Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease.

Many Mendelian disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD. Strikingly, FAN1, previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse FAN1 haplotypes independently modify HD, with rare genetic variants diminishing DNA binding or nuclease activity of the FAN1 protein, hastening HD onset. However, the mechanism behind the frequent and the most significant onset-delaying FAN1 haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3'-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant FAN1 expression quantitative trait loci signal and allelic imbalance in FAN1 messenger ribonucleic acid (mRNA), accounting for the most significant and frequent onset-delaying modifier haplotype in HD. Specifically, miR-124-3p selectively targets the reference allele at rs3512, diminishing the stability of FAN1 mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3'-UTR reporter vectors with swapped alleles, confirmed the specificity of miR-124-3p at rs3512. Together, these findings indicate that the alternative allele at rs3512 renders the FAN1 mRNA less susceptible to miR-124-3p-mediated posttranscriptional regulation, resulting in increased FAN1 levels and a subsequent delay in HD onset by mitigating CAG repeat instability.

Refining Classification of Cholangiocarcinoma Subtypes via Proteogenomic Integration Reveals New Therapeutic Prospects.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficult diagnosis, and overall poor prognosis. The iCC molecular classification for developing precision medicine strategies was investigated. METHODS: Comprehensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses were performed on treatment-naïve tumor samples from 102 patients with iCC who underwent surgical resection with curative intent. An organoid model was constructed for testing therapeutic potential. RESULTS: Three clinically supported subtypes (stem-like, poorly immunogenic, and metabolism) were identified. NCT-501 (aldehyde dehydrogenase 1 family member A1 [ALDH1A1] inhibitor) exhibited synergism with nanoparticle albumin-bound-paclitaxel in the organoid model for the stem-like subtype. The oncometabolite dysregulations were associated with different clinical outcomes in the stem-like and metabolism subtypes. The poorly immunogenic subtype harbors the non-T-cell tumor infiltration. Integrated multiomics analysis not only reproduced the 3 subtypes but also showed heterogeneity in iCC. CONCLUSIONS: This large-scale proteogenomic analysis provides information beyond that obtained with genomic analysis, allowing the functional impact of genomic alterations to be discerned. These findings may assist in the stratification of patients with iCC and in developing rational therapeutic strategies.

Long-term exposure to air pollution and precocious puberty in South Korea.

BACKGROUND AND AIM: The increasing prevalence of precocious puberty (PP) has emerged as a significant medical and social problem worldwide. However, research on the relationship between long-term air pollution exposure and PP has been relatively limited. We thus investigated the association between long-term air pollution exposure and the onset of PP in South Korea. METHODS: We investigated a retrospective cohort using the Korea National Health Insurance Database. Six-year-old children born from 2007 to 2009 were examined (2013-2015). We included boys ≤10 years and girls aged ≤9 years who visited hospitals for early pubertal development, were diagnosed with PP per the ICD-10 (E228, E301, and E309), and received gonadotropin-releasing hormone agonist treatment. We analyzed data for boys up until 10 years old (60-month follow-up) and for girls up to 9 years old (48-month follow-up). We assessed the association between long-term air pollution exposure and the onset of PP using a Cox proportional hazard model. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) per 1 µg/m3 increase in fine particulate matter (PM2.5) and particulate matter (PM10) and per 1 ppb increase in sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3). RESULTS: This study included 1,205,784 children aged six years old between 2013 and 2015. A positive association was found between the 48-month moving average PM2.5 (HR: 1.019; 95% CI: 1.012, 1.027), PM10 (HR: 1.009; 95% CI: 1.006, 1.013), SO2 (HR: 1.037; 95% CI: 1.018, 1.055), and O3 (HR: 1.006; 95% CI: 1.001, 1.010) exposure and PP in girls but not boys. CONCLUSIONS: This study provides valuable insights into the harmful effects of air pollution during childhood and adolescence, emphasizing that air pollution is a risk factor that should be managed and reduced.

The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.

TRAF7-related disorders represent some of the rarest inherited disorders, exhibiting clinical features that overlap with cardiac, facial, and digital anomalies with developmental delay (CAFDADD) syndrome, as well as blepharophimosis-mental retardation syndrome (BMRS). A 36-year-old male, presenting with total blindness, blepharophimosis, and intellectual disability, was admitted for the assessment of resting dyspnea several months previously. He had a history of being diagnosed with obstructive sleep apnea (OSA). Transesophageal and transthoracic echocardiography unveiled right ventricular dilatation without significant pulmonary hypertension, bicuspid aortic valve with aortic root aneurysm, and aortic regurgitation in the proband. Sanger sequencing identified a de novo TRAF7 variant (c.1964G>A; p.Arg655Gln). Subsequently, aortic root replacement using the Bentall procedure was performed. However, despite the surgery, he continued to experience dyspnea. Upon re-evaluating OSA with polysomnography, it was discovered that continuous positive airway pressure support alleviated his symptoms. The underlying cause of his symptoms was attributed to OSA, likely exacerbated by the vertebral anomaly and short neck associated with CAFDADD syndrome. Clinicians should be attentive to the symptoms associated with OSA as it is a potentially serious medical condition in patients with TRAF7 variants.

Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects.

A recent genome-wide association study of Huntington disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene Fanconi-Associated Nuclease 1 (FAN1). Here, we have carried out detailed genetic, molecular, and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA-binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA-binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hastening modifier signals. We also idenified a third onset-hastening modifier signal whose mechanism of action remains uncertain but does not involve an amino acid change in FAN1. We present additional evidence that a frequent onset-delaying modifier signal does not alter FAN1 coding sequence but is associated with increased FAN1 mRNA expression in the cerebral cortex. Consistent with these findings and other cellular overexpression and/or suppression studies, knockout of FAN1 increased CAG repeat expansion in HD-induced pluripotent stem cells. Together, these studies support the process of somatic CAG repeat expansion as a therapeutic target in HD, and they clearly indicate that multiple genetic variations act by different means through FAN1 to influence HD onset in a manner that is largely additive, except in the rare circumstance that two onset-hastening alleles are present. Thus, an individual's particular combination of FAN1 haplotypes may influence their suitability for HD clinical trials, particularly if the therapeutic agent aims to reduce CAG repeat instability.

Institutional-specific smartphone application as a supplemental tool for an antimicrobial stewardship program in 2 large community-based hospitals: Acceptance of physicians and pharmacists.

PURPOSE: Antimicrobial stewardship programs (ASPs) have been a challenge in less resourceful health care settings. Medical smartphone applications (apps) can be accessible tools to support ASPs under such circumstances. A hospital-specific ASP app was prepared and the acceptance and usability of the study ASP app were evaluated by physicians and pharmacists in 2 community-based academic hospitals. METHODS: The exploratory survey was conducted 5 months following the implementation of the study ASP app. A questionnaire was developed, and the validity and reliability were analyzed using S-CVI/Ave (scale content validity index/Average) and Cronbach's alpha, respectively. The questionnaire consisted of demographics (3 items), acceptance (9 items), usability (10 items), and barriers (2 items). Descriptive analysis was conducted using a 5-point Likert scale, multiple selections, and free-text responses. RESULTS: Approximately 38.7% of 75 respondents (response rate, 23.5%) used the app. Most scored 4 or higher, indicating that the study ASP app was easy to install (89.7%), use (79.3%), and apply to clinical settings (69.0%). Frequently used contents were dosing (39.6%), the spectrum of activity (7.1%), and intravenous-to-oral conversion (7.1%). Barriers included limited time (38.2%) and insufficient content (20.6%). Users indicated that the study ASP app helped improve their knowledge on treatment guidelines (72.4%), antibiotic use (62.1%), and adverse reactions (69.0%). CONCLUSION: The study ASP app was well accepted by physicians and pharmacists and it can be useful to supplement ASPs activities in less resourceful hospitals with a large burden of patient care.

Targeting the Sequences of Circulating Tumor DNA of Cholangiocarcinomas and Its Applications and Limitations in Clinical Practice.

Cholangiocarcinoma is a malignant epithelial tumor arising from bile ducts that is frequently fatal. Diagnosis is difficult due to tumor location in the biliary tract. Earlier diagnosis requires less invasive methods of identifying effective biomarkers for cholangiocarcinoma. The present study investigated the genomic profiles of cell-free DNA (cfDNA) and DNA from corresponding primary cholangiocarcinomas using a targeted sequencing panel. Somatic mutations in primary tumor DNA and circulating tumor DNA (ctDNA) were compared and clinical applications of ctDNA validated in patients with cholangiocarcinoma. A comparison of primary tumor DNA and ctDNA identified somatic mutations in patients with early cholangiocarcinomas that showed clinical feasibility for early screening. The predictive value of single-nucleotide variants (SNVs) of preoperative plasma cfDNA positive for somatic mutations of the primary tumor was 42%. The sensitivity and specificity of postoperative plasma SNVs in detecting clinical recurrence were 44% and 45%, respectively. Targetable fibroblast growth factor receptor 2 (FGFR2) and Kirsten rat sarcoma virus (KRAS) mutations were detected in 5% of ctDNA samples from patients with cholangiocarcinoma. These findings showed that genomic profiling of cfDNA was useful in clinical evaluation, although ctDNA had limited ability to detect mutations in cholangiocarcinoma patients. Serial monitoring of ctDNA is important clinically and in assessing real-time molecular aberrations in cholangiocarcinoma patients.

Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington's disease knock-in mice is blocked by Mlh1 knock-out.

Recent genome-wide association studies of age-at-onset in Huntington's disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability. Simultaneous knock-out of Mlh1, the ortholog of a third HD age-at-onset modifier gene (MLH1), which suppresses somatic expansion of the Htt knock-in CAG repeat, blocked the Fan1 knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the RRM2B modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the FAN1 modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.

Insights into Bacterial Community Structure and Metabolic Diversity of Mercury-Contaminated Sediments from Hyeongsan River, Pohang, South Korea.

This study investigated the bacterial community structure and metabolic diversity and their relationship with Hg and other environmental variables in sediments collected from different locations (HSR-1-HSR-6) in the Hyeongsan River estuary in South Korea. The results showed that the highest total mercury (THg) and methylmercury (MeHg) concentrations were in HSR-2, with values of 4585.3 µg/kg and 13.4 µg/kg, respectively. The lowest THg (31.9 µg/kg) and MeHg (0.1 µg/kg) concentrations were found in HSR-1. Sulfate and organic matter (OM) were more influential environmental variables, revealing a positive association with THg and MeHg and negatively affecting bacterial and metabolic diversities. Bacterial and metabolic diversities were also negatively impacted by the THg and MeHg concentrations. Proteobacteria and Bacteroidetes were abundantly distributed in all the sediments. The dominance of Proteobacteria was upscaled in all the heavily Hg-contaminated sites (HSR-2-HSR-6), and it was the only phylum that showed a significant positive correlation with THg, MeHg, and OM. The genera Sulfurovum and Sulfurimonas were abundantly observed in sites with high Hg contamination, whereas Congregibacter, Gaetbulibacter, Ilumatobacter, Methylotenera, Nevskia, and Sediminibacter were only detected in low Hg-contaminated sites (HSR-1). The community-level physiological profile data showed the highest (1.0) average well color development (AWCD) value in HSR-1 and the lowest (0.45) AWCD value in HSR-2. Overall, these results demonstrated the inhibitory effects of THg, MeHg, and other environmental variables on microbial communities and metabolic diversity. These findings broaden the current knowledge on the dynamics of bacterial and metabolic diversities in Hg-contaminated sediments and might be useful in the management of Hg pollution.

Determinants of adherence to personal preventive behaviours based on the health belief model: a cross-sectional study in South Korea during the initial stage of the COVID-19 pandemic.

BACKGROUND: Along with the rapid transmission of COVID-19, adherence to preventive behaviours plays a crucial role with respect to the control of COVID-19. However, different individuals' psychological characteristics and risk perception result in various forms of response to preventive behaviours. Based on the Health Belief Model, this study identifies the factors associated with preventive behaviours towards COVID-19 in South Korea during the initial stage of the COVID-19 pandemic. METHODS: A cross-sectional study was conducted in April 2020 through an anonymous online survey. A total of 1207 people in the age bracket of 20-59 years participated in the survey. Single and multiple linear regression analyses were conducted to identify the determinants of preventive behaviours against COVID-19. RESULTS: The following factors were associated with preventive behaviours towards COVID-19: female gender (ß = .124, p < 0.001), has a master's degree or above (ß = 0.065, p = 0.010), perceived susceptibility (ß = .197, p < 0.001), self-efficacy (ß = .404, p < 0.001), trust in radio (ß = -.080, p = .006), trust in official government website (ß = .057, p = .045), trust in social networks (ß = .054, p = .033), and trust in family and friends (ß = .068, p = .009), with an explanatory power of 41.5% (R2 = 0.415). CONCLUSIONS: To flatten the epidemic curve, it is important to understand the public's risk perception and the motivation behind behavioural responses that aim to promote preventive behaviours among the public. Thus, this study calls for the provision of accessible and credible information sources and demonstrates a public health campaign that encourages the public's engagement in preventive behaviours towards COVID-19.

Artificial Intelligence Applied to Cardiomyopathies: Is It Time for Clinical Application?

PURPOSE OF REVIEW: Artificial intelligence (AI) techniques have the potential to remarkably change the practice of cardiology in order to improve and optimize outcomes in heart failure and specifically cardiomyopathies, offering us novel tools to interpret data and make clinical decisions. The aim of this review is to describe the contemporary state of AI and digital health applied to cardiomyopathies as well as to define a potential pivotal role of its application by physicians in clinical practice. RECENT FINDINGS: Many studies have been undertaken in recent years on cardiomyopathy screening especially using AI-enhanced electrocardiography (ECG). Even with mild left ventricular (LV) dysfunction, AI-ECG screening for amyloidosis, hypertrophic cardiomyopathy, or dilated cardiomyopathy is now feasible. Introduction of AI-ECG in routine clinical care has resulted in higher detection of LV systolic dysfunction; however, clinical research on a broader scale with diverse populations is necessary and ongoing. In the area of cardiac-imaging, AI automatically assesses the thickness and characteristics of myocardium to differentiate cardiomyopathies, but research on its prognostic capability has yet to be conducted. AI is also being applied to cardiomyopathy genomics, especially to predict pathogenicity of variants and identify whether these variants are clinically actionable. While the implementation of AI in the diagnosis and treatment of cardiomyopathies is still in its infancy, an ever-growing clinical research strategy will ascertain the clinical utility of these AI tools to help improve diagnosis of and outcomes in cardiomyopathies. We also need to standardize the tools used to monitor the performance of AI-based systems which can then be used to expedite decision-making and rectify any hidden biases. Given its potential important role in clinical practice, healthcare providers need to familiarize themselves with the promise and limitations of this technology.

Negative emotion-related eating behaviours in young women with underweight status, overweight status, anorexia nervosa, and bulimia nervosa in Korea.

OBJECTIVE: This study aimed at investigating the negative emotion-related eating behaviours of young women with extreme weights or eating disorders (EDs). METHOD: A total of 808 young women participated including 144 with underweight (UW), 364 with normal-weight (NW) and 137 with overweight (OW; including 27 with obesity) from universities, and 63 patients with anorexia nervosa (AN), and 100 patients with bulimia nervosa (BN) from a hospital. Participants were interviewed and completed questionnaires on eating behaviours related to negative emotions. RESULTS: While both OW and BN groups ate more in response to negative emotions, UW and AN groups ate less compared to NW group. Negative feelings after overeating were prominent in OW group and patients with ED. In negative emotions, patients with EDs preferred sweet tastes, but BN group preferred spicy tastes less. Patients with EDs had increased external eating, and BN group also showed increased restrained eating. Neuroticism had indirect impacts on OW status via emotional eating unlike BN. CONCLUSIONS: The results suggest that UW and OW status were on the spectrum of emotional eating, and AN and BN were on the extremes of external eating, which may be integrated into the development of interventions targeting each status.

Nurses' duty to care during the COVID-19 pandemic: a cross-sectional survey.

BACKGROUND: Despite the increased demand for nurses worldwide, discussion of nurses' duty to care is lacking. This study aimed to examine nurses' duty to care during the coronavirus disease 2019 (COVID-19) pandemic and to identify the influencing factors. METHODS: This was a cross-sectional descriptive research study that used a structured online questionnaire. Registered Korean nurses answered a demographic questionnaire and the Nash Duty to Care Scale. RESULTS: Age and employment at tertiary hospitals increased nurses' duty to care. Male sex, a highly educated status, and employment at tertiary hospitals increased the perceived risk. Male sex and employment at tertiary or general hospitals increased confidence in the employer, while a high level of education and a longer total clinical career decreased the same. Age and a higher monthly wage increased perceived obligation. Age, lack of religious beliefs, and clinical experience of 3-7 years increased professional preparedness. CONCLUSION: Without enough nursing manpower, the disaster response system could prove to be inefficient. Considering that adequate nurse staffing is essential in disaster management, it is crucial to ensure that nurses have a will to provide care in the case of disaster. In the future, a more active discussion on nurses' duty to care and additional research on factors that may hinder and facilitate the same are needed.

Impact of renin angiotensin system inhibitor on 3-year clinical outcomes in acute myocardial infarction patients with preserved left ventricular systolic function: a prospective cohort study from Korea Acute Myocardial Infarction Registry (KAMIR).

BACKGROUND: Patients with acute myocardial infarction (AMI) are usually treated with angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) if ACEIs are not tolerated. However, there is no data regarding the impact of switching from ACEIs to ARBs on long-term clinical outcomes in AMI patients with preserved left ventricular (LV) systolic function especially beyond 1 year. To investigate the effectiveness of treatment with ACEIs or ARBs on clinical outcomes over 3 years in AMI patients with preserved LV systolic function following percutaneous coronary intervention. METHOD: It is a prospective cohort study using data from a nationwide large scale registry with 53 hospitals involved in treatment of acute myocardial infarction (AMI) in Korea. Between March 2011 and September 2015, we enrolled 6236 patients with AMI who underwent primary percutaneous coronary intervention and had a left ventricular ejection fraction ≥ 50%. Main outcome measures composite of total death or recurrent AMI over 3 years after AMI. Patients were divided into an ACEI group (n = 2945), ARB group (n = 2197), or no renin-angiotensin system inhibitor (RASI) treatment (n = 1094). We analyzed patients who changed treatment. Inverse probability of treatment weighting (IPTW) analysis was also performed. RESULTS: After the adjustment with inverse probability weighting, the primary endpoints at 1 year, AMI patients receiving ACEIs showed overall better outcomes than ARBs [ARBs hazard ratio (HR) compared with ACEIs 1.384, 95% confidence interval (CI) 1.15-1.71; P = 0.003]. However, 33% of patients receiving ACEIs switched to ARBs during the first year, while only about 1.5% switched from ARBs to ACEIs. When landmark analysis was performed from 1 year to the end of the study, RASI group showed a 31% adjusted reduction in primary endpoint compared to patients with no RASI group (HR, 0.74; 95% CI 0.56-0.97; P = 0.012). CONCLUSIONS: This result suggests that certain patients got benefit from treatment with ACEIs in the first year if tolerated, but switching to ARBs beyond the first year produced similar outcomes. RASI beyond the first year reduced death or recurrent AMI in AMI patients with preserved LV systolic function. CRIS Registration number: KCT0004990.

Initial diastolic dysfunction is a powerful predictor of 5-year mortality in peripheral arterial disease patients undergoing percutaneous transluminal angioplasty.

Peripheral arterial disease (PAD) and heart failure share common risks and are associated with increased morbidity and mortality. However, it is unknown whether cardiac function can be an independent predictor of long-term mortality in patients with PAD. In total, 902 patients who underwent percutaneous transluminal angioplasty for PAD were enrolled. The patients were categorized into three groups according to the left ventricular ejection fraction (LVEF): reduced EF (< 40%, n = 62); mid-range EF (40-49%, n = 76); and preserved EF (≥ 50%, n = 764). Echocardiographic (EF, ratio of mitral inflow velocity to annular velocity E/e' ≥ 15, and others) and clinical parameters were tested using stepwise logistic regression analysis to determine independent predictors of 5-year mortality. A higher proportion of patients with reduced EF had ischemic heart disease than those with preserved EF (77.4% vs. 56.8%, p < 0.001). Up to 5 years, patients with reduced EF and mid-range EF showed a higher incidence of total death than those with normal EF. However, there was no difference in the incidence of myocardial infarction, stroke, and revascularization among the three groups. After multivariable adjustment, the ratio of E/e' ≥ 15 was the only strong predictor of total mortality (hazard ratio 6.14; 95% confidence interval 3.7-10.1; p < 0.01). Patients with PAD and reduced EF undergoing PTA had a higher incidence of total death during the 5-year follow-up. Initial tissue Doppler E/e' ≥ 15, a non-invasive estimate of left atrial filling pressure, was the only independent predictor of long-term mortality. The relationship between PAD and HF.

Artificial intelligence for detecting electrolyte imbalance using electrocardiography.

INTRODUCTION: The detection and monitoring of electrolyte imbalance is essential for appropriate management of many metabolic diseases; however, there is no tool that detects such imbalances reliably and noninvasively. In this study, we developed a deep learning model (DLM) using electrocardiography (ECG) for detecting electrolyte imbalance and validated its performance in a multicenter study. METHODS AND RESULTS: This retrospective cohort study included two hospitals: 92,140 patients who underwent a laboratory electrolyte examination and an ECG within 30 min were included in this study. A DLM was developed using 83,449 ECGs of 48,356 patients; the internal validation included 12,091 ECGs of 12,091 patients. We conducted an external validation with 31,693 ECGs of 31,693 patients from another hospital, and the result was electrolyte imbalance detection. During internal, the area under the receiving operating characteristic curve (AUC) of a DLM using a 12-lead ECG for detecting hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hypercalcemia, and hypocalcemia were 0.945, 0.866, 0.944, 0.885, 0.905, and 0.901, respectively. The values during external validation of the AUC of hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hypercalcemia, and hypocalcemia were 0.873, 0.857, 0.839, 0.856, 0.831, and 0.813 respectively. The DLM helped to visualize the important ECG region for detecting each electrolyte imbalance, and it showed how the P wave, QRS complex, or T wave differs in importance in detecting each electrolyte imbalance. CONCLUSION: The proposed DLM demonstrated high performance in detecting electrolyte imbalance. These results suggest that a DLM can be used for detecting and monitoring electrolyte imbalance using ECG on a daily basis.

Population-specific genetic modification of Huntington's disease in Venezuela.

Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2-21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.

Detection and classification of arrhythmia using an explainable deep learning model.

BACKGROUND: Early detection and intervention is the cornerstone for appropriate treatment of arrhythmia and prevention of complications and mortality. Although diverse deep learning models have been developed to detect arrhythmia, they have been criticized due to their unexplainable nature. In this study, we developed an explainable deep learning model (XDM) to classify arrhythmia, and validated its performance using diverse external validation data. METHODS: In this retrospective study, the Sejong dataset comprising 86,802 electrocardiograms (ECGs) was used to develop and internally variate the XDM. The XDM based on a neural network-backed ensemble tree was developed with six feature modules that are able to explain the reasons for its decisions. The model was externally validated using data from 36,961 ECGs from four non-restricted datasets. RESULTS: During internal and external validation of the XDM, the average area under the receiver operating characteristic curves (AUCs) using a 12­lead ECG for arrhythmia classification were 0.976 and 0.966, respectively. The XDM outperformed a previous simple multi-classification deep learning model that used the same method. During internal and external validation, the AUCs of explainability were 0.925-0.991. CONCLUSION: Our XDM successfully classified arrhythmia using diverse formats of ECGs and could effectively describe the reason for the decisions. Therefore, an explainable deep learning methodology could improve accuracy compared to conventional deep learning methods, and that the transparency of XDM can be enhanced for its application in clinical practice.

Deep Learning Algorithm to Predict Need for Critical Care in Pediatric Emergency Departments.

BACKGROUND AND OBJECTIVES: Emergency department (ED) overcrowding is a national crisis in which pediatric patients are often prioritized at lower levels. Because the prediction of prognosis for pediatric patients is important but difficult, we developed and validated a deep learning algorithm to predict the need for critical care in pediatric EDs. METHODS: We conducted a retrospective observation cohort study using data from the Korean National Emergency Department Information System, which collected data in real time from 151 EDs. The study subjects were pediatric patients who visited EDs from 2014 to 2016. The data were divided by date into derivation and test data. The primary end point was critical care, and the secondary endpoint was hospitalization. We used age, sex, chief complaint, symptom onset to arrival time, arrival mode, trauma, and vital signs as predicted variables. RESULTS: The study subjects consisted of 2,937,078 pediatric patients of which 18,253 were critical care and 375,078 were hospitalizations. For critical care, the area under the receiver operating characteristics curve of the deep learning algorithm was 0.908 (95% confidence interval, 0.903-0.910). This result significantly outperformed that of the pediatric early warning score (0.812 [0.803-0.819]), conventional triage and acuity system (0.782 [0.773-0.790]), random forest (0.881 [0.874-0.890]), and logistic regression (0.851 [0.844-0.858]). For hospitalization, the deep-learning algorithm (0.782 [0.780-0.783]) significantly outperformed the other methods. CONCLUSIONS: The deep learning algorithm predicted the critical care and hospitalization of pediatric ED patients more accurately than the conventional early warning score, triage tool, and machine learning methods.

Antioxidant, Anti-Inflammatory and Antithrombotic Effects of Ginsenoside Compound K Enriched Extract Derived from Ginseng Sprouts.

Partially purified ginsenoside extract (PGE) and compound K enriched extract (CKE) were prepared from ginseng sprouts, and their antioxidant, anti-inflammatory and antithrombotic effects were investigated. Compared to the 6-year-old ginseng roots, ginseng sprouts were found to have a higher content of phenolic compounds, saponin and protopanaxadiol-type ginsenoside by about 56%, 36% and 43%, respectively. PGE was prepared using a macroporous adsorption resin, and compound K(CK) was converted and enriched from the PGE by enzymatic hydrolysis with a conversion rate of 75%. PGE showed higher effects than CKE on radical scavenging activity in antioxidant assays. On the other hand, CKE reduced nitric oxide levels more effectively than PGE in RAW 264.7 cells. CKE also reduced pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 than PGE. Tail bleeding time and volume were investigated after administration of CKE at 70-150 mg/kg/day to mice. CKE administered group showed a significant increase or increased tendency in bleeding time than the control group. Bleeding volume in the CKE group increased than the control group, but not as much as in the aspirin group. In conclusion, ginseng sprouts could be an efficient source of ginsenoside, and CKE converted from the ginsenosides showed antioxidant, anti-inflammatory and antithrombotic effects. However, it was estimated that the CKE might play an essential role in anti-inflammatory effects rather than antioxidant effects.