human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: In this paper , Choi and colleagues analyzed levels of mitochondrial DNA in two prospect i ve observational cohort studies and found that increased mtDNA levels are associated with ICU mortality , and improve risk prediction in medical ICU patients . The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients The release of " neutrophil extracellular traps " ( NETs ) has been identified as a novel immune response in innate immunity . Neutrophil extracellular traps are composed of neutrophil-derived circulating free DNA ( cf-DNA ) , histones , and neutrophil cytoplasm-derived proteins such as proteases . Here , we studied the putative predictive value of plasma cf-DNA/NETs for the development of sepsis and mortality after multiple trauma . In a prospect i ve pilot study with 45 multiple trauma ( Injury Severity Score > 16 ) patients , cf-DNA was directly quantified in plasma . Blood sample s were sequentially obtained daily from admission to our Trauma Center until day 10 . Because of limited intensive care unit ( ICU ) stay of less than 3 days , 8 patients have been excluded , result ing in 37 patients that were evaluated .  Time kinetics of cf-DNA/NETs was compared with C-reactive protein ( CRP ) , interleukin ( IL ) 6 , leukocyte counts , and myeloperoxidase . The severity of the injury was calculated on the basis of the Injury Severity Score , as well as Multiple Organ Dysfunction Score , Sequential Organ Failure Assessment , and Simplified Acute Physiology Score II on ICU . Initially high cf-DNA/NETs values ( > 800 ng/mL ) with recurrent increased values between days 5 to 9 were associated with subsequent sepsis , multiple organ failure , and death . In conjunction with cf-DNA/NETs , IL-6 was significantly elevated after admission . However , the development of a second hit was not indicated by IL-6 . In contrast to cf-DNA/NETs , no difference in CRP kinetics was observed between patients with and without development of sepsis . Circulating free DNA/NETs kinetics rather followed kinetics of Multiple Organ Dysfunction Score , Sepsis-related Organ Failure Assessment , leukocyte counts , and partially of myeloperoxidase . Circulating free DNA/NETs seems to be a valuable additional marker for the calculation of injury severity and /or prediction of inflammatory second hit on ICU . However , a large clinical trial with severely injured patients should confirm the prognostic value of neutrophil-derived cf-DNA/NETs In a prospect i ve cohort study of heart transplant recipients , sequencing-based quantification of donor-derived DNA in plasma of recipients noninvasively diagnosed transplant rejection .  Donor DNA Indicates Transplant Rejection Not all heart transplants succeed , but early detection of organ rejection could spare the patient severe adverse events and graft dysfunction . De Vlaminck et al. devised a noninvasive , sequencing-based method to monitor and predict rejection , relying on the presence of donor DNA in recipient blood plasma . The fraction of donor DNA is naturally elevated 1 day after transplant ( because organ transplants are essentially genome transplants ) , and these levels decline exponentially over the course of the week , if the organ is accepted . The authors noted that patients who rejected their new heart had high levels of donor DNA even months after transplant . In a prospect i ve trial , elevated donor DNA was detected months before the rejection episode , suggesting that such noninvasive analysis tools could be used in lieu of an invasive biopsy , to let doctors know which patients are likely to reject their transplanted organ . Monitoring allograft health is an important component of posttransplant therapy . Endomyocardial biopsy is the current gold st and ard for cardiac allograft monitoring but is an expensive and invasive procedure . Proof of principle of a universal , noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA ( cfdDNA ) was recently demonstrated in a small retrospective cohort . We present the results of a prospect i ve cohort study ( 65 patients , 565 sample s ) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation . Circulating cell-free DNA was purified from plasma and sequenced ( mean depth , 1.2 giga – base pairs ) to quantify the fraction of cfdDNA . Through a comparison with endomyocardial biopsy results , we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation , with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself . This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk , discomfort , and expense of an invasive biopsy Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes BACKGROUND Mitochondrial DNA ( mtDNA ) , a potent proinflammatory damage-associated molecular pattern , is released in large titers following trauma . The effect of trauma surgery on mtDNA concentration is unknown . We hypothesized that mtDNA and nuclear DNA ( nDNA ) levels would increase proportionately with the magnitude of surgery and both would then decrease rapidly . METHODS In this prospect i ve pilot , plasma was sample d from 35 trauma patients requiring orthopedic surgical intervention at six perioperative time points . Healthy control subjects ( n = 20 ) were sample d. DNA was extracted , and the mtDNA and nDNA were assessed using quantitative polymerase chain reaction . Markers of cell necrosis were also assayed ( creatine kinase , lactate dehydrogenase , and aspartate aminotransferase ) . RESULTS The free plasma mtDNA and nDNA levels ( ng/mL ) were increased in trauma patients compared with healthy controls at all time points ( mtDNA : preoperative period , 108 [ 46–284 ] ; postoperative period , 96 [ 29–200 ] ; 7 hours postoperatively , 88 [ 43–178 ] ; 24 hours , 79 [ 36–172 ] ; 3 days , 136 [ 65–263 ] ; 5 days , 166 [ 101–434 ] [ healthy controls , 11 ( 5–19 ) ] ) ( nDNA : preoperative period , 52 [ 25–130 ] ; postoperative period , 100 [ 35–208 ] ; 7 hours postoperatively , 75 [ 36–139 ] ; 24 hours postoperatively , 85 [ 47–133 ] ; 3 days , 79 [ 48–117 ] ; 5 days , 99 [ 41–154 ] [ healthy controls , 29 ( 16–54 ) ] ) . Elevated DNA levels did not correlate with markers of cellular necrosis . mtDNA was significantly elevated compared with nDNA at preoperative period ( p = 0.003 ) , 3 days ( p = 0.003 ) , and 5 days ( p = 0.0014 ) . Preoperative mtDNA levels were greater with shorter time from injury to surgery ( p = 0.0085 ) . Postoperative mtDNA level negatively correlated with intraoperative crystalloid infusion ( p = 0.0017 ) . Major pelvic surgery ( vs. minor ) was associated with greater mtDNA release 5 days postoperatively ( p < 0.05 ) . CONCLUSION This pilot of heterogeneous orthopedic trauma patients showed that the release of mtDNA and nDNA is sustained for 5 days following orthopedic trauma surgery . Postoperative , circulating DNA is not associated with markers of tissue necrosis but is associated with surgical invasiveness and is inversely related to intraoperative fluid administration . Sustained elevation of mtDNA levels could be of inflammatory origin and may contribute to postinjury dysfunctional inflammation . LEVEL OF EVIDENCE Prospect i ve study , level III Background and Purpose Mitochondrial DNA ( mtDNA ) , a newly identified damage-associated molecular pattern , has been observed in trauma patients , however , little is known concerning the relationship between plasma mtDNA levels and concrete post-traumatic complications , particularly systemic inflammatory response syndrome ( SIRS ) . The aim of this study is to determine whether plasma mtDNA levels are associated with injury severity and cloud predict post-traumatic SIRS in patients with acute traumatic injury . Patients and Methods Eighty-six consecutive patients with acute traumatic injury were prospect ively enrolled in this study . The plasma mtDNA concentration  was measured by a real-time , quantitative PCR assay for the human ND2 gene . The study population ’s clinical and laboratory data were analyzed . Results The median plasma mtDNA was higher in trauma patients than in healthy controls ( 865.196 (251.042 - 2565.40)pg/ml vs 64.2147 (43.9049 - 80.6371)pg/ml , P<0.001 ) and was independently correlated with the ISS score ( r=0.287 , P<0.001 ) . The plasma mtDNA concentration was also significantly higher in patients who developed post-traumatic SIRS than in patients who did not ( 1774.03 (564.870 - 10901.3)pg/ml vs 500.496 (145.415 - 1285.60)pg/ml , P<0.001 ) . Multiple logistic regression analysis revealed that the plasma mtDNA was an independent predictors for post-traumatic SIRS ( OR , 1.183 ( 95%CI , 1.015 - 1.379 ) , P=0.032 ) . Further ROC analysis demonstrated that a high plasma mtDNA level predicted post-traumatic SIRS with a sensitivity of 67 % and a specificity of 76 % , with a cut-off value of 1.3185 µg/ml being established , and the area under the ROC curves ( AUC ) was 0.725 ( 95 % CI 0.613 - 0.837 ) . Conclusions Plasma mtDNA was an independent indictor with moderate discriminative power to predict the risk of post-traumatic SIRS Introduction The aims of this study were to assess the reliability of circulating cell-free DNA ( cf-DNA ) concentrations , compared with C-reactive protein ( CRP ) , procalcitonin ( PCT ) and eosinophil count , in the diagnosis of infections in patients with systemic inflammatory response syndrome ( SIRS ) and their prognostic values in a cohort of critically ill patients . Methods We conducted a prospect i ve cohort study in a medical-surgical intensive care unit of a university hospital .  Eosinophil count and concentrations of cf-DNA , CRP , and PCT  were measured in patients who fulfilled SIRS criteria at admission to the intensive care unit ( ICU ) and a second determination 24 hours later .  DNA levels were determined by a PCR method using primers for the human beta-haemoglobin gene . Results One hundred and sixty consecutive patients were included : 43 SIRS without sepsis and 117 with sepsis .  Levels of CRP and PCT , but not cf-DNA or eosinophil count , were significantly higher in patients with sepsis than in SIRS-no sepsis group on days 1 and 2 . PCT on day 1 achieves the best area under the curve ( AUC ) for sepsis diagnosis ( 0.87 ; 95 % confidence interval = 0.81 - 0.94 ) . Levels of cf-DNA do not predict outcome and the accuracy of these biomarkers for mortality prediction was lower than that shown by APACHE II score . PCT decreases significantly from day 1 to day 2 in survivors in the entire cohort and in patients with sepsis without significant changes in the other biomarkers . Conclusions Our data do not support the clinical utility of cf-DNA measurement in critical care patients with SIRS . PCT is of value especially for infection identification in patients with SIRS at admission to the ICU Objective To investigate the concentration of cell-free plasma DNA and its association with organ dysfunction and hospital mortality in intensive care unit patients . Design and setting Prospect i ve cohort study in a medical and two medical-surgical intensive care units in a university hospital . Patients 228 critically ill patients admitted to the ICUs between January 2004 and July 2005 . Measurements and results Blood sample s were collected as soon as possible after ICU admission , the following morning , and 48 h after the second sample . The cell-free plasma DNA was measured by real-time quantitative PCR assay for the β-globin gene .  Physiological and mortality data were collected to the clinical data base . Hospital mortality rate and SOFA scores were primary outcome measures . The maximum plasma DNA concentrations were correlated significantly with APACHE II points and with maximum SOFA scores . Cell-free plasma DNA concentrations were higher in hospital non-survivors than in survivors ( median 9,366 vs. 6,506 GE/ml ) . Using logistic regression analysis , the maximum plasma DNA was an independent predictor of hospital mortality . Conclusions The maximum plasma DNA concentration measured during the first 96 h of intensive care is associated with the degree of organ dysfunction 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: In this paper , Choi and colleagues analyzed levels of mitochondrial DNA in two prospect i ve observational cohort studies and found that increased mtDNA levels are associated with ICU mortality , and improve risk prediction in medical ICU patients . The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients The release of " neutrophil extracellular traps " ( NETs ) has been identified as a novel immune response in innate immunity . Neutrophil extracellular traps are composed of neutrophil-derived circulating free DNA ( cf-DNA ) , histones , and neutrophil cytoplasm-derived proteins such as proteases . Here , we studied the putative predictive value of plasma cf-DNA/NETs for the development of sepsis and mortality after multiple trauma . In a prospect i ve pilot study with 45 multiple trauma ( Injury Severity Score > 16 ) patients , cf-DNA was directly quantified in plasma . Blood sample s were sequentially obtained daily from admission to our Trauma Center until day 10 . Because of limited intensive care unit ( ICU ) stay of less than 3 days , 8 patients have been excluded , result ing in 37 patients that were evaluated .  Time kinetics of cf-DNA/NETs was compared with C-reactive protein ( CRP ) , interleukin ( IL ) 6 , leukocyte counts , and myeloperoxidase . The severity of the injury was calculated on the basis of the Injury Severity Score , as well as Multiple Organ Dysfunction Score , Sequential Organ Failure Assessment , and Simplified Acute Physiology Score II on ICU . Initially high cf-DNA/NETs values ( > 800 ng/mL ) with recurrent increased values between days 5 to 9 were associated with subsequent sepsis , multiple organ failure , and death . In conjunction with cf-DNA/NETs , IL-6 was significantly elevated after admission . However , the development of a second hit was not indicated by IL-6 . In contrast to cf-DNA/NETs , no difference in CRP kinetics was observed between patients with and without development of sepsis . Circulating free DNA/NETs kinetics rather followed kinetics of Multiple Organ Dysfunction Score , Sepsis-related Organ Failure Assessment , leukocyte counts , and partially of myeloperoxidase . Circulating free DNA/NETs seems to be a valuable additional marker for the calculation of injury severity and /or prediction of inflammatory second hit on ICU . However , a large clinical trial with severely injured patients should confirm the prognostic value of neutrophil-derived cf-DNA/NETs In a prospect i ve cohort study of heart transplant recipients , sequencing-based quantification of donor-derived DNA in plasma of recipients noninvasively diagnosed transplant rejection .  Donor DNA Indicates Transplant Rejection Not all heart transplants succeed , but early detection of organ rejection could spare the patient severe adverse events and graft dysfunction . De Vlaminck et al. devised a noninvasive , sequencing-based method to monitor and predict rejection , relying on the presence of donor DNA in recipient blood plasma . The fraction of donor DNA is naturally elevated 1 day after transplant ( because organ transplants are essentially genome transplants ) , and these levels decline exponentially over the course of the week , if the organ is accepted . The authors noted that patients who rejected their new heart had high levels of donor DNA even months after transplant . In a prospect i ve trial , elevated donor DNA was detected months before the rejection episode , suggesting that such noninvasive analysis tools could be used in lieu of an invasive biopsy , to let doctors know which patients are likely to reject their transplanted organ . Monitoring allograft health is an important component of posttransplant therapy . Endomyocardial biopsy is the current gold st and ard for cardiac allograft monitoring but is an expensive and invasive procedure . Proof of principle of a universal , noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA ( cfdDNA ) was recently demonstrated in a small retrospective cohort . We present the results of a prospect i ve cohort study ( 65 patients , 565 sample s ) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation . Circulating cell-free DNA was purified from plasma and sequenced ( mean depth , 1.2 giga – base pairs ) to quantify the fraction of cfdDNA . Through a comparison with endomyocardial biopsy results , we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation , with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself . This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk , discomfort , and expense of an invasive biopsy Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes BACKGROUND Mitochondrial DNA ( mtDNA ) , a potent proinflammatory damage-associated molecular pattern , is released in large titers following trauma . The effect of trauma surgery on mtDNA concentration is unknown . We hypothesized that mtDNA and nuclear DNA ( nDNA ) levels would increase proportionately with the magnitude of surgery and both would then decrease rapidly . METHODS In this prospect i ve pilot , plasma was sample d from 35 trauma patients requiring orthopedic surgical intervention at six perioperative time points . Healthy control subjects ( n = 20 ) were sample d. DNA was extracted , and the mtDNA and nDNA were assessed using quantitative polymerase chain reaction . Markers of cell necrosis were also assayed ( creatine kinase , lactate dehydrogenase , and aspartate aminotransferase ) . RESULTS The free plasma mtDNA and nDNA levels ( ng/mL ) were increased in trauma patients compared with healthy controls at all time points ( mtDNA : preoperative period , 108 [ 46–284 ] ; postoperative period , 96 [ 29–200 ] ; 7 hours postoperatively , 88 [ 43–178 ] ; 24 hours , 79 [ 36–172 ] ; 3 days , 136 [ 65–263 ] ; 5 days , 166 [ 101–434 ] [ healthy controls , 11 ( 5–19 ) ] ) ( nDNA : preoperative period , 52 [ 25–130 ] ; postoperative period , 100 [ 35–208 ] ; 7 hours postoperatively , 75 [ 36–139 ] ; 24 hours postoperatively , 85 [ 47–133 ] ; 3 days , 79 [ 48–117 ] ; 5 days , 99 [ 41–154 ] [ healthy controls , 29 ( 16–54 ) ] ) . Elevated DNA levels did not correlate with markers of cellular necrosis . mtDNA was significantly elevated compared with nDNA at preoperative period ( p = 0.003 ) , 3 days ( p = 0.003 ) , and 5 days ( p = 0.0014 ) . Preoperative mtDNA levels were greater with shorter time from injury to surgery ( p = 0.0085 ) . Postoperative mtDNA level negatively correlated with intraoperative crystalloid infusion ( p = 0.0017 ) . Major pelvic surgery ( vs. minor ) was associated with greater mtDNA release 5 days postoperatively ( p < 0.05 ) . CONCLUSION This pilot of heterogeneous orthopedic trauma patients showed that the release of mtDNA and nDNA is sustained for 5 days following orthopedic trauma surgery . Postoperative , circulating DNA is not associated with markers of tissue necrosis but is associated with surgical invasiveness and is inversely related to intraoperative fluid administration . Sustained elevation of mtDNA levels could be of inflammatory origin and may contribute to postinjury dysfunctional inflammation . LEVEL OF EVIDENCE Prospect i ve study , level III Background and Purpose Mitochondrial DNA ( mtDNA ) , a newly identified damage-associated molecular pattern , has been observed in trauma patients , however , little is known concerning the relationship between plasma mtDNA levels and concrete post-traumatic complications , particularly systemic inflammatory response syndrome ( SIRS ) . The aim of this study is to determine whether plasma mtDNA levels are associated with injury severity and cloud predict post-traumatic SIRS in patients with acute traumatic injury . Patients and Methods Eighty-six consecutive patients with acute traumatic injury were prospect ively enrolled in this study . The plasma mtDNA concentration  was measured by a real-time , quantitative PCR assay for the human ND2 gene . The study population ’s clinical and laboratory data were analyzed . Results The median plasma mtDNA was higher in trauma patients than in healthy controls ( 865.196 (251.042 - 2565.40)pg/ml vs 64.2147 (43.9049 - 80.6371)pg/ml , P<0.001 ) and was independently correlated with the ISS score ( r=0.287 , P<0.001 ) . The plasma mtDNA concentration was also significantly higher in patients who developed post-traumatic SIRS than in patients who did not ( 1774.03 (564.870 - 10901.3)pg/ml vs 500.496 (145.415 - 1285.60)pg/ml , P<0.001 ) . Multiple logistic regression analysis revealed that the plasma mtDNA was an independent predictors for post-traumatic SIRS ( OR , 1.183 ( 95%CI , 1.015 - 1.379 ) , P=0.032 ) . Further ROC analysis demonstrated that a high plasma mtDNA level predicted post-traumatic SIRS with a sensitivity of 67 % and a specificity of 76 % , with a cut-off value of 1.3185 µg/ml being established , and the area under the ROC curves ( AUC ) was 0.725 ( 95 % CI 0.613 - 0.837 ) . Conclusions Plasma mtDNA was an independent indictor with moderate discriminative power to predict the risk of post-traumatic SIRS Introduction The aims of this study were to assess the reliability of circulating cell-free DNA ( cf-DNA ) concentrations , compared with C-reactive protein ( CRP ) , procalcitonin ( PCT ) and eosinophil count , in the diagnosis of infections in patients with systemic inflammatory response syndrome ( SIRS ) and their prognostic values in a cohort of critically ill patients . Methods We conducted a prospect i ve cohort study in a medical-surgical intensive care unit of a university hospital .  Eosinophil count and concentrations of cf-DNA , CRP , and PCT  were measured in patients who fulfilled SIRS criteria at admission to the intensive care unit ( ICU ) and a second determination 24 hours later .  DNA levels were determined by a PCR method using primers for the human beta-haemoglobin gene . Results One hundred and sixty consecutive patients were included : 43 SIRS without sepsis and 117 with sepsis .  Levels of CRP and PCT , but not cf-DNA or eosinophil count , were significantly higher in patients with sepsis than in SIRS-no sepsis group on days 1 and 2 . PCT on day 1 achieves the best area under the curve ( AUC ) for sepsis diagnosis ( 0.87 ; 95 % confidence interval = 0.81 - 0.94 ) . Levels of cf-DNA do not predict outcome and the accuracy of these biomarkers for mortality prediction was lower than that shown by APACHE II score . PCT decreases significantly from day 1 to day 2 in survivors in the entire cohort and in patients with sepsis without significant changes in the other biomarkers . Conclusions Our data do not support the clinical utility of cf-DNA measurement in critical care patients with SIRS . PCT is of value especially for infection identification in patients with SIRS at admission to the ICU Objective To investigate the concentration of cell-free plasma DNA and its association with organ dysfunction and hospital mortality in intensive care unit patients . Design and setting Prospect i ve cohort study in a medical and two medical-surgical intensive care units in a university hospital . Patients 228 critically ill patients admitted to the ICUs between January 2004 and July 2005 . Measurements and results Blood sample s were collected as soon as possible after ICU admission , the following morning , and 48 h after the second sample . The cell-free plasma DNA was measured by real-time quantitative PCR assay for the β-globin gene .  Physiological and mortality data were collected to the clinical data base . Hospital mortality rate and SOFA scores were primary outcome measures . The maximum plasma DNA concentrations were correlated significantly with APACHE II points and with maximum SOFA scores . Cell-free plasma DNA concentrations were higher in hospital non-survivors than in survivors ( median 9,366 vs. 6,506 GE/ml ) . Using logistic regression analysis , the maximum plasma DNA was an independent predictor of hospital mortality . Conclusions The maximum plasma DNA concentration measured during the first 96 h of intensive care is associated with the degree of organ dysfunction 
    Output:
    