13 research outputs found
An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.
No full textDysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection
An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression
No full textDysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.peer-reviewe
Prospective observational cohort study of the association between antiplatelet therapy, bleeding and thrombosis in patients with coronary stents undergoing noncardiac surgery.
No full textThe perioperative management of antiplatelet therapy in noncardiac surgery patients who have undergone previous percutaneous coronary intervention (PCI) remains a dilemma. Continuing dual antiplatelet therapy (DAPT) may carry a risk of bleeding, while stopping antiplatelet therapy may increase the risk of perioperative major adverse cardiovascular events (MACE). Occurrence of Bleeding and Thrombosis during Antiplatelet Therapy In Non-Cardiac Surgery (OBTAIN) was an international prospective multicentre cohort study of perioperative antiplatelet treatment, MACE, and serious bleeding in noncardiac surgery. The incidences of MACE and bleeding were compared in patients receiving DAPT, monotherapy, and no antiplatelet therapy before surgery. Unadjusted risk ratios were calculated taking monotherapy as the baseline. The adjusted risks of bleeding and MACE were compared in patients receiving monotherapy and DAPT using propensity score matching. A total of 917 patients were recruited and 847 were eligible for inclusion. Ninety-six patients received no antiplatelet therapy, 526 received monotherapy with aspirin, and 225 received DAPT. Thirty-two patients suffered MACE and 22 had bleeding. The unadjusted risk ratio for MACE in patients receiving DAPT compared with monotherapy was 1.9 (0.93-3.88), P=0.08. There was no difference in MACE between no antiplatelet treatment and monotherapy 1.03 (0.31-3.46), P=0.96. Bleeding was more frequent with DAPT 6.55 (2.3-17.96) P=0.0002. In a propensity matched analysis of 177 patients who received DAPT and 177 monotherapy patients, the risk ratio for MACE with DAPT was 1.83 (0.69-4.85), P=0.32. The risk of bleeding was significantly greater in the DAPT group 4.00 (1.15-13.93), P=0.031. OBTAIN showed an increased risk of bleeding with DAPT and found no evidence for protective effects of DAPT from perioperative MACE in patients who have undergone previous PCI
Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA response score
No full textBACKGROUND:
Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters.
METHODS:
We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples.
FINDINGS:
2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).
INTERPRETATION:
We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.
FUNDING:
UK Medical Research Council and University of Milan-Bicocca
Associations of intraoperative end–tidal CO2 levels with postoperative outcome–secondary analysis of a worldwide observational study
No full textBackground: Patients receiving intraoperative ventilation during general anesthesia often have low end–tidal CO2 (etCO2). We examined the association of intraoperative etCO2 levels with the occurrence of postoperative pulmonary complications (PPCs) in a conveniently–sized international, prospective study named ‘Local ASsessment of Ventilatory management during General Anesthesia for Surgery’ (LAS VEGAS). Methods: Patients at high risk of PPCs were categorized as ‘low etCO2’ or ‘normal to high etCO2’ patients, using a cut–off of 35 mmHg. The primary endpoint was a composite of previously defined PPCs; the individual PPCs served as secondary endpoints. The need for unplanned oxygen was defined as mild PPCs and severe PPCs included pneumonia, respiratory failure, acute respiratory distress syndrome, barotrauma, and new invasive ventilation. We performed propensity score matching and LOESS regression to evaluate the relationship between the lowest etCO2 and PPCs. Results: The analysis included 1843 (74 %) ‘low etCO2’ patients and 648 (26 %) ‘normal to high etCO2’ patients. There was no difference in the occurrence of PPCs between ‘low etCO2’ and ‘normal to high etCO2’ patients (20 % vs. 19 %; RR 1.00 [95 %–confidence interval 0.94 to 1.06]; P = 0.84). The proportion of severe PPCs among total occurring PPCs, were higher in ‘low etCO2’ patients compared to ‘normal to high etCO2’ patients (35 % vs. 18 %; RR 1.16 [1.08 to 1.25]; P < 0.001). Propensity score matching did not change these findings. LOESS plot showed an inverse relationship of intraoperative etCO2 levels with the occurrence of PPCs. Conclusions: In this cohort of patients at high risk of PPCs, the overall occurrence of PPCs was not different between ‘low etCO2’ patients and ‘normal to high etCO2’ patients, but severe PPCs occurred more often in ‘low etCO2’, with an inverse dose–dependent relationship between intraoperative etCO2 levels and PPCs. Funding: This analysis was performed without additional funding. LAS VEGAS was partially funded and endorsed by the European Society of Anesthesiology and Intensive Care (ESAIC) and the Amsterdam University Medical Centers, location ‘AMC’. Registration: LAS VEGAS was registered at Clinicaltrials.gov (NCT01601223), first posted on May 17, 2012
Sex dependence of postoperative pulmonary complications – A post hoc unmatched and matched analysis of LAS VEGAS
No full textStudy objective: Male sex has inconsistently been associated with the development of postoperative pulmonary complications (PPCs). These studies were different in size, design, population and preoperative risk. We reanalysed the database of 'Local ASsessment of Ventilatory management during General Anaesthesia for Surgery study' (LAS VEGAS) to evaluate differences between females and males with respect to PPCs. Design, setting and patients: Post hoc unmatched and matched analysis of LAS VEGAS, an international observational study in patients undergoing intraoperative ventilation under general anaesthesia for surgery in 146 hospitals across 29 countries. The primary endpoint was a composite of PPCs in the first 5 postoperative days. Individual PPCs, hospital length of stay and mortality were secondary endpoints. Propensity score matching was used to create a similar cohort regarding type of surgery and epidemiological factors with a known association with development of PPCs. Main results: The unmatched cohort consisted of 9697 patients; 5342 (55.1%) females and 4355 (44.9%) males. The matched cohort consisted of 6154 patients; 3077 (50.0%) females and 3077 (50.0%) males. The incidence in PPCs was neither significant between females and males in the unmatched cohort (10.0 vs 10.7%; odds ratio (OR) 0.93 [0.81-1.06]; P = 0.255), nor in the matched cohort (10.5 vs 10.0%; OR 1.05 [0.89-1.25]; P = 0.556). New invasive ventilation occurred less often in females in the unmatched cohort. Hospital length of stay and mortality were similar between females and males in both cohorts. Conclusions: In this conveniently-sized worldwide cohort of patients receiving intraoperative ventilation under general anaesthesia for surgery, the PPC incidence was not significantly different between sexes. Registration: LAS VEGAS was registered at clinicaltrial.gov (study identifier NCT01601223)
Intraoperative ventilator settings and their association with postoperative pulmonary complications in neurosurgical patients: Post-hoc analysis of LAS VEGAS study
No full textBackground: Limited information is available regarding intraoperative ventilator settings and the incidence of postoperative pulmonary complications (PPCs) in patients undergoing neurosurgical procedures. The aim of this post-hoc analysis of the 'Multicentre Local ASsessment of VEntilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study was to examine the ventilator settings of patients undergoing neurosurgical procedures, and to explore the association between perioperative variables and the development of PPCs in neurosurgical patients. Methods: Post-hoc analysis of LAS VEGAS study, restricted to patients undergoing neurosurgery. Patients were stratified into groups based on the type of surgery (brain and spine), the occurrence of PPCs and the assess respiratory risk in surgical patients in Catalonia (ARISCAT) score risk for PPCs. Results: Seven hundred eighty-four patients were included in the analysis; 408 patients (52%) underwent spine surgery and 376 patients (48%) brain surgery. Median tidal volume (VT) was 8 ml [Interquartile Range, IQR = 7.3-9] per predicted body weight; median positive end-expiratory pressure (PEEP) was 5 [3 to 5] cmH20. Planned recruitment manoeuvres were used in the 6.9% of patients. No differences in ventilator settings were found among the sub-groups. PPCs occurred in 81 patients (10.3%). Duration of anaesthesia (odds ratio, 1.295 [95% confidence interval 1.067 to 1.572]; p = 0.009) and higher age for the brain group (odds ratio, 0.000 [0.000 to 0.189]; p = 0.031), but not intraoperative ventilator settings were independently associated with development of PPCs. Conclusions: Neurosurgical patients are ventilated with low VT and low PEEP, while recruitment manoeuvres are seldom applied. Intraoperative ventilator settings are not associated with PPCs
Association of preoperative smoking with the occurrence of postoperative pulmonary complications: A post hoc analysis of an observational study in 29 countries
No full textIntroduction: While smoking has been consistently identified as a significant contributor to postoperative complications, the existing literature on its association with postoperative pulmonary complications remains conflicting. Aim: We examined the association of preoperative smoking with the occurrence of postoperative pulmonary complications (PPCs). Methods: Post hoc analysis of an observational study in 146 hospitals across 29 countries. We included patients at increased risk of PPCs, according to the Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score (≥ 26 points). The primary endpoint was the occurrence of one or more predefined PPCs in the first five postoperative days, including unplanned postoperative need for supplementary oxygen, respiratory failure, unplanned need for invasive ventilation, ARDS, pneumonia and pneumothorax. Secondary endpoints included length of hospital stay and in–hospital mortality. We performed propensity score matching to correct for factors with a known association with postoperative outcomes. Results: Out of 2632 patients, 531 (20.2 %) patients were smokers and 2102 (79.8 %) non-smokers. At five days after surgery, 101 (19.0 %) smokers versus 404 (19.2) non–smokers had developed one or more PPCs (P = 0.95). Respiratory failure was more common in smokers (5.1 %) than non–smokers (3.0 %) (P = 0.02), while rates of other PPCs like need for supplementary oxygen, invasive ventilation, ARDS, pneumonia, or pneumothorax did not differ between the groups. Length of hospital stay and mortality was not different between groups. Propensity score matching did not change the findings. Conclusion: The occurrence of PPCs in smokers is not different from non–smokers. Funding: This analysis was performed without additional funding. LAS VEGAS was partially funded and endorsed by the European Society of Anaesthesiology through their Clinical Trial Network and the Amsterdam University Medical Centers, Amsterdam, The Netherlands. Registration: LAS VEGAS was registered at Clinicaltrials.gov (NCT01601223). Prior presentation: Preliminary study results have been presented at the Euroanaesthesia 2024 International Congress, in Munich, Germany
Association of preoperative smoking with the occurrence of postoperative pulmonary complications: A post hoc analysis of an observational study in 29 countries
No full textIntroduction: While smoking has been consistently identified as a significant contributor to postoperative complications, the existing literature on its association with postoperative pulmonary complications remains conflicting. Aim: We examined the association of preoperative smoking with the occurrence of postoperative pulmonary complications (PPCs). Methods: Post hoc analysis of an observational study in 146 hospitals across 29 countries. We included patients at increased risk of PPCs, according to the Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score (≥ 26 points). The primary endpoint was the occurrence of one or more predefined PPCs in the first five postoperative days, including unplanned postoperative need for supplementary oxygen, respiratory failure, unplanned need for invasive ventilation, ARDS, pneumonia and pneumothorax. Secondary endpoints included length of hospital stay and in–hospital mortality. We performed propensity score matching to correct for factors with a known association with postoperative outcomes. Results: Out of 2632 patients, 531 (20.2 %) patients were smokers and 2102 (79.8 %) non-smokers. At five days after surgery, 101 (19.0 %) smokers versus 404 (19.2) non–smokers had developed one or more PPCs (P = 0.95). Respiratory failure was more common in smokers (5.1 %) than non–smokers (3.0 %) (P = 0.02), while rates of other PPCs like need for supplementary oxygen, invasive ventilation, ARDS, pneumonia, or pneumothorax did not differ between the groups. Length of hospital stay and mortality was not different between groups. Propensity score matching did not change the findings. Conclusion: The occurrence of PPCs in smokers is not different from non–smokers. Funding: This analysis was performed without additional funding. LAS VEGAS was partially funded and endorsed by the European Society of Anaesthesiology through their Clinical Trial Network and the Amsterdam University Medical Centers, Amsterdam, The Netherlands. Registration: LAS VEGAS was registered at Clinicaltrials.gov (NCT01601223). Prior presentation: Preliminary study results have been presented at the Euroanaesthesia 2024 International Congress, in Munich, Germany
Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score
No full textBackground: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). Interpretation: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. Funding: UK Medical Research Council and University of Milan-Bicocca
