Ultra-bright, efficient and stable perovskite light-emitting diodes.

Metal halide perovskites are attracting a lot of attention as next-generation light-emitting materials owing to their excellent emission properties, with narrow band emission1-4. However, perovskite light-emitting diodes (PeLEDs), irrespective of their material type (polycrystals or nanocrystals), have not realized high luminance, high efficiency and long lifetime simultaneously, as they are influenced by intrinsic limitations related to the trade-off of properties between charge transport and confinement in each type of perovskite material5-8. Here, we report an ultra-bright, efficient and stable PeLED made of core/shell perovskite nanocrystals with a size of approximately 10 nm, obtained using a simple in situ reaction of benzylphosphonic acid (BPA) additive with three-dimensional (3D) polycrystalline perovskite films, without separate synthesis processes. During the reaction, large 3D crystals are split into nanocrystals and the BPA surrounds the nanocrystals, achieving strong carrier confinement. The BPA shell passivates the undercoordinated lead atoms by forming covalent bonds, and thereby greatly reduces the trap density while maintaining good charge-transport properties for the 3D perovskites. We demonstrate simultaneously efficient, bright and stable PeLEDs that have a maximum brightness of approximately 470,000 cd m-2, maximum external quantum efficiency of 28.9% (average = 25.2 ± 1.6% over 40 devices), maximum current efficiency of 151 cd A-1 and half-lifetime of 520 h at 1,000 cd m-2 (estimated half-lifetime >30,000 h at 100 cd m-2). Our work sheds light on the possibility that PeLEDs can be commercialized in the future display industry.

Mobile PEAR transcription factors integrate positional cues to prime cambial growth.

Apical growth in plants initiates upon seed germination, whereas radial growth is primed only during early ontogenesis in procambium cells and activated later by the vascular cambium1. Although it is not known how radial growth is organized and regulated in plants, this system resembles the developmental competence observed in some animal systems, in which pre-existing patterns of developmental potential are established early on2,3. Here we show that in Arabidopsis the initiation of radial growth occurs around early protophloem-sieve-element cell files of the root procambial tissue. In this domain, cytokinin signalling promotes the expression of a pair of mobile transcription factors-PHLOEM EARLY DOF 1 (PEAR1) and PHLOEM EARLY DOF 2 (PEAR2)-and their four homologues (DOF6, TMO6, OBP2 and HCA2), which we collectively name PEAR proteins. The PEAR proteins form a short-range concentration gradient that peaks at protophloem sieve elements, and activates gene expression that promotes radial growth. The expression and function of PEAR proteins are antagonized by the HD-ZIP III proteins, well-known polarity transcription factors4-the expression of which is concentrated in the more-internal domain of radially non-dividing procambial cells by the function of auxin, and mobile miR165 and miR166 microRNAs. The PEAR proteins locally promote transcription of their inhibitory HD-ZIP III genes, and thereby establish a negative-feedback loop that forms a robust boundary that demarks the zone of cell division. Taken together, our data establish that during root procambial development there exists a network in which a module that links PEAR and HD-ZIP III transcription factors integrates spatial information of the hormonal domains and miRNA gradients to provide adjacent zones of dividing and more-quiescent cells, which forms a foundation for further radial growth.

Optimal antithrombotic strategy in patients with atrial fibrillation beyond 1 year after drug-eluting stent implantation: Design and rationale of the randomized ADAPT AF-DES trial.

BACKGROUND: Both anticoagulation and antiplatelet therapies are recommended after percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF). Although contemporary guidelines recommend discontinuation of antiplatelet therapy 1 year after drug-eluting stent (DES) implantation due to excessive bleeding risk, supporting randomized trials are still lacking. METHODS: The ADAPT AF-DES trial is a multicenter, prospective, open-label, randomized, non-inferiority trial, enrolling 960 patients with AF with a CHA2DS2-VASc score > 1, who underwent PCI with DES implantation at least 12 months before enrollment. Eligible patients are randomly assigned to receive either non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy or NOAC plus clopidogrel combination therapy. The primary outcome is net adverse clinical event (NACE) at 1 year after randomization, defined as a composite of all-cause death, myocardial infarction, stent thrombosis, stroke, systemic embolism, and major or clinically relevant non-major bleeding, as defined by the International Society on Thrombosis and Hemostasis criteria. We hypothesize that NOAC monotherapy would be non-inferior to NOAC plus clopidogrel combination therapy for NACE in patients with AF beyond 12 months after DES implantation. CONCLUSIONS: The ADAPT AF-DES trial will evaluate the efficacy and safety of NOAC monotherapy versus NOAC plus clopidogrel combination therapy in patients with AF beyond 12 months after PCI with DES implantation. The ADAPT AF-DES trial will provide robust evidence for an optimal antithrombotic strategy in patients with AF after DES implantation. CLINICAL TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov. Unique identifier: NCT04250116.

Transradial Versus Transfemoral Access for Bifurcation Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stent.

BACKGROUND: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using second-generation drug-eluting stents (DESs). METHODS: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). RESULTS: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). CONCLUSION: The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03068494.

Translating proteome and transcriptome dynamics of periodontal ligament stem cell-derived secretome/conditioned medium in an in vitro model of periodontitis.

BACKGROUND: Periodontal ligament stem cells (PDLSCs) have been proposed as therapeutic candidates in periodontal diseases and periodontium defects. Paracrine factors of PDLSCs, namely, secretome, can contribute to tissue regeneration comparable to direct stem cell application. This study explored restoration effects of PDLSC-derived secretome/conditioned medium (PDLSC-CM) on PDLSCs themselves in an inflammatory microenvironment and identified its action mechanisms using proteomics and transcriptomic profiling. METHODS: PDLSC-CM was prepared from cells under healthy culture conditions. Mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were then performed to analyze the PDLSC-CM proteome. Osteogenic differentiation of PDLSCs under inflammatory conditions or in the presence of PDLSC-CM was then characterized in assays of alkaline phosphatase activity, intracellular calcium levels, protein expression of osteogenic markers, and matrix mineralization. Furthermore, the transcriptomic profile was assessed to identify significantly enriched signaling pathways and associated molecular networks by RNA sequencing. RESULTS: LC-MS/MS proteomics identified a total of 203 proteins and distinguished 187 significant protein changes in PDLSC-CM compared to control-CM. LPS-treated PDLSCs significantly attenuated osteogenic differentiation. When PDLSCs were treated with PDLSC-CM alone, their osteogenic activity was significantly upregulated compared to the control group. Moreover, the LPS-impaired osteogenesis of PDLSCs was reconstituted by PDLSC-CM treatment. RNA sequencing revealed 252, 1,326, and 776 differentially expressed genes in the control vs. LPS, control vs. PDLSC-CM, and LPS vs. LPS + PDLSC-CM groups, respectively. CONCLUSION: This study suggest that PDLSC-CM restores the osteogenic potential of PDLSCs in an inflammatory environment through secretory functions representing potential repair and regenerative mechanisms.

A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19.

Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an in vitro inhibitory potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical trial in mild to moderate COVID-19 patients. We randomly assigned patients to receive either camostat mesylate (DWJ1248) or placebo orally for 14 days. The primary endpoint was time to clinical improvement of subject symptoms within 14 days, measured using a subjective 4-point Likert scale. Three hundred forty-two patients were randomized. The primary endpoint was nonsignificant, where the median times to clinical improvement were 7 and 8 days in the camostat mesylate group and the placebo group, respectively (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 0.84 to 1.43; P = 0.50). A post hoc analysis showed that the difference was greatest at day 7, without reaching significance. In the high-risk group, the proportions of patients with clinical improvement up to 7 days were 45.8% (50/109) in the camostat group and 38.4% (40/104) in the placebo group (odds ratio [OR] = 1.33; 95% CI, 0.77 to 2.31; P = 0.31); the ordinal scale score at day 7 improved in 20.0% (18/90) of the camostat group and 13.3% (12/90) of the placebo group (OR = 1.68; 95% CI, 0.75 to 3.78; P = 0.21). Adverse events were similar in the two groups. Camostat mesylate was safe in the treatment of COVID-19. Although this study did not show clinical benefit in patients with mild to moderate COVID-19, further clinical studies for high-risk patients are needed. (This trial was registered with ClinicalTrials.gov under registration no. NCT04521296).

Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial.

BACKGROUND: Drug combinations rather than increasing doses of one drug can achieve greater efficacy and lower risks. Thus, as an alternative to high-intensity statin monotherapy, moderate-intensity statin with ezetimibe combination therapy can lower LDL cholesterol concentrations effectively while reducing adverse effects. However, evidence from randomised trials to compare long-term clinical outcomes is needed. METHODS: In this randomised, open-label, non-inferiority trial, patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea were randomly assigned (1:1) to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%. This trial is registered with ClinicalTrials.gov, NCT03044665 and is complete. FINDINGS: Between Feb 14, 2017, and Dec 18, 2018, 3780 patients were enrolled: 1894 patients to the combination therapy group and 1886 to the high-intensity statin monotherapy group. The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference -0·78%; 90% CI -2·39 to 0·83). LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p<0·0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p<0·0001). INTERPRETATION: Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction. FUNDING: Hanmi Pharmaceutical.

Engineering homoeologs provide a fine scale for quantitative traits in polyploid.

Numerous staple crops exhibit polyploidy and are difficult to genetically modify. However, recent advances in genome sequencing and editing have enabled polyploid genome engineering. The hexaploid black nightshade species Solanum nigrum has immense potential as a beneficial food supplement. We assembled its genome at the scaffold level. After functional annotations, we identified homoeologous gene sets, with similar sequence and expression profiles, based on comparative analyses of orthologous genes with close diploid relatives Solanum americanum and S. lycopersicum. Using CRISPR-Cas9-mediated mutagenesis, we generated various mutation combinations in homoeologous genes. Multiple mutants showed quantitative phenotypic changes based on the genotype, resulting in a broad-spectrum effect on the quantitative traits of hexaploid S. nigrum. Furthermore, we successfully improved the fruit productivity of Boranong, an orphan cultivar of S. nigrum suggesting that engineering homoeologous genes could be useful for agricultural improvement of polyploid crops.

Selection Criteria for Completion Thyroidectomy in Follicular Thyroid Carcinoma Using Primary Tumor Size and TERT Promoter Mutational Status.

BACKGROUND: A stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to achieve definite characterization of follicular thyroid carcinoma (FTC). Choosing appropriate candidates for completion thyroidectomy has been controversial. OBJECTIVE: The aim of this study was to clarify the selection criteria for completion thyroidectomy using telomerase reverse transcriptase (TERT) promoter mutation. METHODS: A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the World Health Organization (WHO) 2017 classifications were calculated. RESULTS: Of the 87 patients, 8 (9.2%) had initial distant metastasis and 15 (17.2%) had persistent disease or developed structural recurrence. The threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2 cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while that in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT was 4 cm. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification was significantly different only in patients with WT-TERT (p = 0.001, p = 0.019, and p = 0.005, respectively). CONCLUSIONS: The data suggest 2 cm as a critical threshold diameter for performance of completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can help select candidates for completion thyroidectomy.

Retro Diels-Alder-triggered self-assembly of a polymerizable macrocyclic diacetylene.

A new triggered self-assembly method, which utilizes retro Diels-Alder (rDA)-promoted self-assembly of a macrocyclic diacetylene, was developed. The steric bulk present in a Diels-Alder (DA) adduct was released by a thermally promoted rDA reaction, resulting in the generation of a linear diacetylene that readily self-assembles to form a supramolecular polymer. The maleimide-containing blue-colored polydiacetylene, which was generated by UV irradiation, was utilized as a thiol specific colorimetric sensor.

Current Status of Q Fever and the Challenge of Outbreak Preparedness in Korea: One Health Approach to Zoonoses.

Human Q fever, a zoonosis caused by Coxiella burnetii, presents with diverse clinical manifestations ranging from mild self-limited febrile illnesses to life-threatening complications such as endocarditis or vascular infection. Although acute Q fever is a benign illness with a low mortality rate, a large-scale outbreak of Q fever in the Netherlands led to concerns about the possibility of blood transfusion-related transmission or obstetric complications in pregnant women. Furthermore, a small minority (< 5%) of patients with asymptomatic or symptomatic infection progress to chronic Q fever. Chronic Q fever is fatal in 5-50% of patients if left untreated. In South Korea, Q fever in humans was designated as a notifiable infectious disease in 2006, and the number of Q fever cases has increased sharply since 2015. Nonetheless, it is still considered a neglected and under-recognized infectious disease. In this review, recent trends of human and animal Q fever in South Korea, and public health concerns regarding Q fever outbreaks are reviewed, and we consider how a One Health approach could be applied as a preventive measure to prepare for zoonotic Q fever outbreaks.

Physiology of lipid digestion and absorption in poultry: An updated review on the supplementation of exogenous emulsifiers in broiler diets.

Lipids are a concentrated source of energy with at least twice as much energy as the same amount of carbohydrates and protein. Dietary lipids provide a practical alternative toward increasing the dietary energy density of feeds for high-performing modern broilers. However, the digestion and absorption of dietary lipids are much more complex than that of the other macronutrients. In addition, young birds are physiologically limited in their capacity to utilise dietary fats and oils effectively. The use of dietary emulsifiers as one of the strategies aimed at improving fat utilisation has been reported to elicit several physiological responses including improved fat digestibility and growth performance. In practical terms, this allows for the incorporation of lipids into lower-energy diets without compromising broiler performance. Such an approach may potentially lower feed costs and raise revenue gains. The current review revisits lipids and the different roles that they perform in diets and whole-body metabolism. Additional information on the process of dietary lipid digestion and absorption in poultry; and the physiological limitation brought about by age on lipid utilisation in the avian gastrointestinal tract have been discussed. Subsequently, the physiological responses resulting from the dietary supplementation of exogenous emulsifiers as a strategy for improved lipid utilisation in broiler nutrition are appraised. Suggestions of nascent areas for a better understanding of exogenous emulsifiers have been highlighted.

Effectiveness of Pneumococcal Vaccination Against Pneumococcal Pneumonia Hospitalization in Older Adults: A Prospective, Test-Negative Study.

BACKGROUND: Despite use of the 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) over the last decade, the disease burden of pneumococcal pneumonia is still high. We evaluated the field effectiveness of PCV13, PPSV23, and sequential vaccination against pneumococcal pneumonia in older adults. METHODS: This prospective multicenter study was conducted in adults aged ≥65 years hospitalized with community-acquired pneumonia (CAP) between September 2015 and August 2017. The case-control test-negative design was used to estimate vaccine effectiveness (VE) against pneumococcal CAP. RESULTS: Of 1525 cases with CAP hospitalization, 167 (11.0%) were identified as pneumococcal CAP. In the elderly aged ≥65 years, the adjusted VE of pneumococcal vaccines against pneumococcal CAP was statistically insignificant: 40.0% (95% confidence interval [CI], -10.8% to 67.5%) for PCV13 and 11.0% (95% CI, -26.4% to 37.3%) for PPSV23. However, in the younger subgroup (aged 65-74 years), sequential PCV13/PPSV23 vaccination showed the highest adjusted VE of 80.3% (95% CI, 15.9%-95.4%), followed by single-dose PCV13 (adjusted VE, 66.4% [95% CI, .8%-88.6%]) and PPSV23 (adjusted VE, 18.5% [95% CI, -38.6% to 52.0%]). CONCLUSIONS: Sequential PCV13/PPSV23 vaccination is most effective for preventing pneumococcal CAP among the elderly aged 65-74 years.

High-Resolution Cryo-Electron Microscopy Reveals the Unique Striated Hollow Structure of Photocatalytic Macrocyclic Polydiacetylene Nanotubes.

High-resolution structures are crucial for understanding the functional properties of nanomaterials. We applied single-particle cryo-electron microscopy (cryo-EM), a method traditionally used for structure determination of biological macromolecules, to obtain high-resolution structures of synthetic non-biological filaments formed by photopolymerization of macrocyclic diacetylene (MDA) amphiphilic monomers. Tomographic analysis showed that the MDA monomers self-assemble into hollow nanotubes upon dispersion in water. Single-particle analysis revealed tubes consisting of six pairs of covalently bonded filaments held together by hydrophobic interactions, where each filament is composed of macrocyclic rings stacked in parallel "chair" conformations. The hollow MDA nanotube structures we found may account for the efficient scavenging of amphiphilic pollutants in water and subsequent photodegradation of the guest species.

Molecular classification of follicular thyroid carcinoma based on TERT promoter mutations.

Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer-specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification. We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease-free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C-index. CSS was significantly different in encapsulated angioinvasive (EA)-FTC patients stratified by TERT promoter mutations [wild-type (WT-TERT) vs. mutant (M-TERT); P < 0.001] but not in minimally invasive (MI)-FTC and widely invasive (WI)-FTC patients (P = 0.691 and 0.176, respectively). We defined alternative groups as follows: Group 1 (MI-FTC with WT-TERT and M-TERT; EA-FTC with WT-TERT), Group 2 (WI-FTC with WT-TERT), and Group 3 (EA-FTC with M-TERT; WI-FTC with M-TERT). Both PVE (22.44 vs. 9.63, respectively) and C-index (0.831 vs. 0.731, respectively) for CSS were higher in the alternative groups than in the WHO 2017 groups. Likewise, both PVE (27.1 vs. 14.9, respectively) and C-index (0.846 vs. 0.794, respectively) for DFS were also higher in the alternative groups than in the WHO 2017 groups. Alternative group harmonizing of the WHO 2017 classification and TERT promoter mutations is effective in predicting CSS in FTC patients, thereby improving DFS predictability.

The longitudinal effect of oxcarbazepine on thyroid function in children and adolescents with epilepsy.

OBJECTIVE: Thyroid hormone abnormalities have been linked to antiseizure medications (ASMs). Oxcarbazepine is considered safer than carbamazepine because it induces the hepatic cytochrome P450 metabolic enzymes less than the carbamazepine does. However, limited data exist for the influence of oxcarbazepine on thyroid function in children and adolescents. The objective of this study was to determine the effect of oxcarbazepine on thyroid function in these patients. METHODS: A total of 162 pediatric patients with epilepsy who started oxcarbazepine for the first time between April 2003 and May 2020 were enrolled. The longitudinal effects of oxcarbazepine for thyroid functions were confirmed using general estimating equations. RESULTS: Serum triiodothyronine (T3), thyroxine (T4), and free thyroxine (fT4) levels decreased significantly during 5 years of follow-up (all p's < .001). In particular, T3 and fT4 levels were reduced steeply in the first 2 years of oxcarbazepine treatment. There was no significant change in thyroid-stimulating hormone during oxcarbazepine treatment. SIGNIFICANCE: Serum T3, T4, and fT4 levels decreased significantly during oxcarbazepine use, and this change was maintained during the treatment period. In patients receiving oxcarbazepine, it is recommended that periodic thyroid function testing should be performed, especially within the first 2 years after starting this ASM. Our results indicate that oxcarbazepine-induced hypothyroidism does not appear to be accompanied by a significant increase in TSH, and consequently might be missed if TSH alone is monitored as a measure of thyroid dysfunction.

Long-Term Clinical Outcomes and Its Predictors Between the 1- and 2-Stent Strategy in Coronary Bifurcation Lesions　- A Baseline Clinical and Lesion Characteristic-Matched Analysis.

BACKGROUND: Differences in the impact of the 1- or 2-stent strategy in similar coronary bifurcation lesion conditions are not well understood. This study investigated the clinical outcomes and its predictors between 1 or 2 stents in propensity score-matched (PSM) complex bifurcation lesions.Methods and Results: We analyzed the data of patients with bifurcation lesions, obtained from a multicenter registry of 2,648 patients (median follow up, 53 months). The patients were treated by second generation drug-eluting stents (DESs). The primary outcome was target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction (TVMI), and ischemia-driven target lesion revascularization (TLR). PSM was performed to balance baseline clinical and angiographic discrepancies between 1 and 2 stents. After PSM (N=333 from each group), the 2-stent group had more TLRs (hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.42-6.97, P=0.005) and fewer hard endpoints (composite of cardiac death and TVMI; HR 0.44, 95% CI 0.19-1.01, P=0.054), which resulted in a similar TLF rate (HR 1.40, 95% CI 0.83-2.37, P=0.209) compared to the 1-stent group. Compared with 1-stent, the 2-stent technique was more frequently associated with less TLF in the presence of main vessel (pinteraction=0.008) and side branch calcification (pinteraction=0.010). CONCLUSIONS: The 2-stent strategy should be considered to reduce hard clinical endpoints in complex bifurcation lesions, particularly those with calcifications.

Osteoinductive function of fucoidan on periodontal ligament stem cells: Role of PI3K/Akt and Wnt/ß-catenin signaling pathways.

BACKGROUND/OBJECTIVES: Fucoidan has been focused as a multifunctional therapeutic uses including bone health supplements. However, the critical molecular mechanisms of fucoidan for bone therapeutic agents have not been fully understood. We investigated the osteoinductive effect of fucoidan on periodontal ligament stem cells (PDLSCs) and how this polymer encouraged PDLSC osteogenesis. MATERIALS AND METHODS: Osteogenic induction of PDLSCs was processed by culturing cells with fucoidan treatment. Osteogenic differentiation of PDLSCs was verified by alkaline phosphatase (ALP) activity, matrix mineralization assay, intracellular calcium levels, and mRNA expression and protein levels of osteogenic markers. RESULTS: Fucoidan treatment showed higher osteogenic activity in the PDLSCs than the control groups. PDLSCs with fucoidan also presented increased levels of the phosphatidylinositol-3-kinase (PI3K) isoforms, p110α and p110γ compared to control cells. The phosphorylation of Akt, a PI3K downstream effector, was significantly increased at 90 min of fucoidan induction. Expression of ß-catenin, a coactivator of canonical Wnt pathways, was increased in PDLSCs with fucoidan. ß-catenin was found to link with PI3K activation during the fucoidan stimulation. When cells were blocked by PI3K inhibitor or ß-catenin-specific siRNA, fucoidan-induced osteogenic activity of PDLSCs was significantly attenuated. CONCLUSION: These findings suggest that the fucoidan stimulates osteogenic differentiation of PDLSCs via the PI3K/Akt and Wnt/ß-catenin pathways.

Fucoidan (Undaria pinnatifida)/Polydopamine Composite-Modified Surface Promotes Osteogenic Potential of Periodontal Ligament Stem Cells.

Fucoidan, a marine-sulfated polysaccharide derived from brown algae, has been recently spotlighted as a natural biomaterial for use in bone formation and regeneration. Current research explores the osteoinductive and osteoconductive properties of fucoidan-based composites for bone tissue engineering applications. The utility of fucoidan in a bone tissue regeneration environment necessitates a better understanding of how fucoidan regulates osteogenic processes at the molecular level. Therefore, this study designed a fucoidan and polydopamine (PDA) composite-based film for use in a culture platform for periodontal ligament stem cells (PDLSCs) and explored the prominent molecular pathways induced during osteogenic differentiation of PDLSCs through transcriptome profiling. Characterization of the fucoidan/PDA-coated culture polystyrene surface was assessed by scanning electron microscopy and X-ray photoelectron spectroscopy. The osteogenic differentiation of the PDLSCs cultured on the fucoidan/PDA composite was examined through alkaline phosphatase activity, intracellular calcium levels, matrix mineralization assay, and analysis of the mRNA and protein expression of osteogenic markers. RNA sequencing was performed to identify significantly enriched and associated molecular networks. The culture of PDLSCs on the fucoidan/PDA composite demonstrated higher osteogenic potency than that on the control surface. Differentially expressed genes (DEGs) (n = 348) were identified during fucoidan/PDA-induced osteogenic differentiation by RNA sequencing. The signaling pathways enriched in the DEGs include regulation of the actin cytoskeleton and Ras-related protein 1 and phosphatidylinositol signaling. These pathways represent cell adhesion and cytoskeleton organization functions that are significantly involved in the osteogenic process. These results suggest that a fucoidan/PDA composite promotes the osteogenic potential of PDLSCs by activation of critical molecular pathways.

Immunogenicity and Reactogenicity of Ad26.COV2.S in Korean Adults: A Prospective Cohort Study.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) pandemic continues, there are concerns regarding waning immunity and the emergence of viral variants. The immunogenicity of Ad26.COV2.S against wild-type (WT) and variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs to be evaluated. METHOD: This prospective cohort study was conducted between June 2021 and January 2022 at two university hospitals in South Korea. Healthy adults who were scheduled to be vaccinated with Ad26.COV2.S were enrolled in this study. The main outcomes included anti-spike (S) IgG antibody and neutralizing antibody responses, S-specific T-cell responses (interferon-γ enzyme-linked immunospot assay), solicited adverse events (AEs), and serious AEs. RESULTS: Fifty participants aged ≥ 19 years were included in the study. Geometric mean titers (GMTs) of anti-S IgG were 0.4 U/mL at baseline, 5.2 ± 3.0 U/mL at 3-4 weeks, 55.7 ± 2.4 U/mL at 5-8 weeks, and 81.3 ± 2.5 U/mL at 10-12 weeks after vaccination. GMTs of 50% neutralizing dilution (ND50) against WT SARS-CoV-2 were 164.6 ± 4.6 at 3-4 weeks, 313.9 ± 3.6 at 5-8 weeks, and 124.4 ± 2.6 at 10-12 weeks after vaccination. As for the S-specific T-cell responses, the median number of spot-forming units/106 peripheral blood mononuclear cell was 25.0 (5.0-29.2) at baseline, 60.0 (23.3-178.3) at 5-8 weeks, and 35.0 (13.3-71.7) at 10-12 weeks after vaccination. Compared to WT SARS-CoV-2, ND50 against Delta and Omicron variants was attenuated by 3.6-fold and 8.2-fold, respectively. The most frequent AE was injection site pain (82%), followed by myalgia (80%), fatigue (70%), and fever (50%). Most AEs were grade 1-2, and resolved within two days. CONCLUSION: Single-dose Ad26.COV2.S was safe and immunogenic. NAb titer and S-specific T-cell immunity peak at 5-8 weeks and rather decrease at 10-12 weeks after vaccination. Cross-reactive neutralizing activity against the Omicron variant was negligible.