Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council

Postoperative outcomes in oesophagectomy with trainee involvement

BACKGROUND: The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. METHODS: Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. RESULTS: Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). CONCLUSION: Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery

Adding a late fall application of Proxy (ethephon) before two traditional spring applications improves seedhead control of annual bluegrass

Annual bluegrass (ABG) (Poa annua L.) is a prolific seed producer in the spring on golf courses that in turn decreases aesthetic quality and trueness of ball roll on coolseason putting greens. Proxy (ethephon) applied twice in the spring after green-up is the current industry standard after the loss of Embark (mefluidide) from the turf and ornamental market. However, plant growth regulators including Proxy have been used for years to help suppressABGseedheads with inconsistent success. The primary objective of this study was to determine if ABG seedhead suppression is improved by adding a late fall application of Proxy to the two traditional spring applications of plant growth regulators at nine locations with diverse environments.Asecond objectivewas to determine the importance of including Primo Maxx (trinexapac-ethyl) in fall and spring applications. Adding a late fall application of Proxy prior to the two spring applications (F+S+S) improved control of ABG seedheads over the traditional two spring applications (S+S), but themagnitude of improvement varied among locations. When treatments were applied F+S+S, the industry standard tank mixture of Proxy + Primo Maxx provided consistent ABG seedhead control and turf quality, similar to Proxy + Fiata (phosphonate + proprietary pigment) and equal to or better than Proxy alone