Current guidelines recommend dual antiplatelet therapy (DAPT) of aspirin plus a P2Y12 inhibitor for at least 12 months after implantation of drug-eluting stents (DES) in patients with acute coronary ...syndrome. However, available data about the optimal duration of DAPT in patients with acute coronary syndrome undergoing percutaneous coronary intervention are scant. We aimed to investigate whether a 6-month duration of DAPT would be non-inferior to the conventional 12-month or longer duration of DAPT in this population.
We did a randomised, open-label, non-inferiority trial at 31 centres in South Korea. Patients were eligible if they had unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction, and underwent percutaneous coronary intervention. Enrolled patients were randomly assigned, via a web-based system by computer-generated block randomisation, to either the 6-month DAPT group or to the 12-month or longer DAPT group, with stratification by site, clinical presentation, and diabetes. Assessors were masked to treatment allocation. The primary endpoint was a composite of all-cause death, myocardial infarction, or stroke at 18 months after the index procedure in the intention-to-treat population. Secondary endpoints were the individual components of the primary endpoint; definite or probable stent thrombosis as defined by the Academic Research Consortium; and Bleeding Academic Research Consortium (BARC) type 2–5 bleeding at 18 months after the index procedure. The primary endpoint was also analysed per protocol. This trial is registered with ClinicalTrials.gov, number NCT01701453.
Between Sept 5, 2012, and Dec 31, 2015, we randomly assigned 2712 patients; 1357 to the 6-month DAPT group and 1355 to the 12-month or longer DAPT group. Clopidogrel was used as a P2Y12 inhibitor for DAPT in 1082 (79·7%) patients in the 6-month DAPT group and in 1109 (81·8%) patients in the 12-month or longer DAPT group. The primary endpoint occurred in 63 patients in the 6-month DAPT group and in 56 patients in the 12-month or longer DAPT group (cumulative event rate 4·7% vs 4·2%; absolute risk difference 0·5%; upper limit of one-sided 95% CI 1·8%; pnon-inferiority=0·03 with a predefined non-inferiority margin of 2·0%). Although all-cause mortality did not differ significantly between the 6-month DAPT group and the 12-month or longer DAPT group (35 2·6% patients vs 39 2·9%; hazard ratio HR 0·90 95% CI 0·57–1·42; p=0·90) and neither did stroke (11 0·8% patients vs 12 0·9%; 0·92 0·41–2·08; p=0·84), myocardial infarction occurred more frequently in the 6-month DAPT group than in the 12-month or longer DAPT group (24 1·8% patients vs ten 0·8%; 2·41 1·15–5·05; p=0·02). 15 (1·1%) patients had stent thrombosis in the 6-month DAPT group compared with ten (0·7%) in the 12-month or longer DAPT group (HR 1·50 95% CI 0·68–3·35; p=0·32). The rate of BARC type 2–5 bleeding was 2·7% (35 patients) in the 6-month DAPT group and 3·9% (51 patients) in the 12-month or longer DAPT group (HR 0·69 95% CI 0·45–1·05; p=0·09). Results from the per-protocol analysis were similar to those from the intention-to-treat analysis.
The increased risk of myocardial infarction with 6-month DAPT and the wide non-inferiority margin prevent us from concluding that short-term DAPT is safe in patients with acute coronary syndrome undergoing percutaneous coronary intervention with current-generation DES. Prolonged DAPT in patients with acute coronary syndrome without excessive risk of bleeding should remain the standard of care.
Abbott Vascular Korea, Medtronic Vascular Korea, Biosensors Inc, and Dong-A ST.
Data regarding clinical outcomes after intravascular imaging-guided percutaneous coronary intervention (PCI) for complex coronary-artery lesions, as compared with outcomes after angiography-guided ...PCI, are limited.
In this prospective, multicenter, open-label trial in South Korea, we randomly assigned patients with complex coronary-artery lesions in a 2:1 ratio to undergo either intravascular imaging-guided PCI or angiography-guided PCI. In the intravascular imaging group, the choice between intravascular ultrasonography and optical coherence tomography was at the operators' discretion. The primary end point was a composite of death from cardiac causes, target-vessel-related myocardial infarction, or clinically driven target-vessel revascularization. Safety was also assessed.
A total of 1639 patients underwent randomization, with 1092 assigned to undergo intravascular imaging-guided PCI and 547 assigned to undergo angiography-guided PCI. At a median follow-up of 2.1 years (interquartile range, 1.4 to 3.0), a primary end-point event had occurred in 76 patients (cumulative incidence, 7.7%) in the intravascular imaging group and in 60 patients (cumulative incidence, 12.3%) in the angiography group (hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.89; P = 0.008). Death from cardiac causes occurred in 16 patients (cumulative incidence, 1.7%) in the intravascular imaging group and in 17 patients (cumulative incidence, 3.8%) in the angiography group; target-vessel-related myocardial infarction occurred in 38 (cumulative incidence, 3.7%) and 30 (cumulative incidence, 5.6%), respectively; and clinically driven target-vessel revascularization in 32 (cumulative incidence, 3.4%) and 25 (cumulative incidence, 5.5%), respectively. There were no apparent between-group differences in the incidence of procedure-related safety events.
Among patients with complex coronary-artery lesions, intravascular imaging-guided PCI led to a lower risk of a composite of death from cardiac causes, target-vessel-related myocardial infarction, or clinically driven target-vessel revascularization than angiography-guided PCI. (Supported by Abbott Vascular and Boston Scientific; RENOVATE-COMPLEX-PCI ClinicalTrials.gov number, NCT03381872).
Data on P2Y12 inhibitor monotherapy after short-duration dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary intervention are limited.
To determine whether P2Y12 inhibitor ...monotherapy after 3 months of DAPT is noninferior to 12 months of DAPT in patients undergoing PCI.
The SMART-CHOICE trial was an open-label, noninferiority, randomized study that was conducted in 33 hospitals in Korea and included 2993 patients undergoing PCI with drug-eluting stents. Enrollment began March 18, 2014, and follow-up was completed July 19, 2018.
Patients were randomly assigned to receive aspirin plus a P2Y12 inhibitor for 3 months and thereafter P2Y12 inhibitor alone (n = 1495) or DAPT for 12 months (n = 1498).
The primary end point was major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke) at 12 months after the index procedure. Secondary end points included the components of the primary end point and bleeding defined as Bleeding Academic Research Consortium type 2 to 5. The noninferiority margin was 1.8%.
Among 2993 patients who were randomized (mean age, 64 years; 795 women 26.6%), 2912 (97.3%) completed the trial. Adherence to the study protocol was 79.3% of the P2Y12 inhibitor monotherapy group and 95.2% of the DAPT group. At 12 months, major adverse cardiac and cerebrovascular events occurred in 42 patients in the P2Y12 inhibitor monotherapy group and in 36 patients in the DAPT group (2.9% vs 2.5%; difference, 0.4% 1-sided 95% CI, -∞% to 1.3%; P = .007 for noninferiority). There were no significant differences in all-cause death (21 1.4% vs 18 1.2%; hazard ratio HR, 1.18; 95% CI, 0.63-2.21; P = .61), myocardial infarction (11 0.8% vs 17 1.2%; HR, 0.66; 95% CI, 0.31-1.40; P = .28), or stroke (11 0.8% vs 5 0.3%; HR, 2.23; 95% CI, 0.78-6.43; P = .14) between the 2 groups. The rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group than in the DAPT group (2.0% vs 3.4%; HR, 0.58; 95% CI, 0.36-0.92; P = .02).
Among patients undergoing percutaneous coronary intervention, P2Y12 inhibitor monotherapy after 3 months of DAPT compared with prolonged DAPT resulted in noninferior rates of major adverse cardiac and cerebrovascular events. Because of limitations in the study population and adherence, further research is needed in other populations.
ClinicalTrials.gov Identifier: NCT02079194.
Since the rediscovery of graphene in 2004, this material has attracted an enormous amount of interest owing to its unique structural, mechanical, electronic, and optical properties. Beyond this, the ...unique properties of graphene have also triggered extensive research on other two‐dimensional (2D) materials including transition metal dichalcogenides (TMDs), particularly for electronic and optoelectronic device applications. In particular, not only single junction but also various heterojunction devices based on 2D materials have afforded novel functionality and advances in many research fields. The availability of various 2D materials could allow the formation of a wide variety of heterojunctions with desired band alignments, thereby providing a powerful fabrication process platform for high‐performance electronic and optoelectronic devices. In this review, the important fabrication techniques of i) doping, ii) contact engineering, and iii) heterojunction formation for improving the performance of 2D‐material‐based devices are first introduced. Promising 2D‐material‐based electronic and optoelectronic devices are then discussed, including lateral/vertical field‐effect transistors (FETs), negative differential resistance (NDR) devices, memory, photodetectors, photovoltaics, and light‐emitting diode (LED) devices.
Important fabrication techniques of doping, contact engineering, and heterojunction formation are introduced for improving the performance of 2D‐material‐based devices. In addition, promising 2D‐material‐based electronic and optoelectronic devices are discussed: lateral/vertical FETs, NDR devices, memory, photodetectors, photovoltaics, and LED devices.
Abstract
Bone resorption can be caused by excessive differentiation and/or activation of bone‐resorbing osteoclasts. While microbe‐associated molecular patterns can influence the differentiation and ...activation of bone cells, little is known about the role of lipoteichoic acid (LTA), a major cell wall component of Gram‐positive bacteria, in the regulation of bone metabolism. In this study, we investigated the effect of LTA on bone metabolism using wild‐type
Staphylococcus aureus
and the LTA‐deficient mutant strain. LTA‐deficient
S. aureus
induced higher bone loss and osteoclast differentiation than wild‐type
S. aureus
. LTA isolated from
S. aureus
(SaLTA) inhibited osteoclast differentiation from committed osteoclast precursors in the presence of various osteoclastogenic factors by downregulating the expression of NFATc1. Remarkably, SaLTA attenuated the osteoclast differentiation from committed osteoclast precursors of TLR2
−/−
or MyD88
−/−
mice and from the committed osteoclast precursors transfected with paired immunoglobulin‐like receptor B‐targeting siRNA. SaLTA directly interacted with gelsolin, interrupting the gelsolin‐actin dissociation which is a critical process for osteoclastogenesis. Moreover, SaLTA suppressed the mRNA expression of dendritic cell‐specific transmembrane protein, ATPase H
+
transporting V0 subunit D2, and
Integrin
, which encode proteins involved in cell‐cell fusion of osteoclasts. Notably, LTAs purified from probiotics, including
Bacillus subtilis
,
Enterococcus faecalis
, and
Lactobacillus
species, also suppressed Pam2CSK4‐ or RANKL‐induced osteoclast differentiation. Taken together, these results suggest that LTAs have anti‐resorptive activity through the inhibition of osteoclastogenesis by interfering with the gelsolin‐actin dissociation and may be used as effective therapeutic agents for the prevention or treatment of inflammatory bone diseases.
Bone marrow (BM)-derived mesenchymal stem cells (MSCs) hold great promise for cardiovascular cell therapy owing to their multipotency and culture expandability.
The aim of the study was to ...investigate whether MSCs can treat experimental acute myocardial infarction (MI) and diabetic neuropathy.
We isolated mononuclear cells from mouse BM and cultured MSCs in a conventional manner. Flow cytometry analyses of these cultured cells at passage 4 showed expression of typical MSC markers such as CD44 and CD29, but not hematopoietic markers such as c-kit, flk1, and CD34. To determine the therapeutic effects of MSCs, we injected MSCs into the peri-infarct area after ligation of the left anterior descending coronary arteries of mice and, as separate experiments, injected the same batch of MSCs into hindlimb muscles of mice with diabetic neuropathy. During the follow-up at 4 to 8 weeks after cell transplantation, growing tumors were observed in 30% of hearts in the MI model, and in 46% of hindlimbs in the diabetic neuropathy model. Histological examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytological atypia and necrosis, and positive staining for α-smooth muscle actin, indicative of malignant sarcoma with myogenic differentiation. Chromosomal analysis of these MSCs showed multiple chromosomal aberrations including fusion, fragmentation, and ring formation.
Genetically unmodified MSCs can undergo chromosomal abnormalities even at early passages and form malignant tumors when transplanted in vivo. These results suggest that careful monitoring of chromosomal status is warranted when in vitro expanded MSCs are used for cell therapy such as for MI.
Dental caries is a biofilm-dependent oral disease and Streptococcus mutans is the known primary etiologic agent of dental caries that initiates biofilm formation on tooth surfaces. Although some ...Lactobacillus strains inhibit biofilm formation of oral pathogenic bacteria, the molecular mechanisms by which lactobacilli inhibit bacterial biofilm formation are not clearly understood. In this study, we demonstrated that Lactobacillus plantarum lipoteichoic acid (Lp.LTA) inhibited the biofilm formation of S. mutans on polystyrene plates, hydroxyapatite discs, and dentin slices without affecting the bacterial growth. Lp.LTA interferes with sucrose decomposition of S. mutans required for the production of exopolysaccharide, which is a main component of biofilm. Lp.LTA also attenuated the biding of fluorescein isothiocyanate-conjugated dextran to S. mutans, which is known to have a high affinity to exopolysaccharide on S. mutans. Dealanylated Lp.LTA did not inhibit biofilm formation of S. mutans implying that D-alanine moieties in the Lp.LTA structure were crucial for inhibition. Collectively, these results suggest that Lp.LTA attenuates S. mutans biofilm formation and could be used to develop effective anticaries agents.
Bone‐resorbing osteoclasts are differentiated from macrophages (MΦ) by M‐CSF and RANKL. MΦ can be mainly classified into M1 and M2 MΦ, which are proinflammatory and anti‐inflammatory, respectively, ...but little is known about their osteoclastogenic potential. Here, we investigated the osteoclastogenic potential of MΦ subtypes. When the two MΦ subtypes were differentiated into osteoclasts using M‐CSF and RANKL, M2 MΦ more potently differentiated into osteoclasts than M1 MΦ. M2 MΦ generated with IL‐4 or IL‐10 also showed enhanced osteoclast differentiation compared with M1 MΦ induced by IFN‐γ and lipopolysaccharide. In addition, robust bone‐resorptive capacity and giant actin rings, which are features of mature osteoclasts, were observed in M2, but not M1 MΦ, under the osteoclast differentiation condition. Osteoclast differentiation was significantly increased in CD206+ M2 MΦ but not in CD86+ M1 MΦ. Compared with M1 MΦ, c‐Fms and RANK were highly expressed in M2 MΦ. Enhanced osteoclastogenesis of M2 MΦ was mediated through sustained ERK activation, followed by efficient c‐Fos and NFATc1 induction. Notably, the osteoclastogenic potential of M1 MΦ converted into M2 MΦ by exposure to M‐CSF was higher than that of M2 MΦ converted into M1 MΦ by exposure to GM‐CSF. Silencing IRF5, which is responsible for M1 MΦ polarization, increased osteoclast differentiation by enhancing c‐Fms expression and activation of ERK, c‐Fos, CREB, and NFATc1, which was inhibited by overexpression of IRF5. Collectively, M2 MΦ are suggested to be more efficient osteoclast precursors than M1 MΦ because of the attenuated expression of IRF5.
M2 MΦ were more potent osteoclast precursors than M1 MΦ. Unlike M1 MΦ, M2 MΦ exhibited a high level of c‐Fms and prolonged ERK activation upon stimulation with M‐CSF. Furthermore, M2 MΦ‐derived osteoclasts showed high bone‐resorptive capacity and giant actin ring formation. Interestingly, decreased IRF5 expression in M2 MΦ contributed to enhanced osteoclastogenic potential through induction of c‐Fms, c‐Fos, NFATc1, and CREB.
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