Effect of a Boarding Restriction Protocol on Emergency Department Crowding

PurposeAccess block due to the lack of hospital beds causes crowding of emergency departments (ED). We initiated the “boarding restriction protocol” that limits the time of stay in the ED for patients awaiting hospitalization to 24 hours from arrival. The purpose of this study was to determine the effect of the boarding restriction protocol on ED crowding.Materials and MethodsThe primary outcome was ED occupancy rate, which was calculated as the ratio of the number of occupying patients to the total number of ED beds. Time factors, such as length of stay (LOS), treatment time, and boarding time, were investigated.ResultsThe mean of the ED occupancy rate decreased from 1.532±0.432 prior to implementation of the protocol to 1.273±0.353 after (p<0.001). According to time series analysis, the absolute effect caused by the protocol was -0.189 (-0.277 to -0.110) (p=0.001). The proportion of patients with LOS exceeding 24 hours decreased from 7.6% to 4.0% (p<0.001). Among admitted patients, ED LOS decreased from 770.7 (421.4–1587.1) minutes to 630.2 (398.0–1156.8) minutes (p<0.001); treatment time increased from 319.6 (198.5–482.8) minutes to 344.7 (213.4–519.5) minutes (p<0.001); and boarding time decreased from 298.9 (109.5–1149.0) minutes to 204.1 (98.7–545.7) minutes (p<0.001). In pre-protocol period, boarding patients accumulated in the ED during the weekdays and resolved on Friday, but this pattern was alleviated in post-period.ConclusionThe boarding restriction protocol was effective in alleviating ED crowding by reducing the accumulation of boarding patients in the ED during the weekdays.     

Platelet Function and Genotype after DES Implantation in East Asian Patients: Rationale and Characteristics of the PTRG-DES Consortium

PurposePlatelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel.Materials and MethodsSearching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them.ResultsNine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (^*2 or ^*3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively.ConclusionThe PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT04734028","term_id":"NCT04734028"}}NCT04734028.     

Metabolic Dysfunction-Associated Fatty Liver Disease Predicts Long-term Mortality and Cardiovascular Disease

Background/AimsWe investigated the effect of metabolic dysfunction-associated fatty liver disease (MAFLD) on future mortality and cardiovascular disease (CVD) using a prospective community-based cohort study.MethodsIndividuals from two community-based cohorts who were 40 to 70 years old were prospectively followed for 16 years. MAFLD was defined as a high fatty liver index (FLI ≥60) plus one of the following conditions overweight/obesity (body mass index ≥23 kg/m²), type 2 diabetes mellitus, or ≥2 metabolic risk abnormalities. Nonalcoholic fatty liver disease (NAFLD) was defined as FLI ≥60 without any secondary cause of hepatic steatosis.ResultsAmong 8,919 subjects (age 52.2±8.9 years, 47.7% of males), 1,509 (16.9%) had MAFLD. During the median follow-up of 15.7 years, MAFLD independently predicted overall mortality after adjustment for confounders (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.05 to 1.69) but NAFLD did not (HR, 1.20; 95% CI, 0.94 to 1.53). MAFLD also predicted CVD after adjustment for age, sex, and body mass index (HR, 1.35; 95% CI, 1.13 to 1.62), which lost its statistical significance by further adjustments. Stratified analysis indicated that metabolic dysfunction contributed to mortality (HR, 1.51; 95% CI, 1.21 to 1.89) and CVD (HR, 1.27; 95% CI, 1.02 to 1.59). Among metabolic dysfunctions used for defining MAFLD, type 2 diabetes mellitus in MAFLD increased the risk of both mortality (HR, 2.07; 95% CI, 1.52 to 2.81) and CVD (HR, 1.42; 95% CI, 1.09 to 1.85).ConclusionsMAFLD independently increased overall mortality. Heterogeneity in mortality and CVD risk of subjects with MAFLD may be determined by the accompanying metabolic dysfunctions.     

Safety,tolerability, and pharmacokinetics of single and multiple topical ophthalmic administration of imatinib mesylate in healthy subjects

For the long‐term efficacy of dry eye disease treatment, relieving underlying inflammation is necessary. Imatinib mesylate is a novel ophthalmic formulation of imatinib mesylate, which is expected to alleviate inflammation by inhibiting the discoidin domain receptor 1 activity. This study aims to evaluate the safety and pharmacokinetics of imatinib mesylate in healthy subjects. A randomized, double‐blind, placebo‐controlled study was conducted. In a single ascending dose, 16 subjects received a single eye drop of imatinib mesylate 0.1%, 0.3%, or matching placebo. In the multiple ascending dose (MAD), subjects received multiple eye drops of imatinib mesylate 0.1%, 0.3%, or matching placebo once daily for 7 days. Safety and tolerability were assessed by ophthalmic examination, including the visual analog scale (VAS) to monitor the burning sensation in the eyes. A total of four treatment‐emergent adverse events (TEAEs) occurred during the study. All TEAEs were mildly severe with no serious cases. VAS results in the 0.1% MAD group exhibited highest score of two points, whereas it was less than one point in others. Insignificant difference between the imatinib mesylate and placebo groups in the VAS results was seen. After a single dose administration of imatinib mesylate 0.1%, all plasma concentrations were below the lower limit of quantification. The peak plasma concentrations of imatinib were less than 0.54 µg/L in all groups. In conclusion, a single and multiple topical ophthalmic administration of imatinib mesylate was well‐tolerated in healthy subjects. Because there was minimal systemic exposure to imatinib, the adverse effect in the body seems to be insignificant.     

Analytical methods and formulation factors to enhance protein stability in solution

Development of stable protein formulations needs intimate knowledge of the proteins?? physicochemical properties. More specifically, understanding the mechanisms of protein degradation is important in designing and evaluating protein formulations. This review describes briefly the different types of interactions of the major protein degradation pathways. The analytical methods to detect protein degradation are included, along with generalized strategies to suppress protein instability with relevant excipients. With an appreciation of the current practices for stable formulations, the development process will be facilitated in a more efficient way.     

Anaphase-promoting complex/cyclosome protein Cdc27 is a target for curcumin-induced cell cycle arrest and apoptosis

Background  

Curcumin (diferuloylmethane), the yellow pigment in the Asian spice turmeric, is a hydrophobic polyphenol from the rhizome of Curcuma longa. Because of its chemopreventive and chemotherapeutic potential with no discernable side effects, it has become one of the major natural agents being developed for cancer therapy. Accumulating evidence suggests that curcumin induces cell death through activation of apoptotic pathways and inhibition of cell growth and proliferation. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell cycle control mechanism to delay the onset of anaphase during mitosis. One of the key regulators of the SAC is the anaphase promoting complex/cyclosome (APC/C) which ubiquitinates cyclin B and securin and targets them for proteolysis. Because APC/C not only ensures cell cycle arrest upon spindle disruption but also promotes cell death in response to prolonged mitotic arrest, it has become an attractive drug target in cancer therapy.     

Zyflamend Reduces the Expression of Androgen Receptor in a Model of Castrate-Resistant Prostate Cancer

Prostate cancer is the most commonly diagnosed solid malignancy, and tumor cells eventually transform to castrate resistance through multiple pathways including activation of the androgen receptor via insulin-like growth factor receptor (IGF-1R) signaling involving phospho-AKT (pAKT). In this study, a mixture of herbal extracts, Zyflamend®, was used as a treatment in a model of castrate-resistant prostate cancer using CWR22Rv1 cells. Zyflamend reduced androgen receptor and IGF-1R expression along with a reduction of IGF-1-mediated proliferation of CWR22Rv1 cells. IGF-1 induced downstream AKT phosphorylation; however, the induction of pAKT was not associated with androgen receptor expression. Further, constitutively active form of AKT had no effect on nuclear expression of androgen receptor, indicating that upregulation of pAKT did not promote androgen receptor expression or nuclear translocation in castrate-resistant CWR22Rv1 cells. Conversely, Zyflamend reduced androgen receptor expression following IGF-1 stimulation and in cells overexpressing pAKT. These results demonstrated that Zyflamend inhibited IGF-1-stimulated cell growth, IGF-1R expression, and androgen receptor expression and its nuclear localization, but these effects were not dependent upon phosphatidylinositol 3-kinase/pAKT signaling. In conclusion, Zyflamend decreased cell proliferation and inhibited IGF-1R and androgen receptor expression in a phosphatidylinositol 3-kinase/pAKT independent manner.     

Effects of anesthetic agents on cellular <Superscript>123</Superscript>I-MIBG transport and in vivo <Superscript>123</Superscript>I-MIBG biodistribution

Objectives Small animal imaging with meta-iodobenzylguanidine (MIBG) allows characterization of animal models, optimization of tumor treatment strategies, and monitoring of gene expression. Anesthetic agents, however, can affect norepinephrine (NE) transport and systemic sympathetic activity. We thus elucidated the effects of anesthetic agents on MIBG transport and biodistribution. Methods SK-N-SH neuroblastoma and PC-12 pheochromocytoma cells were measured for ¹²³I-MIBG uptake after treatment with ketamine (Ke), xylazine (Xy), Ke/Xy, or pentobarbital (Pb). NE transporters were assessed by Western blots. Normal ICR mice and PC-12 tumor-bearing mice were injected with ¹²³I-MIBG 10 min after anesthesia with Ke/Xy, Ke, Xy, or Pb. Plasma NE levels and MIBG biodistribution were assessed. Results Cellular ¹²³I-MIBG uptake was dose-dependently inhibited by Ke and Xy but not by Pb. Treatment for 2 h with 300 μM Ke, Xy, and Ke/Xy decreased uptake to 46.0 ± 1.6, 24.8 ± 1.5, and 18.3 ± 1.6% of controls. This effect was completely reversed by fresh media, and there was no change in NE transporter levels. In contrast, mice anesthetized with Ke/Xy showed no decrease of MIBG uptake in target organs. Instead, uptakes and organ-to-blood ratios were increased in the heart, lung, liver, and adrenals. Plasma NE was notably reduced in the animals with corresponding decreases in blood MIBG, which partly contributed to the increase in target organ uptake. Conclusion In spite of their inhibitory effect at the transporter level, Ke/Xy anesthesia is a satisfactory method for MIBG imaging that allows favorable target tissue uptake and contrast by reducing circulating NE and MIBG. Bong-Ho Ko and Jin-Young Paik equally contributed to this work. This work was supported by the Korea Research Foundation Grant KRF-2005-202-E00116. Presented in part at the fifth Annual Meeting of the Society for Molecular Imaging, Hawaii, August 30–September 2, 2006.     

Magnetic resonance cholangiography: comparison of two- and three-dimensional sequences for assessment of malignant biliary obstruction

The purpose was to retrospectively compare two-dimensional (2D) magnetic resonance cholangiography (MRC) including breath-hold single-shot rapid acquisition with relaxation enhancement (RARE) and multislice half-Fourier RARE versus navigator-triggered 3D-RARE MRC in the evaluation of biliary malignancy. MRC findings were evaluated in 31 patients with malignant biliary obstruction, including biliary malignancy, gallbladder carcinoma, and ampullary cancer. Two observers independently reviewed the images to assess the overall image quality, artifacts, ductal conspicuity, extent of disease, diagnostic confidence of tumor extent, and origin of tumor. The results were compared with surgical and histopathologic findings. Studies obtained with 3D-MRC were of significantly higher technical quality than those obtained with 2D-MRC. However, the accuracy between two sequences for classification of tumor showed no statistical significance. There was no significant difference between the Az values of 2D- and 3D-MRC for overall tumor extent in bilateral second order branch, intrapancreatic common bile duct (CBD) involvement (Az = 0.889, 0.881 for 2D and Az = 0.903, 0.864 for 3D). Nor was there a significant difference between two sequences in the assessment of the origin of tumor. Although 3D-MRC has superior image quality over 2D-MRC, 3D-MRC showed no statistically significant difference in accuracy compared with 2D-MRC for evaluating the extent of disease in malignant biliary obstructions.