Fossils provide the principal basis for temporal calibrations, which are critical to the accuracy of divergence dating analyses. Translating fossil data into minimum and maximum bounds for ...calibrations is the most important—often least appreciated—step of divergence dating. Properly justified calibrations require the synthesis of phylogenetic, paleontological, and geological evidence and can be difficult for nonspecialists to formulate. The dynamic nature of the fossil record (e.g., new discoveries, taxonomic revisions, updates of global or local stratigraphy) requires that calibration data be updated continually lest they become obsolete. Here, we announce the Fossil Calibration Database (http://fossilcalibrations.org), a new openaccess resource providing vetted fossil calibrations to the scientific community. Calibrations accessioned into this database are based on individual fossil specimens and follow best practices for phylogenetic justification and geochronological constraint. The associated Fossil Calibration Series, a calibration-themed publication series at Palaeontologia Electronica, serve as a key pipeline for peer-reviewed calibrations to enter the database.
Cardiopulmonary bypass (CPB) surgery initiates a systemic inflammatory response, which is associated with postoperative morbidity and mortality. Hemoadsorption (HA) of cytokines may suppress ...inflammatory responses and improve outcomes. We tested a new sorbent used for HA (CytoSorb™; CytoSorbents Europe GmbH, Berlin, Germany) installed in the CPB circuit on changes of pro- and anti-inflammatory cytokines levels, inflammation markers, and differences in patients' perioperative course.
In this first pilot trial, 37 blinded patients were undergoing elective CPB surgery at the Medical University of Vienna and were randomly assigned to HA (n = 19) or control group (n = 18). The primary outcome was differences of cytokine levels (IL-1β, IL-6, IL-18, TNF-α, and IL-10) within the first five postoperative days. We also analyzed whether we can observe any differences in ex vivo lipopolysaccharide (LPS)-induced TNF-α production, a reduction of high-mobility box group 1 (HMGB1), or other inflammatory markers. Additionally, measurements for fluid components, blood products, catecholamine treatment, bioelectrical impedance analysis (BIA), and 30-day mortality were analyzed.
We did not find differences in our primary outcome immediately following the HA treatment, although we observed differences for IL-10 24 hours after CPB (HA: median 0.3, interquartile range (IQR) 0-4.5; control: not traceable, P = 0.0347) and 48 hours after CPB (median 0, IQR 0-1.2 versus not traceable, P = 0.0185). We did not find any differences for IL-6 between both groups, and other cytokines were rarely expressed. We found differences in pretreatment levels of HMGB1 (HA: median 0, IQR 0-28.1; control: median 48.6, IQR 12.7-597.3, P = 0.02083) but no significant changes to post-treatment levels. No differences in inflammatory markers, fluid administration, blood substitution, catecholamines, BIA, or 30-day mortality were found.
We did not find any reduction of the pro-inflammatory response in our patients and therefore no changes in their perioperative course. However, IL-10 showed a longer-lasting anti-inflammatory effect. The clinical impact of prolonged IL-10 needs further evaluation. We also observed strong inter-individual differences in cytokine levels; therefore, patients with an exaggerated inflammatory response to CPB need to be identified. The implementation of HA during CPB was feasible.
ClinicalTrials.gov: NCT01879176, registration date: June 7, 2013.
Background
National and international guidelines support early cholecystectomy after mild gallstone pancreatitis but a recent nationwide study suggested these recommendations are not universally ...followed. Our study sought to quantify the national utilization of same hospitalization cholecystectomy versus non-operative management (NOM) and its association with pancreatitis recurrence, readmissions, and costs after mild gallstone pancreatitis (GP).
Methods
Adult patients admitted with mild GP were identified from the Nationwide Readmission Database 2010–2015. Primary outcomes included the rate of cholecystectomy during the index admission as well as pancreatitis recurrence and readmission at 30 and 180 days (30d, 180d) comparing NOM to same hospitalization cholecystectomy. Mortality upon readmission, total length of stay (LOS), and total costs (combined index-readmission hospital costs) were also explored. Cox proportional hazards regression and generalized linear models controlled for patient/hospital confounders.
Results
Among the 65,067 patients identified, 30% underwent cholecystectomy. The NOM cohort was older (58 vs. 50 years), had more comorbidities (Charlson index > 2, 23.5% vs. 11.5%), fewer female patients (56.7% vs. 67%) and less discharge-to-home (84.9% vs. 94.4%) (all
p
< 0.001). NOM was associated with increase in recurrence and unplanned readmissions at 30d Hazard Ratio 3.53 (95% CI 2.92–4.27), 2.41 (2.11–2.74), respectively, and 180d 4.27 (3.65–4.98), 2.78 (2.54–3.04), respectively, as well as increased mortality during 180d readmission 1.88 (1.06–3.35). This approach was also associated with significant increase in LOS predicted mean difference 2.79 days (95% CI 2.46–3.12) and total costs $2507.89 ($1714.4–$3301.4).
Conclusions
In the USA, most patients presenting with mild GP do not undergo same hospitalization cholecystectomy. This strategy results in higher recurrent pancreatitis, mortality during readmission, and an additional $4.85 M/year in hospital costs nationwide. These data support same hospitalization cholecystectomy as the gold standard for mild GP.
Graphical abstract
The traditional paradigm for pharmaceutical manufacturing is focused primarily upon centralized facilities that enable mass production and distribution. While this system reliably maintains high ...product quality and reproducibility, its rigidity imposes limitations upon new manufacturing innovations that could improve efficiency and support supply chain resiliency. Agile manufacturing methodologies, which leverage flexibility through portability and decentralization, allow manufacturers to respond to patient needs on demand and present a potential solution to enable timely access to critical medicines. Agile approaches are particularly applicable to the production of small-batch, personalized therapies, which must be customized for each individual patient close to the point-of-care. However, despite significant progress in the advancement of agile-enabling technologies across several different industries, there are substantial global regulatory challenges that encumber the adoption of agile manufacturing techniques in the pharmaceutical industry. This review provides an overview of regulatory barriers as well as emerging opportunities to facilitate the use of agile manufacturing for the production of pharmaceutical products. Future-oriented approaches for incorporating agile methodologies within the global regulatory framework are also proposed. Collaboration between regulators and manufacturers to cohesively navigate the regulatory waters is ultimately needed to best serve patients in the rapidly-changing healthcare environment.
Extracorporeal circulation during major cardiac surgery triggers a systemic inflammatory response affecting the clinical course and outcome. Recently, extracellular vesicle (EV) research has shed ...light onto a novel cellular communication network during inflammation. Hemoadsorption (HA) systems have shown divergent results in modulating the systemic inflammatory response during cardiopulmonary bypass (CPB) surgery. To date, the effect of HA on circulating microvesicles (MVs) in patients undergoing CPB surgery is unknown.
Count and function of MVs, as part of the extracellular vesicle fraction, were assessed in a subcohort of a single-center, blinded, controlled study investigating the effect of the CytoSorb device during CPB. A total of 18 patients undergoing elective CPB surgery with (n = 9) and without (n = 9) HA device were included in the study. MV phenotyping and counting was conducted via flow cytometry and procoagulatory potential was measured by tissue factor-dependent MV assays.
Both study groups exhibited comparable counts and post-operative kinetics in MV subsets. Tissue factor-dependent procoagulatory potential was not detectable in plasma at any timepoint. Post-operative course and laboratory parameters showed no correlation with MV counts in patients undergoing CPB surgery.
Additional artificial surfaces to the CPB-circuit introduced by the use of the HA device showed no effect on circulating MV count and function in these patients. Larger studies are needed to assess and clarify the effect of HA on circulating vesicle counts and function. Trial registration ClinicalTrials.Gov Identifier: NCT01879176; registration date: June 17, 2013; https://clinicaltrials.gov/ct2/show/NCT01879176.
Tracheotomy is a common procedure for otolaryngologists. The risk of complications is difficult to predict. This study aims to identify measurable preoperative indicators associated with adverse ...events following tracheotomy.
The charts of adults undergoing tracheotomy for respiratory failure at one of four university-affiliated hospitals between 1/2012 and 8/2018 were reviewed. Complications were analyzed in the context of demographics, physiologic parameters, and comorbidities.
Among 507 tracheotomies performed, the most common complications included infection, bleeding, and cardiac arrest. Mortality was 39 % in patients with pulmonary hypertension, 42 % in those with ejection fraction ≤ 40 and 32 % in those with abnormal right ventricular function, double the rates in patients without each of these findings.
Many critically ill tracheotomy patients experience significant rates of adverse events. Risk factors for mortality include ejection fraction ≤ 40, pulmonary hypertension, and abnormal ventricular function. These should be considered for use in preoperative counseling.
4.
•Mortality reported in this study was extremely rare, and not attributed to the tracheotomy procedure.•Percutaneous technique had higher mortality than open, but open was associated with a higher rate of non-mortal events.•Practices and documentation are not standardized, so it is difficult to compare outcomes across specialties and institutions.•Critically ill patients are known to be prone to poor outcomes; it is difficult to attribute adverse events to tracheotomy.•Future studies would benefit from disease severity-matched controls to better parse any added risk from tracheotomy itself.
The purpose of this study was to analyze the muscle oxygen saturation (SmO
2
) of static and dynamic warm-up and assess their impact on athletic preparation. The acute effects of static and dynamic ...stretching on muscular and functional performance have been well established, with many studies highlighting physiological factors and performance markers (such as range of motion and flexibility). To date, no studies have analyzed the effects of dynamic stretching on muscle oxygenation. Twenty-three recreationally fit participants performed both static (SS) and dynamic stretching (DS) protocols targeting the rectus femoris muscle while the effects on SmO
2
were monitored using near-infrared spectroscopy (NIRS). SmO
2
levels after stretching were significantly (
p
= 0.04;
d
= 2.21) enhanced with DS (62.8 ± 12.6%) compared to SS (55.1 ± 17.8%). The effect persisted for two minutes after stretching had ceased, which may have implications for exercise prescription.
Using the CALPHAD approach to understand zirconium carbide deposition, a series of phase equilibria were calculated from a custom thermodynamic database based on a literature source, and the ...equilibria were used to explore the potential chemical vapor deposition (CVD) processing space in the ZrCl4-CH3SiCl3-CH4-H2 system as a function of pressure, temperature, and gas composition. Several gas ratios were considered. At a given ZrCl4:CH3SiCl3 ratio within the range studied, the most important factor was found to be the ratios of CH4:ZrCl4, wherein the nature of the composition – carbide vs. silicide – could be controlled. A pure binary composition of ZrC and SiC is expected to form by increasing the initial amount of methane and decreasing the amount of hydrogen from values predicted purely based on thermodynamic equilibrium. Rietveld analysis of the x-ray diffractograms from corresponding experimental depositions confirmed that increasing the CH4:ZrCl4 ratio increased the fraction of carbon-containing species (SiC, ZrC) and decreased the fraction of non-carbides (ZrSi, ZrSi2, etc.), as predicted from the CALPHAD results.
•Chemical vapor deposition of refractory carbides and silicides•Thermodynamic analysis of ZrCl4-H2-CH4-CH3SiCl3 system by CALPHAD•Rietveld analysis of experimental samples verify CALPHAD trends
Divergence dating studies, which combine temporal data from the fossil record with branch length data from molecular phylogenetic trees, represent a rapidly expanding approach to understanding the ...history of life. National Evolutionary Synthesis Center hosted the first Fossil Calibrations Working Group (3–6 March, 2011, Durham, NC, USA), bringing together palaeontologists, molecular evolutionists and bioinformatics experts to present perspectives from disciplines that generate, model and use fossil calibration data. Presentations and discussions focused on channels for interdisciplinary collaboration, best practices for justifying, reporting and using fossil calibrations and roadblocks to synthesis of palaeontological and molecular data. Bioinformatics solutions were proposed, with the primary objective being a new database for vetted fossil calibrations with linkages to existing resources, targeted for a 2012 launch.
The first model of a superconducting quadrupole for use in a Linear Accelerator was designed, built and tested at Fermilab. The quadrupole has a 78 mm aperture, and a cold mass length of 680 mm. A ...superferric magnet configuration with iron poles and four racetrack coils was chosen based on magnet performance, cost, and reliability considerations. Each coil is wound using enamel insulated, 0.5 mm diameter, NbTi superconductor. The quadrupole package also includes racetrack type dipole steering coils. The results of the quadrupole design, manufacturing and test, are presented. Specific issues related to the quadrupole magnetic center stability, superconductor magnetization and mechanical stability are discussed. The magnet quench performance and results of magnetic measurements will also be briefly discussed.
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