Selection of Convolutional Neural Network Model for Bladder Tumor Classification of Cystoscopy Images and Comparison with Humans.

Purpose: An investigation of various convolutional neural network (CNN)-based deep learning algorithms was conducted to select the appropriate artificial intelligence (AI) model for calculating the diagnostic performance of bladder tumor classification on cystoscopy images, with the performance of the selected model to be compared against that of medical students and urologists. Methods: A total of 3,731 cystoscopic images that contained 2,191 tumor images were obtained from 543 bladder tumor cases and 219 normal cases were evaluated. A total of 17 CNN models were trained for tumor classification with various hyperparameters. The diagnostic performance of the selected AI model was compared with the results obtained from urologists and medical students by using the receiver operating characteristic (ROC) curve graph and metrics. Results: EfficientNetB0 was selected as the appropriate AI model. In the test results, EfficientNetB0 achieved a balanced accuracy of 81%, sensitivity of 88%, specificity of 74%, and an area under the curve (AUC) of 92%. In contrast, human-derived diagnostic statistics for the test data showed an average balanced accuracy of 75%, sensitivity of 94%, and specificity of 55%. Specifically, urologists had an average balanced accuracy of 91%, sensitivity of 95%, and specificity of 88%, while medical students had an average balanced accuracy of 69%, sensitivity of 94%, and specificity of 44%. Conclusions: Among the various AI models, we suggest that EfficientNetB0 is an appropriate AI classification model for determining the presence of bladder tumors in cystoscopic images. EfficientNetB0 showed the highest performance among several models and showed high accuracy and specificity compared to medical students. This AI technology will be helpful for less experienced urologists or nonurologists in making diagnoses. Image-based deep learning classifies bladder cancer using cystoscopy images and shows promise for generalized applications in biomedical image analysis and clinical decision making.

Hopping the Hurdle: Strategies to Enhance the Molecular Delivery to the Brain through the Blood-Brain Barrier.

Modern medicine has allowed for many advances in neurological and neurodegenerative disease (ND). However, the number of patients suffering from brain diseases is ever increasing and the treatment of brain diseases remains an issue, as drug efficacy is dramatically reduced due to the existence of the unique vascular structure, namely the blood-brain barrier (BBB). Several approaches to enhance drug delivery to the brain have been investigated but many have proven to be unsuccessful due to limited transport or damage induced in the BBB. Alternative approaches to enhance molecular delivery to the brain have been revealed in recent studies through the existence of molecular delivery pathways that regulate the passage of peripheral molecules. In this review, we present recent advancements of the basic research for these delivery pathways as well as examples of promising ventures to overcome the molecular hurdles that will enhance therapeutic interventions in the brain and potentially save the lives of millions of patients.

L-serine restored lysosomal failure in cells derived from patients with BPAN reducing iron accumulation with eliminating lipofuscin.

Defective mitochondria and autophagy, as well as accumulation of lipid and iron in WDR45 mutant fibroblasts, is related to beta-propeller protein-associated neurodegeneration (BPAN). In this study, we found that enlarged lysosomes in cells derived from patients with BPAN had low enzyme activity, and most of the enlarged lysosomes had an accumulation of iron and oxidized lipid. Cryo-electron tomography revealed elongated lipid accumulation, and spectrometry-based elemental analysis showed that lysosomal iron and oxygen accumulation superimposed with lipid aggregates. Lysosomal lipid aggregates superimposed with autofluorescence as free radical generator, lipofuscin. To eliminate free radical stress by iron accumulation in cells derived from patients with BPAN, we investigated the effects of the iron chelator, 2,2'-bipyridine (bipyridyl, BIP). To study whether the defects in patient-derived cells can be rescued by an iron chelator BIP, we tested whether the level of iron and reactive oxygen species (ROS) in the cells and genes related to oxidative stress were rescued BIP treatment. Although BIP treatment decreased some iron accumulation in the cytoplasm and mitochondria, the accumulation of iron in the lysosomes and levels of cellular ROS were unaffected. In addition, the change of specific RNA levels related to free radical stress in patient fibroblasts was not rescued by BIP. To alleviate free radical stress, we investigated whether l-serine can regulate abnormal structures in cells derived from patients with BPAN through the regulation of free radical stress. l-serine treatment alleviated increase of enlarged lysosomes and iron accumulation and rescued impaired lysosomal activity by reducing oxidized lipid accumulation in the lysosomes of the cells. Lamellated lipids in the lysosomes of the cells were identified as lipofuscin through correlative light and electron microscopy, and l-serine treatment reduced the increase of lipofuscin. These data suggest that l-serine reduces oxidative stress-mediated lysosomal lipid oxidation and iron accumulation by rescuing lysosomal activity.

Evaluating the validity and reliability of the Korean version of Scales for Outcomes in Parkinson's Disease-Cognition.

Objective: The Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) was developed to screen for cognition in PD. In this study, we aimed to evaluate the validity and reliability of the Korean version of the SCOPA-cog. Methods: We recruited 129 PD patients from 31 clinics with movement disorders in South Korea. The original version of the SCOPA-cognition was translated into Korean using the translation-retranslation method. The test-rest method with an intraclass correlation coefficient (ICC) and Cronbach's alpha coefficient were used to assess reliability. The Spearman's Rank correlation analysis with Montreal Cognitive Assessment-Korean version (MOCA-K) and Korean Mini-Mental State Examination (K-MMSE) were used to assess concurrent validity. Results: The Cronbach's alpha coefficient was 0.797, and the ICC was 0.887. Spearman's rank correlation analysis showed a significant correlation with the K-MMSE and MOCA-K scores (r = 0.546 and r = 0.683, respectively). Conclusions: Our results demonstrate that K-SCOPA-Cog exhibits good reliability and validity.

Opicapone to Treat Early Wearing-off in Parkinson's Disease Patients: The Korean ADOPTION Trial.

BACKGROUND: Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. OBJECTIVES: To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. METHODS: ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. RESULTS: The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. CONCLUSIONS: Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.

Generation of an induced pluripotent stem cell line (PNUYHi002-A) from a patient with Alzheimer's disease carrying PRNP M232R variant.

We generated a human induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells isolated from a 59-year-old male patient with Alzheimer's disease (AD). The iPSC line was meticulously characterized to confirm its pluripotency, absence of transgenes, and normal karyotype. The unexpected discovery of the M232R variant in PRNP makes this cell line a valuable resource for investigating AD pathogenesis.

Caregiver Burden of Patients With Huntington's Disease in South Korea.

OBJECTIVE: This is the first prospective cohort study of Huntington's disease (HD) in Korea. This study aimed to investigate the caregiver burden in relation to the characteristics of patients and caregivers. METHODS: From August 2020 to February 2022, we enrolled patients with HD from 13 university hospitals in Korea. We used the 12-item Zarit Burden Interview (ZBI-12) to evaluate the caregiver burden. We evaluated the clinical associations of the ZBI-12 scores by linear regression analysis and investigated the differences between the low- and high-burden groups. RESULTS: Sixty-five patients with HD and 45 caregivers were enrolled in this cohort study. The average age at onset of motor symptoms was 49.3 ± 12.3 years, with an average cytosine-adenine-guanine (CAG)n of 42.9 ± 4.0 (38-65). The median ZBI-12 score among our caregivers was 17.6 ± 14.2. A higher caregiver burden was associated with a more severe Shoulson-Fahn stage (p = 0.038) of the patients. A higher ZBI-12 score was also associated with lower independence scale (B = -0.154, p = 0.006) and functional capacity (B = -1.082, p = 0.002) scores of patients. The caregiving duration was longer in the high- than in the low-burden group. Caregivers' demographics, blood relation, and marital and social status did not affect the burden significantly. CONCLUSION: HD patients' neurological status exerts an enormous impact on the caregiver burden regardless of the demographic or social status of the caregiver. This study emphasizes the need to establish an optimal support system for families dealing with HD in Korea. A future longitudinal analysis could help us understand how disease progression aggravates the caregiver burden throughout the entire disease course.

Deep learning system for automated detection of posterior ligamentous complex injury in patients with thoracolumbar fracture on MRI.

This study aimed to develop a deep learning (DL) algorithm for automated detection and localization of posterior ligamentous complex (PLC) injury in patients with acute thoracolumbar (TL) fracture on magnetic resonance imaging (MRI) and evaluate its diagnostic performance. In this retrospective multicenter study, using midline sagittal T2-weighted image with fracture (± PLC injury), a training dataset and internal and external validation sets of 300, 100, and 100 patients, were constructed with equal numbers of injured and normal PLCs. The DL algorithm was developed through two steps (Attention U-net and Inception-ResNet-V2). We evaluate the diagnostic performance for PLC injury between the DL algorithm and radiologists with different levels of experience. The area under the curves (AUCs) generated by the DL algorithm were 0.928, 0.916 for internal and external validations, and by two radiologists for observer performance test were 0.930, 0.830, respectively. Although no significant difference was found in diagnosing PLC injury between the DL algorithm and radiologists, the DL algorithm exhibited a trend of higher AUC than the radiology trainee. Notably, the radiology trainee's diagnostic performance significantly improved with DL algorithm assistance. Therefore, the DL algorithm exhibited high diagnostic performance in detecting PLC injuries in acute TL fractures.

Correlation Between Quantitative Background Suppression on EEG and Serum NSE in Patients With Hypoxic-ischemic Encephalopathy.

PURPOSE: We evaluated the correlation between quantitative background activities on electroencephalography (EEG) and serum neuron specific enolase (NSE) in patients with hypoxic-ischemic encephalopathy as well as a diagnostic value of prognostication. METHODS: This retrospective cohort study enrolled patients with return of spontaneous circulation after cardiac arrest from March 2010 to March 2020. The inclusion criteria were (1) older than the age of 16 years and (2) patients who had both EEG and NSE. The median time for EEG and NSE were 3 days (interquartile range 2-5 days) and 3 days (interquartile range 2-4 days), respectively. The quantification of background activity was conducted with the suppression ratio (SR). We used a machine learning (eXtreme Gradient Boosting algorithm) to evaluate whether the SR could improve the accuracy of prognostication. RESULTS: We enrolled 151 patients. The receiver operating characteristic analysis revealed a cut-off value of serum NSE and the SR for poor outcome, serum NSE (>31.9 µg/L, area under curve [AUC] = 0.88), and the SR (>21.5%, AUC = 0.75 in the right hemisphere, >34.4%, AUC = 0.76 in the left hemisphere). There was a significant positive correlation between the severity of SR and the level of NSE (ρ = 0.57, p < 0.0001 for the right hemisphere, ρ = 0.58, p < 0.0001 for the left hemisphere). The SR showed an excellent diagnostic value for predicting poor outcome (93% specificity, 60% sensitivity in the right hemisphere and 93% specificity, 58% sensitivity in the left hemisphere). With machine learning analysis, there was an increment in distinguishing the neurological outcome by adding SR on clinical factors. CONCLUSIONS: The SR showed a positive correlation with the level of serum NSE. The diagnostic value of the SR for predicting poor outcome was excellent, suggesting that it can be a possible biomarker for neuroprognostication in patients with hypoxic-ischemic encephalopathy.

Plasma neurofilament light-chain and phosphorylated tau as biomarkers of disease severity in Huntington's disease: Korean cohort data.

OBJECTIVE: To investigate neurofilament light chain (NfL), phosphorylated tau (p-Tau) and total tau (t-Tau) as plasma markers for clinical severity in Korean Huntington's disease (HD) cohort. METHODS: Genetically-confirmed 67 HD patients participated from 13 referral hospitals in South Korea. The subjects were evaluated with the Unified Huntington's Disease Rating Scale (UHDRS), total motor score (TMS) and total functional capacity (TFC), Mini-Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and Beck's depression inventory (K-BDI). We measured plasma NfL, p-Tau and t-Tau concentrations using single-molecule array (SIMOA) assays. Stages of HD were classified based on UHDRS-TFC score and plasma markers were analyzed for correlation with clinical severity scales. RESULTS: Plasma NfL was elevated in both 6 premanifest and 61 full manifest HD patients compared to the reference value, which increased further from premanifest to manifest HD groups. The NfL level was not significantly correlated with UHDRS TMS or TFC scores in manifest HD patients. Plasma p-Tau was also elevated in HD patients (p = 0.038). The level was the highest in stage III-V HD (n = 30) group (post-hoc p < 0.05). The p-Tau was correlated with UHDRS TFC scores (adjusted p = 0.002). Plasma t-Tau neither differed among the groups nor associated with any clinical variables. CONCLUSIONS: This study supports plasma NfL being a biomarker for initial HD manifestation in Korean cohort, and a novel suggestion of plasma p-Tau as a potential biomarker reflecting the clinical severity in full-manifest HD.

Neuropsychological, neuroimaging and autopsy findings of butane encephalopathy.

BACKGROUND: Butane is an aliphatic hydrocarbon used in various commercial products. While numerous reports of sudden cardiac-related deaths from butane inhalation have been described, butane-associated acute encephalopathy has rarely been reported. CASE PRESENTATION: A 38-year-old man presented with cognitive dysfunction after butane gas inhalation. Neuropsychological test results showed impairments in verbal and visual memory, and frontal executive function. Diffusion weighted MRI revealed symmetric high-signal changes in the bilateral hippocampus and globus pallidus. FDG-PET demonstrated decreased glucose metabolism in the bilateral precuneus and occipital areas and the left temporal region. At the 8-month follow-up, he showed still significant deficits in memory and frontal functions. Diffuse cortical atrophy with white matter hyperintensities and extensive glucose hypometabolism were detected on follow-up MRI and FDG-PET, respectively. Brain autopsy demonstrated necrosis and cavitary lesions in the globus pallidus. CONCLUSIONS: Only a few cases of butane encephalopathy have been reported to date. Brain lesions associated with butane encephalopathy include lesions in the bilateral thalamus, insula, putamen, and cerebellum. To the best of our knowledge, this is the first report on bilateral hippocampal and globus pallidal involvement in acute butane encephalopathy. The pathophysiology of central nervous system complications induced by butane intoxication is not yet fully understood. However, the direct toxic effects of butane or anoxic injury secondary to cardiac arrest or respiratory depression have been suggested as possible mechanisms of edematous changes in the brain after butane intoxication.

Characterization of AtBAG2 as a Novel Molecular Chaperone.

Bcl-2-associated anthanogene (BAG) family proteins regulate plant defense against biotic and abiotic stresses; however, the function and precise mechanism of action of each individual BAG protein are not yet clear. In this study, we investigated the biochemical and molecular functions of the Arabidopsis thaliana BAG2 (AtBAG2) protein, and elucidated its physiological role under stress conditions using mutant plants and transgenic yeast strains. The T-DNA insertion atbag2 mutant plants were highly susceptible to heat shock, whereas transgenic yeast strains ectopically expressing AtBAG2 exhibited outstanding thermotolerance. Moreover, a biochemical analysis of GST-fused recombinant proteins produced in bacteria revealed that AtBAG2 exhibits molecular chaperone activity, which could be attributed to its BAG domain. The relevance of the molecular chaperone function of AtBAG2 to the cellular heat stress response was confirmed using yeast transformants, and the experimental results showed that overexpression of the AtBAG2 sequence encoding only the BAG domain was sufficient to impart thermotolerance. Overall, these results suggest that the BAG domain-dependent molecular chaperone activity of AtBAG2 is indispensable for the heat stress response of Arabidopsis. This is the first report demonstrating the role of AtBAG2 as a sole molecular chaperone in Arabidopsis.

Optimization of Gelatin Extracting Condition from Korean Native Black Goat Skin and Quality Comparison with Commercial Gelatin.

The practical use of Korean native black goat skin as a source of gelatin extraction is limited. The objective of this study was to optimize the extraction temperature and time of gelatin from Korean native black goat skin, and to compare the quality characteristics of goat skin gelatin and other commercial gelatin products. Response surface methodology was applied to optimize the extraction temperature and time of gelatin obtained from native Korean black goat skin. The effects of temperature (50°C-70°C) and time (2-4 h) on extraction yield and gel strength were investigated using a face-centered central composite design with 13 experiments. Gelatin extraction from Korean native black goat skin was prepared through the serial processes of alkali pre-treatment, bleaching, neutralization, hot-water extraction, and freeze-drying. Using the optimization plot of Minitab software, the optimized conditions for extracting temperature and time of goat skin gelatin were 59.49°C and 3.03 h, and the optimized values of extraction yield and gel strength were 12.52% and 263.37 g, respectively. Based on a quality comparison of goat skin gelatin with commercial gelatin, the pH value of gelatin extracted from Korean native black goat skin was 5.57. The color of gelatin extracted from Korean native black goat skin was darker than that of commercial gelatin (p<0.05). Higher emulsifying properties and gel strength of goat skin gelatin were observed when compared to those of commercial gelatin (p<0.05). Therefore, the results of this study indicate that Korean native black goat skin may be a valuable source for gelatin extraction.

Characterization of human induced pluripotent stem cells line (PNUSCRi004-A) from a Parkinson's disease patient carrying L483P, A495P and V499V mutations.

The hiPSC line was generated from peripheral blood mononuclear cells (PBMCs) collected from a female patient with young onset Parkinson's disease (PD), carrying on heterozygous c.1448 T > C (L483P), c1483 G > C (A495P) and c.1497 G > C (V499V) mutations in the GBA gene. The PBMCs was reprogrammed into an induced pluripotent stem cell (iPSC) line (GBA PD8 or PNUSCRi004-A hiPSCs) using non-integrative Sendai virus. The cell line, PNUSCRi004-A displayed a normal karyotype and expression of pluripotency markers capable of producing derivatives of three germ layers (Ectoderm, Endoderm and Mesoderm).

Deep learning approaches to predict 10-2 visual field from wide-field swept-source optical coherence tomography en face images in glaucoma.

Close monitoring of central visual field (VF) defects with 10-2 VF helps prevent blindness in glaucoma. We aimed to develop a deep learning model to predict 10-2 VF from wide-field swept-source optical coherence tomography (SS-OCT) images. Macular ganglion cell/inner plexiform layer thickness maps with either wide-field en face images (en face model) or retinal nerve fiber layer thickness maps (RNFLT model) were extracted, combined, and preprocessed. Inception-ResNet-V2 was trained to predict 10-2 VF from combined images. Estimation performance was evaluated using mean absolute error (MAE) between actual and predicted threshold values, and the two models were compared with different input data. The training dataset comprised paired 10-2 VF and SS-OCT images of 3,025 eyes of 1,612 participants and the test dataset of 337 eyes of 186 participants. Global prediction errors (MAEpoint-wise) were 3.10 and 3.17 dB for the en face and RNFLT models, respectively. The en face model performed better than the RNFLT model in superonasal and inferonasal sectors (P = 0.011 and P = 0.030). Prediction errors were smaller in the inferior versus superior hemifields for both models. The deep learning model effectively predicted 10-2 VF from wide-field SS-OCT images and might help clinicians efficiently individualize the frequency of 10-2 VF in clinical practice.

Generation of Parkinson's disease patient-derived human induced pluripotent stem cells line (PNUSCRi001-A) carrying a N227S mutation in GBA gene.

The hiPSC line was generated from peripheral blood mononuclear cells (PBMCs) collected by a male patient with young onset Parkinson's disease, carrying on heterozygous c.680 A > G (N227S) mutation in the GBA gene. The PBMCs was reprogrammed into an induced pluripotent stem cell (iPSC) line (PNUSCRi001-A hiPSCs) using non-integrative sendai virus. The hiPSC line, PNUSCRi001-A displayed a normal karyotype and the Expression of pluripotency markers that is capable of producing derivatives of three germ layers (Ectoderm, Endoderm and Mesoderm).

Cerebello-brainstem dominant form of X-linked adrenoleukodystrophy with intrafamilial phenotypic variability.

Objectives: This study aimed to describe the clinical and radiological characteristics of a cerebello-brainstem dominant form of X-linked adrenoleukodystrophy (X-ALD). Methods: Three affected members from a family with cerebellar ataxia received full neurological, laboratory and radiological examinations. Genetic diagnoses were confirmed using whole-exome sequencing and protein structural modeling. Results: All affected members presented with slurred speech, ataxia, and spasticity, but showed obvious differences in phenotypic severity and radiological findings. The levels of very long-chain fatty acids (VLCFA) were elevated in each member, while only one had adrenal dysfunction. Genetic analysis identified a hemizygous missense mutation (c.887A>G, p.Tyr296Cys) of the ATP-binding cassette subfamily D member 1 gene (ABCD1) in all affected members, which is likely to destabilize the overall structure of the ABCD1 protein. Conclusions: We report a cerebello-dominant form of X-ALD caused by a missense variant in ABCD1. This report highlights intrafamilial phenotypic variability in X-ALD.