Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression

Neutrophil elastase (NE) activity is increased in many diseases. Other families of proteases, including cathepsins and matrix metalloproteases (MMPs), are also present at elevated levels in similar disease conditions. We postulated that NE could induce expression of cathepsins and MMPs in human macrophages. NE exposure resulted in macrophages, producing significantly greater amounts of cathepsin B and latent and active MMP-2. Cathepsin B and MMP-2 activities were decreased in Pseudomonas-infected NE knockout mice compared with wild-type littermates. We also demonstrate that NE can activate NF-kappaB in macrophages, and inhibition of NF-kappaB resulted in a reduction of NE-induced cathepsin B and MMP-2. Also, inhibition of TLR-4 or transfection of macrophages with dominant-negative IL-1R-associated kinase-1 resulted in a reduction of NE-induced cathepsin B and MMP-2. This study describes for the first time a novel hierarchy among proteases whereby a serine protease up-regulates expression of MMPs and cathepsins. This has important implications for therapeutic intervention in protease-mediated diseases

A machine learning predictive model for post-ureteroscopy urosepsis needing intensive care unit admission : A case-control yau endourology study from nine european centres

Introduction: With the rise in the use of ureteroscopy and laser stone lithotripsy (URSL), a proportionate increase in the risk of post-procedural urosepsis has also been observed. The aims of our paper were to analyse the predictors for severe urosepsis using a machine learning model (ML) in patients that needed intensive care unit (ICU) admission and to make comparisons with a matched cohort. Methods: A retrospective study was conducted across nine high-volume endourology European centres for all patients who underwent URSL and subsequently needed ICU admission for urosepsis (Group A). This was matched by patients with URSL without urosepsis (Group B). Statistical analysis was performed with 'R statistical software' using the 'randomforests' package. The data were segregated at random into a 70% training set and a 30% test set using the 'sample' command. A random forests ML model was then built with n = 300 trees, with the test set used for internal validation. Diagnostic accuracy statistics were generated using the 'caret' package. Results: A total of 114 patients were included (57 in each group) with a mean age of 60 ± 16 years and a male:female ratio of 1:1.19. The ML model correctly predicted risk of sepsis in 14/17 (82%) cases (Group A) and predicted those without urosepsis for 12/15 (80%) controls (Group B), whilst overall it also discriminated between the two groups predicting both those with and without sepsis. Our model accuracy was 81.3% (95%, CI: 63.7-92.8%), sensitivity = 0.80, specificity = 0.82 and area under the curve = 0.89. Predictive values most commonly accounting for nodal points in the trees were a large proximal stone location, long stent time, large stone size and long operative time. Conclusion: Urosepsis after endourological procedures remains one of the main reasons for ICU admission. Risk factors for urosepsis are reasonably accurately predicted by our innovative ML model. Focusing on these risk factors can allow one to create predictive strategies to minimise post-operative morbidity

Nutrition During Pregnancy, Lactation and Early Childhood and its Implications for Maternal and Long-Term Child Health: The Early Nutrition Project Recommendations

Background: A considerable body of evidence accumulated especially during the last decade, demonstrating that early nutrition and lifestyle have long-term effects on later health and disease ("developmental or metabolic programming"). Methods: Researchers involved in the European Union funded international EarlyNutrition research project consolidated the scientific evidence base and existing recommendations to formulate consensus recommendations on nutrition and lifestyle before and during pregnancy, during infancy and early childhood that take long-term health impact into account. Systematic reviews were performed on published dietary guidelines, standards and recommendations, with special attention to long-term health consequences. In addition, systematic reviews of published systematic reviews on nutritional interventions or exposures in pregnancy and in infants and young children aged up to 3 years that describe effects on subsequent overweight, obesity and body composition were performed. Experts developed consensus recommendations incorporating the wide-ranging expertise from additional 33 stakeholders. Findings: Most current recommendations for pregnant women, particularly obese women, and for young children do not take long-term health consequences of early nutrition into account, although the available evidence for relevant consequences of lifestyle, diet and growth patterns in early life on later health and disease risk is strong. Interpretation: We present updated recommendations for optimized nutrition before and during pregnancy, during lactation, infancy and toddlerhood, with special reference to later health outcomes. These recommendations are developed for affluent populations, such as women and children in Europe, and should contribute to the primary prevention of obesity and associated non-communicable diseases. (c) 2019 S. Karger AG, BaselTransplantation and immunomodulatio

Critical care usage after major gastrointestinal and liver surgery: a prospective, multicentre observational study

Background Patient selection for critical care admission must balance patient safety with optimal resource allocation. This study aimed to determine the relationship between critical care admission, and postoperative mortality after abdominal surgery. Methods This prespecified secondary analysis of a multicentre, prospective, observational study included consecutive patients enrolled in the DISCOVER study from UK and Republic of Ireland undergoing major gastrointestinal and liver surgery between October and December 2014. The primary outcome was 30-day mortality. Multivariate logistic regression was used to explore associations between critical care admission (planned and unplanned) and mortality, and inter-centre variation in critical care admission after emergency laparotomy. Results Of 4529 patients included, 37.8% (n=1713) underwent planned critical care admissions from theatre. Some 3.1% (n=86/2816) admitted to ward-level care subsequently underwent unplanned critical care admission. Overall 30-day mortality was 2.9% (n=133/4519), and the risk-adjusted association between 30-day mortality and critical care admission was higher in unplanned [odds ratio (OR): 8.65, 95% confidence interval (CI): 3.51–19.97) than planned admissions (OR: 2.32, 95% CI: 1.43–3.85). Some 26.7% of patients (n=1210/4529) underwent emergency laparotomies. After adjustment, 49.3% (95% CI: 46.8–51.9%, P<0.001) were predicted to have planned critical care admissions, with 7% (n=10/145) of centres outside the 95% CI. Conclusions After risk adjustment, no 30-day survival benefit was identified for either planned or unplanned postoperative admissions to critical care within this cohort. This likely represents appropriate admission of the highest-risk patients. Planned admissions in selected, intermediate-risk patients may present a strategy to mitigate the risk of unplanned admission. Substantial inter-centre variation exists in planned critical care admissions after emergency laparotomies

Body mass index and complications following major gastrointestinal surgery: A prospective, international cohort study and meta-analysis

Aim Previous studies reported conflicting evidence on the effects of obesity on outcomes after gastrointestinal surgery. The aims of this study were to explore the relationship of obesity with major postoperative complications in an international cohort and to present a metaanalysis of all available prospective data. Methods This prospective, multicentre study included adults undergoing both elective and emergency gastrointestinal resection, reversal of stoma or formation of stoma. The primary end-point was 30-day major complications (Clavien–Dindo Grades III–V). A systematic search was undertaken for studies assessing the relationship between obesity and major complications after gastrointestinal surgery. Individual patient meta-analysis was used to analyse pooled results. Results This study included 2519 patients across 127 centres, of whom 560 (22.2%) were obese. Unadjusted major complication rates were lower in obese vs normal weight patients (13.0% vs 16.2%, respectively), but this did not reach statistical significance (P = 0.863) on multivariate analysis for patients having surgery for either malignant or benign conditions. Individual patient meta-analysis demonstrated that obese patients undergoing surgery formalignancy were at increased risk of major complications (OR 2.10, 95% CI 1.49–2.96, P < 0.001), whereas obese patients undergoing surgery for benign indications were at decreased risk (OR 0.59, 95% CI 0.46–0.75, P < 0.001) compared to normal weight patients. Conclusions In our international data, obesity was not found to be associated with major complications following gastrointestinal surgery. Meta-analysis of available prospective data made a novel finding of obesity being associated with different outcomes depending on whether patients were undergoing surgery for benign or malignant disease