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Cerebral palsy (CP) is the most common motor disability in children, characterized by diverse clinical manifestations and often uncertain etiology, which has spurred increasing interest in genetic diagnostics. This review synthesizes findings from various studies to enhance understanding of CP’s genetic underpinnings. The discussion is structured around five key areas: monogenic causes and copy number variants directly linked to CP, differential genetic disorders including atypical CP and mimics, ambiguous genetic influences, co-occurrence with other neurodevelopmental disorders, and polygenic risk factors. Case studies illustrate the clinical application of these genetic insights, underscoring the complexity of diagnosing CP due to the phenotypic overlap with other conditions and the potential for misdiagnosis. The review highlights the significant role of advanced genetic testing in distinguishing CP from similar neurodevelopmental disorders and assessing cases with unclear clinical presentations. Furthermore, it addresses the ongoing challenges in establishing a consensus on genetic contributors to CP, the need for comprehensive patient phenotyping, and the integration of rigorous genetic and functional studies to validate findings. This comprehensive examination of CP genetics aims to pave the way for more precise diagnostics and personalized treatment plans, urging continued research to overcome the current limitations and refine diagnostic criteria within this field.

Objective Yellow Korean native chicken (KNC-Y) is one of the five pure Korean indigenous chicken breeds that were restored through a government project in 1992. KNC-Y is recognized for its superior egg production performance compared to other KNC lines. In this study, we performed runs of homozygosity (ROH) analysis to discover selection signatures associated with egg production traits in the KNC-Y population. Methods A total of 675 DNA samples from KNC-Y were genotyped to generate single nucleotide polymorphism (SNP) data using custom 60K Affymetrix SNP chips. ROH analysis was performed using PLINK software, with predefined parameters set for the analysis. The threshold of ROH island was defined as the top 1% frequency of SNPs withing the ROH among the population. Results In the KNC-Y population, a total of 29,958 runs of homozygosity (ROH) fragments were identified. The average total length of ROH was 120.84 Mb, with each ROH fragment having an average length of 2.71 Mb. The calculated ROH-based inbreeding coefficient (FROH) was 0.13. Furthermore, we revealed the presence of ROH islands on chromosomes 1, 2, 4, 5, 7, 8, and 11. Within the identified regions, a total of 111 genes were annotated, and among them were genes related to economic traits, including PRMT3, ANO5, HDAC4, LSS, PLA2G4A, and PTGS2. Most of the overlapping quantitative trait locus regions with ROH islands were found to be associated with production traits. Conclusion This study conducted a comprehensive analysis of ROH in the KNC-Y population. Notably, among the findings, the PTGS2 gene is believed to play a crucial role in influencing the laying performance of KNC-Y.

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 Background Whole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex. Methods To address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family. Results We observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females. Conclusions Our findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism’s genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism.

BackgroundSpeech sound disorders (SSDs) are common communication challenges in children, typically assessed by speech-language pathologists (SLPs) using standardized tools. However, traditional evaluation methods are time-intensive and prone to variability, raising concerns about reliability. ObjectiveThis study aimed to compare the evaluation outcomes of SLPs and an automatic speech recognition (ASR) model using two standardized SSD assessments in South Korea, evaluating the ASR model’s performance. MethodsA fine-tuned wav2vec 2.0 XLS-R model, pretrained on 436,000 hours of adult voice data spanning 128 languages, was used. The model was further trained on 93.6 minutes of children’s voices with articulation errors to improve error detection. Participants included children referred to the Department of Rehabilitation Medicine at a general hospital in Incheon, South Korea, from August 19, 2022, to June 14, 2023. Two standardized assessments—the Assessment of Phonology and Articulation for Children (APAC) and the Urimal Test of Articulation and Phonology (U-TAP)—were used, with ASR transcriptions compared to SLP transcriptions. ResultsThis study included 30 children aged 3-7 years who were suspected of having SSDs. The phoneme error rates for the APAC and U-TAP were 8.42% (457/5430) and 8.91% (402/4514), respectively, indicating discrepancies between the ASR model and SLP transcriptions across all phonemes. Consonant error rates were 10.58% (327/3090) and 11.86% (331/2790) for the APAC and U-TAP, respectively. On average, there were 2.60 (SD 1.54) and 3.07 (SD 1.39) discrepancies per child for correctly produced phonemes, and 7.87 (SD 3.66) and 7.57 (SD 4.85) discrepancies per child for incorrectly produced phonemes, based on the APAC and U-TAP, respectively. The correlation between SLPs and the ASR model in terms of the percentage of consonants correct was excellent, with an intraclass correlation coefficient of 0.984 (95% CI 0.953-0.994) and 0.978 (95% CI 0.941-0.990) for the APAC and UTAP, respectively. The z scores between SLPs and ASR showed more pronounced differences with the APAC than the U-TAP, with 8 individuals showing discrepancies in the APAC compared to 2 in the U-TAP. ConclusionsThe results demonstrate the potential of the ASR model in assessing children with SSDs. However, its performance varied based on phoneme or word characteristics, highlighting areas for refinement. Future research should include more diverse speech samples, clinical settings, and speech data to strengthen the model’s refinement and ensure broader clinical applicability.

Objective The analysis of runs of homozygosity (ROH) has been applied to assess the level of inbreeding and identify selection signatures in various livestock species. The objectives of this study were to characterize the ROH pattern, estimate the rate of inbreeding, and identify signatures of selection in the red-brown Korean native chickens. Methods The Illumina 60K single nucleotide polymorphism chip data of 651 chickens was used in the analysis. Runs of homozygosity were analysed using the PLINK v1.9 software. Inbreeding coefficients were estimated using the GCTA software and their correlations were examined. Genomic regions with high levels of ROH were explored to identify selection signatures. Results A total of 32,176 ROH segments were detected in this study. The majority of the ROH segments were shorter than 4 Mb. The average ROH inbreeding coefficients (FROH) varied with the length of ROH segments. The means of inbreeding coefficients calculated from different methods were also variable. The correlations between different inbreeding coefficients were positive and highly variable (r = 0.18–1). Five ROH islands harbouring important quantitative trait loci were identified. Conclusion This study assessed the level of inbreeding and patterns of homozygosity in Red-brown native Korean chickens. The results of this study suggest that the level of recent inbreeding is low which indicates substantial progress in the conservation of red-brown Korean native chickens. Additionally, Candidate genomic regions associated with important production traits were detected in homozygous regions.

Abstract This study addresses challenges related to privacy issues in utilizing medical data, particularly the protection of personal information. To overcome this obstacle, the research focuses on data synthesis using real-world time-series generative adversarial networks (RTSGAN). A total of 53,005 data were synthesized using the dataset of 15,799 patients with colorectal cancer. The results of the quantitative evaluation of the synthetic data’s quality are as follows: the Hellinger distance ranged from 0 to 0.25; the train on synthetic, test on real (TSTR) and train on real, test on synthetic (TRTS) results showed an average area under the curve of 0.99 and 0.98; a propensity mean squared error was 0.223. The synthetic and real data were similar in the qualitative methods including t-SNE and histogram analyses. The application of synthetic data in predicting five-year survival in colorectal cancer patients demonstrates comparable performance to models based on real data. This study employs distance to closest records and membership inference test to assess potential privacy exposure, revealing minimal risk. This study demonstrated that it is feasible to synthesize medical data, including time-series data, using the RTSGAN, and the synthetic data can be evaluated to accurately reflect the characteristics of real data through quantitative and qualitative methods as well as by utilizing real-world artificial intelligence models.

This study compared the immediate effects of two common post-exercise cool-down methods to a control condition on subsequent morphologic change in femoral cartilage and vascular response in the posterior tibial artery after running. Sixteen healthy young males (23.6 ± 2.2 years, 172.8 ± 4.9 cm, 72.2 ± 7.1 kg) visited the laboratory during three separate sessions and performed 30-min of treadmill running (7.5 km/h for the initial 5-min, followed 8.5 km/h for 25-min). After running, participants experienced one of three 30-min cool-down protocols: active cool-down, cold application, or control (seated rest with their knee fully extended), in a counterbalanced order. Ultrasonographic assessments of femoral cartilage thickness (intercondylar, lateral, and medial) and posterior tibial artery blood flow were compared. To test condition effects over time, two-way analysis of variances and Tukey tests were used (p < 0.05) with Cohen’s d effect sizes (ES). There was no condition by time interaction in femoral cartilage thickness (intercondylar: F30,705 = 0.91, p = 0.61; lateral: F30,705 = 1.24, p = 0.18; medial: F30,705 = 0.49, p = 0.99). Regardless of time (condition effect: F2,705 > 3.24, p < 0.04 for all tests), femoral cartilage in the cold application condition was thicker than the control condition (intercondylar: p = 0.01, ES = 0.16; lateral: p < 0.0001, ES = 0.24; medial: p = 0.04. ES = 0.16). Regardless of condition (time effect: F15,705 > 10.31, p < 0.0001 for all tests), femoral cartilage thickness was decreased after running (intercondylar: p < 0.0001, ES = 1.37; lateral: p < 0.0001, ES = 1.58; medial: p < 0.0001, ES = 0.81) and returned to baseline levels within 40-min (intercondylar: p = 0.09; lateral: p = 0.64; medial: p = 0.26). Blood flow volume was different (condition × time: F30,705 = 2.36, p < 0.0001) that running-induced blood flow volume was maintained for 30-min for the active cool-down condition (p < 0.0001, ES = 1.64), whereas it returned to baseline levels within 10-min for other conditions (cold application: p = 0.67; control: p = 0.62). Neither blood flow nor temperature had a significant impact on the recovery in femoral cartilage after running.

Objective The major histocompatibility complex in chicken demonstrates a great range of variations within varities, breeds, populations and that can eventually influence their immuneresponses. The preset study was conducted to understand the major histocompatibility complex-B (MHC-B) variability in five major populations of Bangladesh native chicken: Aseel, Hilly, Junglefowl, Non-descript Deshi, and Naked Neck. Methods These five major populations of Bangladesh native chicken were analyzed with a subset of 89 single nucleotide polymorphisms (SNPs) in the high-density MHC-B SNP panel and Kompetitive Allele-Specific polymerase chain reaction genotyping was applied. To explore haplotype diversity within these populations, the results were analyzed both manually and computationally using PHASE 2.1 program. The phylogenetic investigations were also performed using MrBayes program. Results A total of 136 unique haplotypes were identified within these five Bangladesh chicken populations, and only one was shared (between Hilly and Naked Neck). Phylogenetic analysis showed no distinct haplotype clustering among the five populations, although they were shared in distinct clades; notably, the first clade lacked Naked Neck haplotypes. Conclusion The present study discovered a set of unique MHC-B haplotypes in Bangladesh chickens that could possibly cause varied immune reponses. However, further investigations are required to evaluate their relationships with global chicken populations.

Abstract Social decision-making is known to be influenced by predictive emotions or the perceived reciprocity of partners. However, the connection between emotion, decision-making, and contextual reciprocity remains less understood. Moreover, arguments suggest that emotional experiences within a social context can be better conceptualised as prosocial rather than basic emotions, necessitating the inclusion of two social dimensions: focus, the degree of an emotion's relevance to oneself or others, and dominance, the degree to which one feels in control of an emotion. For better representation, these dimensions should be considered alongside the interoceptive dimensions of valence and arousal. In an ultimatum game involving fair, moderate, and unfair offers, this online study measured the emotions of 476 participants using a multidimensional affective rating scale. Using unsupervised classification algorithms, we identified individual differences in decisions and emotional experiences. Certain individuals exhibited consistent levels of acceptance behaviours and emotions, while reciprocal individuals' acceptance behaviours and emotions followed external reward value structures. Furthermore, individuals with distinct emotional responses to partners exhibited unique economic responses to their emotions, with only the reciprocal group exhibiting sensitivity to dominance prediction errors. The study illustrates a context-specific model capable of subtyping populations engaged in social interaction and exhibiting heterogeneous mental states.

Objectives This study investigated the prevalence of ophthalmic diseases in Quang Tri and Thai Nguyen, Vietnam, utilizing a smartphone-based fundus imaging (SBFI) system. Methods This cross-sectional study included nearly 10,000 patients who visited community health centers between July and August 2019. All participants underwent visual acuity testing and fundus imaging. We collected demographic data and medical histories, and fundus images were captured using the EYELIKE system. Data were compiled on an online platform, allowing clinicians from other regions to make diagnoses. Results The study revealed significant variations in visual acuity and the prevalence of ophthalmic diseases between the two regions. Quang Tri had a higher proportion of individuals with good eyesight compared to Thai Nguyen. In Quang Tri, nearly 50% of the population had media haze, while in Thai Nguyen, about one-third of the population was affected. The prevalence of glaucomatous optic nerve and age-related macular degeneration was approximately 1% higher in Quang Tri than in Thai Nguyen. These findings provide valuable insights into the eye health status of these regions, indicating that eye health in Quang Tri was poorer than in Thai Nguyen. Conclusions The prevalence rates of ophthalmic conditions in this study were within the expected ranges compared to those in other Asian countries, though they were somewhat low. The SBFI method, being simpler and more efficient than the Rapid Assessment of Avoidable Blindness, offers a promising approach for measuring and estimating the prevalence of ophthalmic diseases.

Muscle regeneration and functional restoration are crucial for patients with sarcopenia. Antarctic fish, which are well-adapted to extreme conditions, offer potential pharmacotherapeutic insights. Our study assessed muscle extracts from Trematomus bernacchii (TB) and T. newnesi (TN) in a BaCl2-muscle injury mouse model. TB and TN extracts notably enhanced myofiber formation during muscle regeneration, showing potent proregenerative properties. Grip strength restoration was significantly improved, accompanied by increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial content, which are vital for post-injury recovery. The activation of the mammalian target of rapamycin and insulin-like growth factor 2 muscle enhancer activity underpinned these effects. Ultra-performance liquid chromatography-mass spectrometry and Global Natural Product Social analysis annotated taurocholic acid and its derivatives, along with denatorium, as bioactive substances that contribute to muscle enhancement. These findings have implications for therapeutic development for muscle regeneration and functional recovery in patients with musculoskeletal injuries and sarcopenia.

Abstract Despite the current widespread use of chromosomal microarray analysis (CMA) and exome/genome sequencing for the genetic diagnosis of unexplained intellectual disability (ID) in children, gaining improved diagnostic yields and defined guidelines remains a significant challenge. This is a cohort study of children with unexplained ID. We analyzed the diagnostic yield and its correlation to clinical phenotypes in children with ID who underwent concurrent CMA and clinical exome sequencing (CES). A total of 154 children were included (110 [71.4%] male; mean [SD] age, 51.9 [23.1] months). The overall diagnosis yield was 26.0–33.8%, with CMA contributing 12.3–14.3% and CES contributing 13.6–19.4%, showing no significant difference. The diagnostic rate was significantly higher when gross motor delay (odds ratio, 6.69; 95% CI, 3.20–14.00; P

Anthracnose, caused by the Colletotrichum genus, comprises a significant number of plant pathogens and poses a major threat to fruit production worldwide, including South Korea. Colletotrichum species were identified associated with anthracnose in fruits such as apple, persimmon, plum, peach, jujube, walnut, and grape. A polyphasic approach, including morphology, multigene phylogenetics, and pathogenicity testing, was used. Additionally, the in-vitro sensitivity of identified Colletotrichum species to common fungicides was also evaluated. A total of nine Colletotrichum species within two complexes, namely gloeosporioides and acutatum, have been identified as the causal agents of anthracnose in common fruits in South Korea. In the gloeosporioides complex, we found Colletotrichum aenigma, C. fructicola, C. gloeosporioides, C. horii, C. siamense, and C. viniferum. Meanwhile, in the acutatum complex, C. fioriniae, C. nymphaeae, and C. orientalis were identified. Notably, C. fructicola, C. siamense, C. fioriniae, and C. nymphaeae were reported for the first time from apple, C. siamense, C. fioriniae and C. nymphaeae from plum, C. siamense, C. fructicola, and C. fioriniae from peach, C. siamense and C. horii from persimmon, C. fioriniae from Omija (Schisandra), C. orientalis from walnut, C. nymphaeae from jujube, and C. aenigma, C. fructicola, and C. siamense from grape. Fungicide sensitivity tests revealed significant variation in the EC50 values among specific Colletotrichum species when exposed to different fungicides. Moreover, the same Colletotrichum species isolated from different host plants displayed varying sensitivity to the same fungicide.

Alzheimer’s disease (AD) remains a significant public health challenge with limited effective treatment options. Ramalin, a compound derived from Antarctic lichens, has shown potential in the treatment of AD because of its strong antioxidant and anti-inflammatory properties. However, its instability and toxicity have hindered the development of Ramalin as a viable therapeutic agent. The primary objective of this study was to synthesize and evaluate novel Ramalin derivatives with enhanced stabilities and reduced toxic profiles, with the aim of retaining or improving their therapeutic potential against AD. The antioxidant, anti-inflammatory, anti-BACE-1, and anti-tau activities of four synthesized Ramalin derivatives (i.e., RA-Hyd-Me, RA-Hyd-Me-Tol, RA-Sali, and RA-Benzo) were evaluated. These derivatives demonstrated significantly improved stabilities compared to the parent compound, with RA-Sali giving the most promising results. More specifically, RA-Sali exhibited a potent BACE-1 inhibitory activity and effectively reduced tau phosphorylation, a critical factor in AD pathology. Despite exhibiting reduced antioxidant activities compared to the parent compound, these derivatives represent a potential multi-targeted approach for AD treatment, marking a significant step forward in the development of stable and effective AD therapeutics.

Purpose: To evaluate the reliability of various reference areas for digital alignment between 3D resting and smiling facial models. Materials and Methods: 3D posed and natural smiling faces of 33 adults were registered to the respective neutral faces, using six matching strategies with different reference matching surfaces: nose (N), nose + central forehead (NFc), nose + whole forehead (NFw), nose + chin (NC), nose + central forehead + chin (NFcC), and nose + whole forehead + chin (NFwC). The positional discrepancies of the registered images were measured at the left and right pupil centers. Results: Two-way ANOVA and post hoc multiple pairwise t test with Bonferroni correction (α = .05) were used to evaluate the measurements. As a result, the use of larger reference areas increases the trueness of image-matching, whereas there was no statistically significant difference between the matching strategies within the same smiling type. Meanwhile, the image registration of posed smiles resulted in fewer positional disparities than the natural smiles with significant differences observed for the registration using the NC and NFcC surface-based matching areas at the right pupil (P = .030 and .026, respectively). Conclusions: The findings of this study suggest that the reference surface areas and smiling types have some impact on the accuracy of 3D smiling facial image alignments. Large and evenly distributed matching surfaces are recommended for posed smiles, whereas caution should be taken when using the chin area as a reference surface for matching natural smile facial images. [ABSTRACT FROM AUTHOR]

COVID-19, caused by SARS-CoV-2, has resulted in serious economic and health burdens. Current treatments remain inadequate to extinguish the epidemic, and efficient therapeutic approaches for COVID-19 are urgently being sought. Interestingly, accumulating evidence suggests that microenvironmental disorder plays an important role in the progression of COVID-19 in patients. In addition, recent advances in nanomaterial technologies provide promising opportunities for alleviating the altered homeostasis induced by a viral infection, providing new insight into COVID-19 treatment. Most literature reviews focus only on certain aspects of microenvironment alterations and fail to provide a comprehensive overview of the changes in homeostasis in COVID-19 patients. To fill this gap, this review systematically discusses alterations of homeostasis in COVID-19 patients and potential mechanisms. Next, advances in nanotechnology-based strategies for promoting homeostasis restoration are summarized. Finally, we discuss the challenges and prospects of using nanomaterials for COVID-19 management. This review provides a new strategy and insights into treating COVID-19 and other diseases associated with microenvironment disorders.

Abstract The development of efficient drug delivery systems is essential for improving the efficacy and safety of cancer drugs, particularly for aggressive and difficult‐to‐treat cancers. Covalent organic frameworks (COFs) are emerging as innovative porous nanomaterials in drug delivery systems (DDS), due to their unique properties, including the metal‐free organic skeleton, predetermined structures and pore geometries, high porosity, large surface area, facile surface modification potential, and good biocompatibility. These characteristics make COFs excellent candidates for improving drug delivery by enhancing drug loading capacity and enabling precise encapsulation. This review emphasizes the importance of donor‐acceptor‐based COFs, which provide channels for charge transportation, and we also explore how the π‐conjugated skeleton of COFs enhances its long‐acting fluorescent properties and facilitates drug uptake via cell endocytosis. While this review primarily focuses on recent advancements in COF‐based targeted DDS, it also acknowledges the challenges posed by the diverse pore geometries in porous materials and discusses potential solutions. Further, it underlines the potential of developing future drug carriers that can successfully and specifically target cancer cells, improving treatment efficiency while reducing adverse side effects.

Abstract Ventilation should be assisted without asynchrony or cardiorespiratory instability during anesthesia emergence until sufficient spontaneous ventilation is recovered. In this multicenter cohort study, we develop and validate a reinforcement learning-based Artificial Intelligence model for Ventilation control during Emergence (AIVE) from general anesthesia. Ventilatory and hemodynamic parameters from 14,306 surgical cases at an academic hospital between 2016 and 2019 are used for training and internal testing of the model. The model’s performance is also evaluated on the external validation cohort, which includes 406 cases from another academic hospital in 2022. The estimated reward of the model’s policy is higher than that of the clinicians’ policy in the internal (0.185, the 95% lower bound for best AIVE policy vs. −0.406, the 95% upper bound for clinicians’ policy) and external validation (0.506, the 95% lower bound for best AIVE policy vs. 0.154, the 95% upper bound for clinicians’ policy). Cardiorespiratory instability is minimized as the clinicians’ ventilation matches the model’s ventilation. Regarding feature importance, airway pressure is the most critical factor for ventilation control. In conclusion, the AIVE model achieves higher estimated rewards with fewer complications than clinicians’ ventilation control policy during anesthesia emergence.

Abstract Background We aimed to quantify the identification of mild cognitive impairment and/or Alzheimer’s disease using olfactory-stimulated functional near-infrared spectroscopy using machine learning through a post hoc analysis of a previous diagnostic trial and an external additional trial. Methods We conducted two independent, patient-level, single-group, diagnostic interventional trials (original and additional trials) involving elderly volunteers (aged > 60 years) with suspected declining cognitive function. All volunteers were assessed by measuring the oxygenation difference in the orbitofrontal cortex using an open-label olfactory-stimulated functional near-infrared spectroscopy approach, medical interview, amyloid positron emission tomography, brain magnetic resonance imaging, Mini-Mental State Examination, and Seoul Neuropsychological Screening Battery. Results In total, 97 (original trial) and 36 (additional trial) elderly volunteers with suspected decline in cognitive function met the eligibility criteria. The statistical model reported classification accuracies of 87.3% in patients with mild cognitive impairment and Alzheimer’s disease in internal validation (original trial) but 63.9% in external validation (additional trial). The machine learning algorithm achieved 92.5% accuracy with the internal validation data and 82.5% accuracy with the external validation data. For the diagnosis of mild cognitive impairment, machine learning performed better than statistical methods with internal (86.0% versus 85.2%) and external validation data (85.4% versus 68.8%). Interpretation In two independent trials, machine learning models using olfactory-stimulated oxygenation differences in the orbitofrontal cortex were superior in diagnosing mild cognitive impairment and Alzheimer’s disease compared to classic statistical models. Our results suggest that the machine learning algorithm is stable across different patient groups and increases generalization and reproducibility. Trial registration Clinical Research Information Service (CRiS) of Republic of Korea; CRIS numbers, KCT0006197 and KCT0007589. Graphical Abstract

Magnesium (Mg) alloys have a low density among the structural metals, but it is hard to be plastically deformed due to their crystallographic nature. Wire arc additive manufacturing (WAAM) could be one of the alternative processes to fabricate the Mg products for various industrial applications. Nonetheless, it is used in limited industrial fields due to challenging issues such as low commercial availability of wire, high oxygen affinity, explosive and flammable hazard, and typical defects of WAAM like distortion and side collapse, grain coarsening, etc. In this research, it was tried to find out the better way to fabricate the WAAM of AZ31 alloy. An additional Ar gas side shielding was given during the WAAM process, and compared with the conventional shielding method. It was observed that the global shielding affects the microstructural evolution of the WAAM product, and influences the mechanical property in a positive way.

Developmental delays (DD) and congenital anomalies (CA) are prevalent yet often remain undiagnosed despite comprehensive genetic testing. This study aims to investigate the diagnostic yield of trio whole-genome sequencing (WGS) in children presenting with DD or CA who remained undiagnosed after previous genetic testing. A prospective cohort study was conducted on children with undiagnosed DD or CA at a single tertiary hospital. All participants suspected of genetic conditions had undergone chromosome analysis, chromosome microarray analysis (CMA), and clinical exome sequencing (CES); however, a subset remained undiagnosed. The WGS test was administered to both the affected children and their parents. A total of 52 children were included, and 10 (19.2%) had undergone a genetic diagnosis through WGS. Eight of these cases were associated with autosomal dominant and de novo variants. WGS led to successful diagnosis due to several factors, including small structural variants, genes not covered in the CES panel, the discovery of newly implicated genes, issues related to coverage depth, low variant allele frequency, challenges in variant interpretation, and differences in the interpretation of variants of unknown significance among clinicians. This study highlights the clinical value of trio WGS testing in undiagnosed children with DD or CA. Notably, an additional 19.2% of affected children were diagnosed through this method.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer’s disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.

Candida albicans is an oral mucosal commensal fungus that transforms into an opportunistic pathogen under specific conditions, including immunosuppression. It causes oral and systemic candidiasis, which results in a significant health burden. Furthermore, an alarming rise in antifungal drug resistance in Candida species raises the urgent need for novel drugs and drug targets. C. albicans Dfg5 and Dcw1 are homologous cell wall alpha-1,6-mannosidases with critical functions and represent potential new drug targets. Our past studies have shown that Dfg5 and Dcw1 function in cell wall biogenesis through the cross-linking of glycoproteins into the cell wall, thus playing a key role in cell wall integrity. Additionally, Dfg5 and Dcw1 are required for hyphal morphogenesis. However, the exact functions of Dfg5 and Dcw1 in cell wall integrity, hyphal morphogenesis, and pathogenesis are not known. In this study, we determined the relation of Dfg5 and Dcw1 with Hog1 MAPK, which plays a key role in cell wall integrity via the regulation of chitin synthesis in C. albicans. Additionally, we also determined the effects of dfg5 and dcw1 mutations on the gene expression of transcriptional regulators of hyphal morphogenesis. Furthermore, we determined the effects of dfg5 and dcw1 mutations on pathogenesis in a mouse model of oral candidiasis. Our results demonstrate that dfg5 and dcw1 mutations, as well as a hog1 knockout mutation, result in the dysregulation of chitin synthesis, resulting in a cell separation defect. Heterozygous and conditional mutations in dfg5 and dcw1 resulted in decreased transcriptional levels of cst20, a positive regulator of hyphal morphogenesis. However, dfg5 and dcw1 mutations resulted in increased levels of all the five negative regulators of hyphal morphogenesis—Tup1, Nrg1, Mig1, Rbf1, and Rfg1. Additionally, Tup1 levels were significantly higher than other negative regulators, indicating that Dfg5 and Dcw1 function in hyphal morphogenesis by repressing Tup1. Finally, dfg5 and dcw1 mutations affected the ability of C. albicans to cause oral candidiasis in mice. Thus, the cell wall glycosidases Dfg5 and Dcw1 are required for virulence and pathogenesis and represent novel drug targets.

Abstract Transcranial focused ultrasound stimulation is a promising therapeutic modality for human brain disorders because of its noninvasiveness, long penetration depth, and versatile spatial control capability through beamforming and beam steering. However, the skull presents a major hurdle for successful applications of ultrasound stimulation. Specifically, skull-induced focal aberration limits the capability for accurate and versatile targeting of brain subregions. In addition, there lacks a fully functional preclinical neuromodulation system suitable to conduct behavioral studies. Here, we report a miniature ultrasound system for neuromodulation applications that is capable of highly accurate multiregion targeting based on acoustic holography. Our work includes the design and implementation of an acoustic lens for targeting brain regions with compensation for skull aberration through time-reversal recording and a phase conjugation mirror. Moreover, we utilize MEMS and 3D-printing technology to implement a 0.75-g lightweight neuromodulation system and present in vivo characterization of the packaged system in freely moving mice. This preclinical system is capable of accurately targeting the desired individual or multitude of brain regions, which will enable versatile and explorative behavior studies using ultrasound neuromodulation to facilitate widespread clinical adoption.

Nanomedicines for drug delivery and imaging-guided cancer therapy is a rapidly growing research area. The unique properties of nanomedicines have a massive potential in solving longstanding challenges of existing cancer drugs, such as poor localization at the tumor site, high drug doses and toxicity, recurrence, and poor immune response. However, inadequate biocompatibility restricts their potential in clinical translation. Therefore, advanced nanomaterials with high biocompatibility and enhanced therapeutic efficiency are highly desired to fast-track the clinical translation of nanomedicines. Intrinsic properties of nanoscale covalent organic frameworks (nCOFs), such as suitable size, modular pore geometry and porosity, and straightforward post-synthetic modification via simple organic transformations, make them incredibly attractive for future nanomedicines. The ability of COFs to disintegrate in a slightly acidic tumor microenvironment also gives them a competitive advantage in targeted delivery. This review summarizes recently published applications of COFs in drug delivery, photo-immuno therapy, sonodynamic therapy, photothermal therapy, chemotherapy, pyroptosis, and combination therapy. Herein we mainly focused on modifications of COFs to enhance their biocompatibility, efficacy and potential clinical translation. This review will provide the fundamental knowledge in designing biocompatible nCOFs-based nanomedicines and will help in the rapid development of cancer drug carriers and theranostics.

Time-to-digital converters (TDCs) based on the tapped delay line (TDL) architecture have been widely used in various applications requiring a precise time measurement. However, the poor uniformity of the propagation delays in the TDL implemented on FPGA leads to bubble error and large nonlinearity of the TDC. The purpose of this study was to develop an advanced TDC architecture capable of minimizing the bubble errors and improving the linearity. To remove the bubble errors, the decimated delay line (DDL) architecture was implemented on the UltraScale + FPGA; meanwhile, to improve the linearity of the TDC, a histogram uniformization (HU) and multi-chain TDL (MCT) methods were developed and implemented on the FPGA. The integral nonlinearities (INLs) and differential nonlinearities (DNLs) of the plain TDCs with the ‘HU method’ (HU TDC) and with ‘both HU and MCT methods’ (HU-MCT TDC) were measured and compared to those of the TDC with ‘DDL alone’ (plain TDC). The linearity of HU-MCT TDC were superior to those of the plain TDC and HU TDC. The experiment results indicated that HU-MCT TDC developed in this study was useful for improving the linearity of the TDC, which allowed for high timing resolution to be achieved.

Abstract Stretchable electronics is playing an integral role in fields such as wearable electronics and soft robots. Among soft conductive materials, liquid metal is drawing intense attention as an electrode material due to its liquid nature at room temperature. However, the merits of liquid metal conductor are limited by the presence of substrates or enclosed microchannels from physical disturbances by the underlying substrate when applying it to 3D surface and modifying complex circuit. To overcome this limitation, we develop freestanding patterned liquid metal thin-film conductor (FS-GaIn). FS-GaIn was achieved by introducing metal nanowires to liquid metal and subsequent sequential selective laser processing and etching of directly patterned traces. FS-GaIn can be applied directly to nonflat surface without substrates. When incorporated into electrical circuits, FS-GaIn shows high electrical conductivity, stretchability, and stability. The concept of freestanding liquid metal can open a functionality to the conventional liquid metal electronics.

Background There are many models for predicting diabetes mellitus (DM), but their clinical implication remains vague. Therefore, we aimed to create various DM prediction models using easily accessible health screening test parameters. Methods Two sets of variables were used to develop eight DM prediction models. One set comprised 62 easily accessible examination results of commonly used variables from a tertiary university hospital. The second set comprised 27 of the 62 variables included in the national routine health checkups. Gradient boosting and random forest algorithms were used to develop the models. Internal validation was performed using the stratified 10-fold cross-validation method. Results The area under the receiver operating characteristic curve (ROC-AUC) for the 62-variable DM model making 12-month predictions for subjects without diabetes was the largest (0.928) among those of the eight DM prediction models. The ROC-AUC dropped by more than 0.04 when training with the simplified 27-variable set but still showed fairly good performance with ROC-AUCs between 0.842 and 0.880. The accuracy was up to 11.5% higher (from 0.807 to 0.714) when fasting glucose was included. Conclusion We created easily applicable diabetes prediction models that deliver good performance using parameters commonly assessed during tertiary university hospital and national routine health checkups. We plan to perform prospective external validation, hoping that the developed DM prediction models will be widely used in clinical practice.

Aim: To compare muscle mass in the upper and lower extremities between ambulatory children with cerebral palsy (CP) and typically developing (TD) children. Materials and Methods: A total of 21 children aged 2 to 12 years with CP and a Gross Motor Function Classification System (GMFCS) level of I, II, or III were matched with 21 TD children for age, sex, and body mass index. The lean body mass (LBM) of each extremity was calculated from whole-body dual-energy X-ray absorptiometry. Results: The LBM of the upper extremities was greater in children with CP compared to TD children, and the difference was significant in the GMFCS level II group (1340.6 g vs. 1004.2 g, p = 0.027). There was no significant difference in the LBM of the lower extremities between the CP and TD groups (p = 0.190). The ratio of lower extremity LBM to total extremity LBM was lower in children with CP, while the ratio of upper extremity LBM to total extremity LBM was higher in children with CP (73.2% vs. 78.5% [p < 0.001] and 26.7% vs. 21.5% [p < 0.001], respectively). Conclusions: Ambulatory children with CP, especially in the GMFCS level II group, exhibit greater muscle mass in the upper extremities compared to TD children.

R134a, a vehicle refrigerant used in the vehicle heat pump system, is regulated according to the Montreal Protocol. Refrigerants such as R1234yf, R744, and R290 in vehicle heat pump systems are being investigated to identify their alternatives. Because developing a new system exclusively for new refrigerants is costly, an empirical test was conducted on the R1234yf refrigerant in a heat pump system designed for the R134a refrigerant in an actual vehicle system. The heating, cooling, and battery-cooling modes were tested for the amount of refrigerant charge, and operability tests were conducted for the compressor load; heating, ventilation, air conditioning (HVAC) air flow rate; coolant temperature; and flow rate of each mode. The optimal refrigerant charge in heating mode was 0.7 kg, and the optimal refrigerant charge in the cooling and battery-cooling modes was 0.9 kg. To yield the highest coefficient of performance of the system, the compressor load was 50%, the HVAC fan was 12 V, and the coolant flow rate was 10 LPM. The most efficient system operation was possible at a coolant temperature of 30 °C in the cooling and heating modes and at 20 °C in battery-cooling mode.

Abstract Background Our objective was to report on the prospective outcomes in the areas of depression, quality of life, angina, and frailty in SAVR and TAVR patients with aortic stenosis undergoing aortic valve intervention. Methods We recruited 300 patients across 3 groups (TAVR, SAVR, and CABG) over 12 months. Depression, quality of life, frailty, and angina were assessed followed by propensity score matching. Results Using logistical regression when all patient factors considered for all patients who had SAVR and TAVR, the only preoperative factors that impacted on 1 year mortality was hypertension and STS score. Quality of life improvements within each group over 12 months was significant (p value = 0.0001). Depression at 12 months between groups (p value = 0.0395) and within each group was significant (p value = 0.0073 for SAVR and 0.0001 for TAVR). Angina was most frequent in TAVR at 12 months in the QL (p = 0.0001), PL (p = 0.0007), and improvement was significant in the QL (SAVR p = 0.0010, TAVR p = 0.0001) and PL (SAVR p = 0.0002), TAVR p = 0.0007) domains in both groups. Frailty at 12 months improved in both groups, but was greatest in TAVR (p value = 0.00126). Conclusions This 12 months follow up of cardiac surgical patients has revealed significant improvement in PROMs and frailty in all groups by 3 months postoperative regardless of surgical or transcatheter approach. Outcome measures of quality of life and frailty could be utilized as a measure of outcome more regularly in patients undergoing aortic valve surgery regardless of approach.

Abstract Introduction Basic studies suggest that olfactory dysfunction and functional near-infrared spectroscopy (fNIRS) can be used as tools for the diagnosis of mild cognitive impairment (MCI); however, real-world evidence is lacking. We investigated the potential diagnostic efficacy of olfactory-stimulated fNIRS for early detection of MCI and/or Alzheimer disease (AD). Methods We conducted a patient-level, single-group, diagnostic interventional trial involving elderly volunteers (age >60 years) suspected of declining cognitive function. Patients received open-label olfactory-stimulated fNIRS for measurement of oxygenation difference in the orbitofrontal cortex. All participants underwent amyloid PET, MRI, Mini-Mental State Examination (MMSE), and Seoul Neuropsychological Screening Battery (SNSB). Results Of 97 subjects, 28 (28.9%) were cognitively normal, 32 (33.0%) had preclinical AD, 21 (21.6%) had MCI, and 16 (16.5%) had AD. Olfactory-stimulated oxygenation differences in the orbitofrontal cortex were associated with cognitive impairment; the association was more pronounced with cognitive severity. Olfactory-stimulated oxygenation difference was associated with MMSE (adjusted β [aβ] 1.001; 95% CI 0.540−1.463), SNSB language and related function (aβ, 1.218; 95% CI, 0.020−2.417), SNSB memory (aβ, 1.963; 95% CI, 0.841−3.084), SNSB frontal/executive function (aβ, 1.715; 95% CI, 0.401−3.029) scores, standard uptake value ratio from amyloid PET (aβ, −10.083; 95% CI, −19.063 to −1.103), and hippocampal volume from MRI (aβ, 0.002; 95% CI, 0.001−0.004). Olfactory-stimulated oxygenation difference in the orbitofrontal cortex was superior in diagnosing MCI and AD (AUC, 0.909; 95% CI, 0.848−0.971), compared to amyloid PET (AUC, 0.793; 95% CI, 0.694−0.893) or MRI (AUC, 0.758; 95% CI, 0.644−0.871). Discussion Our trial showed that olfactory-stimulated oxygenation differences in the orbitofrontal cortex detected by fNIRS were associated with cognitive impairment and cognitive-related objectives. This novel approach may be a potential diagnostic tool for patients with MCI and/or AD. Trial registration CRIS number, KCT0006197 .