SEALONE (Safety and Efficacy of Coronary Computed Tomography Angiography with Low Dose in Patients Visiting Emergency Room) trial: study protocol for a randomized controlled trial

Objective Chest pain is one of the most common complaints in the emergency department (ED). Cardiac computed tomography angiography (CCTA) is a frequently used tool for the early triage of patients with low- to intermediate-risk acute chest pain. We present a study protocol for a multicenter prospective randomized controlled clinical trial testing the hypothesis that a low-dose CCTA protocol using prospective electrocardiogram (ECG)-triggering and limited-scan range can provide sufficient diagnostic safety for early triage of patients with acute chest pain. Methods The trial will include 681 younger adult (aged 20 to 55) patients visiting EDs of three academic hospitals for acute chest pain or equivalent symptoms who require further evaluation to rule out acute coronary syndrome. Participants will be randomly allocated to either low-dose or conventional CCTA protocol at a 2:1 ratio. The low-dose group will undergo CCTA with prospective ECG-triggering and restricted scan range from sub-carina to heart base. The conventional protocol group will undergo CCTA with retrospective ECG-gating covering the entire chest. Patient disposition is determined based on computed tomography findings and clinical progression and all patients are followed for a month. The primary objective is to prove that the chance of experiencing any hard event within 30 days after a negative low-dose CCTA is less than 1%. The secondary objectives are comparisons of the amount of radiation exposure, ED length of stay and overall cost. Results and Conclusion Our low-dose protocol is readily applicable to current multi-detector computed tomography devices. If this study proves its safety and efficacy, dose-reduction without purchasing of expensive newer devices would be possible

Changes in car and bus usage amid the COVID-19 pandemic: Relationship with land use and land price

This study aimed to explore the impacts of COVID-19 on car and bus usage and their relationships with land use and land price. Large-scale trip data of car and bus usage in Daejeon, South Korea, were tested. We made a trip-chain-level data set to analyze travel behavior based on activity-based travel volumes. Hexagonal cells were used to capture geographical explanatory variables, and a mixed-effect regression model was adopted to determine the impacts of COVID-19. The modeling outcomes demonstrated behavioral differences associated with using cars and buses amid the pandemic. People responded to the pandemic by reducing their trips more intensively during the daytime and weekends. Moreover, they avoided crowded or shared spaces by reducing bus trips and trips toward commercial areas. In terms of social equity, trips of people living in wealthier areas decreased more than those of people living in lower-priced areas, especially trips by buses. The findings contribute to the previous literature by adding a fundamental reference for the different impacts of pandemics on two universal transportation modes

Comparative analysis of gene expression profiles of papillary thyroid microcarcinoma and papillary thyroid carcinoma

Purpose: Papillary thyroid carcinomas (PTCs) measuring 1.0 cm or less were separately defined as papillary thyroid microcarcinomas (PTMs) by the World Health Organization, emphasizing on their benign behavior. However, some reported that PTMs may have aggressive behavior, can cause regional, or even distant metastases. But till now, the characteristics of PTMs were only reviewed and described by the clinicopathological parameters, and no analysis of PTM by the gene level is available. We report on the gene expression profiles of PTMs by the oligonucleotide microarrays and the results of comparative analysis with those of PTCs. Materials and Methods: The gene expression profiles of 25 pairs of PTMs and their normal thyroid tissue counterparts, and 11 pairs of PTCs and their normal counterparts, were analyzed by Affymetrix Human Genome U133A. Data were analyzed by the SAM and the DAVID 2008 program to detect differentially expressed genes in supervised sample classification. Results: Two-hundred thirteen statistically significant up-regulated genes and -183 significant down-regulated genes of PTMs compared with their normal counterpart thyroid tissues, which were mainly cell adhesion-related genes and immune response genes, were detected. Two-hundred sixty-one up-regulated and -157 down-regulated genes of PTCs were also detected. In the comparative analyses of gene expression profiles of PTMs and PTCs, no significant difference was found. Conclusion: PTM should not be considered as the simple occult indolent thyroid cancer, but as the earlier stage of disease which eventually evolves into PTC, because the gene expression profiles of PTMs were not different from those of PTCs.Montero-Conde C, 2008, ONCOGENE, V27, P1554, DOI 10.1038/sj.onc.1210792Eszlinger M, 2007, ENDOCR REV, V28, P322, DOI 10.1210/er.2006-0047Lubitz CC, 2006, J MOL DIAGN, V8, P490, DOI 10.2353/jmoldx.2006.060080Kebebew E, 2006, WORLD J SURG, V30, P767, DOI 10.1007/s00268-005-0308-2Lubitz CC, 2005, SURGERY, V138, P1042, DOI 10.1016/j.surg.2005.09.009Baris O, 2005, ONCOGENE, V24, P4155, DOI 10.1038/sj.onc.1208578Sunde M, 2004, CANCER RES, V64, P2766Yano Y, 2004, CLIN CANCER RES, V10, P2035Eszlinger M, 2004, ONCOGENE, V23, P795, DOI 10.1038/sj.onc.1207186DELELLIS RA, 2004, WHO CLASSIFICATION T, P73Chow SM, 2003, CANCER, V98, P31, DOI 10.1002/cncr.11442Ito Y, 2003, THYROID, V13, P381Wasenius VM, 2003, CLIN CANCER RES, V9, P68Zembutsu H, 2002, CANCER RES, V62, P518Huang Y, 2001, P NATL ACAD SCI USA, V98, P15044AREM R, 1999, ENDOCR PRACT, V5, P148Baudin E, 1998, CANCER, V83, P553Noguchi S, 1996, ARCH SURG-CHICAGO, V131, P187HEFER T, 1995, J LARYNGOL OTOL, V109, P1109HAY LD, 1992, SURGERY, V112, P1139HAY ID, 1990, ENDOCRIN METAB CLIN, V19, P545GRANT CS, 1988, SURGERY, V104, P956CARCANGIU ML, 1985, CANCER, V55, P805GIKAS PW, 1967, CANCER, V20, P2100

HIF-1 alpha activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice

Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1 alpha and HIF-2 alpha are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1 alpha in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1 alpha activation in myeloid cells critically regulates IBD progressio

HIF-1α activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice

Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1α activation in myeloid cells critically regulates IBD progression

Hypoxia-inducible factor-1 (HIF-1) activation in myeloid cells accelerates DSS-induced colitis progression in mice

nflammatory bowel disease (IBD) is a chronic inflammatory disease where the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated a role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways created by Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium binding protein as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice where HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared to wild-type (WT) mice. These parameters were restored to, if not better than the WT levels when we examined hMRP8 Hif-1α KO mice upon 5% DSS feeding. hMRP8 Hif-2α KO mice on the other hand exhibited similar degree of DSS-induced colitis to WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1α KO mice exhibited comparable levels of colorectal tumors to WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1 activation in myeloid cells critically regulates IBD progression.112sciescopu

Machine learning application for classification of Alzheimer's disease stages using 18F-flortaucipir positron emission tomography

Abstract Background The progression of Alzheimer’s dementia (AD) can be classified into three stages: cognitive unimpairment (CU), mild cognitive impairment (MCI), and AD. The purpose of this study was to implement a machine learning (ML) framework for AD stage classification using the standard uptake value ratio (SUVR) extracted from 18F-flortaucipir positron emission tomography (PET) images. We demonstrate the utility of tau SUVR for AD stage classification. We used clinical variables (age, sex, education, mini-mental state examination scores) and SUVR extracted from PET images scanned at baseline. Four types of ML frameworks, such as logistic regression, support vector machine (SVM), extreme gradient boosting, and multilayer perceptron (MLP), were used and explained by Shapley Additive Explanations (SHAP) to classify the AD stage. Results Of a total of 199 participants, 74, 69, and 56 patients were in the CU, MCI, and AD groups, respectively; their mean age was 71.5 years, and 106 (53.3%) were men. In the classification between CU and AD, the effect of clinical and tau SUVR was high in all classification tasks and all models had a mean area under the receiver operating characteristic curve (AUC) > 0.96. In the classification between MCI and AD, the independent effect of tau SUVR in SVM had an AUC of 0.88 (p < 0.05), which was the highest compared to other models. In the classification between MCI and CU, the AUC of each classification model was higher with tau SUVR variables than with clinical variables independently, which yielded an AUC of 0.75(p < 0.05) in MLP, which was the highest. As an explanation by SHAP for the classification between MCI and CU, and AD and CU, the amygdala and entorhinal cortex greatly affected the classification results. In the classification between MCI and AD, the para-hippocampal and temporal cortex affected model performance. Especially entorhinal cortex and amygdala showed a higher effect on model performance than all clinical variables in the classification between MCI and CU. Conclusions The independent effect of tau deposition indicates that it is an effective biomarker in classifying CU and MCI into clinical stages using MLP. It is also very effective in classifying AD stages using SVM with clinical information that can be easily obtained at clinical screening

Lead Optimization of a Novel Series of Imidazo[1,2‑<i>a</i>]pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and Extensively-Drug-Resistant Anti-tuberculosis Agent

A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo­[1,2-<i>a</i>]­pyridine amide (IPA) lead compound <b>1</b>, which led to the design and synthesis of Q203 (<b>50</b>). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs <b>49</b> and <b>50</b> showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log₁₀ reduction at 10 mg/kg dosing level, respectively) in mouse lung