Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models.

Neuronal hyperactivity is a key feature of early stages of Alzheimer's disease (AD). Genetic studies in AD support that microglia act as potential cellular drivers of disease risk, but the molecular determinants of microglia-synapse engulfment associated with neuronal hyperactivity in AD are unclear. Here, using super-resolution microscopy, 3D-live imaging of co-cultures, and in vivo imaging of lipids in genetic models, we found that spines become hyperactive upon Aß oligomer stimulation and externalize phosphatidylserine (ePtdSer), a canonical "eat-me" signal. These apoptotic-like spines are targeted by microglia for engulfment via TREM2 leading to amelioration of Aß oligomer-induced synaptic hyperactivity. We also show the in vivo relevance of ePtdSer-TREM2 signaling in microglia-synapse engulfment in the hAPP NL-F knock-in mouse model of AD. Higher levels of apoptotic-like synapses in mice as well as humans that carry TREM2 loss-of-function variants were also observed. Our work supports that microglia remove hyperactive ePtdSer+ synapses in Aß-relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD.

Prolonged viral shedding in an immunocompromised Korean patient infected with hMPXV, sub-lineage B.1.3, with acquired drug resistant mutations during tecovirimat treatment.

Following the worldwide surge in mpox (monkeypox) in 2022, cases have persisted in Asia, including South Korea, and sexual contact is presumed as the predominant mode of transmission, with a discernible surge in prevalence among immunocompromised patients. Drugs such as tecovirimat can result in drug-resistant mutations, presenting obstacles to treatment. This study aimed to ascertain the presence of tecovirimat-related resistant mutations through genomic analysis of the monkeypox virus isolated from a reported case involving prolonged viral shedding in South Korea. Here, tecovirimat-resistant mutations, previously identified in the B.1 clade, were observed in the B.1.3 clade, predominant in South Korea. These mutations exhibited diverse patterns across different samples from the same patient and reflected the varied distribution of viral subpopulations in different anatomical regions. The A290V and A288P mutant strains we isolated hold promise for elucidating these mechanisms, enabling a comprehensive analysis of viral pathogenesis, replication strategies, and host interactions. Our findings imply that acquired drug-resistant mutations, may present a challenge to individual patient treatment. Moreover, they have the potential to give rise to transmitted drug-resistant mutations, thereby imposing a burden on the public health system. Consequently, the meticulous genomic surveillance among immunocompromised patients, conducted in this research, assumes paramount importance.

Progression of non-obstructive coronary plaque: a practical CCTA-based risk score from the PARADIGM registry.

OBJECTIVES: No clear recommendations are endorsed by the different scientific societies on the clinical use of repeat coronary computed tomography angiography (CCTA) in patients with non-obstructive coronary artery disease (CAD). This study aimed to develop and validate a practical CCTA risk score to predict medium-term disease progression in patients at a low-to-intermediate probability of CAD. METHODS: Patients were part of the Progression of AtheRosclerotic PlAque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry. Specifically, 370 (derivation cohort) and 219 (validation cohort) patients with two repeat, clinically indicated CCTA scans, non-obstructive CAD, and absence of high-risk plaque (≥ 2 high-risk features) at baseline CCTA were included. Disease progression was defined as the new occurrence of ≥ 50% stenosis and/or high-risk plaque at follow-up CCTA. RESULTS: In the derivation cohort, 104 (28%) patients experienced disease progression. The median time interval between the two CCTAs was 3.3 years (2.7-4.8). Odds ratios for disease progression derived from multivariable logistic regression were as follows: 4.59 (95% confidence interval: 1.69-12.48) for the number of plaques with spotty calcification, 3.73 (1.46-9.52) for the number of plaques with low attenuation component, 2.71 (1.62-4.50) for 25-49% stenosis severity, 1.47 (1.17-1.84) for the number of bifurcation plaques, and 1.21 (1.02-1.42) for the time between the two CCTAs. The C-statistics of the model were 0.732 (0.676-0.788) and 0.668 (0.583-0.752) in the derivation and validation cohorts, respectively. CONCLUSIONS: The new CCTA-based risk score is a simple and practical tool that can predict mid-term CAD progression in patients with known non-obstructive CAD. CLINICAL RELEVANCE STATEMENT: The clinical implementation of this new CCTA-based risk score can help promote the management of patients with non-obstructive coronary disease in terms of timing of imaging follow-up and therapeutic strategies. KEY POINTS: • No recommendations are available on the use of repeat CCTA in patients with non-obstructive CAD. • This new CCTA score predicts mid-term CAD progression in patients with non-obstructive stenosis at baseline. • This new CCTA score can help guide the clinical management of patients with non-obstructive CAD.

Association of body adiposity with left ventricular concentric remodeling and diastolic dysfunction.

BACKGROUND: Obesity is a significant risk factor for heart failure with preserved ejection fraction (HFpEF). In this study, we explore the relationships between body mass index (BMI) and adipose tissue compartments such as visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT), with respect to left ventricular (LV) structure and function in subjects with preserved LV systolic function. METHODS: Between January and December 2020, this retrospective study included 749 participants who exhibited preserved LV systolic function and underwent transthoracic echocardiography along with abdominal computed tomography. LV structural and functional variables as well as EAT, VAT, and SAT thickness were evaluated using echocardiography and computed tomography. RESULTS: SAT decreased, while VAT and EAT progressively increased with age. There were significant correlations between BMI and various adipose tissues, with the strongest correlation observed with SAT (r = .491, p < .001) compared to VAT (r = .371, p < .001) or EAT (r = .135, p < .001). However, EAT demonstrated the most substantial association with decreased LV end-diastolic dimension, LV end-systolic dimension, and septal mitral annular velocity and increased relative wall thickness (all p < .05), while VAT and SAT did not show significant associations with LV remodeling and functional parameters after adjusting for clinical variables. CONCLUSION: EAT is the most critical adipose tissue influencing LV geometric and functional changes, compared with VAT or SAT. Thick EAT is associated small LV chamber size, concentric remodeling, and relaxation abnormalities.

SCAMP5 plays a critical role in axonal trafficking and synaptic localization of NHE6 to adjust quantal size at glutamatergic synapses.

Glutamate uptake into synaptic vesicles (SVs) depends on cation/H+ exchange activity, which converts the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane at the presynaptic terminals. Thus, the proper recruitment of cation/H+ exchanger to SVs is important in determining glutamate quantal size, yet little is known about its localization mechanism. Here, we found that secretory carrier membrane protein 5 (SCAMP5) interacted with the cation/H+ exchanger NHE6, and this interaction regulated NHE6 recruitment to glutamatergic presynaptic terminals. Protein-protein interaction analysis with truncated constructs revealed that the 2/3 loop domain of SCAMP5 is directly associated with the C-terminal region of NHE6. The use of optical imaging and electrophysiological recording showed that small hairpin RNA-mediated knockdown (KD) of SCAMP5 or perturbation of SCAMP5/NHE6 interaction markedly inhibited axonal trafficking and the presynaptic localization of NHE6, leading to hyperacidification of SVs and a reduction in the quantal size of glutamate release. Knockout of NHE6 occluded the effect of SCAMP5 KD without causing additional defects. Together, our results reveal that as a key regulator of axonal trafficking and synaptic localization of NHE6, SCAMP5 could adjust presynaptic strength by regulating quantal size at glutamatergic synapses. Since both proteins are autism candidate genes, the reduced quantal size by interrupting their interaction may underscore synaptic dysfunction observed in autism.

Genomic Analysis of Monkeypox Virus During the 2023 Epidemic in Korea.

We aimed to characterize the genomes of monkeypox virus isolates from the Far East, providing insights into viral transmission and evolution. Genomic analysis was conducted on 8 isolates obtained from patients with monkeypox virus disease in the Republic of Korea between May 2022 and early 2023. These isolates were classified into Clade IIb. Distinct lineages, including B.1.1, A.2.1, and B.1.3, were observed in 2022 and 2023 isolates, with only the B.1.3 lineage detected in six isolates of 2023. These genetic features were specific to Far East isolates (the Republic of Korea, Japan, and Taiwan), distinguishing them from the diverse lineages found in the Americas, Europe, Africa, and Oceania. In early 2023, the prevalence of the B.1.3 lineage of monkeypox virus identified in six patients with no overseas travel history is considered as an indicator of the potential initiation of local transmission in the Republic of Korea.

Real-World Eligibility and Cost-Effectiveness Analysis of Empagliflozin for Heart Failure in Korea.

BACKGROUND: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved empagliflozin for reducing cardiovascular mortality and heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). However, limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and potential cost-effectiveness based on a nationwide prospective HF registry. METHODS: A total of 3,108 HFrEF and 2,070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analyzed. Eligibility was estimated by inclusion and exclusion criteria of EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trials and by FDA & EMA label criteria. The cost-utility analysis was done using a Markov model to project the lifetime medical cost and quality-adjusted life year (QALY). RESULTS: Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The incremental cost-effectiveness ratio of empagliflozin was calculated at US$6,764 per QALY in the overall population, which is far below a threshold of US$18,182 per QALY. The cost-effectiveness benefit was more evident in patients with HFrEF (US$5,012 per QALY) than HFpEF (US$8,971 per QALY). CONCLUSION: There is a large discrepancy in real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. Empagliflozin is cost-effective in HF patients regardless of ejection fraction in South Korea health care setting. The efficacy and safety of empagliflozin in real-world HF patients should be further investigated for a broader range of clinical applications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01389843.

VISTA (PD-1H) Is a Crucial Immune Regulator to Limit Pulmonary Fibrosis.

VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is upregulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated after VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of patients with IPF. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA upregulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limits the fibrotic innate immune landscape and consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment.

Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends.

Formation of single-strand DNA (ssDNA) tails at a double-strand break (DSB) is a key step in homologous recombination and DNA-damage signaling. The enzyme(s) producing ssDNA at DSBs in eukaryotes remain unknown. We monitored 5'-strand resection at inducible DSB ends in yeast and identified proteins required for two stages of resection: initiation and long-range 5'-strand resection. We show that the Mre11-Rad50-Xrs2 complex (MRX) initiates 5' degradation, whereas Sgs1 and Dna2 degrade 5' strands exposing long 3' strands. Deletion of SGS1 or DNA2 reduces resection and DSB repair by single-strand annealing between distant repeats while the remaining long-range resection activity depends on the exonuclease Exo1. In exo1Deltasgs1Delta double mutants, the MRX complex together with Sae2 nuclease generate, in a stepwise manner, only few hundred nucleotides of ssDNA at the break, resulting in inefficient gene conversion and G2/M damage checkpoint arrest. These results provide important insights into the early steps of DSB repair in eukaryotes.

Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.

Mechanism underlying pruritus in recessive dystrophic epidermolysis bullosa: Role of interleukin-31 from mast cells and macrophages.

BACKGROUND: Pruritus is a highly burdensome symptom in patients with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa (RDEB); however, only a few studies have assessed the molecular pathogenesis of RDEB-associated pruritus. Interleukin (IL)-31 is a key cytokine implicated in pruritus associated with dermatologic diseases such as atopic dermatitis and prurigo nodularis. OBJECTIVE: To investigate the role and cellular source of IL-31 in RDEB-associated pruritus. METHODS: Serum and skin samples were obtained from 11 RDEB patients and 11 healthy controls. Pruritus visual analogue scale scores were determined. Serum levels of IL-31 and thymic stromal lymphopoietin (TSLP) were examined by enzyme-linked immunosorbent assay (ELISA). The expression of IL-31 and other pruritus mediators in the skin were examined through immunofluorescence staining, and their correlation with pruritus severity was analysed. RESULTS: Serum IL-31 and TSLP were elevated in RDEB patients. IL-31 expression was increased in RDEB skin and positively correlated with pruritus severity. Most of the IL-31-expressing cells were mast cells, and some were CD206(+) M2-like macrophages. The number of substance P(+) cells was also increased in the patients' skin, and most of them were mast cells. The number of substance P(+) mast cells was correlated with the number of IL-31(+) dermal infiltrates. The number of IL-4Rα- and IL-13-expressing cells and expression of TSLP and periostin increased in RDEB skin, but without a correlation to pruritus score. CONCLUSION: The increased production of skin IL-31 from mast cells and M2-like macrophages may be the mechanism underlying pruritus in RDEB.

Two cases of KRT1 mutation-associated epidermolytic ichthyosis without typical epidermolytic hyperkeratosis in the neonatal skin lesions.

Epidermolytic ichthyosis (EI) is a rare genetic disorder of keratinization caused by mutations in either KRT1 or KRT10. Histopathologically, epidermolytic hyperkeratosis (EHK) is a hallmark of EI. Here, we report two EI cases in which KRT1 mutation was confirmed by molecular study, but without typical EHK present on skin biopsies performed within 1 week of age. Our cases demonstrate that EHK may not be evident in EI if skin biopsy is performed during the neonatal period.

Iron Deficiency in Korean Patients With Heart Failure.

BACKGROUND: Although iron deficiency (ID) is an important and treatable risk factor for heart failure (HF), data on ID are scarce in Asian patients with HF. Therefore, we sought to determine the prevalence and clinical characteristics of ID in hospitalized Korean patients with HF. METHODS: In this prospective, multicenter cohort study, 461 patients with acute HF seen at five tertiary centers from January to November 2019 in Korea were enrolled. ID was defined as serum ferritin < 100 µg/L or ferritin 100-299 µg/L in combination with transferrin saturation < 20%. RESULTS: The patients' mean age was 67.6 ± 14.9 years, and 61.8% were male. Among total 461 patients, ID was present in 248 patients (53.8%). The prevalence of ID was significantly higher in women than in men (65.3% vs. 47.3%, P < 0.001). In a multivariable logistic regression analysis, the independent predictors of ID were female sex (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.47-3.30), valvular heart disease (OR, 2.10; 95% CI, 1.10-4.17), higher heart rate (OR, 1.10; 95% CI, 1.01-1.21), anemia (OR, 1.60; 95% CI, 1.07-2.40), and the use of clopidogrel (OR, 1.56; 95% CI, 1.00-2.45). Among women, the prevalence of ID did not significantly differ between younger and older women (< 65 years: 73.7% vs. ≥ 65 years: 63.0%, P = 0.222), those with low and high body mass index (BMI < 25 kg/m²: 66.2% vs. BMI ≥ 25 kg/m²: 69.6%, P = 0.703), or those with low and high natriuretic peptide (NP) levels (NP < median: 69.8% vs. NP ≥ median: 61.1%, P = 0.295). Only 0.2% patients with acute HF received intravenous iron supplementation in Korea. CONCLUSION: The prevalence of ID is high in hospitalized Korean patients with HF. Because ID cannot be diagnosed by clinical parameters, routine laboratory examinations are necessary to identify patients with ID. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04812873.

DNA Damage and Repair in Eye Diseases.

Vision is vital for daily activities, and yet the most common eye diseases-cataracts, DR, ARMD, and glaucoma-lead to blindness in aging eyes. Cataract surgery is one of the most frequently performed surgeries, and the outcome is typically excellent if there is no concomitant pathology present in the visual pathway. In contrast, patients with DR, ARMD and glaucoma often develop significant visual impairment. These often-multifactorial eye problems can have genetic and hereditary components, with recent data supporting the role of DNA damage and repair as significant pathogenic factors. In this article, we discuss the role of DNA damage and the repair deficit in the development of DR, ARMD and glaucoma.

Adsorption Capacity and Desorption Efficiency of Activated Carbon for Odors from Medical Waste.

Five types of odor-emitting exhaust gases from medical waste were selected, and their adsorption capacity and desorption efficiency were investigated using activated carbon. The selected gases included polar gases (hydrogen sulfide (H2S) and ammonia (NH3)) and non-polar gases (acetaldehyde (AA), methyl mercaptan (MM), and trimethylamine (TMA))). Commercial activated carbon with a specific surface area of 2276 m2/g was used as the adsorbent. For the removal of odor from medical waste, we investigated: (1) the effective adsorption capacity of a single gas (<1 ppm), (2) the effect of the adsorbed NH3 gas concentration and flow rate, and (3) the desorption rate using NH3 gas. The values of the effective adsorption capacity of the single gas were in the following order: H2S < NH3 < AA < MM < TMA, at 0.2, 4.2, 6.3, 6.6, and 35.7 mg/g, respectively. The results indicate that polar gases have a lower effective adsorption capacity than that of non-polar gases, and that the size of the gas molecules and effective adsorption capacity exhibit a proportional relationship. The effective adsorption performance of NH3 gas showed an increasing trend with NH3 concentration. Therefore, securing optimal conditions for adsorption/desorption is imperative for the highly efficient removal of odor from medical waste.

The Effect of Perceived Organizational and Supervisory Support on Employee Engagement During COVID-19 Crises: Mediating Effect of Work-Life Balance Policy.

This article examines how organizational and supervisory supports, directly and indirectly, impact employee engagement in U.S. federal agencies during the COVID-19 pandemic. This study applies two analysis models for two different sample groups: federal workers who were required to be physically present at a worksite during the pandemic and those who were not required to do so. Drawing from the sampling frame comprised of "permanently employed, non-political, non-seasonal, full- or part-time federal employees" in pay status as of October 2019, the findings from the U.S. Federal Employment Viewpoint Survey 2020 indicate that organizational and supervisory supports directly impact employee engagement regardless of employees' work arrangements. However, work engagement is not increased by organizational and supervisory supports that actively encourage employees to use conventional incentives such as work-life balance policies. At the organizational level, this study suggests the need to redesign strategies to motivate public agents to engage in the agency's mission because conventional and systemic employee support may be ineffective as currently designed. Overall, this study sheds more light on existing studies of public human resource management by examining employee engagement according to work arrangements during the pandemic.

Household Secondary Attack Rates of SARS-CoV-2 Omicron Variant, South Korea, February 2022.

We studied the effect of booster vaccinations on reducing household transmission of SARS-CoV-2 B.1.1529 (Omicron) variant in a February 2022 sampling of contacts in South Korea. The secondary attack rate was lower for vaccinated versus unvaccinated contacts, and booster vaccination resulted in a lower incidence rate ratio.

Serial Intervals and Household Transmission of SARS-CoV-2 Omicron Variant, South Korea, 2021.

To clarify transmissibility of the severe acute respiratory syndrome coronavirus 2 Omicron variant, we determined serial intervals and secondary attack rates among household contacts in South Korea. Mean serial interval for 12 transmission pairs was 2.9 days, and secondary attack rate among 25 households was 50.0%, raising concern about a rapid surge in cases.

Time from Exposure to Diagnosis among Quarantined Close Contacts of SARS-CoV-2 Omicron Variant Index Case-Patients, South Korea.

To determine optimal quarantine duration, we evaluated time from exposure to diagnosis for 107 close contacts of severe acute respiratory syndrome coronavirus 2 Omicron variant case-patients. Average time from exposure to diagnosis was 3.7 days; 70% of diagnoses were made on day 5 and 99.1% by day 10, suggesting 10-day quarantine.

Community Transmission of SARS-CoV-2 Omicron Variant, South Korea, 2021.

In South Korea, a November 2021 outbreak caused by severe acute respiratory syndrome coronavirus 2 Omicron variant originated from 1 person with an imported case and spread to households, kindergartens, workplaces, restaurants, and hospitals, resulting in 11 clusters within 3 weeks. An epidemiologic curve indicated rapid community transmission of the Omicron variant.