Mortality after surgery in Europe: a 7 day cohort study

SummaryBackgroundClinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe.MethodsWe did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ2 and Fisher's exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p<0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries.FindingsWe included 46 539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9–3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0–3·0] for Iceland to 21·5% [16·9–26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19–1·05; p=0·06] for Finland to 6·92 [2·37–20·27; p=0·0004] for Poland).InterpretationThe mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.FundingEuropean Society of Intensive Care Medicine, European Society of Anaesthesiology

Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial

BACKGROUND: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke or other cardiovascular events. We compared the selective thromboxane-prostaglandin receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event. METHODS: This randomised, double-blind, parallel-group trial was undertaken in 802 centres in 46 countries. Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were randomly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin. Patients and investigators were masked to treatment allocation. The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (excluding haemorrhagic death). We planned a sequential statistical analysis of non-inferiority (margin 1.05) followed by analysis of superiority. Analysis was by intention to treat. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee. This study is registered, number ISRCTN66157730. FINDINGS: 9562 patients were assigned to terutroban (9556 analysed) and 9558 to aspirin (9544 analysed); mean follow-up was 28.3 months (SD 7.7). The primary endpoint occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1.02, 95% CI 0.94-1.12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1147 [12%] vs 1045 [11%]; HR 1.11, 95% CI 1.02-1.21), but no significant differences in other safety endpoints. INTERPRETATION: The trial did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban. In a worldwide perspective, aspirin remains the gold standard antiplatelet drug for secondary stroke prevention in view of its efficacy, tolerance, and cost. FUNDING: Servier, France

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

Aim The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. Methods This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. Results Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P &lt; 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. Conclusion One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

International audienceIn 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Development and external validation of the ‘Global Surgical-Site Infection’ (GloSSI) predictive model in adult patients undergoing gastrointestinal surgery

Background: Identification of patients at high risk of surgical-site infections may allow surgeons to minimize associated morbidity. However, there are significant concerns regarding the methodological quality and transportability of models previously developed. The aim of this study was to develop a novel score to predict 30-day surgical-site infection risk after gastrointestinal surgery across a global context and externally validate against existing models. Methods: This was a secondary analysis of two prospective international cohort studies: GlobalSurg-1 (July-November 2014) and GlobalSurg-2 (January-July 2016). Consecutive adults undergoing gastrointestinal surgery were eligible. Model development was performed using GlobalSurg-2 data, with novel and previous scores externally validated using GlobalSurg-1 data. The primary outcome was 30-day surgical-site infections, with two predictive techniques explored: penalized regression (least absolute shrinkage and selection operator ('LASSO')) and machine learning (extreme gradient boosting ('XGBoost')). Final model selection was based on prognostic accuracy and clinical utility. Results: There were 14 019 patients (surgical-site infections = 12.3%) for derivation and 8464 patients (surgical-site infections = 11.4%) for external validation. The LASSO model was selected due to similar discrimination to extreme gradient boosting (AUC 0.738 (95% c.i. 0.725 to 0.750) versus 0.737 (95% c.i. 0.709 to 0.765)), but greater explainability. The final score included six variables: country income, ASA grade, diabetes, and operative contamination, approach, and duration. Model performance remained good on external validation (AUC 0.730 (95% c.i. 0.715 to 0.744); calibration intercept -0.098 and slope 1.008) and demonstrated superior performance to the external validation of all previous models. Conclusion: The 'Global Surgical-Site Infection' score allows accurate prediction of the risk of surgical-site infections with six simple variables that are routinely available at the time of surgery across global settings. This can inform the use of intraoperative and postoperative interventions to modify the risk of surgical-site infections and minimize associated harm

Science with the Cherenkov Telescope Array

The Cherenkov Telescope Array, CTA, will be the major global observatory for very high energy gamma-ray astronomy over the next decade and beyond. The scientific potential of CTA is extremely broad: from understanding the role of relativistic cosmic particles to the search for dark matter. CTA is an explorer of the extreme universe, probing environments from the immediate neighbourhood of black holes to cosmic voids on the largest scales. Covering a huge range in photon energy from 20 GeV to 300 TeV, CTA will improve on all aspects of performance with respect to current instruments. The observatory will operate arrays on sites in both hemispheres to provide full sky coverage and will hence maximize the potential for the rarest phenomena such as very nearby supernovae, gamma-ray bursts or gravitational wave transients. With 99 telescopes on the southern site and 19 telescopes on the northern site, flexible operation will be possible, with sub-arrays available for specific tasks. CTA will have important synergies with many of the new generation of major astronomical and astroparticle observatories. Multi-wavelength and multi-messenger approaches combining CTA data with those from other instruments will lead to a deeper understanding of the broad-band non-thermal properties of target sources. The CTA Observatory will be operated as an open, proposal-driven observatory, with all data available on a public archive after a pre-defined proprietary period. Scientists from institutions worldwide have combined together to form the CTA Consortium. This Consortium has prepared a proposal for a Core Programme of highly motivated observations. The programme, encompassing approximately 40% of the available observing time over the first ten years of CTA operation, is made up of individual Key Science Projects (KSPs), which are presented in this document

Science with the Cherenkov Telescope Array

The Cherenkov Telescope Array, CTA, will be the major global observatory for very high energy gamma-ray astronomy over the next decade and beyond. The scientific potential of CTA is extremely broad: from understanding the role of relativistic cosmic particles to the search for dark matter. CTA is an explorer of the extreme universe, probing environments from the immediate neighbourhood of black holes to cosmic voids on the largest scales. Covering a huge range in photon energy from 20 GeV to 300 TeV, CTA will improve on all aspects of performance with respect to current instruments. The observatory will operate arrays on sites in both hemispheres to provide full sky coverage and will hence maximize the potential for the rarest phenomena such as very nearby supernovae, gamma-ray bursts or gravitational wave transients. With 99 telescopes on the southern site and 19 telescopes on the northern site, flexible operation will be possible, with sub-arrays available for specific tasks. CTA will have important synergies with many of the new generation of major astronomical and astroparticle observatories. Multi-wavelength and multi-messenger approaches combining CTA data with those from other instruments will lead to a deeper understanding of the broad-band non-thermal properties of target sources. The CTA Observatory will be operated as an open, proposal-driven observatory, with all data available on a public archive after a pre-defined proprietary period. Scientists from institutions worldwide have combined together to form the CTA Consortium. This Consortium has prepared a proposal for a Core Programme of highly motivated observations. The programme, encompassing approximately 40% of the available observing time over the first ten years of CTA operation, is made up of individual Key Science Projects (KSPs), which are presented in this document