By examining the sources, quality and organization of transplant data available, as well as making observations about data reporting patterns and accuracy, we hope to improve understanding of ...existing results, help researchers with study design and stimulate new exploratory initiatives.
The primary data source, collected by the OPTN, has benefited from extensive recent technological advances. Transplant professionals now report patient and donor data more easily, quickly, and accurately, improving data timeliness and precision. Secondary sources may be incorporated, improving the accuracy and expanding the scope of analyses. For example, auxiliary mortality data allows more accurate survival analysis and conclusions regarding the completeness of center‐reported post‐transplant follow‐up. Furthermore, such sources enable examination of outcomes not reported by centers, such as mortality after waiting list removal, providing more appropriate comparisons of waiting list and post‐transplant mortality.
Complex collection and reporting processes require specific analytical methods and may lead to potential pitfalls. Patterns in the timing of reporting adverse events differ from those for ‘positive’ events, yielding the need for care in choosing cohorts and censor dates to avoid bias. These choices are further complicated by the use of multiple sources of data, with different time lags and reporting patterns.
Purpose
To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic ...shock.
Methods
Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay.
Results
From 2395 initially eligible abstracts, five randomised clinical trials (
n
= 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2 % 495/2134 versus control: 22.4 % 582/2601; pooled OR 1.01 95 % CI 0.88–1.16,
P
= 0.9, with heterogeneity
I
2
= 57 %;
P
= 0.055). The pooled estimate of 90-day mortality from the three recent multicentre studies (
n
= 4063) also showed no difference pooled OR 0.99 (95 % CI 0.86–1.15),
P
= 0.93 with no heterogeneity (
I
2
= 0.0 %;
P
= 0.97). EGDT increased vasopressor use (OR 1.25 95 % CI 1.10–1.41;
P
< 0.001) and ICU admission OR 2.19 (95 % CI 1.82–2.65);
P
< 0.001. Including six non-ED randomised trials increased heterogeneity (
I
2
= 71 %;
P
< 0.001) but did not change overall results pooled OR 0.94 (95 % CI 0.82 to 1.07);
P
= 0.33.
Conclusion
EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources.
Cyclohexanediones are one of four known structural classes of herbicides that inhibit graminaceous acetyl coenzyme-A carboxylase (ACCase; EC 6.4.1.2). Five monoclonal antibodies were raised against ...cyclohexanediones conjugated to bovine serum albumin. Cross-reactivity studies using a homologous competitive indirect enzyme-linked immunosorbent assay (ciELISA) against 24 cyclohexanedione analogues revealed that two monoclonal antibodies (mAb A and mAb B) could segregate the analogues into active and inactive ACCase inhibitors on the basis of the analogue concentration required to inhibit 50% of antibody binding to the coating conjugate (IC50). Both mAb A and mAb B were also found to cross-react with various members of the indolizidinedione structural class of ACCase inhibitors in ciELISA, suggesting that both cyclohexanediones and indolizidinediones possess features recognized by monoclonal antibodies important for the inhibition of ACCase activity. In conclusion, pharmacophore-specific antibodies may be potentially valuable screening tools for the identification of new lead chemistries in a pesticide discovery program. Keywords: Monoclonal; cyclohexanedione herbicides; ACCase
Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have ...identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.
Discrete sequence elements known as exonic splicing enhancers (ESEs) have been shown to influence both the efficiency of splicing and the profile of mature mRNAs in multicellular eukaryotes. While ...the existence of ESEs has not been demonstrated previously in unicellular eukaryotes, the factors known to recognize these elements and mediate their communication with the core splicing machinery are conserved and essential in the fission yeast Schizosaccharomyces pombe. Here, we provide evidence that ESE function is conserved through evolution by demonstrating that three exonic splicing enhancers derived from vertebrates (chicken ASLV, mouse IgM, and human cTNT) promote splicing of two distinct S. pombe pre-messenger RNAs (pre-mRNAs). Second, as in extracts from mammalian cells, ESE function in S. pombe is compromised by mutations and increased distance from the 3'-splice site. Third, three-hybrid analyses indicate that the essential SR (serine/arginine-rich) protein Srp2p, but not the dispensable Srp1p, binds specifically to both native and heterologous purine-rich elements; thus, Srp2p is the likely mediator of ESE function in fission yeast. Finally, we have identified five natural purine-rich elements from S. pombe that promote splicing of our reporter pre-mRNAs. Taken together, these results provide strong evidence that the genesis of ESE-mediated splicing occurred early in eukaryotic evolution.
Absorption of di- and tripeptides from the gastrointestinal tract is accepted as being an important biological phenomenon. The extent to which peptides axe absorbed and the nutritional and metabolic ...significance of peptide absorption remain unclear. Evidence is strong for the existence of multiple peptide transport systems, including one type that is electrogenic in nature and that requires a protonmotive force and cotransports two H+ for every peptide transported. The rate of absorption of peptides can be responsive to level of dietary intake and level of dietary protein. Peptide absorption seems to be an important physiological process in ruminants, and this process may account for a large portion of absorbed amino acids. An important new observation is that the nonmesenteric portion of the portal-drained viscera of the ruminant is a major site of peptide absorption. These new observations may result in a reshaping of the currently accepted theory concerning protein utilization by ruminants
To determine whether the up-regulation of chondrocyte tumor necrosis factor receptor (TNF-R) expression in osteoarthritis (OA) is due to molecules released within the OA knee joint.
Non-arthritic ...(NA) human articular chondrocytes were incubated with normal serum, OA synovial fluid, or supernatants from either cultured NA or OA synovium, and TNF-R expression measured by flow cytometry.
OA synovial fluid, but not normal serum, significantly up-regulated the proportion of chondrocytes expressing p55 TNF-R as well as the number of p55 TNF-R/chondrocyte. Similarly, supernatants from OA, but not NA, synovia significantly up-regulated chondrocyte p55 TNF-R expression. Chondrocyte p75 TNF-R expression was also significantly increased by some of the OA supernatants but not others, and overall no significant increase was seen. OA synovium supernatants contained higher concentrations of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) than NA synovium supernatants and neutralizing antibodies to these cytokines either partially or totally abrogated the ability of the OA supernatants to increase chondrocyte p55 TNF-R expression. Finally, various concentrations of recombinant human (rh)IL-1 beta and rhIL-6 up-regulated chondrocyte p55 TNF-R expression.
These results suggest that IL-1 and IL-6 produced by OA synovium contribute to the progression of the disease by rendering chondrocytes more susceptible to stimulation by catabolic cytokines.
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