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This study aimed to assess the safety and effectiveness of the highly cross-linked hyaluronic acid—LBSA0103—in patients with knee osteoarthritis (OA) as per the prescribing information (PI) in South Korea. A total of 3,140 subjects aged ≥19 years were enrolled in this post-marketing surveillance (PMS) study from 2013 to 2019. The subjects received one or two injections of LBSA0103. The median duration of follow-up was 308 days. Adverse events (AEs), adverse drug reactions (ADRs), and serious AEs (SAEs) were monitored. Effectiveness was evaluated based on an index of effectiveness in accordance with the guidelines established by the Ministry of Food and Drug Safety and using a 100-mm visual analog scale (VAS) for weight-bearing pain. Overall, 250 subjects (7.96%) experienced 292 AEs and of these, unexpected AEs occurred in 114 subjects (3.63% [95% CI: 3.00–4.35]). Injection site pain was the most frequent AE reported by 81 subjects (2.58% [95% confidence intervals (CI): 2.05–3.20]). One hundred subjects experienced 108 ADRs (3.18% [95% CI: 2.60, 3.86]) and 15 unexpected ADRs were experienced by 13 subjects (0.41% [95% CI: 0.22–0.71]). Seventeen subjects experienced 22 SAEs (0.54% [95% CI: 0.32–0.87]) during the entire PMS period, and all were considered “unlikely” related to the study drug. Most AEs were mild in terms of severity and resolved during the study period. LBSA0103 was also effective in relieving symptomatic pain in knee OA patients. The condition in more than 80% of the subjects was considered to be improved when assessed by the investigators. LBSA0103 resulted in a significant reduction in the mean VAS score at 12 weeks after the first and second injections (24.79 (± 20.55) mm and 17.63 (±12.31) mm, respectively; p

Background Anti-spasmodic agents are commonly injected during esophagogastroduodenoscopy (EGD) to improve visualization of the gastric mucosa by inhibiting gastrointestinal (GI) peristalsis. The availability of oral anti-spasmodic agents would increase convenience. In this study, we evaluated the effectiveness of oral phloroglucinol (Flospan®) as a premedication for unsedated EGD. Methods A prospective, double-blinded, placebo-controlled, randomized controlled trial was conducted in a tertiary hospital. Individuals scheduled to undergo unsedated EGD were randomly assigned to receive either oral phloroglucinol or matching placebo 15 min before EGD. The primary outcome was the rate of complete gastric peristalsis suppression. Outcomes were assessed by independent investigators according to the classification of gastric peristalsis and ease of intragastric observation at the beginning (Period A) and end (Period B) of EGD. Results Overall, 71 phloroglucinol-treated and 71 placebo-treated participants (n = 142 total) were included. The phloroglucinol group showed significantly higher proportions of participants with complete gastric peristalsis suppression than the placebo group (22.5% vs. 9.9%, P = 0.040). The ease of intragastric observation was significantly better in the phloroglucinol group than in the placebo group at Periods A (P < 0.001) and B (P = 0.005). Patients in both groups had comparable adverse events and showed willingness to take the premedication at their next examination. Conclusions Oral phloroglucinol significantly suppressed gastrointestinal peristalsis during unsedated EGD compared with placebo (Clinical trial registration number: NCT03342118).

ObjectivePrognosis of myocardial infarction tends to be worse when serum C-reactive protein (CRP) level is high. miRNAs are also known to be involved in different pathogeneses of heart diseases such as myocardial infarction. However, how CRP is involved in myocardial infarction has not been fully elucidated. We hypothesized that serum CRP changes the miRNA profile during ischemia-reperfusion injury (IRI) of the myocardium. To confirm this hypothesis, we performed global miRNA expression profiling of myocardium using IRI and CRP infusion rat model.MethodsAfter ligation of the coronary artery of rat hearts, human serum CRP was intravenously injected, and reperfusion was performed (I/R+CRP group, n = 6). Control group consisted of the sham group (n = 3), IV CRP infusion group (CRP only, n = 3), and the I/R-only group (I/R only, n = 5). We evaluated 423 miRNA expression in non-ischemic areas and areas at risk (AAR) of each group using NanoString nCounter miRNA expression assay.ResultsMiR-124 was downregulated in non-ischemic myocardium in CRP-only group. In AAR, 7 miRNAs were commonly upregulated in both I/R-only and I/R+CRP groups. And additional 6 miRNAs were upregulated in the I/R+CRP group (miR-33, miR-409-3p, miR-384-3p, miR-3562, miR-101a, and miR-340-5p). Similarly, in the non-ischemic areas, 6 miRNAs were commonly upregulated in both I/R-only and I/R+CRP groups, and additional 5 miRNAs changed in the I/R+CRP group (upregulation of miR-3559-5p, miR-499, and miR-21 and downregulation of miR-500 and miR-532-3p).ConclusionWe showed that when serum CRP level is high, IRI results in multiple miRNA profile changes not only in ischemic areas but also in non-ischemic myocardium. Our results may provide a strong basis for studying the role of CRP and miRNAs in ischemic heart disease.

Chorioamnionitis has recently been reported as a risk factor for various neonatal diseases, including cerebral palsy, bronchopulmonary dysplasia, and necrotizing enterocolitis, but its effect on patent ductus arteriosus (PDA) is unclear. We performed a systematic review and meta-analysis to evaluate the effect of chorioamnionitis on PDA.We searched PubMed, EMBASE, Cochrane Library, and KoreaMed databases using the terms: "intrauterine infection" or "maternal infection" or "antenatal infection" or "chorioamnionitis" or "placenta inflammation" or "placenta pathology" or "neonatal outcome" or "neonatal morbidity" or "PDA or patent ductus arteriosus" or "ductus arteriosus," and "prematurity" or "very low birth weight infant." Studies were included if they were randomized controlled trials, case-control studies, or cohort studies that included information relating to chorioamnionitis and PDA.Among 1,571 studies, a total of 23 studies (17,708 cases) were included in the meta-analysis to analyze the relationship between chorioamnionitis and PDA, except one study that only included PDA requiring surgical ligation. The association between chorioamnionitis and PDA was statistically significant (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.19, 1.72; P < 0.0001). In subgroup analysis, clinical chorioamnionitis was not associated with PDA (OR 1.28; 95% CI 1.00, 1.64, 1.790; P = 0.05), whereas histologic chorioamnionitis (OR 1.54; 95% CI 1.10, 2.15; P = 0.01) and chorioamnionitis diagnosed from both clinical and histologic findings (OR 1.75; 95% CI 1.07, 2.86; P = 0.03) showed significant associations with PDA. Chorioamnionitis did not increase the risk of PDA requiring surgical ligation (OR 1.23; 95% CI 0.69, 2.17; P = 0.48), and antenatal steroid use reduced the risk of PDA (OR 0.62; 95% CI 0.42, 0.90; P = 0.01) after chorioamnionitis.The results from this meta-analysis support an association between maternal chorioamnionitis and PDA in offspring.

A robust method for the in vivo cloning of large gene clusters was developed based on homologous recombination (HR), requiring only the transformation of PCR products into Escherichia coli cells harboring a receiver plasmid. Positive clones were selected by an acquired antibiotic resistance, which was activated by the recruitment of a short ribosome-binding site plus start codon sequence from the PCR products to the upstream position of a silent antibiotic resistance gene in receiver plasmids. This selection was highly stringent and thus the cloning efficiency of the GFPuv gene (size: 0.7 kb) was comparable to that of the conventional restriction-ligation method, reaching up to 4.3 × 10(4) positive clones per μg of DNA. When we attempted parallel cloning of GFPuv fusion genes (size: 2.0 kb) and carotenoid biosynthesis pathway clusters (sizes: 4 kb, 6 kb, and 10 kb), the cloning efficiency was similarly high regardless of the DNA size, demonstrating that this would be useful for the cloning of large DNA sequences carrying multiple open reading frames. However, restriction analyses of the obtained plasmids showed that the selected cells may contain significant amounts of receiver plasmids without the inserts. To minimize the amount of empty plasmid in the positive selections, the sacB gene encoding a levansucrase was introduced as a counter selection marker in receiver plasmid as it converts sucrose to a toxic levan in the E. coli cells. Consequently, this method yielded completely homogeneous plasmids containing the inserts via the direct transformation of PCR products into E. coli cells.

YKL-40 is associated with various neurological disorders. However, circulatory YKL-40 levels early after onset of acute ischemic stroke (AIS) have not been systematically assessed. We aimed to identify the temporal changes and clinical usefulness of measuring serum YKL-40 immediately following AIS.Serum YKL-40 and C-reactive protein (CRP) levels were monitored over time in AIS patients (n = 105) and compared with those of stroke-free controls (n = 34). Infarct volume and stroke severity (National Institutes of Health Stroke Scale; NIHSS) were measured within 48 hours of symptom onset, and functional outcome (modified Rankin Scale; mRS) was measured 3 months after AIS.Within 12 hours of symptom onset, levels of YKL-40 (251 vs. 41 ng/mL) and CRP (1.50 vs. 0.96 µg/mL) were elevated in AIS patients compared to controls. The power of YKL-40 for discriminating AIS patients from controls was superior to that of CRP (area under the curve 0.84 vs. 0.64) and YKL-40 (r = 0.26, P

The epidermal growth factor receptor (EGFR) is a well-established target for cancer treatment. EGFR tyrosine kinase (TK) inhibitors, such as gefinitib and erlotinib, have been developed as anti-cancer drugs. Although non-small cell lung carcinoma with an activating EGFR mutation, L858R, responds well to gefinitib and erlotinib, tumors with a doubly mutated EGFR, T790M-L858R, acquire resistance to these drugs. The C. elegans EGFR homolog LET-23 and its downstream signaling pathway have been studied extensively to provide insight into regulatory mechanisms conserved from C. elegans to humans. To develop an in vivo screening system for potential cancer drugs targeting specific EGFR mutants, we expressed three LET-23 chimeras in which the TK domain was replaced with either the human wild-type TK domain (LET-23::hEGFR-TK), a TK domain with the L858R mutation (LET-23::hEGFR-TK[L858R]), or a TK domain with the T790M-L858R mutations (LET-23::hEGFR-TK[T790M-L858R]) in C. elegans vulval cells using the let-23 promoter. The wild-type hEGFR-TK chimeric protein rescued the let-23 mutant phenotype, and the activating mutant hEGFR-TK chimeras induced a multivulva (Muv) phenotype in a wild-type C. elegans background. The anti-cancer drugs gefitinib and erlotinib suppressed the Muv phenotype in LET-23::hEGFR-TK[L858R]-expressing transgenic animals, but not in LET-23::hEGFR-TK[T790M-L858R] transgenic animals. As a pilot screen, 8,960 small chemicals were tested for Muv suppression, and AG1478 (an EGFR-TK inhibitor) and U0126 (a MEK inhibitor) were identified as potential inhibitors of EGFR-mediated biological function. In conclusion, transgenic C. elegans expressing chimeric LET-23::hEGFR-TK proteins are a model system that can be used in mutation-specific screens for new anti-cancer drugs.

LIN-12/Notch signaling is important for cell-cell interactions during development, and mutations resulting in constitutive LIN-12/Notch signaling can cause cancer. Loss of negative regulators of lin-12/Notch activity has the potential for influencing cell fate decisions during development and the genesis or aggressiveness of cancer.We describe two negative modulators of lin-12 activity in C. elegans. One gene, sel-11, was initially defined as a suppressor of a lin-12 hypomorphic allele; the other gene, cdc-42, is a well-studied Rho GTPase. Here, we show that SEL-11 corresponds to yeast Hrd1p and mammalian Synoviolin. We also show that cdc-42 has the genetic properties consistent with negative regulation of lin-12 activity during vulval precursor cell fate specification.Our results underscore the multiplicity of negative regulatory mechanisms that impact on lin-12/Notch activity and suggest novel mechanisms by which constitutive lin-12/Notch activity might be exacerbated in cancer.

Aspirin-intolerant asthma (AIA) is a rare condition that is characterized by the development of bronchoconstriction in asthmatic patients after ingestion of non-steroidal anti-inflammatory drugs including aspirin. However, the underlying mechanisms of AIA occurrence are still not fully understood. To identify the genetic variations associated with aspirin intolerance in asthmatics, the first stage of genome-wide association study with 109,365 single nucleotide polymorphisms (SNPs) was undertaken in a Korean AIA (n = 80) cohort and aspirin-tolerant asthma (ATA, n = 100) subjects as controls. For the second stage of follow-up study, 150 common SNPs from 11 candidate genes were genotyped in 163 AIA patients including intermediate AIA (AIA-I) subjects and 429 ATA controls. Among 11 candidate genes, multivariate logistic analyses showed that SNPs of CEP68 gene showed the most significant association with aspirin intolerance (P values of co-dominant for CEP68, 6.0×10(-5) to 4.0×10(-5)). All seven SNPs of the CEP68 gene showed linkage disequilibrium (LD), and the haplotype of CEP68_ht4 (T-G-A-A-A-C-G) showed a highly significant association with aspirin intolerance (OR= 2.63; 95% CI= 1.64-4.21; P = 6.0×10(-5)). Moreover, the nonsynonymous CEP68 rs7572857G>A variant that replaces glycine with serine showed a higher decline of forced expiratory volume in 1s (FEV(1)) by aspirin provocation than other variants (P = 3.0×10(-5)). Our findings imply that CEP68 could be a susceptible gene for aspirin intolerance in asthmatics, suggesting that the nonsynonymous Gly74Ser could affect the polarity of the protein structure.

Background: LIN-12/Notch signaling is important for cell-cell interactions during development, and mutations resulting in constitutive LIN-12/Notch signaling can cause cancer. Loss of negative regulators of lin-12/Notch activity has the potential for influencing cell fate decisions during development and the genesis or aggressiveness of cancer. Methodology/Principal Findings: We describe two negative modulators of lin-12 activity in C. elegans. One gene, sel-11, was initially defined as a suppressor of a lin-12 hypomorphic allele; the other gene, cdc-42, is a well-studied Rho GTPase. Here, we show that SEL-11 corresponds to yeast Hrd1p and mammalian Synoviolin. We also show that cdc-42 has the genetic properties consistent with negative regulation of lin-12 activity during vulval precursor cell fate specification. Conclusions/Significance: Our results underscore the multiplicity of negative regulatory mechanisms that impact on lin-12/ Notch activity and suggest novel mechanisms by which constitutive lin-12/Notch activity might be exacerbated in cancer. [ABSTRACT FROM AUTHOR]

Background Although the study of respiratory microbiota has been an active field of research, obtaining the appropriate respiratory samples for healthy controls remains to be a challenge. As such, this study aims to evaluate the use of endotracheal tube washing as a viable control for sputum samples. Methods A total of 14 subjects, including 8 healthy respiratory controls and 6 diabetic patients without any respiratory disease, were enrolled in this study, during which the endotracheal tubes used in their scheduled routine surgery were collected. Pre-operative oral gargles were also collected from non-diabetic subjects. Results 16S amplicon sequencing revealed similar taxa composition in endotracheal tube washings and oral gargles in the healthy control subjects, although the relative abundance of 11 genus level operational taxonomic units was significantly different between the two sample sources. The diabetic subjects showed relatively lower diversity than those of non-diabetic subjects. The proportion range of the most abundant taxa detected in each endotracheal tube washings were 10.1–33.2%. Conclusion Endotracheal tube washing fluid may provide healthy control samples for upper respiratory investigations without incurring any additional risk to the subject.

BACKGROUND:Brachial-ankle pulse wave velocity (baPWV) is the simple, non-invasive, gold-standard method for assessing arterial stiffness. However, baPWV has been shown to be associated with renal dyfunction, with a few reports demonstrating an association between baPWV and postoperative acute kidney injury (AKI) among surgical patients. METHODS:We retrospectively analyzed preoperative baPWV data that were prospectively collected from 164 patients who underwent off-pump coronary artery bypass grafting (CABG) between April 2013 and July 2019 (mean age: 66.2 ± 10.3 years, 29.3% females). Primarily, baPWV was investigated as an independent predictor of postoperative AKI development; secondarily, the patients were divided into high and low PWV groups according to the optimal baPWV cut-off value. Postoperative complications, mortality, and mid-term survival were compared between the two groups. RESULTS:AKI developed in 30 patients (18.3%). Univariate analysis showed that AKI was significantly associated with baPWV (20.2±7.3 vs. 16.2±2.8 m/s, p < 0.001), age, preoperative serum creatinine, and EuroSCORE. Multivariable logistic regression analysis revealed baPWV as independently associated with postoperative AKI even after adjustment for preoperative creatinine, old age (> 75 years), hypertension, diabetes under insulin therapy, and EuroSCORE. Moreover, area under the curve (AUC) analysis indicated that PWV can predict AKI better than preoperative creatinine levels (AUC, 0.781 [95% confidence interval, 0.688-0.874] vs. 0.680 [0.568-0.792]). The group-dividing baPWV cut-off value for AKI was 19 m/s. There were no 30-day mortality. The in-hospital mortality rates in the high and the low PWV groups were 2.2% (n = 1) and 0.8% (n = 1), respectively (p = 0.484). Midterm survival rates were not different between the two groups, but the rate of composite neurologic complication composed of stroke and delirium, was higher, and rate of mechanical ventilatory support was longer, in the high PWV group. CONCLUSION:Brachial-ankle pulse wave velocity was an independent predictor of postoperative AKI following off-pump CABG, and high baPWVs may affect the composite neurologic outcome and the duration of mechanical ventilatory support.

The aim of this study was to investigate the association between image characteristics on preoperative chest CT and severe pleural adhesion during surgery in lung cancer patients. We included consecutive 124 patients who underwent lung cancer surgeries. Preoperative chest CT was retrospectively reviewed to assess pleural thickening or calcification, pulmonary calcified nodules, active pulmonary inflammation, extent of emphysema, interstitial pneumonitis, and bronchiectasis in the operated thorax. The extent of pleural thickening or calcification was visually estimated and categorized into two groups: localized and diffuse. We measured total size of pulmonary calcified nodules. The extent of emphysema, interstitial pneumonitis, and bronchiectasis was also evaluated with a visual scoring system. The occurrence of severe pleural adhesion during lung cancer surgery was retrospectively investigated from the electrical medical records. We performed logistic regression analysis to determine the association of image characteristic on chest CT with severe pleural adhesion. Localized pleural thickening was found in 8 patients (6.5%), localized pleural calcification in 8 (6.5%), pulmonary calcified nodules in 28 (22.6%), and active pulmonary inflammation in 22 (17.7%). There was no patient with diffuse pleural thickening or calcification in this study. Trivial, mild, and moderate emphysema was found in 31 (25.0%), 21 (16.9%), and 12 (9.7%) patients, respectively. Severe pleural adhesion was found in 31 (25.0%) patients. The association of localized pleural thickening or calcification on CT with severe pleural adhesion was not found (P = 0.405 and 0.107, respectively). Size of pulmonary calcified nodules and extent of emphysema were significant variables in a univariate analysis (P = 0.045 and 0.005, respectively). In a multivariate analysis, moderate emphysema was significantly associated with severe pleural adhesion (odds ratio of 11.202, P = 0.001). In conclusion, severe pleural adhesion might be found during lung cancer surgery, provided that preoperative chest CT shows substantial pulmonary calcified nodules or emphysema.