45.5-tesla direct-current magnetic field generated with a high-temperature superconducting magnet.

Strong magnetic fields are required in many fields, such as medicine (magnetic resonance imaging), pharmacy (nuclear magnetic resonance), particle accelerators (such as the Large Hadron Collider) and fusion devices (for example, the International Thermonuclear Experimental Reactor, ITER), as well as for other diverse scientific and industrial uses. For almost two decades, 45 tesla has been the highest achievable direct-current (d.c.) magnetic field; however, such a field requires the use of a 31-megawatt, 33.6-tesla resistive magnet inside 11.4-tesla low-temperature superconductor coils1, and such high-power resistive magnets are available in only a few facilities worldwide2. By contrast, superconducting magnets are widespread owing to their low power requirements. Here we report a high-temperature superconductor coil that generates a magnetic field of 14.4 tesla inside a 31.1-tesla resistive background magnet to obtain a d.c. magnetic field of 45.5 tesla-the highest field achieved so far, to our knowledge. The magnet uses a conductor tape coated with REBCO (REBa2Cu3Ox, where RE = Y, Gd) on a 30-micrometre-thick substrate3, making the coil highly compact and capable of operating at the very high winding current density of 1,260 amperes per square millimetre. Operation at such a current density is possible only because the magnet is wound without insulation4, which allows rapid and safe quenching from the superconducting to the normal state5-10. The 45.5-tesla test magnet validates predictions11 for high-field copper oxide superconductor magnets by achieving a field twice as high as those generated by low-temperature superconducting magnets.

Immunotherapy for advanced or metastatic urothelial carcinoma: an abridged Cochrane review.

OBJECTIVES: To assess the effects of immunotherapy compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. METHODS: Based on a published protocol, we performed a systematic search of multiple databases. Two review authors independently performed the literature selection, identified relevant studies, assessed the eligibility of studies for inclusion, and extracted data. We performed statistical analyses using a random-effects model and assessed the quality of the evidence on a per-outcome basis according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included five randomised controlled trials and also identified seven single-arm studies. When used as first-line therapy, immunotherapy probably has little to no effect on the risk of death from any cause compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87-1.07; moderate-certainty evidence). immunotherapy probably has little to no effect on health-related quality of life (mean difference [MD] 4.10, 95% CI 3.83-4.37; moderate). Immunotherapy probably reduces grade 3-5 adverse events (risk ratio [RR] 0.47, 95% CI 0.29-0.75; moderate). In the second-line setting immunotherapy may reduce the risk of death from any cause (HR 0.72, 95% CI 0.63-0.81; low). Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; low). Immunotherapy may reduce grade 3-5 adverse events (RR 0.89, 95% CI 0.81-0.97; low). CONCLUSIONS: Compared to chemotherapy, immunotherapy has little to no effect on the risk of death from any cause in a first-line setting. Nevertheless, it may reduce the risk of death from any cause when used as second-line therapy. The health-related quality of life of participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce grade 3-5 adverse events when used as first- and second-line therapy, respectively.

Immunotherapy for advanced or metastatic urothelial carcinoma.

BACKGROUND: Immune checkpoint inhibitors are increasingly important in the treatment algorithm for locally advanced and metastatic bladder cancer. Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance therapy setting. OBJECTIVES: To assess the effects of immune checkpoint inhibitors compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. SEARCH METHODS: We performed a comprehensive search including the Cochrane Library, MEDLINE, Embase, three other databases, several trial registers, other sources of gray literature, and conference proceedings, with no restrictions on language of publication. We limited the search period to run from 2000 until August 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) using immunotherapy versus chemotherapy and would have considered non-randomized trials in the absence of randomized trial data. Participants had locally advanced inoperable (cT4b or N+, or both) or metastatic (M1) (or both) urothelial carcinoma of the bladder or upper urinary tract. We excluded studies of people in whom immunotherapy was used in combination with chemotherapy or in a surveillance setting. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion and abstracted data from included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence on a per-outcome basis. MAIN RESULTS: We included five RCTs and identified seven single-armed studies. The RCTs included 3572 participants comparing immunotherapy versus chemotherapy for the treatment of locally advanced and metastatic bladder cancer. First-line therapy Immunotherapy probably has little to no effect on the risk of death from any cause when used as first-line therapy compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87 to 1.07; I2 = 0%; 3 studies, 2068 participants; moderate-certainty evidence). This corresponds to 750 deaths per 1000 participants with chemotherapy and 11 fewer (45 fewer to 26 more) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy probably has little to no effect on health-related quality of life (mean difference (MD) 4.10, 95% CI 3.83 to 4.37; 1 study, 393 participants; moderate-certainty evidence), when assuming a minimal clinically important difference (MCID) of at least 6 points (using the Functional Assessment of Cancer Therapy - Bladder [FACT-BL] tool; scale 0 to 156 with higher scores representing better quality of life). Immunotherapy probably reduces adverse events grade 3 to 5 (RR 0.47, 95% CI 0.29 to 0.75; I2 = 97%; 3 studies, 2046 participants; moderate-certainty evidence). This corresponds to 908 grade 3 to 5 adverse events per 1000 participants with chemotherapy, with 481 fewer (644 fewer to 227 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome time to death from bladder cancer. Immunotherapy probably increases the risk of time to disease progression (HR 1.33, 95% CI 1.17 to 1.50; I2 = 0%; 2 studies, 1349 participants; moderate-certainty evidence). This corresponds to 660 events per 1000 participants with chemotherapy and 102 more (57 more to 152 more) events per 1000 participants with immunotherapy at 36 months. Immunotherapy may reduce discontinuations due to adverse effects (RR 0.47, 95% CI 0.20 to 1.10; I2 = 94%; 3 studies, 2046 participants; low-certainty evidence). This corresponds to 338 discontinuations per 1000 participants with chemotherapy and 179 fewer (271 fewer to 34 more) discontinuations per 1000 participants with immunotherapy. Second-line therapy Immunotherapy may reduce the risk of death from any cause when used as second-line therapy (HR 0.72, 95% CI 0.63 to 0.81; I2 = 0%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 920 deaths per 1000 participants with chemotherapy (vinflunine, paclitaxel, docetaxel) and 59 fewer (95 fewer to 28 fewer) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; I2 = 85%; 2 studies, 727 participants; low-certainty evidence), assuming an MCID of at least 10 points (using the EORTC QLQ tool; scale 0 to 100 with higher scores representing better quality of life). Immunotherapy may reduce adverse events grade 3 to 5 in participants undergoing second-line therapy (RR 0.89, 95% CI 0.81 to 0.97; I2 = 9%; 2 studies, 1423 participants; low-certainty evidence). This corresponds to 630 grade 3 to 5 adverse events per 1000 participants with chemotherapy and 76 fewer (126 fewer to 25 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome of time to death from bladder cancer. We are very uncertain if immunotherapy reduces the risk of disease progression (HR 0.99, 95% CI 0.84 to 1.16; I2 = 0%; 2 studies, 1473 participants; very low-certainty evidence). Immunotherapy may reduce discontinuations due to adverse events in participants undergoing second-line therapy (RR 0.35, 95% CI 0.17 to 0.72; I2 = 69%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 110 discontinuations per 1000 participants with chemotherapy and 72 fewer (91 fewer to 31 fewer) discontinuations per 1000 participants with immunotherapy. AUTHORS' CONCLUSIONS: Compared to chemotherapy, immunotherapy for treating advanced or metastatic urothelial carcinoma probably has little to no effect on the risk of death from any cause when used as first-line therapy. Still, it may reduce the risk of death from any cause when used as second-line therapy. Health-related quality of life for participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce adverse events grade 3 to 5 when used as first- and second-line therapy, respectively.

Expression of Immune-Related and Inflammatory Markers and Their Prognostic Impact in Colorectal Cancer Patients.

The tumor microenvironment of colorectal cancer (CRC) is heterogenous; thus, it is likely that multiple immune-related and inflammatory markers are simultaneously expressed in the tumor. The aim of this study was to identify immune-related and inflammatory markers expressed in freshly frozen CRC tissues and to investigate whether they are related to the clinicopathological features and prognosis of CRC. Seventy patients with CRC who underwent curative surgical resection between December 2014 and January 2017 were included in this study. Tissue samples were obtained from tumor and non-tumor areas in the patients' colons. The concentrations of immune-related markers (APRIL/TNFSF13, BAFF, LAG-3, PD-1, PD-L1, and CTLA-4) and inflammatory markers (CHIT, MMP-3, osteocalcin, pentraxin-3, sTNF-R1, and sTNF-R2) in the samples were measured using the Bio-plex Multiplex Immunoassay system. The concentrations of APRIL/TNFSF13, BAFF, and MMP-3 in the samples were significantly high; thus, we conducted analyses based on the cut-off values for these three markers. The high-APRIL/TNFSH13-expression group showed a significantly higher rate of metastatic lesions than the low-expression group, whereas the high-MMP-3-expression group had higher CEA levels, more lymph node metastases, and more advanced disease stages than the low-expression group. The five-year disease-free survival of the high-MMP-3-expression group was significantly shorter than that of the low-expression group (65.1% vs. 90.2%, p = 0.033). This study provides evidence that the APRIL/TNFSF13, BAFF, and MMP-3 pathway is overexpressed in CRC tissues and is associated with unfavorable clinicopathological features and poor prognosis in CRC patients. These markers could serve as diagnostic or prognostic biomarkers for CRC.

Biomarkers to Predict Multiorgan Distress Syndrome and Acute Kidney Injury in Critically Ill Surgical Patients.

Background and Objectives: Critically ill surgical patients are susceptible to various postoperative complications, including acute kidney injury (AKI) and multiorgan distress syndrome (MODS). These complications intensify patient suffering and significantly increase morbidity and mortality rates. This study aimed to identify the biomarkers for predicting AKI and MODS in critically ill surgical patients. Materials and Methods: We prospectively enrolled critically ill surgical patients admitted to the intensive care unit via the emergency department between July 2022 and July 2023. A total of 83 patients were recruited, and their data were used to analyze MODS. Three patients who showed decreased creatinine clearance at the initial presentation were excluded from the analysis for AKI. Patient characteristics and laboratory parameters including white blood cell (WBC) count, neutrophil count, delta neutrophil index, urine and serum ß2-microglobulin, and urine serum mitochondrial DNA copy number (mtDNAcn) were analyzed to determine the reliable biomarker to predict AKI and MODS. Results: The following parameters were independently correlated with MODS: systolic blood pressure (SBP), initial neutrophil count, and platelet count, according to a logistic regression model. The optimal cut-off values for SBP, initial neutrophil count, and platelet count were 113 mmHg (sensitivity 66.7%; specificity 73.9%), 8.65 (X3) (109/L) (sensitivity 72.2%; specificity 64.6%), and 195.0 (X3) (109/L) (sensitivity 66.7%; specificity 81.5%), respectively. According to the logistic regression model, diastolic blood pressure (DBP) and initial urine mtDNAcn were independently correlated with AKI. The optimal cut-off value for DBP and initial urine mtDNAcn were 68.5 mmHg (sensitivity 61.1%; specificity 79.5%) and 1225.6 copies/µL (sensitivity 55.6%; specificity 95.5%), respectively. Conclusions: SBP, initial neutrophil count, and platelet count were independent predictors of MODS in critically ill patients undergoing surgery. DBP and initial urine mtDNAcn levels were independent predictors of AKI in critically ill surgical patients. Large-scale multicenter prospective studies are needed to confirm our results.

Delta neutrophil index as a prognostic factor for mortality in patients with Fournier's gangrene.

OBJECTIVES: The delta neutrophil index represents the fraction of circulating immature granulocytes and is a marker of infection and sepsis. Our study aimed to evaluate the usefulness of the delta neutrophil index in predicting mortality in patients with Fournier's gangrene. METHODS: We enrolled patients with Fournier's gangrene who were admitted to the Wonju Severance Christian Hospital (Wonju, Korea) between September 2010 and December 2021. We retrospectively analyzed the patients' characteristics, factors related to management, scoring systems such as the Fournier's Gangrene Severity Index, and laboratory data measured at initial presentation. RESULTS: There were 58 (68.2%) survivors and 27 (31.8%) non-survivors. The initial levels of serum lactate, hemoglobin, delta neutrophil index, albumin, international normalized ratio, creatinine, Fournier's Gangrene Severity Index, Uludag Fournier's Gangrene Severity Index, and prognostic nutritional index differed between survivors and non-survivors. Age, international normalized ratio, and delta neutrophil index were independent predictors of mortality in Fournier's gangrene. In receiver operating characteristic curve analysis, delta neutrophil index on the day of admission was the best indicator of mortality (area under the curve, 0.804; 95% confidence interval [0.679-0.929]). The optimal cutoff for delta neutrophil index in predicting mortality was 11.25% (sensitivity, 74.1%; specificity, 91.4%). The initial delta neutrophil index was the best indicator of mortality (area under the curve, 0.804; 95% confidence interval 0.679-0.929). CONCLUSION: The delta neutrophil index can be useful for predicting mortality in patients with Fournier's gangrene. A delta neutrophil index >11.25% at initial presentation is a reliable predictor of Fournier's gangrene.

Outcomes improvement despite continuous visits of severely injured patients during the COVID-19 outbreak: experience at a regional trauma centre in South Korea.

BACKGROUND: Understanding the changes in characteristics of patients who visited trauma centres during the coronavirus disease 2019 (COVID-19) pandemic is important to facilitate aneffective response. This retrospective study was conducted to analyse differences in the characteristics and outcomes of patients who visited our trauma centre between pre-COVID-19 and COVID-19 eras. METHODS: Medical data of trauma patients enrolled in the Korean trauma database from 1 January 2018 to 31 August 2021 were collected. The number of trauma centre visits, patient characteristics, factors associated with in-hospital intervention, and outcomes werecompared between patients in the two time periods. Propensity score matching was performed to analyse the outcomes in patients with similar characteristics and severitybetween patients in the two time periods. RESULTS: The number of emergency department (ED) trauma service visits reduced in the COVID-19 era. Based on the mean age, the patients were older in the COVID-19 era. Abbreviated injury scale (AIS) 1, AIS3, AIS5, and injury severity score (ISS) were higher in the COVID-19 era. The proportion of motor vehicle collisions decreased, whereas falls increased during the COVID-19 era. Ambulance transportation, admission to the general ward, and time from injury to ED visit significantly increased. Patient outcomes, such as hospital length of stay (LOS), intensive care unit (ICU) LOS, and duration of mechanical ventilation improved, while injury severity worsened during the COVID-19 era. After adjusting for patient characteristics and severity, similar findings were observed. CONCLUSION: The small reduction in the number of trauma patients and visits by patients who hadhigher ISS during the COVID-19 pandemic highlights the importance of maintaining trauma service capacity and capability during the pandemic. A nationwide or nationalmulticentre study will be more meaningful to examine the impact of the COVID-19 outbreak on the changes in trauma patterns, volume, and patient outcomes.

Effectiveness of Mesenchymal Stem Cell Therapy for COVID-19-Induced ARDS Patients: A Case Report.

Purpose: This study assessed the safety, feasibility, and tolerability of mesenchymal stem cells for patients diagnosed with COVID (Coronavirus disease 2019-induced ARDS (acute respiratory distress syndrome)). Materials and Methods: Critically ill adult COVID-19 patients who were admitted to Wonju Severance Christian Hospital were enrolled in this study. One patient received human bone marrow-derived mesenchymal stem cell (hBMSC) transplantation and received a total dose of 9 × 107 allogeneic hBMSCs via intravenous infusion. The main outcome of this study was to assess the safety, adverse events, and efficacy following transplantation of hBMSCs in COVID-19- induced ARDS patients. Efficacy was assessed radiologically based on pneumonia improvement, changes in PaO2/FiO2, and O2 saturation. Results: A 73-year-old man visited Wonju Severance Christian Hospital presenting with fever and fatigue. A throat swab was performed for real-time polymerase chain reaction to confirm COVID-19, and the result was positive. The patient developed ARDS on Day 5. MSC transplantation was performed on that day and administered on Day 29. Early adverse events, including allergic reactions, were not observed following MSC transplantation. Subsequently, clinical symptoms, signs, and laboratory findings, including PaO2/FiO2 and O2 saturation, improved. Conclusion: The results of this case report suggest that intravenous injection of MSC derived from the bone marrow is safe and acceptable and can lead to favorable outcomes for critically ill COVID-19 patients.

Perioperative Probiotics Application for Preventing Postoperative Complications in Patients with Colorectal Cancer: A Systematic Review and Meta-Analysis.

Background and Objectives: Perioperative probiotic administration in patients who undergo gastrointestinal surgery can reduce postoperative infectious complications. This systematic review and meta-analysis aimed to evaluate the effect of probiotics on postoperative outcomes in patients who underwent colorectal cancer surgery. Materials and Methods: For this study, we followed the protocol published by PROSPERO (registration number: CRD42021247277). We included studies on patients undergoing open, laparoscopic, or robotic colorectal cancer surgery for curative intent. We conducted a comprehensive search with online databases (trial registries and ClinicalTrials.gov), other literature sources, and conference proceedings, with no language restriction, up until 12 August 2022. We assessed risk of bias, extracted data, and conducted statistical analyses by using a random-effects model and interpreted the results based on the Cochrane Handbook for Systematic Reviews of Interventions. We rated the certainty of evidence (CoR) according to the GRADE approach. Results: We identified 20 published full-text studies. The use of probiotics probably results in little to no difference in perioperative mortality (risk ratio (RR): 0.17, 95% CI: 0.02 to 1.38; I2 = 0%; moderate CoE) and may result in reducing the overall postoperative infectious complications (RR: 0.45, 95% CI: 0.27 to 0.76; I2 = 38%; low CoE) after colorectal cancer surgery. Probiotics may result in little to no difference in probiotics-related adverse events (RR: 0.73, 95% CI: 0.45 to 1.19; I2 = 0%; low CoE). While probiotics may result in reducing the overall postoperative complications (RR: 0.47, 95% CI: 0.30 to 0.74; I2 = 8%; low CoE), it may result in little to no difference in hospital length of stay (LOS) (MD: -1.06, 95% CI: -1.64 to -0.47; I2 = 8%; low CoE) and postoperative quality of life (QOL) (MD: +5.64, 95% CI: 0.98 to 10.3; low CoE). Conclusions: Perioperative probiotic administration may reduce complications, including overall infectious complications, in patients undergoing colorectal cancer surgery without any additional adverse effects. In addition, probiotics may have similar effects on perioperative mortality; procedure-related complications such as anastomotic leakage, and hospital LOS; or improve the QOL. Thus, probiotics may be considered a beneficial supplement to routine perioperative care for colorectal cancer surgery.

High Versus Low Ligation of the Inferior Mesenteric Artery in Colorectal Cancer Surgery: A Systematic Review and Meta-Analysis.

Background and Objectives: This study aimed to compare the effects of high ligation (HL) versus low ligation (LL) in colorectal cancer surgery. Materials and Methods: We performed a comprehensive search using multiple databases (trial registries and ClinicalTrials.gov), other sources of grey literature, and conference proceedings, with no restrictions on the language or publication status, up until 10 March 2021. We included all parallel-group randomized controlled trials (RCTs) and considered cluster RCTs for inclusion. The risk of bias domains were "low risk," "high risk," or "unclear risk." We performed statistical analyses using a random-effects model and interpreted the results according to the Cochrane Handbook for Systematic Reviews of Interventions. We used the GRADE guidelines to rate the certainty of evidence (CoE) of the randomized controlled trials. Results: We found 12 studies (24 articles) from our search. We were very uncertain about the effects of HL on overall mortality, disease recurrence, cancer-specific mortality, postoperative mortality, and anastomotic leakage (very low CoE). There may be little to no difference between HL and LL in postoperative complications (low CoE). For short-term follow-up (within 6 months), HL may reduce defecatory function (constipation; low CoE). While HL and LL may have similar effects on sexual function in men, HL may reduce female sexual function compared with LL (low CoE). For long-term follow-up (beyond 6 months), HL may reduce defecatory function (constipation; low CoE). There were discrepancies in the effects regarding urinary dysfunction according to which questionnaire was used in the studies. HL may reduce male and female sexual function (low CoE). Conclusions: We are very uncertain about the effects of HL on survival outcomes, and there is no difference in the incidence of postoperative complications between HL and LL. More rigorous RCTs are necessary to evaluate the effect of HL and LL on functional outcomes.

Context-aware multi-token concept recognition of biological entities.

BACKGROUND: Concept recognition is a term that corresponds to the two sequential steps of named entity recognition and named entity normalization, and plays an essential role in the field of bioinformatics. However, the conventional dictionary-based methods did not sufficiently addressed the variation of the concepts in actual use in literature, resulting in the particularly degraded performances in recognition of multi-token concepts. RESULTS: In this paper, we propose a concept recognition method of multi-token biological entities using neural models combined with literature contexts. The key aspect of our method is utilizing the contextual information from the biological knowledge-bases for concept normalization, which is followed by named entity recognition procedure. The model showed improved performances over conventional methods, particularly for multi-token concepts with higher variations. CONCLUSIONS: We expect that our model can be utilized for effective concept recognition and variety of natural language processing tasks on bioinformatics.

Increasing Mortality in Korean Patients With Breast Cancer: High Mortality Rate in Elderly Breast Cancer Population Due to Suboptimal Treatment and Other Diseases.

BACKGROUND: The incidence of breast cancer in Asia, including Korea, has rapidly increased. Each country has shown different clinical features. This study presents a comprehensive understanding of breast cancer in different age groups in Korea and determines potential measures for improving patient survival. METHODS: Patients diagnosed with invasive breast cancer stages I to III with available clinicopathologic and follow-up data were included in the study. Kaplan-Meier survival graphs were generated for each group and compared using log-rank test. The hazard ratio for each risk factor was calculated using the Cox regression model and the 95% confidence interval. RESULTS: The final cohort included 833 patients with a mean age of 51.3±11.3 years (range, 22-89 years), and 191 (22.9%) of them were aged >60 years. Patients aged ≥60 years had worse overall survival (OS) and distant disease-free survival than those aged <60 years. Although no difference was observed in the tumor biology, elderly patients showed significant differences in practice patterns: they tended to undergo mastectomy (40.2% vs 62.8%, P<0.001), did not receive the standard chemotherapy (88.4% vs 69.3%, P < 0.001), and had a higher risk of developing second primary cancer or diseases other than breast cancer (1.2% vs 6.8%, P < 0.001), which significantly correlated with poor survival in elderly patients. CONCLUSION: Less-than-the-standard treatment of care or development of a second primary disease resulted in poor prognosis in elderly patients in Korea. A multi-institutional and multinational study is warranted to elucidate the clinical features of breast cancer in Asian patients.

Neutralizing Human Antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 Isolated from a Human Synthetic Fab Phage Display Library.

Since it was first reported in Wuhan, China, in 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic outbreak resulting in a tremendous global threat due to its unprecedented rapid spread and an absence of a prophylactic vaccine or therapeutic drugs treating the virus. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is a key player in the viral entry into cells through its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor protein, and the RBD has therefore been crucial as a drug target. In this study, we used phage display to develop human monoclonal antibodies (mAbs) that neutralize SARS-CoV-2. A human synthetic Fab phage display library was panned against the RBD of the SARS-CoV-2 spike protein (SARS-2 RBD), yielding ten unique Fabs with moderate apparent affinities (EC50 = 19-663 nM) for the SARS-2 RBD. All of the Fabs showed no cross-reactivity to the MERS-CoV spike protein, while three Fabs cross-reacted with the SARS-CoV spike protein. Five Fabs showed neutralizing activities in in vitro assays based on the Fabs' activities antagonizing the interaction between the SARS-2 RBD and ACE2. Reformatting the five Fabs into immunoglobulin Gs (IgGs) greatly increased their apparent affinities (KD = 0.08-1.0 nM), presumably due to the effects of avidity, without compromising their non-aggregating properties and thermal stability. Furthermore, two of the mAbs (D12 and C2) significantly showed neutralizing activities on pseudo-typed and authentic SARS-CoV-2. Given their desirable properties and neutralizing activities, we anticipate that these human anti-SARS-CoV-2 mAbs would be suitable reagents to be further developed as antibody therapeutics to treat COVID-19, as well as for diagnostics and research tools.

Black rice with giant embryo ameliorates serum C-reactive protein in adults with metabolic syndrome.

Metabolic syndrome is well known to increase the risk of cardiovascular diseases. We have reported that phytochemicals rich black rice with giant embryo reduced fat mass and metabolic disorders in an animal model. However, such effects have not been evaluated in humans. Subjects with metabolic syndrome (n = 49, 38 male, 44.3 ± 6.1 years) were randomly assigned into two groups and ingested roasted black-rice with giant embryo (BR, n = 26, 20 male) or white-rice (WR, n = 23, 18 male) powders mixed with water for breakfast for three months. Subjects were evaluated for various metabolic parameters before and after intervention. All parameters were not significantly different between groups before starting the intervention. After three months of consumption of either BR or WR, changes of body weight in BR vs WR groups (-1.54 kg vs -1.29 kg, p = 0.649) as well as waist circumference (-1.63 cm vs -1.02 cm, p = 0.365) were not significantly different between groups. However, changes in highly-sensitive C reactive proteins in BR vs WR groups (-0.110 mg/dl vs 0.017 mg/dl, p = 0.003) had significant differences. Three months of meal replacement with BR had a significant reduction of highly-sensitive C reactive protein compared to those with WR in adults with metabolic syndrome.

Characterization of Brain Dysfunction Induced by Bacterial Lipopeptides That Alter Neuronal Activity and Network in Rodent Brains.

The immunopathological states of the brain induced by bacterial lipoproteins have been well characterized by using biochemical and histological assays. However, these studies have limitations in determining functional states of damaged brains involving aberrant synaptic activity and network, which makes it difficult to diagnose brain disorders during bacterial infection. To address this, we investigated the effect of Pam3CSK4 (PAM), a synthetic bacterial lipopeptide, on synaptic dysfunction of female mice brains and cultured neurons in parallel. Our functional brain imaging using PET with [18F]fluorodeoxyglucose and [18F] flumazenil revealed that the brain dysfunction induced by PAM is closely aligned to disruption of neurotransmitter-related neuronal activity and functional correlation in the region of the limbic system rather than to decrease of metabolic activity of neurons in the injection area. This finding was verified by in vivo tissue experiments that analyzed synaptic and dendritic alterations in the regions where PET imaging showed abnormal neuronal activity and network. Recording of synaptic activity also revealed that PAM reorganized synaptic distribution and decreased synaptic plasticity in hippocampus. Further study using in vitro neuron cultures demonstrated that PAM decreased the number of presynapses and the frequency of miniature EPSCs, which suggests PAM disrupts neuronal function by damaging presynapses exclusively. We also showed that PAM caused aggregation of synapses around dendrites, which may have caused no significant change in expression level of synaptic proteins, whereas synaptic number and function were impaired by PAM. Our findings could provide a useful guide for diagnosis and treatment of brain disorders specific to bacterial infection.SIGNIFICANCE STATEMENT It is challenging to diagnose brain disorders caused by bacterial infection because neural damage induced by bacterial products involves nonspecific neurological symptoms, which is rarely detected by laboratory tests with low spatiotemporal resolution. To better understand brain pathology, it is essential to detect functional abnormalities of brain over time. To this end, we investigated characteristic patterns of altered neuronal integrity and functional correlation between various regions in mice brains injected with bacterial lipopeptides using PET with a goal to apply new findings to diagnosis of brain disorder specific to bacterial infection. In addition, we analyzed altered synaptic density and function using both in vivo and in vitro experimental models to understand how bacterial lipopeptides impair brain function and network.

Concept embedding to measure semantic relatedness for biomedical information ontologies.

There have been many attempts to identify relationships among concepts corresponding to terms from biomedical information ontologies such as the Unified Medical Language System (UMLS). In particular, vector representation of such concepts using information from UMLS definition texts is widely used to measure the relatedness between two biological concepts. However, conventional relatedness measures have a limited range of applicable word coverage, which limits the performance of these models. In this paper, we propose a concept-embedding model of a UMLS semantic relatedness measure to overcome the limitations of earlier models. We obtained context texts of biological concepts that are not defined in UMLS by utilizing Wikipedia as an external knowledgebase. Concept vector representations were then derived from the context texts of the biological concepts. The degree of relatedness between two concepts was defined as the cosine similarity between corresponding concept vectors. As a result, we validated that our method provides higher coverage and better performance than the conventional method.

Differences in clinical features and oncologic outcomes between metastatic right and left colon cancer.

Approximately 20% to 25% of patients with colorectal cancer (CRC) have distant organ metastasis at the time of initial diagnosis. The primary tumor location has been suggested as a prognostic factor for patients with metastatic CRC. In recent years, the distinction between right colon cancer (RCC) and left colon cancer (LCC) has been brought into focus due to their different outcomes, prognoses, and clinical responses to chemotherapy. In this article we aimed to review the underlying differences between metastatic RCC and LCC in terms of epidemiology, clinical features, and oncologic outcomes. The outcomes of patients with left-sided tumors were better than those of patients with right-sided tumors in terms of overall survival (OS) and objective response rate (ORR) after treatment with chemotherapy + panitumumab in the PRIME and 20050181 trials. The outcomes of patients with LCC were better than those of patients with RCC in terms of OS, progression-free survival (PFS) and ORR after treatment with FOLFIRI + cetuximab in the CRYSTAL and CALGB 80405 trials. In the FIRE-3 trial, the OS and PFS, but not the ORR, of patients with LCC were superior to those of patients with RCC. LCC and RCC exhibit distinctive clinical features and epidemiology. However, we must further investigate the impact of these distinctive features and how they influence the differential oncologic outcomes.

The association of testosterone, sex hormone-binding globulin, and insulin-like growth factor-1 with bone parameters in Korean men aged 50 years or older.

Testosterone and insulin-like growth factor-1 (IGF-1) are essential factors for the maintenance of bone health in men. However, the results for the association of testosterone and IGF-1 with bone parameters were not consistent in prior studies. We evaluated the relationship of testosterone, sex hormone-binding globulin (SHBG), and IGF-1 with bone mineral density (BMD) and bone turnover markers (BTMs) in Korean men. We enrolled 1227 men aged ≥50 years in this cross-sectional study. Serum levels of total testosterone (TT), SHBG, IGF-1, osteocalcin, and C-terminal cross-linking telopeptide of type I collagen (CTX) were measured. Free testosterone (FT) was calculated using Vermeulen's method. BMD was measured by dual-energy X-ray absorptiometry. TT level was not related to BMD or BTMs in the unadjusted model; however, after adjusting for SHBG and IGF-1, the association between TT and BTMs was significant (ß = -0.139 for osteocalcin and ß = -0.204 for CTX). SHBG levels were negatively associated with lumbar BMD, and positively associated with BTMs in all models. As SHBG level increased, the prevalence of osteopenia or osteoporosis defined by BMD significantly increased (OR of 1SD change, 1.24). IGF-1 levels were significantly related with BMD, but not with BTMs. Meanwhile, FT levels were positively associated with BMD and negatively associated with BTMs. In conclusion, SHBG levels were independently related with bone parameters and osteopenia in men aged ≥50 years. IGF-1 levels were positively associated with BMD, but not with BTMs. SHBG may play a role in regulating age-related bone loss in men after middle-age.

Decreased muscle mass is not an independent risk factor for metabolic syndrome in Korean population aged 70 or older.

CONTEXT: The association of low muscle mass with cardiometabolic risks is still controversial. OBJECTIVE: The aim of this study was to investigate the relationship between low muscle mass and metabolic syndrome (MetS) according to the various muscle mass indices and to evaluate the influence of muscle mass on MetS independent of fat mass. DESIGN: Cross-sectional study SUBJECTS: About 841 men and 1106 women aged 70 or older from Korea National Health and Nutrition Examination Survey 2008-2010 MEASUREMENTS: We used various muscle mass indices: appendicular skeletal muscle mass (ASM) divided by height squared (ASM/Ht(2) ), ASM divided by body weight (ASM/Wt) and ASM adjusted for height and fat mass (residual). Low muscle mass is defined as ASM/Ht(2) and ASM/Wt below 2 SD of the sex-specific mean for healthy young adults. The sex-specific lowest quintile of the distribution of the residual was regarded as low muscle mass. RESULTS: The prevalence of MetS was higher in the population with low muscle mass defined by ASM/Wt, but lower in those defined by ASM/Ht(2) . However, after stratification according to the central obesity, low muscle mass was barely related with MetS. Meanwhile, when both ASM and fat mass were included in a logistic regression model, the odds ratios of 1 SD change of ASM for MetS were 1·07 (0·85-1·34) for men and 1·24 (1·04-1·47) for women, respectively. CONCLUSIONS: The relationship between low muscle mass and MetS was different according to the various muscle mass indices. After controlling the influence of fat mass, decreased muscle mass was not an independent risk factor for MetS.

Coronary artery calcification is associated with high serum concentration of undercarboxylated osteocalcin in asymptomatic Korean men.

CONTEXT: Osteocalcin is associated with energy metabolism and atherosclerosis, besides bone metabolism. However, the association between osteocalcin or its undercarboxylated form (ucOC) and coronary artery calcification is controversial. OBJECTIVE: To evaluate the relationship between coronary artery calcium score (CACS) and the concentration of serum osteocalcin and ucOC. DESIGN: Cross-sectional. PATIENTS: A total of 162 subjects (114 men and 48 women) with no angina symptom. MEASUREMENTS: Serum analyses included glucose, insulin and lipid profiles as well as osteocalcin and ucOC. Bone mineral density (BMD) was measured by dual X-ray absorptiometry. CACS was measured using multidetector computed tomography and categorized into CACS = 0 and CACS > 0. RESULTS: The mean osteocalcin concentration in men was 15·6 ± 4·2 for CACS = 0 group and 14·1 ± 4·0 for CACS > 0 group, respectively (P = 0·050). In women, the osteocalcin concentration, ucOC concentration and ucOC to osteocalcin ratio (OCR) were not different between the CACS groups. However, the concentrations of osteocalcin and ucOC were significantly lower in women with hypertension or diabetes than those without, respectively. In the multivariate logistic regression models adjusted for medical history, body mass index, lipid profiles, insulin resistance and BMD in men, the higher concentration of ucOC and higher OCR showed significant association with coronary calcification (CACS > 0). CONCLUSION: Higher ucOC concentration was associated with coronary artery calcification independent of conventional cardiovascular risk factors and BMD in men.