Tapcin, an In Vivo Active Dual Topoisomerase I/II Inhibitor Discovered by Synthetic Bioinformatic Natural Product (Syn-BNP)-Coupled Metagenomics.

DNA topoisomerases are attractive targets for anticancer agents. Dual topoisomerase I/II inhibitors are particularly appealing due to their reduced rates of resistance. A number of therapeutically relevant topoisomerase inhibitors are bacterial natural products. Mining the untapped chemical diversity encoded by soil microbiomes presents an opportunity to identify additional natural topoisomerase inhibitors. Here we couple metagenome mining, bioinformatic structure prediction algorithms, and chemical synthesis to produce the dual topoisomerase inhibitor tapcin. Tapcin is a mixed p-aminobenzoic acid (PABA)-thiazole with a rare tri-thiazole substructure and picomolar antiproliferative activity. Tapcin reduced colorectal adenocarcinoma HT-29 cell proliferation and tumor volume in mouse hollow fiber and xenograft models, respectively. In both studies it showed similar activity to the clinically used topoisomerase I inhibitor irinotecan. The study suggests that the interrogation of soil microbiomes using synthetic bioinformatic natural product methods has the potential to be a rewarding strategy for identifying potent, biomedically relevant, antiproliferative agents.

The association between famotidine and in-hospital mortality of patients with COVID-19.

Famotidine has been considered to be a potential treatment for COVID-19 but the current data is conflicting. This retrospective study was conducted by utilizing data of 9565 COVID-19 hospitalized patients. Patients treated with and without famotidine were matched by propensity score using a 1:1 matching scheme. A total of 1593 patients (16.7%) received famotidine. In-hospital mortality was similar in patients treated with and without famotidine in the propensity-matched cohorts (28.3% vs. 28.2%, p = 0.97), which remains similar irrespective of severity or concomitant treatment by steroids. Famotidine treatment was not associated with a lower risk of in-hospital mortality of COVID-19 patients.

Prediction of in-hospital mortality with machine learning for COVID-19 patients treated with steroid and remdesivir.

We aimed to create the prediction model of in-hospital mortality using machine learning methods for patients with coronavirus disease 2019 (COVID-19) treated with steroid and remdesivir. We reviewed 1571 hospitalized patients with laboratory confirmed COVID-19 from the Mount Sinai Health System treated with both steroids and remdesivir. The important variables associated with in-hospital mortality were identified using LASSO (least absolute shrinkage and selection operator) and SHAP (SHapley Additive exPlanations) through the light gradient boosting model (GBM). The data before February 17th, 2021 (N = 769) was randomly split into training and testing datasets; 80% versus 20%, respectively. Light GBM models were created with train data and area under the curves (AUCs) were calculated. Additionally, we calculated AUC with the data between February 17th, 2021 and March 30th, 2021 (N = 802). Of the 1571 patients admitted due to COVID-19, 331 (21.1%) died during hospitalization. Through LASSO and SHAP, we selected six important variables; age, hypertension, oxygen saturation, blood urea nitrogen, intensive care unit admission, and endotracheal intubation. AUCs using training and testing datasets derived from the data before February 17th, 2021 were 0.871/0.911. Additionally, the light GBM model has high predictability for the latest data (AUC: 0.881) (https://risk-model.herokuapp.com/covid). A high-value prediction model was created to estimate in-hospital mortality for COVID-19 patients treated with steroid and remdesivir.

Prophylactic versus therapeutic anticoagulation for survival of patients with COVID-19 on steroid.

Previous observational and randomized studies suggested potential benefit of therapeutic anticoagulation during hospitalization, but this treatment remains controversial. As of June 30th 2021, steroids is the standard treatment of COVID patients. We aimed to investigate the association of prophylactic and therapeutic anticoagulation with mortality for patients with COVID-19 who were treated with steroids. We retrospectively reviewed the medical records of 2533 patients discharged between March 1st, 2020 and March 30th, 2021, with laboratory-confirmed COVID-19 in the Mount Sinai Health System and treated with steroids. We evaluated the effect of therapeutic versus prophylactic anticoagulation on the outcomes using propensity score analyses. Subgroup analyses were conducted by stratification of patients by endotracheal intubation. Among the 2533 eligible patients, 465 (18.4%) received therapeutic anticoagulation. After 1:1 propensity score matching (N = 383 pairs), in-hospital mortality was similar between those with therapeutic versus prophylactic anticoagulation (36.0% versus 30.0%, P = 0.091). In-hospital mortality regardless of endotracheal intubation were not significantly different between the two groups. Therapeutic anticoagulation was not associated with reduced or increased risk of in-hospital mortality in patients with COVID-19 treated with steroids.

U shape association of hemoglobin level with in-hospital mortality for COVID-19 patients.

Our hypothesis was that high hemoglobin (Hb) level might be associated with hypercoagulable state and death due to COVID-19. Of the 9467 hospitalized COVID-19 patients, patients were subdivided into 5 groups based on the level of Hb; Hb < 10 g/dL, 10 g/dL ≤ Hb < 12 g/dL, 12 g/dL ≤ Hb < 14 g/dL, 14 g/dL ≤ Hb < 16 g/dL, and Hb ≥ 16 g/dL. Compared to patients with 12 g/dL ≤ Hb < 14 g/dL, patients with Hb ≥ 16 g/dL had significantly higher adjusted in-hospital mortality (OR [95% CI] 1.62 [1.15-2.27], P = 0.005).

Hospital factor and prognosis of COVID-19 in New York City, the United States of America: insights from a retrospective cohort study.

BACKGROUND: April 22nd, 2020, New York City (NYC) was the epicenter of the pandemic of Coronavirus disease 2019 (COVID-19) in the US with differences of death rates among its 5 boroughs. We aimed to investigate the difference in mortality associated with hospital factors (teaching versus community hospital) in NYC. DESIGN: Retrospective cohort study. METHODS: We obtained medical records of 6509 hospitalized patients with laboratory confirmed COVID-19 from the Mount Sinai Health System including 4 teaching hospitals in Manhattan and 2 community hospitals located outside of Manhattan (Queens and Brooklyn) retrospectively. Propensity score analysis using inverse probability of treatment weighting (IPTW) with stabilized weights was performed to adjust for differences in the baseline characteristics of patients initially presenting to teaching or community hospitals, and those who were transferred from community hospitals to teaching hospitals. RESULTS: Among 6509 patients, 4653 (72.6%) were admitted in teaching hospitals, 1462 (22.8%) were admitted in community hospitals, and 293 (4.6%) were originally admitted in community and then transferred into teaching hospitals. Patients in community hospitals had higher mortality (42.5%) than those in teaching hospitals (17.6%) or those transferred from community to teaching hospitals (23.5%, P < 0.001). After IPTW-adjustment, when compared to patients cared for at teaching hospitals, the hazard ratio (HR) and 95% confidence interval (CI) of mortality were as follows: community hospitals 2.47 (2.03-2.99); transfers 0.80 (0.58-1.09)). CONCLUSIONS: Patients admitted to community hospitals had higher mortality than those admitted to teaching hospitals.

The association of remdesivir and in-hospital outcomes for COVID-19 patients treated with steroids.

BACKGROUND: Remdesivir has been shown to decrease SARS-CoV-2 viral loads and the duration of COVID-19 symptoms. However, current evidence regarding the association between remdesivir and in-hospital mortality for patients with COVID-19 steroid treatments is limited. We aimed to investigate whether remdesivir reduces in-hospital mortality among patients with COVID-19 treated with steroids. METHODS: In this retrospective multicentre study, we reviewed the medical records of 3372 patients discharged between 1 March 2020 and 30 March 2021, with laboratory confirmed COVID-19 in the Mount Sinai Health System and treated with steroids. We evaluated the effect of remdesivir on the outcomes using propensity score analyses. Subgroup analyses were conducted by stratification of patients by endotracheal intubation and COVID-19 antibody status. Acute kidney injury (AKI) was defined as an absolute serum creatinine increase of 0.3 mg/dL or a relative increase of 50%. RESULTS: Of the 3372 eligible patients, 1336 (39.6%) received remdesivir. After 1:1 propensity score matching (N = 999 pairs), in-hospital mortality was similar between those with and without remdesivir (21.4% versus 21.6%, respectively, P = 0.96). Remdesivir was not significantly associated with in-hospital mortality regardless of endotracheal intubation or COVID-19 antibody status. However, there was a signal that remdesivir was associated with a reduced risk of AKI in the propensity matched analysis (17.5% versus 23.4%, respectively, P = 0.001). CONCLUSIONS: Remdesivir was not associated with reduced risk of in-hospital mortality in patients with COVID-19 treated with steroids but potentially associated with decreased risk of AKI. These findings should be confirmed in prospective studies focusing on COVID-19 patients treated with steroids.

The association of COVID-19 antibody with in-hospital outcomes in COVID-19 infected patients.

We aimed to investigate whether hospitalizations of patients who tested positive for coronavirus disease 2019 (COVID-19) antibodies are associated with reduced in-hospital mortality. Of the 2459 patients admitted due to COVID-19 and tested for antibodies, 937 (38.1%) had positive tests. After adjustment for patient characteristics and treatments, patients with positive COVID-19 antibody test had lower in-hospital mortality compared with those with negative test results (odds ratio [OR]: 0.62; 95% confidential interval [95% CI] 0.46-0.83, p = 0.001). In conclusion, positive COVID-19 antibody test results were associated with the reduced risk of in-hospital mortality for COVID-19 patients.

The characteristics and outcomes of critically Ill patients with COVID-19 who received systemic thrombolysis for presumed pulmonary embolism: an observational study.

Coronavirus disease 2019 (COVID-19) is associated with abnormal hemostasis, autopsy evidence of systemic microthrombosis, and a high prevalence of venous thromboembolic disease. Tissue plasminogen activator (tPA) has been used in patients with critically ill COVID-19 with high clinical suspicion of pulmonary embolism (PE). A retrospective cohort study of 6095 hospitalized COVID-19 patients at 5 acute care hospitals in New York was conducted. 57 patients received tPA for presumed PE during March 10th to April 27th. The mean age was 60.8 ± 10.8 years, and 71.9% (41/57) were male. We defined strongly suspected PE among 75.4% (43/57) of patients who had acute worsening of hypoxia and acute hypotension requiring pressors. The findings suggestive of PE included right ventricular (RV) strain in 15.8% (9/57), deep venous thrombosis (DVT) in 7.0% (4/57), increased dead space ventilation (Vd) in 31.6% (18/57) of patients, respectively. RV strain and RV thrombus were present in 3.5% (2/57), RV strain and DVT in 5.3% (3/57), RV strain and increased Vd in 8.8% (5/57), and DVT and increased Vd in 3.5% (2/57) of patients. Chest CT Angiography was not performed in any of the patients. Following tPA infusion, 49.1% (28/57) of patients demonstrated improvement. Six patients (10.5%) survived to discharge, of whom 2 received extracorporeal membrane oxygenation and were transferred to other facilities for lung transplant, 2 were discharged home, and 2 were discharged to a rehabilitation facility. However, overall mortality was 89.5%. The utility of tPA for critically ill patients with COVID-19 and presumed PE warrants further studies.

Cardiovascular comorbidities, cardiac injury, and prognosis of COVID-19 in New York City.

Using Mt. Sinai (New York City) EMR health system data, we retrospectively analyzed a cohort of 8438 COVID-19 patients seen between March 1 and April 22, 2020. Risk of intubation and of death rose as a function of increasing age and as a function of greater cardiovascular comorbidity. Combining age and specific comorbidity markers showed patterns suggesting that cardiovascular comorbidities increased relative risks for adverse outcomes most substantially in the younger subjects with progressively diminishing relative effects at older ages.

Increased extracellular vesicle miRNA-466 family in the bronchoalveolar lavage fluid as a precipitating factor of ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS. METHODS: Here, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model. RESULTS: Transfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1ß) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1ß expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs. CONCLUSIONS: These findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.

Reclassification of Flexibacter tractuosus NBRC 15981T as Marivirga harenae sp. nov. in the family Flammeovirgaceae.

Flexibacter tractuosa [Lewin, 1969] was reclassified as Marivirga tractuosa. Flexibacter tractuosus NBRC 15981T was reclassified herein by using a polyphasic taxonomic approach. Cells of the strain were strictly aerobic, Gram-stain-negative, slender rods, which were motile by gliding. The major respiratory quinone was menaquinone-7 and the predominant (>5 %) cellular fatty acids were iso-C15 : 0, iso-G-C15 : 1, C16 : 1ω7c and iso-C17 : 0 3-OH. The polar lipid pattern indicated the presence of a phosphatidylethanolamine, several unidentified aminolipids, glycolipids and five unidentified polar lipids. The G+C content of the genomic DNA was 35.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain NBRC 15981T clustered with members of the genus Marivirga in the family Flammeovirgaceae of the phylum Bacteroidetes. Levels of DNA-DNA relatedness were less than 16 % between strain NBRC 15981T and the two closely related species, Marivirga sericea NBRC 15983T and Marivirga tractuosa NBRC 15989T. Strain NBRC 15981T could be differentiated from these type strains in the genus Marivirga based on the polar lipid pattern and the activity of α-chymotrypsin, as well as by α-glucosidase and ß-glucosidase activity. On the basis of these results, NBRC 15981T is proposed as representing a novel species of the genus Marivirga, named Marivirga harenae sp. nov. The type strain is JK11T (=NBRC 15981T=NCIMB 1429T).

A novel mutation in HESX1 causes combined pituitary hormone deficiency without septo optic dysplasia phenotypes.

Heterozygous and/or homozygous HESX1 mutations have been reported to cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD), in association with septo optic dysplasia (SOD). We report a novel heterozygous HESX1 mutation in a CPHD patient without SOD phenotypes. The propositus was a one-year-old Japanese girl. Shortly after birth, she was found to be hypoglycemic. She was diagnosed with central adrenal insufficiency based on low cortisol and ACTH at a time of severe hypoglycemia. Further endocrine studies indicated that the patient also had central hypothyroidism and growth hormone deficiency. Using a next-generation sequencing strategy, we identified a novel heterozygous HESX1 mutation, c.326G>A (p.Arg109Gln). Western blotting and subcellular localization revealed no significant difference between wild type and mutant HESX1. Electrophoretic mobility shift assays showed that the mutant HESX1 abrogated DNA-binding ability. Mutant HESX1 was unable to repress PROP1-mediated activation. In conclusion, this study identified Arg109 as a critical residue in the HESX1 protein and extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in HESX1. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.

[Temporary use of centrifugal pump for pump thrombosis in patients with paracorporeal ventricular assist device].

Nipro paracorporeal ventricular assist device( VAD) is often associated with pump thrombosis which causes severe complications such as brain infarction, often requiring pump change. However, Nipro VAD pump is an expensive device and it is difficult to change pumps frequently at a short interval. We have temporarily used Rotaflow centrifugal pump for recurrent pump thrombosis in patients with Nipro VADs. From January 2012 through December 2013, 19 patients underwent Nipro VADs implantation at our institution, and 9 of them underwent pump change from Nipro pumps to Rotaflow centrifugal pumps. A total of 25 Rotaflow centrifugal pumps were used in these 9 patients, with the total circulatory support duration of 526 days. The median support period was 15 days (range;2-128 days). There were 2 cerebrovascular accidents and 1 Rotaflow pump circuit thrombosis during this period. Change from Rotaflow to Nipro VAD pump resulted in decrease in hematocrit by about 3 point. There was no difference in liver or renal function between before and after the pump change. Our results suggest that temporary use of Rotaflow centrifugal pump for recurrent pump thrombosis in patients with Nipro VADs may be a promising alternative.

Correlation of magnetic resonance imaging optic nerve parameters to optical coherence tomography and the visual field in glaucoma.

BACKGROUND: To determine the viability of using magnetic resonance imaging measurement of optic nerve morphology as an objective analysis of glaucomatous damage. DESIGN: Retrospective study conducted at Tohoku University Hospital. PARTICIPANTS: Thirty-eight eyes of 19 patients with open-angle glaucoma. METHODS: Patients were scanned with T2-weighted and 3-T diffusion tensor magnetic resonance imaging, and parameters of the optic nerve, including fractional anisotropy, apparent diffusion coefficient and cross-sectional area, were determined. Conventional parameters of glaucomatous damage, including circumpapillary and macular retinal nerve fibre layer thickness, and mean deviation and average total deviation of the central 16 test points from the Humphrey Field Analyzer, were then compared with the magnetic resonance imaging-derived parameters. Spearman's coefficient of correlation was calculated to determine the significance of the correlation. MAIN OUTCOME MEASURE: Correlation coefficient between the magnetic resonance imaging parameters and the parameters of glaucomatous damage. RESULTS: Mean deviation was significantly correlated with all magnetic resonance imaging parameters (fractional anisotropy: r = 0.53, apparent diffusion coefficient: r = -0.44, cross-sectional area: r = 0.70). Circumpapillary retinal nerve fibre layer thickness was significantly correlated with fractional anisotropy (r = 0.60) and cross-sectional area (r = 0.47), but not apparent diffusion coefficient (r = -0.29). Central macular function and macular retinal nerve fibre layer thickness were also significantly correlated with magnetic resonance imaging parameters. CONCLUSIONS: Optic nerve magnetic resonance imaging parameters were significantly correlated to glaucomatous damage. Magnetic resonance imaging analysis of the optic nerve may, thus, have value as an objective instrument to assess glaucomatous degeneration, including the function of the macula.

The usefulness of combined analysis using CIScore and VSRAD parameters for differentiating between dementia with Lewy body and Alzheimer's disease.

PURPOSE: The Cingulate Island score (CIScore) is useful index for differentiating between dementia with Lewy body (DLB) and Alzheimer's disease (AD) using regional cerebral blood flow (rCBF) SPECT. The Z score standing for medial temporal lobe (MTL) atrophy and the ratio of Z score between dorsal brain stem (DBS) to MTL are useful indices for differentiating between DLB and AD using MRI with VSRAD. The current study investigated the diagnostic ability by the combined use of rCBF SPECT and MRI in the differentiation between AD and DLB. MATERIALS AND METHODS: In cases with 42 AD and 28 DLB undertaken Tc-99m-ECD SPECT and MRI, we analyzed differential diagnostic ability between AD and DLB among following conditions by single or combined settings. Namely, they were (1) the CIScore as a parameter of rCBF SPECT (DLB â‰¦ 0.25), (2) Z score value of MTL atrophy (DLB â‰¦ 2.05), (3) the ratio of Z score of DBS to medial temporal gray matter as a parameter of brain atrophy using VSRAD (DLB â‰§ 0.38). Also, we analyzed them both including and omitting the elderly (over 75 years old). RESULTS: The accuracy of differential diagnosis in this condition was 74% for (1), 69% for (2), and 67% for (3). The accuracy by combination condition was 84% for (1) and (2), 81% for (1) and (3), and 67% for (2) and (3), respectively. The combination method by CIScore and the Z score of MTL showed the best accuracy. When we confined condition to ages younger than 75 years, the accuracy improved to 94% in the combination method. CONCLUSION: The combined use of CIScore and Z score of MTL was suggested to be useful in the differential diagnosis between DLB and AD particularly in younger than 75 years old.

Development and web deployment of prediction model for pulmonary arterial pressure in chronic thromboembolic pulmonary hypertension using machine learning.

BACKGROUND AND PURPOSE: Mean pulmonary artery pressure (mPAP) is a key index for chronic thromboembolic pulmonary hypertension (CTEPH). Using machine learning, we attempted to construct an accurate prediction model for mPAP in patients with CTEPH. METHODS: A total of 136 patients diagnosed with CTEPH were included, for whom mPAP was measured. The following patient data were used as explanatory variables in the model: basic patient information (age and sex), blood tests (brain natriuretic peptide (BNP)), echocardiography (tricuspid valve pressure gradient (TRPG)), and chest radiography (cardiothoracic ratio (CTR), right second arc ratio, and presence of avascular area). Seven machine learning methods including linear regression were used for the multivariable prediction models. Additionally, prediction models were constructed using the AutoML software. Among the 136 patients, 2/3 and 1/3 were used as training and validation sets, respectively. The average of R squared was obtained from 10 different data splittings of the training and validation sets. RESULTS: The optimal machine learning model was linear regression (averaged R squared, 0.360). The optimal combination of explanatory variables with linear regression was age, BNP level, TRPG level, and CTR (averaged R squared, 0.388). The R squared of the optimal multivariable linear regression model was higher than that of the univariable linear regression model with only TRPG. CONCLUSION: We constructed a more accurate prediction model for mPAP in patients with CTEPH than a model of TRPG only. The prediction performance of our model was improved by selecting the optimal machine learning method and combination of explanatory variables.