + 2T>G) in trans with a missense variant (NM_004452.4(ESRRB): c.1144C>T p.(Arg382Cys)) whose pathogenicity remains unclear. The splicing variant (c.397 + 2T>G) caused exon 4 skipping, leading to premature stop codon formation and nonsense-mediated decay. The p.(Arg382Cys) variant was classified as a VUS due to its particularly higher allele frequency among East Asian population despite disease-causing in-silico predictions. However, functional assays showed that p.(Arg382Cys) variant disrupted key intramolecular interactions, leading to protein instability. This variant also reduced transcriptional activity and altered expression of downstream target genes essential for inner ear function, suggesting genetic contribution to disease phenotype. This study expanded the phenotypic and genotypic spectrum of ESRRB in DFNB35 and revealed molecular mechanisms underlying ESRRB-associated DFNB35. These findings suggest that variants with high allele frequencies can also possess functional pathogenicity, providing a breakthrough for cases where VUS, previously unexplored, could be reinterpreted by elucidating their functional roles and disease-causing characteristics.

Abstract Immune checkpoint blockades are actively adopted in diverse cancer types including metastatic melanoma and lung cancer. Despite of durable response in 20–30% of patients, we still lack molecular markers that could predict the patient responses reliably before treatment. Here we present a composite model for predicting anti-PD-1 response based on tumor mutation burden (TMB) and transcriptome sequencing data of 85 lung adenocarcinoma (LUAD) patients who received anti-PD-(L)1 treatment. We found that TMB was a good predictor (AUC = 0.81) for PD-L1 negative patients (n = 20). For PD-L1 positive patients (n = 65), we built an ensemble model of 100 XGBoost learning machines where gene expression, gene set activities and cell type composition were used as input features. The transcriptome-based models showed excellent accuracy (AUC > 0.9) and highlighted the contribution of T cell activities. Importantly, nonresponder patients with high prediction score turned out to have high CTLA4 expression, which suggested that neoadjuvant CTLA4 combination therapy might be effective for these patients. Our data and analysis results provide valuable insights into developing biomarkers and strategies for treating LUAD patients using immune checkpoint inhibitors.

Abstract This study focused on the challenges posed by the fluctuating demand for COVID-19 vaccines, considering factors such as side effects, religious objections, and absenteeism, which result in the accumulation of excess vaccines. Recognizing the resulting social, economic, and environmental issues, this study investigated the application of a lateral transshipment policy for the management of the inventory of short-term vaccines, considering related unpredictabilities. A discrete event simulation built on foundational principles derived from a mixed-integer linear programming model was employed to explore the dynamics of mRNA-based vaccine distribution among two hospitals based on lateral transshipment and reordering policies. Through the simulation of various scenarios over periods of 1-30 days, transshipment based on the availability policy is employed to determine the quantity of vaccines to be transshipped, constrained to vial amounts, and the (s, S) inventory system for reordering. The results of this study underscore the efficacy of lateral transshipment, particularly in situations where demand discrepancies exist between hospitals, thereby revealing its superiority over non-transshipment strategies within 7 days.