Risk of Atrial Fibrillation and Adverse Outcomes in Patients With Cardiac Implantable Electronic Devices.

BACKGROUND AND OBJECTIVES: Comprehensive epidemiological data are lacking on the incident atrial fibrillation (AF) in patients with cardiac implantable electronic devices (CIEDs). This study aimed to examine the incidence, risk factors, and AF-related adverse outcomes of patients with CIEDs. METHODS: This was an observational cohort study that analyzed patients without prevalent AF who underwent CIED implantation in 2009-2018 using a Korean nationwide claims database. The subjects were divided into three groups by CIED type and indication: pacemaker (n=21,438), implantable cardioverter defibrillator (ICD)/cardiac resynchronization therapy (CRT) with heart failure (HF) (n=3,450), and ICD for secondary prevention without HF (n=2,146). The incidence of AF, AF-associated predictors, and adverse outcomes were evaluated. RESULTS: During follow-up, the incidence of AF was 4.3, 7.3, and 5.1 per 100 person-years in the pacemaker, ICD/CRT with HF, and ICD without HF cohorts, respectively. Across the three cohorts, older age and valvular heart disease were commonly associated with incident AF. Incident AF was consistently associated with an increased risk of ischemic stroke (3.8-11.4-fold), admission for HF (2.6-10.5-fold), hospitalization for any cause (2.4-2.7-fold), all-cause death (4.1-5.0-fold), and composite outcomes (3.4-5.7-fold). Oral anticoagulation rates were suboptimal in patients with incident AF (pacemaker, 51.3%; ICD/CRT with HF, 51.7%; and ICD without HF, 33.8%, respectively). CONCLUSIONS: A substantial proportion of patients implanted CIED developed newly diagnosed AF. Incident AF was associated with a higher risk of adverse events. The importance of awareness, early detection, and appropriate management of AF in patients with CIED should be emphasized.

Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation.

SARS-CoV-2 infection causes spike-dependent fusion of infected cells with ACE2 positive neighboring cells, generating multi-nuclear syncytia that are often associated with severe COVID. To better elucidate the mechanism of spike-induced syncytium formation, we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical stimulator for spike-induced cell-cell fusion. We show that HS binds spike and promotes spike-induced ACE2 clustering, forming synapse-like cell-cell contacts that facilitate fusion pore formation between ACE2-expresing and spike-transfected human cells. Chemical or genetic inhibition of HS mitigates ACE2 clustering, and thus, syncytium formation, whereas in a cell-free system comprising purified HS and lipid-anchored ACE2, HS stimulates ACE2 clustering directly in the presence of spike. Furthermore, HS-stimulated syncytium formation and receptor clustering require a conserved ACE2 linker distal from the spike-binding site. Importantly, the cell fusion-boosting function of HS can be targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice. Thus, HS, as a host factor exploited by SARS-CoV-2 to facilitate receptor clustering and a stimulator of infection-associated syncytium formation, may be a promising therapeutic target for severe COVID.

Heparan sulfate promotes ACE2 super-cluster assembly to enhance SARS-CoV-2-associated syncytium formation.

The mechanism of syncytium formation, caused by spike-induced cell-cell fusion in severe COVID-19, is largely unclear. Here we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical host factor exploited by SARS-CoV-2 to enhance spike’s fusogenic activity. HS binds spike to facilitate ACE2 clustering, generating synapse-like cell-cell contacts to promote fusion pore formation. ACE2 clustering, and thus, syncytium formation is significantly mitigated by chemical or genetic elimination of cell surface HS, while in a cell-free system consisting of purified HS, spike, and lipid-anchored ACE2, HS directly induces ACE2 clustering. Importantly, the interaction of HS with spike allosterically enables a conserved ACE2 linker in receptor clustering, which concentrates spike at the fusion site to overcome fusion-associated activity loss. This fusion-boosting mechanism can be effectively targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice.

Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization.

The terminase complex of human cytomegalovirus (HCMV) is required for viral genome packaging and cleavage. Critical to the terminase functions is a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We have previously reported metal-chelating N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human immunodeficiency virus 1 (HIV-1) RNase H. In the current work, we have synthesized new analogs and resynthesized known analogs of two isomeric HtPD subtypes, anti-HtPD (13), and syn-HtPD (14), and characterized them as inhibitors of pUL89-C. Remarkably, the vast majority of analogs strongly inhibited pUL89-C in the biochemical endonuclease assay, with IC50 values in the nM range. In the cell-based antiviral assay, a few analogs inhibited HCMV in low µM concentrations. Selected analogs were further characterized in a biophysical thermal shift assay (TSA) and in silico molecular docking, and the results support pUL89-C as the protein target of these inhibitors. Collectively, the biochemical, antiviral, biophysical, and in silico data reported herein indicate that the isomeric HtPD chemotypes 13-14 can serve as valuable chemical platforms for designing improved inhibitors of HCMV pUL89-C.

Zika Virus Inhibitors Based on a 1,3-Disubstituted 1H-Pyrazolo[3,4-d]pyrimidine-amine Scaffold.

To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7H-pyrrolo[2,3-d]pyrimidines by examining an alternative substitution pattern of their central scaffold, leading to compound 5 with low micromolar antiviral activity. To circumvent the synthetic difficulties associated with compound 5, we have exploited a 1H-pyrazolo[3,4-d]pyrimidine scaffold and performed structure-activity relationship studies on its peripheral rings A and B. While ring B is less sensitive to structural modifications, an electron-withdrawing group at the para position of ring A is preferred for enhanced antiviral activity. Overall, we have not only discovered an alternative substitution pattern centered on a 1H-pyrazolo[3,4-d]pyrimidine scaffold but also generated anti-ZIKV compounds including 6 and 13, which possess low micromolar antiviral activity and relatively low cytotoxicity. These compounds represent new chemotypes that will be further optimized in our continued efforts to discover anti-ZIKV agents.

Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase.

Taking advantage of the uniquely constricted active site of SARS-CoV-2 Nsp14 methyltransferase, we have designed bisubstrate inhibitors interacting with the SAM and RNA substrate binding pockets. Our efforts have led to nanomolar inhibitors including compounds 3 and 10. As a prototypic inhibitor, compound 3 also has an excellent selectivity profile over a panel of human methyltransferases. Remarkably, C-nucleoside 10 exhibits high antiviral activity and low cytotoxicity, leading to a therapeutic index (CC50/EC50) greater than 139. Furthermore, a brief metabolic profiling of these two compounds suggests that they are less likely to suffer from major metabolic liabilities. Moreover, computational docking studies point to protein-ligand interactions that can be exploited to enhance inhibitory activity. In short, discovery of inhibitor 10 clearly demonstrates that potent and selective anti-SARS-CoV-2 activity can be achieved by targeting the Nsp14 methyltransferase. Therefore, the current work strongly supports the continued pursuit of Nsp14 methyltransferase inhibitors as COVID-19 therapeutics.

8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease.

Human cytomegalovirus (HCMV) replication requires a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C) for viral genome packaging and cleavage. We have previously shown that pUL89-C can be pharmacologically inhibited with designed metal-chelating compounds. We report herein the synthesis of a few 8-hydroxy-1,6-naphthyridine subtypes, including 5-chloro (subtype 15), 5-aryl (subtype 16), and 5-amino (subtype 17) variants. Analogs were studied for the inhibition of pUL89-C in a biochemical endonuclease assay, a biophysical thermal shift assay (TSA), in silico molecular docking, and for the antiviral potential against HCMV in cell-based assays. These studies identified eight analogs of 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes for further characterization, most of which inhibited pUL89-C with single-digit µM IC50 values, and conferred antiviral activity in µM range. TSA and molecular modeling of selected analogs corroborate their binding to pUL89-C. Collectively, our biochemical, antiviral, biophysical and in silico data suggest that 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes can be used for designing inhibitors of HCMV pUL89-C.

"Elbow-Lock" Chest Compression Method in the Setting of Single Rescuer Pediatric Cardiopulmonary Resuscitation: A Crossover Simulation Study.

BACKGROUND: We designed a new 1-handed chest compression method, the "elbow-lock" chest compression (ELCC), for a single rescuer in pediatric cardiopulmonary resuscitation (CPR). Then, we compared the effectiveness between the ELCC and standard chest compression (SCC) method. METHODS: This prospective, randomized controlled, crossover simulation trial studied 34 emergency medical professionals, including physicians, nurses, and EMTs. We compare the quality of chest compression and fatigue point time between the ELCC and the SCC. RESULTS: Participants who performed the ELCC method maintained a proper depth of compression compared with SCC method (50.0 ± 0.3 mm vs 40.5 ± 0.4 mm, P < 0.001). However, the 2 methods did not differ in terms of compression velocity since neither reached the standard velocity (96.7 ± 7.1/minutes vs 91.7 ± 7.0/minutes, P < 0.016). With respect to the overall score, ELCC was more effective than the SCC (91.6 ± 3.7% vs 85.3 ± 8.8%, P = 0.002). In addition, the fatigue point time was slower in the ELCC group than the SCC group (7.3 ± 0.3/minutes vs 6.1 ± 0.4/minutes, P < 0.001). CONCLUSIONS: The single rescuer ELCC method is an effective alternative to the SCC method for pediatric CPR because the ELCC method can prevent elbow flexion.Trial registration: Our research is simulation manikin study. So we do not need to "trial registration".

4,7-Disubstituted 7H-Pyrrolo[2,3-d]pyrimidines and Their Analogs as Antiviral Agents against Zika Virus.

Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs including compounds 1, 8 and 11 as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens.

Added Value of Deep Learning-based Detection System for Multiple Major Findings on Chest Radiographs: A Randomized Crossover Study.

Background Previous studies assessing the effects of computer-aided detection on observer performance in the reading of chest radiographs used a sequential reading design that may have biased the results because of reading order or recall bias. Purpose To compare observer performance in detecting and localizing major abnormal findings including nodules, consolidation, interstitial opacity, pleural effusion, and pneumothorax on chest radiographs without versus with deep learning-based detection (DLD) system assistance in a randomized crossover design. Materials and Methods This study included retrospectively collected normal and abnormal chest radiographs between January 2016 and December 2017 (https://cris.nih.go.kr/; registration no. KCT0004147). The radiographs were randomized into two groups, and six observers, including thoracic radiologists, interpreted each radiograph without and with use of a commercially available DLD system by using a crossover design with a washout period. Jackknife alternative free-response receiver operating characteristic (JAFROC) figure of merit (FOM), area under the receiver operating characteristic curve (AUC), sensitivity, specificity, false-positive findings per image, and reading times of observers with and without the DLD system were compared by using McNemar and paired t tests. Results A total of 114 normal (mean patient age ± standard deviation, 51 years ± 11; 58 men) and 114 abnormal (mean patient age, 60 years ± 15; 75 men) chest radiographs were evaluated. The radiographs were randomized to two groups: group A (n = 114) and group B (n = 114). Use of the DLD system improved the observers' JAFROC FOM (from 0.90 to 0.95, P = .002), AUC (from 0.93 to 0.98, P = .002), per-lesion sensitivity (from 83% [822 of 990 lesions] to 89.1% [882 of 990 lesions], P = .009), per-image sensitivity (from 80% [548 of 684 radiographs] to 89% [608 of 684 radiographs], P = .009), and specificity (from 89.3% [611 of 684 radiographs] to 96.6% [661 of 684 radiographs], P = .01) and reduced the reading time (from 10-65 seconds to 6-27 seconds, P < .001). The DLD system alone outperformed the pooled observers (JAFROC FOM: 0.96 vs 0.90, respectively, P = .007; AUC: 0.98 vs 0.93, P = .003). Conclusion Observers including thoracic radiologists showed improved performance in the detection and localization of major abnormal findings on chest radiographs and reduced reading time with use of a deep learning-based detection system. © RSNA, 2021 Online supplemental material is available for this article.

Relationship between the activities of daily living, oral health-related quality of life and dementia.

AIM: The aim of the present study was to investigate the association between the activities of daily living and the oral health-related quality of life and dementia in older adults. METHODS: Over a period of 18 months, we visited 12 elderly care facilities and recruited 375 participants, 345 of whom were selected to undergo oral health examinations and oral health-related surveys. Each investigation was carried out face-to-face by a professional worker. RESULTS: Cognitive ability was found to be good when the results of the activities of daily living and the oral health-related quality of life examinations were good. If the results of the activities of daily living examination were bad, the odds ratio of dementia was 2.66, and adjusted odds ratio for age, sex, residence type, education level and denture was 2.99, representing a significant difference (P < 0.05). CONCLUSIONS: Most oral problems are not simply the outcome of aging, with oral hygiene management being the most important determining factor. Oral health problems can be prevented, and in order to improve the quality of life of older adults, attention must be paid to oral healthcare. Geriatr Gerontol Int 2018; 18: 943-949.

Prevalence and related factors of irregular menstrual cycles in Korean women: the 5th Korean National Health and Nutrition Examination Survey (KNHANES-V, 2010-2012).

INTRODUCTION: There have been few population-based studies reporting medical, lifestyle and psychological factors associated with irregular menstrual cycles. This study aimed to elucidate the prevalence and related factors of irregular menstrual cycles in Korean women. METHODS: Cross-sectional data from the 5th Korean National Health and Nutrition Examination Survey were used. Eligible women were 19-40 years old, not currently taking oral contraceptives or using intrauterine devices, and not currently pregnant or breast feeding, and had no medical history of hysterectomy, thyroid diseases, cancers or renal failure. Finally, 3194 premenopausal women were recruited in this study. The prevalence and related factors of irregular cycles were obtained using a general linear model and logistic regression analyses in a complex sampling design. RESULTS: The prevalence of irregular cycles was 14.3%. Age and high-education level were associated with lower odds ratios (ORs) for irregular cycles (OR 0.91, 95% confidence interval (95% CI) 0.87-0.96, and OR 0.58, 95% CI 0.38-0.88, respectively). The ORs of body mass index, perceived stress and depressive mood were 1.05 (95% CI 1.01-1.10), 1.46 (95% CI 1.11-1.92) and 2.07 (95% CI 1.18-3.63), respectively. CONCLUSIONS: Age, perceived stress, body mass index, depressive mood and education level, rather than obstetric factors or metabolic diseases were significant factors associated with irregular menstrual cycles in Korean women. Of these factors, perceived stress is the most significant factor associated with increased irregular menstrual cycles.

Antimicrobial activity of the chloroform fraction of Drynaria fortunei against oral pathogens.

Drynaria fortunei (D. fortunei), widely used in traditional Korean medicine, is reportedly effective in treating inflammation, hyperlipidemia, bone fractures, oxidative damage, arteriosclerosis, rheumatism, and gynecological diseases. The objective of this study was to evaluate the antibacterial effects of the chloroform fraction of D. fortunei (DFCF) and assess the synergistic effects of DFCF with antibiotics against bacterial pathogens. This was carried out by calculating the minimal inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) and performing checkerboard dilution test and time-kill assays. The MICs/MBCs for DFCF, ampicillin, and gentamicin against all oral strains were >39-2,500/5,000 µg/mL, 0.25-64/0.25-64 µg/mL, and 0.5-256/1-512 µg/mL, respectively. DFCF exhibited the highest activity against the periodontic pathogens Prevotella intermedia and Porphylomonas gingivalis. DFCF in combination with ampicillin showed a strong synergistic effect against oral bacteria (fractional inhibitory concentration (FIC) index ≤0.5), whereas on combining with gentamicin, it reduced the on half-eighth times than used alone (FICI ≤ 0.5). DFCF combined with ampicillin or gentamicin killed 100% of most tested bacteria within 3-4 h. The results of this study demonstrate the antimicrobial and synergistic activity of DFCF and antibiotics against oral pathogens.

Enantioselective Synthesis of 2,3-Disubstituted Benzomorpholines: Analogues of Lignan Natural Products.

The enantioselective synthesis of 2,3-disubstituted benzomorpholines, analogues of 1,4-benzodioxane natural products, has been achieved via addition of electron-rich aromatic donors to acyl-iminium ions derived from benzomorpholine aminols. Subsequent modification of the benzomorpholine scaffold allows side chains mimicking those found in 1,4-benzodioxane lignans to be added. Antiproliferative testing of the prepared analogues showed promising results against MDA-MB-231 and HCT116 cancer cell lines.

Synthesis and biological activity of pyrrole analogues of combretastatin A-4.

A series of pyrrole analogues of combretastatin (CA-4) were synthesized and tested for their anti-proliferative activity. The highly diastereoselective acyl-Claisen rearrangement was used to provide 2,3-syn disubstituted morpholine amides which were used as precursors for the various analogues. This synthesis allows for the preparation of 1,2- and 2,3-diaryl-1H-pyrroles which are both geometrically similar to CA-4. These pyrrolic analogues were tested for their anti-proliferative activity against two human cell lines, K562 and MDA-MB-231 with 2,3-diaryl-1H-pyrrole 35 exhibiting the most potent activity with IC50 value of 0.07µM against MDA-MB-231 cell line.

Physicochemical properties and antimicrobial activity of Roselle (Hibiscus sabdariffa L.).

BACKGROUND: The therapeutic action of a plant depends on its chemical constituents. In this study, experiments were carried out in order to evaluate the effect of extraction conditions on the antioxidative and antimicrobial activities of Roselle (Hibiscus sabdariffa L.). RESULTS: Roselle was found to be rich in malic acid, anthocyanins, ascorbic acid and minerals, especially Ca and Fe, but low in glucose. More than 18 volatile compounds were identified by gas chromatography and gas chromatography-mass spectrometry. This herb, which is rich in phenolic compounds and displays DPPH radical scavenging activity, could be a good source of natural antioxidants. The antimicrobial activity of the Roselle water and ethanol extracts was tested with Bacillus subtilis (ATCC6633), Staphylococcus aureus (ATCC6538) and Escherichia coli (ATCC 8739). The inhibition of the Roselle ethanol extract against B. subtilis and S. aureus was slightly higher than that of water extract but this difference was not significant. However, E. coli was strongly inhibited by the Roselle water extract at concentrations of 25 and 50 mg mL(-1) as determined by a paper disc method. CONCLUSION: The obtained results indicated that antioxidant and antimicrobial activity was related to different methods of extraction and Roselle extracts could be a source of therapeutically useful products.

Roselle (Hibiscus sabdariffa L.) and soybean oil effects on quality characteristics of pork patties studied by response surface methodology.

Response surface methodology was used to investigate the effect and interactions of processing variables such as roselle extract (0.1-1.3%), soybean oil (5-20%) on physicochemical, textural and sensory properties of cooked pork patties. It was found that reduction in thickness, pH, L* and b* values decreased; however, water-holding capacity, reduction in diameter and a* values increased, respectively, as the amount of roselle increased. Soybean oil addition increased water-holding capacity, reduction in thickness, b* values of the patties. The hardness depended on the roselle and soybean oil added, as its linear effect was negative at p<0.01. The preference of color, tenderness, juiciness, and overall quality depend on the addition of roselle and soybean oil. The maximum overall quality score (5.42) was observed when 12.5 g of soybean oil and 0.7 g of roselle extract was added. The results of this optimization study would be useful for meat industry that tends to increase the product yield for patties using the optimum levels of ingredients by RSM.

Antibacterial activity of sophoraflavanone G isolated from the roots of Sophora flavescens against methicillin-resistant Staphylococcus aureus.

In this study, sophoraflavanone G obtained from Sophora flavescens was evaluated against 10 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), either alone or in combination with ampicillin or oxacillin, via checkerboard assay. At the end point of an optically clear well, the minimum inhibitory concentrations (MICs) ranged from 0.5 to 8 microg/ml for sophoraflavanone G, from 64 to 1024 microg/ml for ampicillin, and from 256 to 1024 microg/ml for oxacillin. The combination of sophoraflavanone G and ampicillin or oxacillin yielded a fractional inhibitory concentration index ranging from 0.188 to 0.375, thereby indicating a principally synergistic effect. The synergistic interaction was verified by time-kill studies using sophoraflavanone G and/or antibiotics. Thirty minutes of treatment with sophoraflavanone G with ampicillin or oxacillin resulted in an increase in the rate of killing in units of CFU/ml to a greater degree than was observed with Sophoraflavanone G alone. These findings indicated that the application of the tested sophoraflavanone G alone or in combination with antibiotics might prove useful in the control and treatment of MRSA infections.

Chemical composition and antibacterial activity of essential oil from Artemisia feddei.

The chemical components of the essential oil from Artemisia feddei LEV. et VNT. were analyzed using GC-MS. Ninety-nine compounds, accounting for 96.23% of the extracted essential oil, were identified. The main oil compounds were 1,8-cineole (16.86%), chamazulene (9.04%), alpha-terpineol (8.18%), alpha-phellandrene (5.78%), alpha-thujone (5.51%), alpha-terpinyl acetate (5.07%), borneol (5.08%), beta- caryophyllene (4.71%), camphor (4.04%), and terpinen-4-ol (3.04%). The antimicrobial activity of the essential oil and some of its compounds was tested against 15 different genera of oral bacteria. The essential oil from A. feddei had a considerable inhibitory effect on all the obligate anaerobic bacteria tested (MICs, 0.025 to 0.05 mg/ml; MBCs, 0.025 to 0.1mg/ml), whereas the major compounds demonstrated different degrees of growth inhibition.