Precise control over doping of photocatalysts is required to modulate their photocatalytic activity in visible light‐driven reactions. Here, a single precursor‐employing bottom‐up approach is ...developed to produce different heteroatom‐doped graphene quantum dots (GQDs) with unique photocatalytic activities. The solvothermal reaction of a norepinephrine precursor with redox active and condensable moieties effectively produces both nitrogen/sulfur codoped GQDs (NS‐GQDs) and nitrogen‐doped GQDs (N‐GQDs) by simply varying solvents (from dimethyl sulfoxide to water) under microwave irradiation. As‐prepared NS‐GQDs and N‐GQDs show similar lateral sizes (3–4 nm) and heights (1–2 nm), but they include different dopant types and doping constitution and content, which lead to changes in photocatalytic activity in aerobic oxidative coupling reactions of various amines. NS‐GQDs exhibit much higher photocatalytic activity in reactions under visible light than N‐GQDs and oxygen‐doped GQDs (O‐GQDs). The mechanism responsible for the outstanding photocatalytic activity of NS‐GQDs in visible light‐driven oxidative coupling reactions of amines is also fully investigated.
Modulation of the photocatalytic activity of heteroatom‐doped graphene quantum dots (GQDs) is reported. A single precursor, norepinephrine, is used to effectively produce N,S‐co‐doped GQDs and N‐doped GQDs under microwave irradiation. Tailoring dopant types, constitution, and content imparts much higher photocatalytic activity to N,S‐codoped GQDs than N‐doped GQDs and O‐doped GQDs in the visible‐light‐driven oxidative coupling reaction of various amines.
Visible-light-driven photocatalysis has been emerging as an efficient and sustainable approach for chemical transformation in organic reactions, in which photostable and cost-effective ...photosensitizers are required to trigger and promote it. Monolayer WS2 nanosheets smaller than 120 nm were prepared by means of a modified liquid exfoliation method, and they showed strong photoluminescence in the visible range of the electromagnetic spectrum from 450 to 650 nm. These photoactive WS2 nanosheets were exploited as photocatalysts in the oxidative coupling reactions of various amines under visible-light irradiation. They showed excellent photocatalytic activity and reusability without the loss of their catalytic activity in the visible-light-driven oxidative coupling reactions of various amines. In addition, the mechanism responsible for WS2 nanosheet catalyzed imine production under visible-light irradiation was fully investigated.
Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O2 concentration. Herein, we design biocompatible manganese ferrite ...nanoparticle-anchored mesoporous silica nanoparticles (MFMSNs) to overcome hypoxia, consequently enhancing the therapeutic efficiency of PDT. By exploiting the continuous O2-evolving property of MnFe2O4 nanoparticles through the Fenton reaction, MFMSNs relieve hypoxic condition using a small amount of nanoparticles and improve therapeutic outcomes of PDT for tumors in vivo. In addition, MFMSNs exhibit T2 contrast effect in magnetic resonance imaging (MRI), allowing in vivo tracking of MFMSNs. These findings demonstrate great potential of MFMSNs for theranostic agents in cancer therapy.
The association between maternal pregnancy-induced hypertension (PIH) and neonatal mortality and morbidities in preterm infants has not been consistent. This study aimed to evaluate the influence of ...maternal PIH on mortality and morbidities in singleton infants with very low birth weight born before 30 weeks of gestational age using the Korean Neonatal Network (KNN) database. A total of 5340 singleton infants with very low birth weight were registered in the KNN registry, who were born at 23
to 29
weeks of gestational age between January 2015 and December 2020. Baseline characteristics and neonatal mortality and morbidities were compared between infants with PIH and non-PIH mothers. After adjustment for potential confounders, infants with PIH mothers had significantly higher odds of respiratory distress syndrome (OR 1.983; 95% CI 1.285-3.061, p = 0.002) and bronchopulmonary dysplasia (OR 1.458; 95% CI 1.190-1.785, p < 0.001), and severe bronchopulmonary dysplasia (OR 1.411; 95% CI 1.163-1.713, p < 0.001) than infants with non-PIH mothers, while there were no significant differences in severe intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or death during neonatal intensive care unit admission between infants with PIH and non-PIH mothers. This study showed that preterm infants with PIH mothers had an increased risk of neonatal respiratory morbidities, including respiratory distress syndrome and bronchopulmonary dysplasia.
The cost-effectiveness of antiviral treatment in adult immune-tolerant (IT) phase chronic hepatitis B (CHB) patients is uncertain.
We designed a Markov model to compare expected costs and ...quality-adjusted life-years (QALYs) of starting antiviral treatment at IT-phase ('treat-IT') vs delaying the therapy until active hepatitis phase ('untreat-IT') in CHB patients over a 20-year horizon. A cohort of 10 000 non-cirrhotic 35-year-old patients in IT-phase CHB (hepatitis B e antigen-positive, mean serum hepatitis B virus (HBV) DNA levels 7.6 log
IU/mL, and normal alanine aminotransferase levels) was simulated. Input parameters were obtained from previous studies at Asan Medical Center, Korea. The incremental cost-effectiveness ratio (ICER) between the treat-IT and untreat-IT strategies was calculated.
From a healthcare system perspective, the treat-IT strategy with entecavir or tenofovir had an ICER of US$16 516/QALY, with an annual hepatocellular carcinoma (HCC) incidence of 0.73% in the untreat-IT group. With the annual HCC risk ≥0.54%, the treat-IT strategy was cost-effective at a willingness-to-pay threshold of US$20 000/QALY. From a societal perspective considering productivity loss by premature death, the treat-IT strategy was extremely cost-effective, and was dominant (ICER <0) if the HCC risk was ≥0.43%, suggesting that the treat-IT strategy incurs less costs than the untreat-IT strategy. The most influential parameters on cost-effectiveness of the treat-IT strategy were those related with HCC risk (HBV DNA levels, platelet counts and age) and drug cost.
Starting antiviral therapy in IT phase is cost-effective compared with delaying the treatment until the active hepatitis phase in CHB patients, especially with increasing HCC risk, decreasing drug costs and consideration of productivity loss.
Cellular senescence is closely related to tissue aging including bone. Bone homeostasis is maintained by the tight balance between bone-forming osteoblasts and bone-resorbing osteoclasts, but it ...undergoes deregulation with age, causing age-associated osteoporosis, a main cause of which is osteoblast dysfunction. Oxidative stress caused by the accumulation of reactive oxygen species (ROS) in bone tissues with aging can accelerate osteoblast senescence and dysfunction. However, the regulatory mechanism that controls the ROS-induced senescence of osteoblasts is poorly understood. Here, we identified Peptidyl arginine deiminase 2 (PADI2), a post-translational modifying enzyme, as a regulator of ROS-accelerated senescence of osteoblasts via RNA-sequencing and further functional validations. PADI2 downregulation by treatment with H
2
O
2
or its siRNA promoted cellular senescence and suppressed osteoblast differentiation. CCL2, 5, and 7 known as the elements of the senescence-associated secretory phenotype (SASP) which is a secretome including proinflammatory cytokines and chemokines emitted by senescent cells and a representative feature of senescence, were upregulated by H
2
O
2
treatment or
Padi2
knockdown. Furthermore, blocking these SASP factors with neutralizing antibodies or siRNAs alleviated the senescence and dysfunction of osteoblasts induced by H
2
O
2
treatment or
Padi2
knockdown. The elevated production of these SASP factors was mediated by the activation of NFκB signaling pathway. The inhibition of NFκB using the pharmacological inhibitor or siRNA effectively relieved H
2
O
2
treatment- or
Padi2
knockdown-induced senescence and osteoblast dysfunction. Together, our study for the first time uncover the role of PADI2 in ROS-accelerated cellular senescence of osteoblasts and provide new mechanistic and therapeutic insights into excessive ROS-promoted cellular senescence and aging-related bone diseases.
In anti-N-methyl-
d
-aspartate receptor (NMDAR) encephalitis, we analysed the efficacy of a combined immunotherapy protocol consisting of teratoma removal, steroid, intravenous immunoglobulin (IVIG), ...rituximab and tocilizumab (T-SIRT). This cohort study included seventy-eight consecutive patients treated for anti-NMDAR encephalitis between Jan 2014 and Oct 2019 in a national referral hospital. Detailed 2-year disease time course was analysed using Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at every 2 weeks for 12 weeks from baseline, every month for the next 3 months and then every 3 months. Treatment regimens at each time point were categorized as SI, SIR, or SIRT with/without teratoma removal (T). Adverse events were classified according to the Common Terminology Criteria for Adverse-Events (CTCAE v5.0), where a severe adverse event was defined as an adverse event with CATAE grade 4. In a linear mixed model analysis, using the SIRT regimen was more effective than SIR or SI regimens in lowering CASE scores (
P
< 0.001 and
P
= 0.001, respectively). The presence of teratoma (
P
= 0.001), refractory status epilepticus (
P
< 0.001) and a higher CASE score at baseline (
P
< 0.001) predicted a higher CASE score at each time point. Completion of the (T)-SIRT regimen within 1 month of onset resulted in better 1-year improvements in CASE score (
P
< 0.001) and modified Rankin scale scores (
P
= 0.001), compared to those of using other regimens within 1 month or delaying teratoma removal for more than 1 month. Pneumonia was a frequent adverse event (52/78, 66.7%) in the whole study population and neutropenia was frequent during SIRT (11/52, 21.2%), but the regimen was well tolerated in most patients. We concluded that the early application of combined immunotherapy consisting of T-SIRT had better efficacy than was found for delayed or partial application of this combination in anti-NMDAR encephalitis.
Heart failure remains a major public health concern with a 5-year mortality rate higher than that of most cancers. Myocardial disease in heart failure is frequently accompanied by impairment of the ...specialized electrical conduction system and myocardium. We introduce an epicardial mesh made of electrically conductive and mechanically elastic material, to resemble the innate cardiac tissue and confer cardiac conduction system function, to enable electromechanical cardioplasty. Our epicardium-like substrate mechanically integrated with the heart and acted as a structural element of cardiac chambers. The epicardial device was designed with elastic properties nearly identical to the epicardial tissue itself and was able to detect electrical signals reliably on the moving rat heart without impeding diastolic function 8 weeks after induced myocardial infarction. Synchronized electrical stimulation over the ventricles by the epicardial mesh with the high conductivity of 11,210 S/cm shortened total ventricular activation time, reduced inherent wall stress, and improved several measures of systolic function including increases of 51% in fractional shortening, ~90% in radial strain, and 42% in contractility. The epicardial mesh was also capable of delivering an electrical shock to terminate a ventricular tachyarrhythmia in rodents. Electromechanical cardioplasty using an epicardial mesh is a new pathway toward reconstruction of the cardiac tissue and its specialized functions.
Implantable electronic devices for recording electrophysiological signals and for stimulating muscles and nerves have been widely used throughout clinical medicine. Mechanical mismatch between ...conventional rigid biomedical devices and soft curvilinear tissues, however, has frequently resulted in a low signal to noise ratio and/or mechanical fatigue and scarring. Multifunctionality ranging from various sensing modalities to therapeutic functions is another important goal for implantable biomedical devices. Here, a stretchable and transparent medical device using a cell‐sheet–graphene hybrid is reported, which can be implanted to form a high quality biotic/abiotic interface. The hybrid is composed of a sheet of C2C12 myoblasts on buckled, mesh‐patterned graphene electrodes. The graphene electrodes monitor and actuate the C2C12 myoblasts in vitro, serving as a smart cell culture substrate that controls their aligned proliferation and differentiation. This stretchable and transparent cell‐sheet–graphene hybrid can be transplanted onto the target muscle tissue, to record electromyographical signals, and stimulate implanted sites electrically and/or optically in vivo. Additional cellular therapeutic effect of the cell‐sheet–graphene hybrid is obtained by integrated myobalst cell sheets. Any immune responses within implanted muscle tissues are not observed. This multifunctional device provides many new opportunities in the emerging field of soft bioelectronics.
Stretchable and transparent cell‐sheet–graphene hybrid composed of cultured C2C12 myoblast sheets on mesh‐patterned, and buckled graphene electrodes brings high quality biotic/abiotic interface with multifunctional properties ranging from various sensing and actuating modalities to therapeutic functions in vitro and in vivo. Reduced acute immune responses due to the cell sheet support the advantage of the cell‐sheet–graphene hybrid.
Objective
Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large‐scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. ...Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity.
Methods
Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information—including efficacy, toxicity, and concomitant drugs—was collected.
Results
The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 μg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 μg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6–9 μg/ml).
Significance
Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.
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