Driving pressure during general anesthesia for open abdominal surgery (DESIGNATION) : study protocol of a randomized clinical trial

Background Intraoperative driving pressure (Delta P) is associated with development of postoperative pulmonary complications (PPC). When tidal volume (V-T) is kept constant, Delta P may change according to positive end-expiratory pressure (PEEP)-induced changes in lung aeration. Delta P may decrease if PEEP leads to a recruitment of collapsed lung tissue but will increase if PEEP mainly causes pulmonary overdistension. This study tests the hypothesis that individualized high PEEP, when compared to fixed low PEEP, protects against PPC in patients undergoing open abdominal surgery. Methods The "Driving prESsure durIng GeNeral AnesThesIa for Open abdomiNal surgery trial" (DESIGNATION) is an international, multicenter, two-group, double-blind randomized clinical superiority trial. A total of 1468 patients will be randomly assigned to one of the two intraoperative ventilation strategies. Investigators screen patients aged >= 18 years and with a body mass index <= 40 kg/m(2), scheduled for open abdominal surgery and at risk for PPC. Patients either receive an intraoperative ventilation strategy with individualized high PEEP with recruitment maneuvers (RM) ("individualized high PEEP") or one in which PEEP of 5 cm H2O without RM is used ("low PEEP"). In the "individualized high PEEP" group, PEEP is set at the level at which Delta P is lowest. In both groups of the trial, V-T is kept at 8 mL/kg predicted body weight. The primary endpoint is the occurrence of PPC, recorded as a collapsed composite of adverse pulmonary events. Discussion DESIGNATION will be the first randomized clinical trial that is adequately powered to compare the effects of individualized high PEEP with RM versus fixed low PEEP without RM on the occurrence of PPC after open abdominal surgery. The results of DESIGNATION will support anesthesiologists in their decisions regarding PEEP settings during open abdominal surgery

Evidence for Hitchhiking of Deleterious Mutations within the Human Genome

Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles

TGF-β activation and function in immunity.

The cytokine TGF-β plays an integral role in regulating immune responses. TGF-β has pleiotropic effects on adaptive immunity, especially in the regulation of effector and regulatory CD4(+) T cell responses. Many immune and nonimmune cells can produce TGF-β, but it is always produced as an inactive complex that must be activated to exert functional effects. Thus, activation of latent TGF-β provides a crucial layer of regulation that controls TGF-β function. In this review, we highlight some of the important functional roles for TGF-β in immunity, focusing on its context-specific roles in either dampening or promoting T cell responses. We also describe how activation of TGF-β controls its function in the immune system, with a focus on the key roles for members of the integrin family in this process

Associations of dynamic driving pressure and mechanical power with postoperative pulmonary complications–posthoc analysis of two randomised clinical trials in open abdominal surgery

Background: While an association of the intraoperative driving pressure with postoperative pulmonary complications has been described before, it is uncertain whether the intraoperative mechanical power is associated with postoperative pulmonary complications. Methods: Posthoc analysis of two international, multicentre randomised clinical trials (ISRCTN70332574 and NCT02148692) conducted between 2011–2013 and 2014–2018, in patients undergoing open abdominal surgery comparing the effect of two different positive end–expiratory pressure (PEEP) levels on postoperative pulmonary complications. Time–weighted average dynamic driving pressure and mechanical power were calculated for individual patients. A multivariable logistic regression model adjusted for confounders was used to assess the independent associations of driving pressure and mechanical power with the occurrence of a composite of postoperative pulmonary complications, the primary endpoint of this posthoc analysis. Findings: In 1191 patients included, postoperative pulmonary complications occurrence was 35.9%. Median time–weighted average driving pressure and mechanical power were 14·0 [11·0–17·0] cmH2O, and 7·6 [5·1–10·0] J/min, respectively. While driving pressure was not independently associated with postoperative pulmonary complications (odds ratio, 1·06 [95% CI 0·88–1·28]; p=0.534), the mechanical power had an independent association with the occurrence of postoperative pulmonary complications (odds ratio, 1·28 [95% CI 1·05–1·57]; p=0.016). These findings were independent of body mass index or the level of PEEP used, i.e., independent of the randomisation arm. Interpretation: In this merged cohort of surgery patients, higher intraoperative mechanical power was independently associated with postoperative pulmonary complications. Mechanical power could serve as a summary ventilatory biomarker for the risk for postoperative pulmonary complications in these patients, but our findings need confirmation in other, preferably prospective studies. Funding: The two original studies were supported by unrestricted grants from the European Society of Anaesthesiology and the Amsterdam University Medical Centers, Location AMC. For this current analysis, no additional funding was requested. The funding sources had neither a role in the design, collection of data, statistical analysis, interpretation of data, writing of the report, nor in the decision to submit the paper for publication

Associations of dynamic driving pressure and mechanical power with postoperative pulmonary complications–posthoc analysis of two randomised clinical trials in open abdominal surgery

Background While an association of the intraoperative driving pressure with postoperative pulmonary complications has been described before, it is uncertain whether the intraoperative mechanical power is associated with postoperative pulmonary complications. Methods Posthoc analysis of two international, multicentre randomised clinical trials (ISRCTN70332574 and NCT02148692) conducted between 2011–2013 and 2014–2018, in patients undergoing open abdominal surgery comparing the effect of two different positive end–expiratory pressure (PEEP) levels on postoperative pulmonary complications. Time–weighted average dynamic driving pressure and mechanical power were calculated for individual patients. A multivariable logistic regression model adjusted for confounders was used to assess the independent associations of driving pressure and mechanical power with the occurrence of a composite of postoperative pulmonary complications, the primary endpoint of this posthoc analysis. Findings In 1191 patients included, postoperative pulmonary complications occurrence was 35.9%. Median time–weighted average driving pressure and mechanical power were 14·0 [11·0–17·0] cmH2O, and 7·6 [5·1–10·0] J/min, respectively. While driving pressure was not independently associated with postoperative pulmonary complications (odds ratio, 1·06 [95% CI 0·88–1·28]; p=0.534), the mechanical power had an independent association with the occurrence of postoperative pulmonary complications (odds ratio, 1·28 [95% CI 1·05–1·57]; p=0.016). These findings were independent of body mass index or the level of PEEP used, i.e., independent of the randomisation arm. Interpretation In this merged cohort of surgery patients, higher intraoperative mechanical power was independently associated with postoperative pulmonary complications. Mechanical power could serve as a summary ventilatory biomarker for the risk for postoperative pulmonary complications in these patients, but our findings need confirmation in other, preferably prospective studies. Funding The two original studies were supported by unrestricted grants from the European Society of Anaesthesiology and the Amsterdam University Medical Centers, Location AMC. For this current analysis, no additional funding was requested. The funding sources had neither a role in the design, collection of data, statistical analysis, interpretation of data, writing of the report, nor in the decision to submit the paper for publication

Associations of dynamic driving pressure and mechanical power with postoperative pulmonary complications–posthoc analysis of two randomised clinical trials in open abdominal surgery

Background While an association of the intraoperative driving pressure with postoperative pulmonary complications has been described before, it is uncertain whether the intraoperative mechanical power is associated with postoperative pulmonary complications. Methods Posthoc analysis of two international, multicentre randomised clinical trials (ISRCTN70332574 and NCT02148692) conducted between 2011–2013 and 2014–2018, in patients undergoing open abdominal surgery comparing the effect of two different positive end–expiratory pressure (PEEP) levels on postoperative pulmonary complications. Time–weighted average dynamic driving pressure and mechanical power were calculated for individual patients. A multivariable logistic regression model adjusted for confounders was used to assess the independent associations of driving pressure and mechanical power with the occurrence of a composite of postoperative pulmonary complications, the primary endpoint of this posthoc analysis. Findings In 1191 patients included, postoperative pulmonary complications occurrence was 35.9%. Median time–weighted average driving pressure and mechanical power were 14·0 [11·0–17·0] cmH2O, and 7·6 [5·1–10·0] J/min, respectively. While driving pressure was not independently associated with postoperative pulmonary complications (odds ratio, 1·06 [95% CI 0·88–1·28]; p=0.534), the mechanical power had an independent association with the occurrence of postoperative pulmonary complications (odds ratio, 1·28 [95% CI 1·05–1·57]; p=0.016). These findings were independent of body mass index or the level of PEEP used, i.e., independent of the randomisation arm. Interpretation In this merged cohort of surgery patients, higher intraoperative mechanical power was independently associated with postoperative pulmonary complications. Mechanical power could serve as a summary ventilatory biomarker for the risk for postoperative pulmonary complications in these patients, but our findings need confirmation in other, preferably prospective studies. Funding The two original studies were supported by unrestricted grants from the European Society of Anaesthesiology and the Amsterdam University Medical Centers, Location AMC. For this current analysis, no additional funding was requested. The funding sources had neither a role in the design, collection of data, statistical analysis, interpretation of data, writing of the report, nor in the decision to submit the paper for publication

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients. OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference. DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries. MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8\u200aml\u200akg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation. RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500\u200aml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml\u200akg-1 PBW, P\u200a&lt;\u200a0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P\u200a&lt;\u200a0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT. CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Assessing the Impact of 10 years of FTA Research: a synthesis of the 5 integrated impact studies

In 2021, the CGIAR Research Program on Forests, Trees and Agroforestry (FTA) completed a set of studies, under the guidance and oversight of its Independent Steering Committee (ISC), to document its progress in addressing five key global challenges. These studies had the following purposes: (i) to design a workable approach and operational method to assess impacts at scale at the level of the FTA program, since 2011; (ii) to deploy the method effectively on a set of five identified development challenges addressed by FTA; (iii) to learn lessons from the exercise for FTA post 2021. This document provides a synthesis of the five studies and draws lessons and recommendations for research for development programs