Genomic epidemiology of highly pathogenic avian influenza A (H5N1) virus in wild birds in South Korea during 2021-2022: Changes in viral epidemic patterns.

Clade 2.3.4.4b highly pathogenic avian influenza A (HPAI) viruses have been detected in wild birds worldwide, causing recurrent outbreaks since 2016. During the winter of 2021-2022, we detected one H5N8 and forty-three H5N1 clade 2.3.4.4b HPAI viruses from wild birds in South Korea. Phylogenetic analysis revealed that HA gene of H5N1 viruses was divided into two genetically distinct groups (N1.G1 and N1.G2). Bayesian phylodynamic analysis demonstrated that wild birds play a vital role in viral transmission and long-term maintenance. We identified five genotypes (N1.G1.1, N1.G2, N1.G2.1, N1.G2.2, and N1.G2.2.1) having distinct gene segment constellations most probably produced by reassortments with low-pathogenic avian influenza viruses. Our results suggest that clade 2.3.4.4b persists in wild birds for a long time, causing continuous outbreaks, compared with previous clades of H5 HPAI viruses. Our study emphasizes the need for enhancing control measures in response to the changing viral epidemiology.

Detection of multiple recombinations of avian coronavirus in South Korea by whole-genome analysis.

Infectious bronchitis virus (IBV), an avian coronavirus, has caused considerable damage to the poultry industry. In Korea, indigenous KM91-like and newly introduced QX-like lineages belonging to the GI-19 lineage have been prevalent despite constant vaccination. In this study, complete genome sequences of 23 IBV isolates in Korea from 2010 to 2020 were obtained using next-generation sequencing, and their phylogenetic relationship and recombination events were analyzed. Phylogenetic analysis based on the S1 gene showed that all isolates belonged to the GI-19 lineage and were divided into five subgroups (KM91-like, K40/09-like, and QX-like II to IV). Among the 23 isolates, 14 recombinants were found, including frequent recombination between KM91-like and QX-like strains. In addition, it was observed that other lineages, such as GI-1, GI-13, and GI-16, were involved in recombination. Most recombination breakpoints were detected in the ORF1ab gene, particularly nsp3. However, when considering the size of each genome, recombination occurred more frequently in the 3a, E and 5a genes. Taken together, genetic recombination frequently occurred throughout the entire genome between various IBV strains in Korea, including live attenuated vaccine strain. Our study suggests the necessity of further research on the contribution of recombination of genomes outside the spike region to the biological characteristics of IBV.

Three distinct ORF1a recombinants of the SARS-CoV-2 Delta variant of concern.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergency of various lineages through mutations and recombination. In the Delta lineage, we identified recombination events in the ORF1a gene, which divided the Delta sublineages into three different genotypes (Delta R1-R3). The regional distributions of Delta R1 and Delta R2 were not correlated, indicating that recombination occurred early in the Delta outbreak. The impact of the ORF1a gene on SARS-CoV-2 transmission remains unclear; however, our findings suggest that recombination may have contributed to the evolution and global spread of the Delta lineage.

A circulating cell-free DNA methylation signature for the detection of hepatocellular carcinoma.

To address the shortcomings of current hepatocellular carcinoma (HCC) surveillance tests, we set out to find HCC-specific methylation markers and develop a highly sensitive polymerase chain reaction (PCR)-based method to detect them in circulating cell-free DNA (cfDNA). The analysis of large methylome data revealed that Ring Finger Protein 135 (RNF135) and Lactate Dehydrogenase B (LDHB) are universally applicable HCC methylation markers with no discernible methylation level detected in any other tissue types. These markers were used to develop Methylation Sensitive High-Resolution Analysis (MS-HRM), and their diagnostic accuracy was tested using cfDNA from healthy, at-risk, and HCC patients. The combined MS-HRM RNF135 and LDHB analysis detected 57% of HCC, outperforming the alpha-fetoprotein (AFP) test's sensitivity of 45% at comparable specificity. Furthermore, when used with the AFP test, the methylation assay can detect 70% of HCC. Our findings suggest that the cfDNA methylation assay could be used for HCC liquid biopsy.

Pan-cancer analysis reveals multifaceted roles of retrotransposon-fusion RNAs.

Transposon-derived transcripts are abundant in RNA sequences, yet their landscape and function, especially for fusion transcripts derived from unannotated or somatically acquired transposons, remains underexplored. Here, we developed a new bioinformatic tool to detect transposon-fusion transcripts in RNA-sequencing data and performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 3,088 normal tissue samples. We identified 52,277 cancer-specific fusions with ~30 events per cancer and hotspot loci within transposons vulnerable to fusion formation. Exonization of intronic transposons was the most prevalent genic fusions, while somatic L1 insertions constituted a small fraction of cancer-specific fusions. Source L1s and HERVs, but not Alus showed decreased DNA methylation in cancer upon fusion formation. Overall cancer-specific L1 fusions were enriched in tumor suppressors while Alu fusions were enriched in oncogenes, including recurrent Alu fusions in EZH2 predictive of patient survival. We also demonstrated that transposon-derived peptides triggered CD8+ T-cell activation to the extent comparable to EBV viruses. Our findings reveal distinct epigenetic and tumorigenic mechanisms underlying transposon fusions across different families and highlight transposons as novel therapeutic targets and the source of potent neoantigens.

Detection of intercontinental reassortant H6 avian influenza viruses from wild birds in South Korea, 2015 and 2017.

Avian influenza viruses (AIVs) in wild birds are phylogenetically separated in Eurasian and North American lineages due to the separated distribution and migration of wild birds. However, AIVs are occasionally dispersed between two continents by migratory wild birds flying across the Bering Strait. In this study, we isolated three AIVs from wild bird feces collected in South Korea that contain gene segments derived from American lineage AIVs, including an H6N2 isolated in 2015 and two H6N1 in 2017. Phylogenetic analysis suggests that the H6N2 virus had American lineage matrix gene and the H6N1 viruses had American lineage nucleoprotein and non-structural genes. These results highlight that novel AIVs have continuously emerged by reassortment between viruses from the two continents. Therefore, continuous monitoring for the emergence and intercontinental spread of novel reassortant AIV is required to prepare for a possible future outbreak.

Phylodynamic analysis revealed that human mobility and vaccination were correlated to the local spread of SARS-CoV-2 in Republic of Korea.

Following the global emergence of the SARS-CoV-2 Alpha variant of concern (VOC) in 2020, the Delta variant triggered another wave in 2021. The AY.69 lineage, a Delta VOC, was particularly prevalent in Republic of Korea (South Korea) from May 2021 to January 2022, despite the synchronized implementation of vaccination programmes and non-pharmaceutical interventions (NPIs) such as social distancing. In this study, we used phylogeographic analysis combined with a generalized linear model (GLM) to examine the impact of human movement and vaccination on viral transmission. Our findings indicated that transmission primarily originated in South Korea's metropolitan areas, and a positive correlation was observed between total human mobility (tracked by GPS on mobile phones and estimated through credit card consumption) and viral spread. The phylodynamic analysis further revealed that non-vaccinated individuals were the primary transmitters of the virus during the study period, even though vaccination programmes had commenced three months prior to the AY.69 outbreak. Our study emphasizes the need to focus on controlling SARS-CoV-2 transmission in metropolitan regions and among unvaccinated populations. Furthermore, the positive correlation between mobility data and viral dissemination could contribute to the development of more accurate predictive models for local spread of pandemics.

Time-Varying Risk Factors for Incident Fractures in Kidney Transplant Recipients: A Nationwide Cohort Study in South Korea.

Little is known about the time-varying risk factors for fractures in kidney transplant recipients (KTRs). Using the Korea Organ Transplantation Registry, a nationwide cohort study of KTRs, the incidence, locations, and time-varying predictors of fractures were analyzed, including at baseline and post-transplant 6-month variables in KTRs who underwent KT between January 2014 and June 2019. Among 4134 KTRs, with a median follow-up of 2.94 years (12,441.04 person-years), 63 patients developed fractures. The cumulative 5-year incidence was 2.10%. The most frequent locations were leg (25.40%) and foot/ankle (22.22%). In multivariable analysis, older recipient age at baseline (hazard ratio [HR], 1.035; 95% confidence interval [CI], 1.007-1.064; p = 0.013) and higher tacrolimus trough level (HR, 1.112; 95% CI, 1.029-1.202; p = 0.029) were associated with higher risks for fractures. Pretransplant diabetes mellitus had a time-dependent impact on fractures, with increasing risk as time elapses (HR for diabetes mellitus 1.115; 95% CI, 0.439-2.832; HR for diabetes mellitus × time, 1.049; 95% CI, 1.007-1.094; p = 0.022). In conclusion, KTRs had a high risk of peripheral skeletal fractures in the first 5 years. At baseline recipient age, pretransplant diabetes mellitus and tacrolimus trough level after KT were responsible for the fractures in KTRs.

Genomic epidemiology of SARS- CoV-2 Omicron variants in the Republic of Korea.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic since 2019. Variants of concern (VOCs) declared by the World Health Organization require continuous monitoring because of their possible changes in transmissibility, virulence, and antigenicity. The Omicron variant, a VOC, has become the dominant variant worldwide since November 2021. In the Republic of Korea (South Korea), the number of confirmed cases increased rapidly after the detection of Omicron VOC on November 24, 2021. In this study, we estimated the underlying epidemiological processes of Omicron VOC in South Korea using time-scaled phylodynamic analysis. Three distinct phylogenetic subgroups (Kor-O1, Kor-O2, and Kor-O3) were detected in South Korea. The Kor-O1 subgroup circulated in the Daegu region, whereas Kor-O2 and Kor-O3 circulated in Incheon and Jeollanam-do, respectively. The viral population size and case number of the Kor-O1 subgroup increased more rapidly than those of the other subgroups, indicating the rapid spread of the virus. The results indicated the multiple introductions of Omicron sub-lineages into South Korea and their subsequent co-circulation. The evolution and transmission of SARS-CoV-2 should be continuously monitored, and control strategies need to be improved to control the multiple variants.

Methylation-sensitive high-resolution melting analysis of the USP44 promoter can detect early-stage hepatocellular carcinoma in blood samples.

Hepatocellular carcinoma (HCC) is dangerous cancer that often evades early detection because it is asymptomatic and an effective detection method is lacking. For people with chronic liver inflammation who are at high risk of developing HCC, a sensitive detection method for HCC is needed. In a meta-analysis of The Cancer Genome Atlas pan-cancer methylation database, we identified a CpG island in the USP44 promoter that is methylated specifically in HCC. We developed methylation-sensitive high-resolution melting (MS-HRM) analysis to measure the methylation levels of the USP promoter in cell-free DNA isolated from patients. Our MS-HRM assay correctly identified 40% of patients with early-stage HCC, whereas the α-fetoprotein test, which is currently used to detect HCC, correctly identified only 25% of early-stage HCC patients. These results demonstrate that USP44 MS-HRM analysis is suitable for HCC surveillance. [BMB Reports 2022; 55(11): 553-558].

Geometrically engineered rigid island array for stretchable electronics capable of withstanding various deformation modes.

Integration of rigid components in soft polymer matrix is considered as the most feasible architecture to enable stretchable electronics. However, a method of suppressing cracks at the interface between soft and rigid materials due to excessive and repetitive deformations of various types remains a formidable challenge. Here, we geometrically engineered Ferris wheel-shaped islands (FWIs) capable of effectively suppressing crack propagation at the interface under various deformation modes (stretching, twisting, poking, and crumpling). The optimized FWIs have notable increased strain at failure and fatigue life compared with conventional circle- and square-shaped islands. Stretchable electronics composed of various rigid components (LED and coin cell) were demonstrated using intrinsically stretchable printed electrodes. Furthermore, electronic skin capable of differentiating various tactile stimuli without interference was demonstrated. Our method enables stretchable electronics that can be used under various geometrical forms with notable enhanced durability, enabling stretchable electronics to withstand potentially harsh conditions of everyday usage.

The combined clinical impact of red blood cell distribution width and vascular calcification on cardiovascular events and mortality in patients with endstage kidney disease.

BACKGROUND: Little is known about how the interaction between red blood cell distribution width (RDW) and vascular calcification (VC) affects cardiovascular (CV) events and mortality in end-stage kidney disease (ESKD) patients. This study investigated the combined prognostic effect of RDW and VC in ESKD patients starting dialysis. METHODS: A retrospective single-center study of 582 ESKD patients was conducted. VC was assessed by calculating the aortic calcification index (ACI) using computed tomography. Patients were divided into low ACI-low RDW, low ACI-high RDW, high ACI-low RDW, and high ACI-high RDW groups based on median ACI (17.12) and RDW (14.3) values. The association between RDW and VC and the composite endpoint of CV events and death was analyzed. RESULTS: During a median follow-up of 3.1 years (range, 1.5-5.5 years), 165 CV events (28.4%) and 124 deaths (21.4%) occurred. Cox regression showed that the low ACI-high RDW (adjusted hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.04-2.66; p = 0.03) and high ACI-low RDW (adjusted HR, 1.95; 95% CI, 1.21-3.14; p = 0.006) groups had a greater risk of CV events and death than the low ACI-low RDW group. The high ACI-high RDW group had the greatest risk (adjusted HR, 2.23; 95% CI, 1.42-3.52; p = 0.001). The effect of the interaction between ACI and RDW on CV events and mortality was statistically significant (p = 0.005). CONCLUSION: High RDW and VC interact to increase the risk of CV events and death in ESKD patients.

Dendrimers for cancer immunotherapy: Avidity-based drug delivery vehicles for effective anti-tumor immune response.

Cancer immunotherapy, or the utilization of a patient's own immune system to treat cancer, has shifted the paradigm of cancer treatment. Despite meaningful responses being observed in multiple studies, currently available immunotherapy platforms have only proven effective to a small subset of patients. To address this, nanoparticles have been utilized as a novel carrier for immunotherapeutic drugs, achieving robust anti-tumor effects with increased adaptive and durable responses. Specifically, dendrimer nanoparticles have attracted a great deal of scientific interest due to their versatility in various therapeutic applications, resulting from their unique physicochemical properties and chemically well-defined architecture. This review offers a comprehensive overview of dendrimer-based immunotherapy technologies, including their formulations, biological functionalities, and therapeutic applications. Common formulations include: (1) modulators of cytokine secretion of immune cells (adjuvants); (2) facilitators of the recognition of tumorous antigens (vaccines); (3) stimulators of immune effectors to selectively attack cells expressing specific antigens (antibodies); and (4) inhibitors of immune-suppressive responses (immune checkpoint inhibitors). On-going works and prospects of dendrimer-based immunotherapies are also discussed. Overall, this review provides a critical overview on rapidly growing dendrimer-based immunotherapy technologies and serves as a guideline for researchers and clinicians who are interested in this field. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Genomic epidemiology reveals the reduction of the introduction and spread of SARS-CoV-2 after implementing control strategies in Republic of Korea, 2020.

Genomic epidemiology is a core component in investigating the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, the efficacy of control strategies in South Korea was evaluated using genomic epidemiology based on viral genome sequences of 2,065 SARS-CoV-2 cases identified in South Korea from January 2020 to December 2020. Phylogenetic analysis revealed that the majority of viruses introduced from inbound travelers did not further spread throughout South Korea; however, four distinct subgroups (KR.1-4, belonging to B.1.497, B.1, K.1 and B.41) of viruses caused local epidemics. After the introduction of enhanced social distancing, the viral population size and daily case numbers decreased, and KR.2-4 subgroups were extinguished from South Korea. Nevertheless, there was a subsequent increase in KR.1 subgroups after the downgrading of social distancing level. These results indicate that the international traveler quarantine system implemented in South Korea along with social distancing measures efficiently reduced the introduction and spread of SARS-CoV-2, but it was not completely controlled. An improvement of control strategies will be required to better control SARS-CoV-2, its variants, and future pandemic viruses.

Relationships between monocyte count to high-density lipoprotein cholesterol ratio and cardiovascular outcomes in patients commencing dialysis.

OBJECTIVE: High monocyte to high-density lipoprotein cholesterol ratio (MHR) is known to be a risk factor for cardiovascular (CV) complications. We aimed to evaluate the relationship between MHR and CV outcomes in patients commencing dialysis. METHODS: The medical records of patients who started maintenance dialysis between January 2006 and July 2017 were reviewed. The primary outcomes were all-cause mortality and overall CV mortality and the secondary outcomes were CV event-free survival and the incidence of CV complications. RESULTS: Five hundred ninety-seven patients were enrolled and allocated to low- or high-MHR groups. All-cause mortality did not differ between the groups during a mean follow-up period of 3.9 years. In addition, overall CV mortality did not differ between the groups. However, CV event-free survival was significantly lower in the high-MHR group than in the low-MHR group (47.5% vs. 59.0%). Multivariate Cox regression analysis showed that high MHR was an independent predictor of CV events (HR 1.886, 95% CI 1.015-3.505). CONCLUSION: High MHR at the time of initiation of dialysis may represent a useful predictor of CV complications.

Corrigendum to: Genomic epidemiology reveals the reduction of the introduction and spread of SARS-CoV-2 after implementing control strategies in Republic of Korea, 2020.

[This corrects the article DOI: 10.1093/ve/veab077.].

A pilot trial to evaluate the clinical usefulness of contrast-enhanced ultrasound in predicting renal outcomes in patients with acute kidney injury.

OBJECTIVES: Contrast-enhanced ultrasound (CEUS) enables the assessment of real-time renal microcirculation. This study investigated CEUS-driven parameters as hemodynamic predictors for renal outcomes in patients with acute kidney injury (AKI). METHODS: Forty-eight patients who were diagnosed with AKI were prospectively enrolled and underwent CEUS at the occurrence of AKI. Parameters measured were the wash-in slope (WIS), time to peak intensity, peak intensity (PI), area under the time-intensity curve (AUC), mean transit time (MTT), time for full width at half maximum, and rise time (RT). The predictive performance of the CEUS-driven parameters for Kidney Disease Improving Global Outcomes (KDIGO) AKI stage, initiation of renal replacement therapy (RRT), AKI recovery, and chronic kidney disease (CKD) progression was assessed. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of CEUS. RESULTS: Cortical RT (Odds ratio [OR] = 1.21) predicted the KDIGO stage 3 AKI. Cortical MTT (OR = 1.07) and RT (OR = 1.20) predicted the initiation of RRT. Cortical WIS (OR = 76.23) and medullary PI (OR = 1.25) predicted AKI recovery. Medullary PI (OR = 0.78) and AUC (OR = 1.00) predicted CKD progression. The areas under the ROC curves showed reasonable performance for predicting the initiation of RRT and AKI recovery. The sensitivity and specificity of the quantitative CEUS parameters were 60-83% and 62-77%, respectively, with an area under the curve of 0.69-0.75. CONCLUSION: CEUS may be a supplemental tool in diagnosing the severity of AKI and predicting renal prognosis in patients with AKI.

Sex-specific relationship between vascular calcification and incident fracture in patients with end-stage renal disease.

BACKGROUND: Vascular calcification (VC) is a major component of mineral bone disorders in patients with endstage renal disease (ESRD). Bone metabolism is affected by various factors, including sex hormones. This study investigated whether there was a sex-specific relationship between VC and incident fracture in patients with ESRD. METHODS: This was a retrospective cohort study of dialysis patients from a single center. VC was assessed by the aortic calcification index (ACI) using abdominal computed tomography. Patients were grouped by sex and stratified into low or high ACI groups, according to the median ACI value. The association between ACI and incident fracture was analyzed. RESULTS: Data from 593 patients (male: n = 328, median ACI, 14.57; female: n = 265, median ACI, 19.44) were included. During a median follow-up of 36.7 months, 71 patients (12.0%) developed fractures. The fracturefree survival rate was significantly lower in the high ACI group versus the low ACI group, both in males (P = 0.021) and females (P = 0.001). In males, multivariate analysis showed that the high ACI group and ACI per se were not significant risks for fracture. However, in females, both the high ACI group (adjusted hazard ratio, 2.720; P = 0.003) and ACI per se (adjusted hazard ratio, 1.768; P = 0.035) were independently associated with fracture after adjustment for confounding variables. CONCLUSION: VC was independently associated with incident fracture in female patients with ESRD. There may be a sex-specific relationship between VC and fracture in patients with ESRD.

The combined prognostic significance of alkaline phosphatase and vascular calcification in patients with end-stage kidney disease.

BACKGROUND AND AIMS: Little is known about the interaction between serum alkaline phosphatase (ALP) and vascular calcification (VC) affecting cardiovascular events (CVE) and mortality in end-stage kidney disease (ESKD) patients. This study investigated the combined effect of ALP and VC on prognosis in ESKD patients starting dialysis. METHODS AND RESULTS: Data from 587 ESKD patients treated at a single center between January 2006 and July 2017 were retrospectively evaluated. VC was assessed by the aortic calcification index (ACI) using abdominal computed tomography. Patients were stratified into four groups according to the median ACI (17.18) and serum ALP value (108.0 U/L) as low ACI-low ALP, low ACI-high ALP, high ACI-low ALP, or high ACI-high ALP. The association between ALP and VC and the composite of CVE and death was analyzed. During a median follow-up of 3.1 years (range, 1.5-5.6 years), 140 patients (23.8%) developed CVE and 130 deaths (22.1%) occurred. In the stratified analysis, patients with high ACI-low ALP had a greater risk of the composite endpoint than patients with low ACI-low ALP (adjusted hazard ratio, 2.09; 95% confidence interval, 1.58-2.60; P = 0.004). Patients with high ACI-high ALP had the greatest risk (adjusted hazard ratio, 2.25; 95% confidence interval, 1.77-2.72; P = 0.001). The interaction between ACI and ALP on CVE and mortality was statistically significant (P < 0.05). CONCLUSIONS: The combined effect of VC and higher ALP was associated with a greater risk of CVE and death, and high serum ALP amplified the risk associated with VC in ESKD patients starting dialysis.

Neuromorphic Processing of Pressure Signal Using Integrated Sensor-Synaptic Device Capable of Selective and Reversible Short- and Long-Term Plasticity Operation.

To mimic the tactile sensing properties of the human skin, signals from tactile sensors need to be processed in an efficient manner. The integration of the tactile sensor with a neuromorphic device can potentially address this issue, as the neuromorphic device has both signal processing and memory capability through which parallel and efficient processing of information is possible. In this article, an intelligent haptic perception device (IHPD) is presented that combines pressure sensing with an organic electrochemical transistor-based synaptic device into a simple device architecture. More importantly, the IHPD is capable of rapid and reversible switching between short-term plasticity (STP) and long-term plasticity (LTP) operation through which accelerated learning, processing of new information, and distinctive operation of STP and LTP are possible. Various types of pressure information such as magnitude, rate, and duration were processed utilizing STP by which error-tolerant perception was demonstrated. Meanwhile, memorization and learning of pressure through a stepwise change in a conductive state was demonstrated using LTP. These demonstrations present unique approaches to process and learn tactile information, which can potentially be utilized in various electronic skin applications in the future.