A machine learning approach using conditional normalizing flow to address extreme class imbalance problems in personal health records.

BACKGROUND: Supervised machine learning models have been widely used to predict and get insight into diseases by classifying patients based on personal health records. However, a class imbalance is an obstacle that disrupts the training of the models. In this study, we aimed to address class imbalance with a conditional normalizing flow model, one of the deep-learning-based semi-supervised models for anomaly detection. It is the first introduction of the normalizing flow algorithm for tabular biomedical data. METHODS: We collected personal health records from South Korean citizens (n = 706), featuring genetic data obtained from direct-to-customer service (microarray chip), medical health check-ups, and lifestyle log data. Based on the health check-up data, six chronic diseases were labeled (obesity, diabetes, hypertriglyceridemia, dyslipidemia, liver dysfunction, and hypertension). After preprocessing, supervised classification models and semi-supervised anomaly detection models, including conditional normalizing flow, were evaluated for the classification of diabetes, which had extreme target imbalance (about 2%), based on AUROC and AUPRC. In addition, we evaluated their performance under the assumption of insufficient collection for patients with other chronic diseases by undersampling disease-affected samples. RESULTS: While LightGBM (the best-performing model among supervised classification models) showed AUPRC 0.16 and AUROC 0.82, conditional normalizing flow achieved AUPRC 0.34 and AUROC 0.83 during fifty evaluations of the classification of diabetes, whose base rate was very low, at 0.02. Moreover, conditional normalizing flow performed better than the supervised model under a few disease-affected data numbers for the other five chronic diseases - obesity, hypertriglyceridemia, dyslipidemia, liver dysfunction, and hypertension. For example, while LightGBM performed AUPRC 0.20 and AUROC 0.75, conditional normalizing flow showed AUPRC 0.30 and AUROC 0.74 when predicting obesity, while undersampling disease-affected samples (positive undersampling) lowered the base rate to 0.02. CONCLUSIONS: Our research suggests the utility of conditional normalizing flow, particularly when the available cases are limited, for predicting chronic diseases using personal health records. This approach offers an effective solution to deal with sparse data and extreme class imbalances commonly encountered in the biomedical context.

Harnessing Artificial Intelligence in Multimodal Omics Data Integration: Paving the Path for the Next Frontier in Precision Medicine.

The integration of multiomics data with detailed phenotypic insights from electronic health records marks a paradigm shift in biomedical research, offering unparalleled holistic views into health and disease pathways. This review delineates the current landscape of multimodal omics data integration, emphasizing its transformative potential in generating a comprehensive understanding of complex biological systems. We explore robust methodologies for data integration, ranging from concatenation-based to transformation-based and network-based strategies, designed to harness the intricate nuances of diverse data types. Our discussion extends from incorporating large-scale population biobanks to dissecting high-dimensional omics layers at the single-cell level. The review underscores the emerging role of large language models in artificial intelligence, anticipating their influence as a near-future pivot in data integration approaches. Highlighting both achievements and hurdles, we advocate for a concerted effort toward sophisticated integration models, fortifying the foundation for groundbreaking discoveries in precision medicine.

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration.

ATB1651 gel is an antifungal drug candidate that enhances antifungal activity through substitution of several aryl rings, alkyl chains, and methyl groups. To ensure safety of use of ATB1651 gel, assessment of its potentially toxic side effects is necessary. In this study, we examined the repeated-dose toxicity of ATB1651 gel to Yucatan minipigs (Sus scrofa) in accordance with the Good Laboratory Practice guidelines. Five doses of ATB1651 gel (0%, 0.2%, 0.5%, 1.0%, 3.0%) were administered dermally to the left and right flanks of 38 minipigs daily for 4 weeks. Mortality, clinical symptoms, dermal scores, body weights, and physiological, biochemical, pathological, and toxicokinetic analyses were performed after the treatment period. No systemic toxicological damage was observed in either male or female minipigs regardless of dose; however, dermal application of ATB1651 gel caused some skin alterations at the application sites. Specifically, erythema and eschar formation, edema, and scabs or raise spots were observed at the application site(s) in males in the 3.0% ATB1651 gel treatment group and in females at ATB1651 gel concentrations ≥ 1.0%, with dermal scores ranging from grade 1 to 2. Additionally, histopathological assay indicated infiltration of different types of inflammatory cells and the presence of pustule/crust at the application site(s) in both males and females at ATB1651 gel concentrations ≥ 0.5%. However, these changes were reversible after a 2-week recovery period and were considered a local irritation effect of ATB1651 gel. The no-observed-adverse-effect level of ATB1651 gel was 3.0% with regard to topical and systemic toxicity in both male and female minipigs. Collectively, our results imply that ATB1651 gel is a safe candidate for clinical development as an antifungal drug with a wide therapeutic window.

Extreme ultraviolet pellicle wrinkles influence on mask 3D effects: experimental demonstration.

Extreme ultraviolet (EUV) lithography uses reflective optics and a thick mask absorber, leading to mask 3D (M3D) effects. These M3D effects cause disparities in the amplitudes and phases of EUV mask diffractions, impacting mask imaging performance and reducing process yields. Our findings demonstrate that wrinkles in the EUV pellicle can exacerbate M3D effects. This imbalance results in critical dimension variation, image contrast loss, and pattern shift in mask images. Therefore, the use of a pellicle material with thermodynamic characteristics that minimize wrinkles when exposed to EUV rays is imperative.

Study on ZrSi2 as a Candidate Material for Extreme Ultraviolet Pellicles.

An extreme ultraviolet (EUV) pellicle is an ultrathin membrane at a stand-off distance from the reticle surface that protects the EUV mask from contamination during the exposure process. EUV pellicles must exhibit high EUV transmittance, low EUV reflectivity, and superior thermomechanical durability that can withstand the gradually increasing EUV source power. This study proposes an optimal range of optical constants to satisfy the EUV pellicle requirements based on the optical simulation results. Based on this, zirconium disilicide (ZrSi2), which is expected to satisfy the optical and thermomechanical requirements, was selected as the EUV pellicle candidate material. An EUV pellicle composite comprising a ZrSi2 thin film deposited via co-sputtering was fabricated, and its thermal, optical, and mechanical properties were evaluated. The emissivity increased with an increase in the thickness of the ZrSi2 thin film. The measured EUV transmittance (92.7%) and reflectivity (0.033%) of the fabricated pellicle satisfied the EUV pellicle requirements. The ultimate tensile strength of the pellicle was 3.5 GPa. Thus, the applicability of the ZrSi2 thin film as an EUV pellicle material was verified.

Trans-ethnic genomic informed risk assessment for Alzheimer's disease: An International Hundred K+ Cohorts Consortium study.

BACKGROUND: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). METHODS: The GIRA model was created to include polygenic risk score calculated from the AD genome-wide association study loci, the apolipoprotein E haplotypes, and non-genetic covariates including age, sex, and the first three principal components of population substructure. RESULTS: We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD. CONCLUSIONS: As the initial effort by the IHCC to leverage existing large-scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications.

Clinicopathological and Genetic Characteristics of Patients of Different Ages with Diffuse Sclerosing Variant Papillary Thyroid Carcinoma.

Diffuse sclerosing variant papillary thyroid carcinoma (DSVPTC) is commonly observed in young patients, with a median age at diagnosis in the third decade of life. Further, the risk of recurrence is higher for DSVPTC than for classical PTC. Therefore, this study aimed to describe the clinicopathological and genetic characteristics of patients of different ages with DSVPTC. We retrospectively reviewed 397 patients who underwent thyroidectomy for DSVPTC at Gangnam Severance Hospital, Yonsei University, from January 2005 to December 2017. The mean age at diagnosis was 36.7 ± 11.6 years, with most patients (163, 41.1%) aged 31-40 years. DSVPTC was predominant in women (276, 69.5%). We observed recurrence in 46 (11.6%) patients, with regional nodal recurrence being the most common type of recurrence (32 patients, 69.6%). The mean tumour size was larger in younger patients than in older patients. DSVPTC was more aggressive in paediatric patients with a larger-sized tumour, more common multiplicity, and lateral neck metastasis. Through random sampling, we selected 41 patients by age group and examined the mutations in 119 genes using next-generation sequencing. BRAF, KRAS, and TERT displayed relatively higher mutation rates than other genes. DSVPTC displays different clinical, pathological, and molecular profiles than classical PTC. The BRAF, KRAS, and TERT mutations are the most important, with age-specific differences.

Prospective classification of Alzheimer's disease conversion from mild cognitive impairment.

Alzheimer's disease (AD) is emerging as a serious problem with the rapid aging of the population, but due to the unclear cause of the disease and the absence of therapy, appropriate preventive measures are the next best thing. For this reason, it is important to early detect whether the disease converts from mild cognitive impairment (MCI) which is a prodromal phase of AD. With the advance in brain imaging techniques, various machine learning algorithms have become able to predict the conversion from MCI to AD by learning brain atrophy patterns. However, at the time of diagnosis, it is difficult to distinguish between the conversion group and the non-conversion group of subjects because the difference between groups is small, but the within-group variability is large in brain images. After a certain period of time, the subjects of conversion group show significant brain atrophy, whereas subjects of non-conversion group show only subtle changes due to the normal aging effect. This difference on brain atrophy makes the brain images more discriminative for learning. Motivated by this, we propose a method to perform classification by projecting brain images into the future, namely prospective classification. The experiments on the Alzheimer's Disease Neuroimaging Initiative dataset show that the prospective classification outperforms ordinary classification. Moreover, the features of prospective classification indicate the brain regions that significantly influence the conversion from MCI to AD.

The bHLH Transcription Factors in Neural Development and Therapeutic Applications for Neurodegenerative Diseases.

The development of functional neural circuits in the central nervous system (CNS) requires the production of sufficient numbers of various types of neurons and glial cells, such as astrocytes and oligodendrocytes, at the appropriate periods and regions. Hence, severe neuronal loss of the circuits can cause neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Treatment of such neurodegenerative diseases caused by neuronal loss includes some strategies of cell therapy employing stem cells (such as neural progenitor cells (NPCs)) and gene therapy through cell fate conversion. In this report, we review how bHLH acts as a regulator in neuronal differentiation, reprogramming, and cell fate determination. Moreover, several different researchers are conducting studies to determine the importance of bHLH factors to direct neuronal and glial cell fate specification and differentiation. Therefore, we also investigated the limitations and future directions of conversion or transdifferentiation using bHLH factors.

Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans.

The KEOPS (kinase, putative endopeptidase, and other proteins of small size) complex has critical functions in eukaryotes; however, its role in fungal pathogens remains elusive. Herein, we comprehensively analyzed the pathobiological functions of the fungal KEOPS complex in Cryptococcus neoformans (Cn), which causes fatal meningoencephalitis in humans. We identified four CnKEOPS components: Pcc1, Kae1, Bud32, and Cgi121. Deletion of PCC1, KAE1, or BUD32 caused severe defects in vegetative growth, cell cycle control, sexual development, general stress responses, and virulence factor production, whereas deletion of CGI121 led to similar but less severe defects. This suggests that Pcc1, Kae1, and Bud32 are the core KEOPS components, and Cgi121 may play auxiliary roles. Nevertheless, all KEOPS components were essential for C. neoformans pathogenicity. Although the CnKEOPS complex appeared to have a conserved linear arrangement of Pcc1-Kae1-Bud32-Cgi121, as supported by physical interaction between Pcc1-Kae1 and Kae1-Bud32, CnBud32 was found to have a unique extended loop region that was critical for the KEOPS functions. Interestingly, CnBud32 exhibited both kinase activity-dependent and -independent functions. Supporting its pleiotropic roles, the CnKEOPS complex not only played conserved roles in t6A modification of ANN codon-recognizing tRNAs but also acted as a major transcriptional regulator, thus controlling hundreds of genes involved in various cellular processes, particularly ergosterol biosynthesis. In conclusion, the KEOPS complex plays both evolutionarily conserved and divergent roles in controlling the pathobiological features of C. neoformans and could be an anticryptococcal drug target. IMPORTANCE The cellular function and structural configuration of the KEOPS complex have been elucidated in some eukaryotes and archaea but have never been fully characterized in fungal pathogens. Here, we comprehensively analyzed the pathobiological roles of the KEOPS complex in the globally prevalent fungal meningitis-causing pathogen C. neoformans. The CnKEOPS complex, composed of a linear arrangement of Pcc1-Kae1-Bud32-Cgi121, not only played evolutionarily conserved roles in growth, sexual development, stress responses, and tRNA modification but also had unique roles in controlling virulence factor production and pathogenicity. Notably, a unique extended loop structure in CnBud32 is critical for the KEOPS complex in C. neoformans. Supporting its pleiotropic roles, transcriptome analysis revealed that the CnKEOPS complex governs several hundreds of genes involved in carbon and amino acid metabolism, pheromone response, and ergosterol biosynthesis. Therefore, this study provides novel insights into the fungal KEOPS complex that could be exploited as a potential antifungal drug target.

Effect of wrinkles on extreme ultraviolet pellicle reflectivity and local critical dimension.

Extreme ultraviolet (EUV) pellicles must have an EUV reflectance (EUVR) below 0.04% to prevent the reduction of critical dimension (CD). However, pellicle wrinkles cause localized CD variation by locally amplifying the EUVR. This study demonstrates that wrinkles can increase the pellicle's EUVR by approximately four times, and the CD drop depends on the relative position of the reflected light from the wrinkle to the 0th- or 1st-order diffracted light. The CD decreases by 6 nm. Therefore, even if the pellicle satisfies the requirement for the EUVR, we need to tightly control the generation of wrinkles to suppress CD variation during the entire exposure process.

Cystitis Induces Altered CREB Expression Related with Micturition Reflex.

Background and objectives: Bladder stimulation upregulates neurotrophins associated with voiding reflex. Bacterial cystitis can be a stimulant that activates this system, resulting in a pathological state. Phosphorylated responsive element of binding protein (p-CREB) is a pivotal transcriptional factor in the neurotrophin signaling cascade. The goal of our study was to examine the change in expression of p-CREB in dorsal root ganglia (DRG) of rats after uropathogenic Escherichia coli infection of the bladder. Materials and methods: A total of 19 adult female Sprague−Dawley rats were induced with acute E. coli infection (n = 7), chronic E. coli infection (n = 6), or served as controls (n = 6). In each group, the profiles of p-CREB cell were counted in 6−10 sections of each of the DRG collected. DRG cells exhibiting intense nuclear staining were considered to be positive for p-CREB immunoreactivity (p-CREB-IR). Results: Overall, the immunoreactivity of p-CREB was examined in smaller cell profiles with nuclear staining or nuclear and cytoplasmic staining in the DRGs (L1−L6, S1). In the chronic cystitis group, p-CREB-IR in the L1−L6 and S1 DRG was significantly higher than the control group (p < 0.05). Further, p-CREB-IR in the L3−L6 and S1 DRG of the chronic cystitis group was significantly greater than that in the acute cystitis group (p < 0.05). In the control and acute cystitis groups, p-CREB-IR in the L4−L5 DRG was significantly lower than that found in the other DRG sections (p < 0.05). Conclusions: Altogether, acute or chronic E.coli cystitis changed the immunoreactivity of p-CREB in lumbosacral DRG cells. In particular, chronic E. coli infection triggered p-CREB overexpression in L1−L6 and S1 DRG, indicating subsequent pathologic changes.

Independent replication of advanced brain age in mild cognitive impairment and dementia: detection of future cognitive dysfunction.

We previously developed a novel machine-learning-based brain age model that was sensitive to amyloid. We aimed to independently validate it and to demonstrate its utility using independent clinical data. We recruited 650 participants from South Korean memory clinics to undergo magnetic resonance imaging and clinical assessments. We employed a pretrained brain age model that used data from an independent set of largely Caucasian individuals (n = 757) who had no or relatively low levels of amyloid as confirmed by positron emission tomography (PET). We investigated the association between brain age residual and cognitive decline. We found that our pretrained brain age model was able to reliably estimate brain age (mean absolute error = 5.68 years, r(650) = 0.47, age range = 49-89 year) in the sample with 71 participants with subjective cognitive decline (SCD), 375 with mild cognitive impairment (MCI), and 204 with dementia. Greater brain age was associated with greater amyloid and worse cognitive function [Odds Ratio, (95% Confidence Interval {CI}): 1.28 (1.06-1.55), p = 0.030 for amyloid PET positivity; 2.52 (1.76-3.61), p < 0.001 for dementia]. Baseline brain age residual was predictive of future cognitive worsening even after adjusting for apolipoprotein E e4 and amyloid status [Hazard Ratio, (95% CI): 1.94 (1.33-2.81), p = 0.001 for total 336 follow-up sample; 2.31 (1.44-3.71), p = 0.001 for 284 subsample with baseline Clinical Dementia Rating ≤ 0.5; 2.40 (1.43-4.03), p = 0.001 for 240 subsample with baseline SCD or MCI]. In independent data set, these results replicate our previous findings using this model, which was able to delineate significant differences in brain age according to the diagnostic stages of dementia as well as amyloid deposition status. Brain age models may offer benefits in discriminating and tracking cognitive impairment in older adults.

Novel electrochemical PMI marker biosensor based on quantum dot dissolution using a double-label strategy.

A novel and facile post-mortem interval (PMI) biosensor was fabricated using a double-label strategy to detect the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) biomarker. A monoclonal anti-GAPDH antibody was immobilized on a surface label containing cadmium selenide quantum dots (CdSe QDs) on a cysteamine graphene oxide (Cys-GO) self-assembled monolayer. Glucose oxidase (GOx) was used as a signal label to conjugate with GAPDH. GAPDH recognition was achieved through the dissolution of the surface-attached CdSe QDs by hydrogen peroxide generated through GAPDH-conjugated GOx-catalyzed ß-glucose oxidation. To enhance sensitivity, a competitive interaction was introduced between free and conjugated GAPDH to the active site of the anti-GAPDH antibody. The electrochemical response due to CdSe dissolution decreased proportionally with the concentration of free GAPDH. Differential pulsed voltammetry was conducted to determine the analytical characteristics of the immunosensor, including the limit of detection, linear dynamic range, target selectivity, system stability, and applicability toward the analysis of real samples.

The novel antifungal agent AB-22 displays in vitro activity against hyphal growth and biofilm formation in Candida albicans and potency for treating systemic candidiasis.

Systemic candidiasis, which is mainly caused by Candida albicans, is a serious acute fungal infection in the clinical setting. In a previous study, we reported that compound 22h (designated as AB-22 in this study), a vinyl sulfate compound, is a fast-acting fungicidal agent against a broad spectrum of fungal pathogens. In this study, we aimed to further analyze the in vitro and in vivo efficacy of AB-22 against filamentation, biofilm formation, and virulence of C. albicans. Under in vitro hyphal growth-inducing condition, AB-22 effectively inhibited germ tube formation and hyphal growth, which are required for the initiation of biofilm formation. Indeed, AB-22 significantly suppressed C. albicans biofilm formation in a dose-dependent manner. Moreover, AB-22 treatment inhibited the normal induction of ALS3, HWP1, and ECE1, which are all required for hyphal transition in C. albicans. Furthermore, AB-22 treatment increased the survival of mice systemically infected with C. albicans. In conclusion, in addition to its fungicidal activity, AB-22 inhibits filamentation and biofilm formation in C. albicans, which could collectively contribute to its potent in vivo efficacy against systemic candidiasis.

Baseline Clinical and Biomarker Characteristics of Biobank Innovations for Chronic Cerebrovascular Disease With Alzheimer's Disease Study: BICWALZS.

OBJECTIVE: We aimed to present the study design and baseline cross-sectional participant characteristics of biobank innovations for chronic cerebrovascular disease with Alzheimer's disease study (BICWALZS) participants. METHODS: A total of 1,013 participants were enrolled in BICWALZS from October 2016 to December 2020. All participants underwent clinical assessments, basic blood tests, and standardized neuropsychological tests (n=1,013). We performed brain magnetic resonance imaging (MRI, n=817), brain amyloid positron emission tomography (PET, n=713), single nucleotide polymorphism microarray chip (K-Chip, n=949), locomotor activity assessment (actigraphy, n=200), and patient-derived dermal fibroblast sampling (n=175) on a subset of participants. RESULTS: The mean age was 72.8 years, and 658 (65.0%) were females. Based on clinical assessments, total of 168, 534, 211, 80, and 20 had subjective cognitive decline, mild cognitive impairment (MCI), Alzheimer's dementia, vascular dementia, and other types of dementia or not otherwise specified, respectively. Based on neuroimaging biomarkers and cognition, 199, 159, 78, and 204 were cognitively normal (CN), Alzheimer's disease (AD)-related cognitive impairment, vascular cognitive impairment, and not otherwise specified due to mixed pathology (NOS). Each group exhibited many differences in various clinical, neuropsychological, and neuroimaging results at baseline. Baseline characteristics of BICWALZS participants in the MCI, AD, and vascular dementia groups were generally acceptable and consistent with 26 worldwide dementia cohorts and another independent AD cohort in Korea. CONCLUSION: The BICWALZS is a prospective and longitudinal study assessing various clinical and biomarker characteristics in older adults with cognitive complaints. Details of the recruitment process, methodology, and baseline assessment results are described in this paper.

Investigating the Degradation of EUV Transmittance of an EUV Pellicle Membrane.

The extreme ultraviolet (EUV) pellicle is a freestanding membrane that protects EUV masks from particle contamination during EUV exposure. Although a high EUV transmittance of the pellicle is required to minimize the loss of throughput, the degradation of EUV transmittance during the extended exposure of the pellicle has been recently reported. This may adversely affect the throughput of the lithography process. However, the cause of this phenomenon has not yet been clarified. Therefore, we investigated the cause of the degradation in the EUV transmittance by observing the compositional change when the Ru/SiNx pellicle composite was heated in an emulated EUV scanner environment. The Ru thin film that was deposited at high pressure had more void networks but was not oxidized, whereas the SiNx thin film was oxidized after heating. This was because the void network in the Ru thin film served as a preferential diffusion path for oxygen and caused oxidation of the SiNx thin film. It was confirmed that the degradation of the EUV transmittance was due to the oxidation of SiNx. The results verified the effect of diffusivity in the thin film due to the void network on oxidation and EUV transmittance.

Congenital Renal Arteriovenous Malformation: Diagnostic Clues and Methods.

Background and objectives: Renal arteriovenous malformation (AVM) is a rare disease and is difficult to be diagnosed by conventional methods because of its rarity. In this study, we investigated the diagnostic clues, and made an algorithm for the better diagnosis of renal AVM. Materials and Methods: We reviewed 13 patients who were diagnosed with AVM by using renal angiography from 1986 to 2020 at our institutes. We evaluated clinical features, diagnostic tools, treatment modalities, and outcomes after the treatment of patients. Results: All patients were female, and the mean age was 36.9 years (range 19 to 54 years). Twelve (92.3%) patients complained of gross hematuria. Four (30.8%) patients showed symptoms in relation with pregnancy and delivery. Angiographic findings demonstrated cirsoid type in 10 patients and aneurysmal type in 3 patients. Among the 11 patients who underwent computed tomography, AVMs were detected in 3 (27.3%) patients. Renal duplex Doppler was performed in 6 patients, and all of these patients were diagnosed with AVM, demonstrating a vascular turbulence or blood-rich area. Twelve patients were initially treated with transarterial embolization. Nephrectomy was performed in two patients due to persistent bleeding with hypovolemic shock. Conclusions: We should consider possible AVMs in patients who were not detected by conventional work up for hematuria, especially in mid-aged, pregnant, or recently delivered women. Renal duplex Doppler might be the optimal diagnostic modality in these patients. Our diagnostic algorithm could be aid to diagnosis and treatment for renal AVM patients.

Urothelial Cell Carcinoma of the Renal Pelvis Misdiagnosed as Ureteropelvic Junction Obstruction: A Case Report.

Urothelial tumors are typically a disease affecting elderly individuals and are rare in young patients. Moreover, upper urinary tract urothelial carcinoma is extremely rare in the young age group. In this study, we present a case of urothelial cell carcinoma of the renal pelvis and ureter in a young man without risk factors of urothelial carcinoma, which was misdiagnosed as ureteropelvic junction obstruction and treated with a laparoscopic pyeloplasty.

Optimization and Evaluation of Novel Antifungal Agents for the Treatment of Fungal Infection.

Due to the increased morbidity and mortality by fungal infections and the emergence of severe antifungal resistance, there is an urgent need for new antifungal agents. Here, we screened for antifungal activity in our in-house library through the minimum inhibitory concentration test and derived two hit compounds with moderate antifungal activities. The hit compounds' antifungal activities and drug-like properties were optimized by substituting various aryl ring, alkyl chain, and methyl groups. Among the optimized compounds, 22h was the most promising candidate with good drug-like properties and exhibited potent fast-acting fungicidal antifungal effects against various fungal pathogens and synergistic antifungal activities with some known antifungal drugs. Additionally, 22h was further confirmed to disturb fungal cell wall integrity by activating multiple cell wall integrity pathways. Furthermore, 22h exerted significant antifungal efficacy in both the subcutaneous infection mouse model and ex vivo human nail infection model.