A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin ( 1) and variecolactone ( 2) was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues ( 5- 7). Analysis of the compounds' anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities, 5 was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EWSs)and three shock indices in early sepsis prediction in the emergency department(ED). METHODS:We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong.The primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED presentation.Using c-statistics and the DeLong test,we compared 11 EWSs,including the National Early Warning Score 2(NEWS2),Modified Early Warning Score,and Worthing Physiological Scoring System(WPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ Failure Assessment(qSOFA)in predicting the primary outcome,intensive care unit admission,and mortality at different time points. RESULTS:We analyzed 601 patients,of whom 166(27.6%)developed sepsis.NEWS2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOFA,other EWSs and shock indices,except WPS,at predicting the primary outcome.However,the pooled sensitivity and specificity of NEWS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),respectively.The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION:NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

Objectives: Osteoblast is known to regulate hematopoiesis according to preclinical studies but the causal rela tionship in human remains uncertain. We aimed to evaluate causal relationships of bone mineral density (BMD) with blood cell traits using genetic data. Methods: Summary statistics from the largest available genome-wide association study were retrieved for total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and 29 blood cell traits including red blood cell, white blood cell and platelet-related traits. Using two-sample Mendelian randomization (MR) approach, inverse-variance weighted method was adopted as main univariable MR analysis. Multivariable MR (MVMR) analysis was conducted to evaluate whether the casual effect is independent of confounders. Results: BMD was positively associated with reticulocyte-related traits, including high light scatter reticulocyte count and percentage, immature reticulocyte fraction, reticulocyte count and percentage, with causal effect estimate (beta) ranging from 0.023 to 0.064. Conversely, inverse association of BMD with hematocrit, hemo globin, and red blood cell count was observed, with beta ranging from − 0.038 to − 0.019. The association remained significant in MVMR analysis after adjustment for confounders. For white blood cells, BMD was inversely associated with neutrophil count (beta: 0.029 to − 0.019) and white blood cell count (beta: 0.024 to − 0.02). Results across TBBMD, LSBMD, and FNBMD were consistent. Conclusions This study suggested bone metabolism had a causal effect on hematopoietic system in humans. Its causal effect on red blood cell traits was independent of confounders. Further studies on how improving bone health can reduce risk of hematological disorders are warranted.

Objectives: Osteoblast is known to regulate hematopoiesis according to preclinical studies but the causal rela tionship in human remains uncertain. We aimed to evaluate causal relationships of bone mineral density (BMD) with blood cell traits using genetic data. Methods: Summary statistics from the largest available genome-wide association study were retrieved for total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and 29 blood cell traits including red blood cell, white blood cell and platelet-related traits. Using two-sample Mendelian randomization (MR) approach, inverse-variance weighted method was adopted as main univariable MR analysis. Multivariable MR (MVMR) analysis was conducted to evaluate whether the casual effect is independent of confounders. Results: BMD was positively associated with reticulocyte-related traits, including high light scatter reticulocyte count and percentage, immature reticulocyte fraction, reticulocyte count and percentage, with causal effect estimate (beta) ranging from 0.023 to 0.064. Conversely, inverse association of BMD with hematocrit, hemo globin, and red blood cell count was observed, with beta ranging from − 0.038 to − 0.019. The association remained significant in MVMR analysis after adjustment for confounders. For white blood cells, BMD was inversely associated with neutrophil count (beta: 0.029 to − 0.019) and white blood cell count (beta: 0.024 to − 0.02). Results across TBBMD, LSBMD, and FNBMD were consistent. Conclusions This study suggested bone metabolism had a causal effect on hematopoietic system in humans. Its causal effect on red blood cell traits was independent of confounders. Further studies on how improving bone health can reduce risk of hematological disorders are warranted.

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EWSs)and three shock indices in early sepsis prediction in the emergency department(ED). METHODS:We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong.The primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED presentation.Using c-statistics and the DeLong test,we compared 11 EWSs,including the National Early Warning Score 2(NEWS2),Modified Early Warning Score,and Worthing Physiological Scoring System(WPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ Failure Assessment(qSOFA)in predicting the primary outcome,intensive care unit admission,and mortality at different time points. RESULTS:We analyzed 601 patients,of whom 166(27.6%)developed sepsis.NEWS2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOFA,other EWSs and shock indices,except WPS,at predicting the primary outcome.However,the pooled sensitivity and specificity of NEWS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),respectively.The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION:NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EWSs)and three shock indices in early sepsis prediction in the emergency department(ED). METHODS:We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong.The primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED presentation.Using c-statistics and the DeLong test,we compared 11 EWSs,including the National Early Warning Score 2(NEWS2),Modified Early Warning Score,and Worthing Physiological Scoring System(WPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ Failure Assessment(qSOFA)in predicting the primary outcome,intensive care unit admission,and mortality at different time points. RESULTS:We analyzed 601 patients,of whom 166(27.6%)developed sepsis.NEWS2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOFA,other EWSs and shock indices,except WPS,at predicting the primary outcome.However,the pooled sensitivity and specificity of NEWS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),respectively.The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION:NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EWSs)and three shock indices in early sepsis prediction in the emergency department(ED). METHODS:We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong.The primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED presentation.Using c-statistics and the DeLong test,we compared 11 EWSs,including the National Early Warning Score 2(NEWS2),Modified Early Warning Score,and Worthing Physiological Scoring System(WPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ Failure Assessment(qSOFA)in predicting the primary outcome,intensive care unit admission,and mortality at different time points. RESULTS:We analyzed 601 patients,of whom 166(27.6%)developed sepsis.NEWS2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOFA,other EWSs and shock indices,except WPS,at predicting the primary outcome.However,the pooled sensitivity and specificity of NEWS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),respectively.The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION:NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EWSs)and three shock indices in early sepsis prediction in the emergency department(ED). METHODS:We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong.The primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED presentation.Using c-statistics and the DeLong test,we compared 11 EWSs,including the National Early Warning Score 2(NEWS2),Modified Early Warning Score,and Worthing Physiological Scoring System(WPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ Failure Assessment(qSOFA)in predicting the primary outcome,intensive care unit admission,and mortality at different time points. RESULTS:We analyzed 601 patients,of whom 166(27.6%)developed sepsis.NEWS2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOFA,other EWSs and shock indices,except WPS,at predicting the primary outcome.However,the pooled sensitivity and specificity of NEWS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),respectively.The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION:NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EWSs)and three shock indices in early sepsis prediction in the emergency department(ED). METHODS:We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong.The primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED presentation.Using c-statistics and the DeLong test,we compared 11 EWSs,including the National Early Warning Score 2(NEWS2),Modified Early Warning Score,and Worthing Physiological Scoring System(WPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ Failure Assessment(qSOFA)in predicting the primary outcome,intensive care unit admission,and mortality at different time points. RESULTS:We analyzed 601 patients,of whom 166(27.6%)developed sepsis.NEWS2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOFA,other EWSs and shock indices,except WPS,at predicting the primary outcome.However,the pooled sensitivity and specificity of NEWS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),respectively.The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION:NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EWSs)and three shock indices in early sepsis prediction in the emergency department(ED). METHODS:We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong.The primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED presentation.Using c-statistics and the DeLong test,we compared 11 EWSs,including the National Early Warning Score 2(NEWS2),Modified Early Warning Score,and Worthing Physiological Scoring System(WPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ Failure Assessment(qSOFA)in predicting the primary outcome,intensive care unit admission,and mortality at different time points. RESULTS:We analyzed 601 patients,of whom 166(27.6%)developed sepsis.NEWS2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOFA,other EWSs and shock indices,except WPS,at predicting the primary outcome.However,the pooled sensitivity and specificity of NEWS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),respectively.The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION:NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.