The expansion of distinct immune suppressive cells in the liver of tumor bearing hosts may bear on the propensity of patients with intra‐abdominal cancers to develop liver metastases.
The liver is ...the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune‐suppressive cells in the liver of tumor‐bearing hosts inhibit anti‐tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor‐enabling function of immune‐suppressive cells in the liver of tumor‐bearing hosts. We found that in mice with intra‐abdominal malignancies, two distinct CD11b+Gr1+ populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b+Gr1+ populations in other tissues of tumor‐bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b+Gr1+ cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid‐derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra‐abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics.
British Columbia (BC) Emergency Health Services implemented a strategy to improve outcomes for out-of-hospital cardiac arrest (OHCA), focusing on paramedic-led high-quality on-scene resuscitation. We ...measured changes in care metrics and survival trends.
This was a post-hoc study of prospectively identified consecutive non-traumatic ambulance-treated adult OHCAs from 2006 to 2016 within BC’s four metropolitan areas. The primary outcome was survival to hospital discharge; we also described available favourable neurological outcomes (mRS ≤3). We tested the significance of year-by-year trends in baseline characteristics, and calculated risk-adjusted survival rates using multivariable Poisson regression.
We included 15 145 patients. In univariate analyses there were significant increases in bystander CPR, chest compression fraction, advanced life support attendance, duration of resuscitation until advanced airway placement, duration of resuscitation until termination, and overall scene time. There was a significant decrease in initial shockable rhythms, bystander witnessed arrests, and transports initiated prior to ROSC. Survival and the proportion of survivors with favourable neurological outcomes increased significantly. In adjusted analyses, there was an improvement in return of spontaneous circulation (risk-adjusted rate 41% in 2006 to 51% in 2016; adjusted rate ratio per year 1.02, 95% CI 1.01–1.02, p < 0.01 for trend) and survival at hospital discharge (risk-adjusted rate 8.6% in 2006 to 16% in 2016; adjusted rate ratio per year 1.05, 95% CI 1.04–1.06, p < 0.01 for trend).
From 2006 to 2016 BC’s provincial ambulance system prioritized paramedic-led on-scene resuscitation, during which time there were significant improvements in patient outcomes. Our data may assist other systems, providing a model for prehospital resuscitation quality improvement.
Abstract
Aims
The prognosis of patients with atrial fibrillation (AF) and ischemic stroke while taking oral anticoagulation is poorly understood. This study aimed to characterize the outcomes of ...patients following a stroke event while on oral anticoagulation.
Methods and results
Individual participant data from five pivotal randomized trials of antithrombotic therapy in AF were used to assess the outcomes of patients with a post-randomization ischemic stroke while on study medication (warfarin, standard-, or lower-dose direct oral anticoagulant regimen) during trial follow-up. The primary outcome was recurrent ischemic stroke after the first post-randomization ischemic stroke. The primary analysis included 1163 patients with a first post-randomization ischemic stroke while on study medication (median age 73 years, 39.3% female, 35.4% history of stroke before trial enrollment). During a median continued follow-up of 337 days, 74 patients had a recurrent ischemic stroke cumulative incidence at 1 year: 7.0%, 95% confidence interval (CI) 5.2%–8.7%. The cumulative incidence of mortality at 3 months after stroke was 12.4% (95% CI 10.5%–14.4%). Consistent results for the incidence of recurrent ischemic stroke at 1 year were obtained in an analysis accounting for the competing risk of death (6.2%, 95% CI 4.8%–7.9%) and in a landmark analysis excluding the first 2 weeks after the index stroke and only including patients without permanent study drug discontinuation since then (6.8%, 95% CI 4.6%–8.9%).
Conclusion
Patients with AF and ischemic stroke while on oral anticoagulation are at increased risk of recurrent ischemic stroke and death. These patients currently have an unmet medical need.
Structured Graphical Abstract
Structured Graphical Abstract
Outcomes of patients with atrial fibrillation and ischemic stroke while on oral anticoagulation. Abbreviations: ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, AVERROES, Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment, CI, confidence interval, COMBINE AF, A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation, DOAC, direct oral anticoagulant, ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48, RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy, ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.
Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic ...stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case-cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow-up was used for identification. Validation was provided by a similar case-cohort sample of patients with AF from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase-9, NT-proBNP (N-terminal pro-B-type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor-3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00-1.38), 1.55 (1.28-1.88), 1.28 (1.07-1.53), 1.19 (1.02-1.39), 1.23 (1.05-1.45), and 1.19 (0.97-1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase-9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT-proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor-3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.
Negative information processing biases have been hypothesised to serve as precursors for the development of depression. The current study examined negative self-referent information processing and ...depressive symptoms in a community sample of adolescents (N = 291, M
age
at baseline = 12.34 ± 0.61, 53% female, 47.4% African-American, 49.5% Caucasian and 3.1% Biracial). Participants completed a computerised self-referent encoding task (SRET) and a measure of depressive symptoms at baseline and completed an additional measure of depressive symptoms nine months later. Several negative information processing biases on the SRET were associated with concurrent depressive symptoms and predicted increases in depressive symptoms at follow-up. Findings partially support the hypothesis that negative information processing biases are associated with depressive symptoms in a nonclinical sample of adolescents, and provide preliminary evidence that these biases prospectively predict increases in depressive symptoms.
OBJECTIVE: This study was undertaken to assess human fetal behavior and fetal blood flow after insulin-induced symptomatic maternal hypoglycemia of sufficient magnitude to elicit counterregulatory ...hormones and a symptomatic response.
STUDY DESIGN: Plasma glucose was lowered from approximately 95 mg/dl to 45 mg/dl in decrements of 10 mg/dl every 40 minutes with the insulin clamp technique. In 10 insulin-dependent diabetic women in the third trimester, the fetus was studied by monitoring fetal heart rate and recording fetal body and beathing movements and by performing Doppler waveform analysis with real-time ultrasonography. Maternal levels of glucagon, cortisol, epinephrine, and growth hormone were measured at each plasma glucose level.
RESULTS: The mean number of fetal limb and body movements at the start of the study was 25 +- 16 per 15 minutes, which increased to a mean of 38 ± 28 at a glucose level of 60 mg/dl and then declined to a mean of 23 ± 10 at a glucose level of approximately 45 mg/dl. These changes, however, did not achieve statistical significance. In addition, no significant reductions in fetal breathing movements or heart rate were observed, although maternal epinephrine and growth hormone levels were significantly (
p < 0.001) increased. No consistent changes in Doppler velocity waveforms were observed.
CONCLUSION: These data suggest that fetal well-being remains unaltered in spite of moderate maternal hypoglycemia in diabetic women.
Fe–Mg staurolite is a typical and widespread mineral of medium-temperature high-alumina metapelites, whereas magnesian staurolite is only relatively rarely found in metamorphosed mafic rocks ...(metabasites). The most significant factors controlling staurolite stability in metabasites were identified by thermodynamic modeling and analysis of the common features of the mineral-forming processes. In contrast to staurolite in low- and medium-pressure metapelites, staurolite in metabasites is stable at medium- and high-pressure metamorphism. An increase in the proportion of carbon dioxide in the water–carbon dioxide fluid shifts the staurolite-forming mineral reactions to lower temperatures and higher pressures. Al, Fe, Mg, and Ca are the major components of rocks that are critically important for the formation of magnesian staurolite in these rocks, and the contents and ratios of these components are of crucial importance for the stability of staurolite in metabasites. To understand the processes forming the mineral in metabasites, it is instrumental to subdivide metabasites into subgroups of predominantly magnesian, ferruginous–magnesian, and ferruginous protoliths. With regard to this subdivision, three petrochemical modules are proposed in the form of ratios of major components: MgO/CaO, CaO/FM, and Al
2
O
3
/FM, based on which it is possible to predict the stability of staurolite in mafic rocks at appropriate
P–T
parameters of metamorphism.
We report on studies of the viability and sensitivity of the Askaryan Radio Array (ARA), a new initiative to develop a Teraton-scale ultra-high energy neutrino detector in deep, radio-transparent ice ...near Amundsen-Scott station at the South Pole. An initial prototype ARA detector system was installed in January 2011, and has been operating continuously since then. We describe measurements of the background radio noise levels, the radio clarity of the ice, and the estimated sensitivity of the planned ARA array given these results, based on the first five months of operation. Anthropogenic radio interference in the vicinity of the South Pole currently leads to a few-percent loss of data, but no overall effect on the background noise levels, which are dominated by the thermal noise floor of the cold polar ice, and galactic noise at lower frequencies. We have also successfully detected signals originating from a 2.5km deep impulse generator at a distance of over 3 km from our prototype detector, confirming prior estimates of kilometer-scale attenuation lengths for cold polar ice. These are also the first such measurements for propagation over such large slant distances in ice. Based on these data, ARA-37, the ∼200km2 array now in its initial construction phase, will achieve the highest sensitivity of any planned or existing neutrino detector in the 1016–1019eV energy range.
To examine the injury and illness characteristics, treatments, and outcomes at elite ultra-endurance triathlon events.
We quantified participant demographics, injury types, treatments, and ...disposition for medical encounters at 27 Ironman-distance triathlon championships from 1989-2019. We then calculated the likelihood of concurrent medical complaints in each encounter.
We analyzed 10,533 medical encounters among 49,530 race participants for a cumulative incidence of 221.9/1000 (95% Confidence Interval 217.7-226.2) participants. Younger (<35 years; 259.3/1000, 95% CI 251.6-267.2) and older athletes (70+ years; 254.0/1000, 95% CI 217.8-294.4) presented to the medical tent at higher rates than middle-aged adults (36-69 years; 180.1/1000, 95% CI 175.4-185.0). Female athletes also presented at higher rates when compared to males (243.9/1000, 95% CI 234.9-253.2 vs. 198.0/1000, 95% CI 193.4-202.6). The most common complaints were dehydration (438.7/1000, 95% CI 426.2-451.6) and nausea (400.4/1000, 95% CI 388.4-412.6). Intravenous fluid was the most common treatment (483/1000; 95% CI 469.8-496.4). Of the athletes who received medical care, 116.7/1000 (95% CI 110.1-123.4) did not finish the race, and 17.1/1000 (95% CI 14.7-19.8) required hospital transport. Athletes rarely presented with an isolated medical condition unless their injury was dermatologic or musculoskeletal in nature.
Ultra-endurance triathlon events have high rates of medical encounters among female athletes, as well as both younger and older age categories. Gastrointestinal and exertional-related symptoms are among the most common complaints. IV infusions were the most common treatment after basic medical care. Most athletes entering the medical tent finished the race and a small percentage were dispatched to the hospital. A more thorough understanding of common medical occurrences, including concurrent presentations and treatments, will allow for improved care and optimal race management.
Abstract
Aims
Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex ...analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF.
Methods and results
A case–cohort design with 1.8- to 1.9-year follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analysed with conventional immunoassays and the OLINK proximity extension assay panels: CVDII, CVDIII, and Inflammation. Association between biomarkers and CV death was evaluated using Random Survival Forest, Boruta, and adjusted Cox-regression analyses. The biomarkers most strongly and consistently associated with CV death were as follows (hazard ratio for inter-quartile comparison 95% CI): N-terminal pro-B-type natriuretic peptide NT-proBNP; 1.63 (1.37–1.93), cardiac troponin T cTnT-hs; 1.60 (1.35–1.88), interleukin-6 IL-6; 1.29 (1.13–1.47), growth differentiation factor-15 GDF-15; 1.30 (1.10–1.53), fibroblast growth factor 23 FGF-23; 1.21 (1.10–1.33), urokinase receptor uPAR; 1.38 (1.16–1.64), trefoil factor 3 TFF3; 1.27 (1.10–1.46), tumour necrosis factor receptor 1 TNFR1; 1.21 (1.01–1.45), TNF-related apoptosis-inducing ligand receptor 2 TRAILR2; 1.18 (1.04–1.34), and cathepsin L1 CTSL1; 1.22 (1.07–1.39).
Conclusion
In this comprehensive screening of 268 biomarkers in anticoagulated patients with AF, the underlying mechanisms most strongly associated with CV death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR), and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV death in AF.
ClinicalTrials.gov identifier
NCT00412984 and NCT00262600.
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