Abstract Purpose Within a multicenter randomized trial comparing protocolized sedation with protocolized sedation plus daily interruption (DI), we sought perspectives of intensive care unit (ICU) ...clinicians regarding each strategy. Methods At 5 ICUs, we administered a questionnaire daily to nurses and physicians, asking whether they liked using the assigned strategy, reasons for their responses, and concerns regarding DI. Results A total of 301 questionnaires were completed, for 31 patients (15 protocol only and 16 DI); 117 (59 physicians and 58 nurses) were the first questionnaire completed by that health care provider for that patient and were included in analyses. Most respondents liked using the assigned strategy (81% protocol only and 81% DI); more physicians than nurses liked DI (100% vs 61%; P < .001). Most common reasons for liking the assigned sedation strategy were better neurologic assessment (70% DI), ease of use (58% protocol only), and improved patient outcomes (51% protocol only and 44% DI). Only 19% of clinicians disliked the assigned sedation strategy (equal numbers for protocol only and DI). Respondents' concerns during DI were respiratory compromise (61%), pain (48%), agitation (45%), and device removal (26%). More questionnaires from nurses than physicians expressed concerns about DI. Conclusions Most respondents liked both sedation strategies. Nurses and physicians had different preferences and rationales for liking or disliking each strategy.
FoundationOne®CDx (F1CDx) is a United States (US) Food and Drug Administration (FDA)-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the ...approved therapeutic product labeling for 28 drug therapies. F1CDx utilizes next-generation sequencing (NGS)-based comprehensive genomic profiling (CGP) technology to examine 324 cancer genes in solid tumors. F1CDx reports known and likely pathogenic short variants (SVs), copy number alterations (CNAs), and select rearrangements, as well as complex biomarkers including tumor mutational burden (TMB) and microsatellite instability (MSI), in addition to genomic loss of heterozygosity (gLOH) in ovarian cancer. CGP services can reduce the complexity of biomarker testing, enabling precision medicine to improve treatment decision-making and outcomes for cancer patients, but only if test results are reliable, accurate, and validated clinically and analytically to the highest standard available. The analyses presented herein demonstrate the extensive analytical and clinical validation supporting the F1CDx initial and subsequent FDA approvals to ensure high sensitivity, specificity, and reliability of the data reported. The analytical validation included several in-depth evaluations of F1CDx assay performance including limit of detection (LoD), limit of blank (LoB), precision, and orthogonal concordance for SVs (including base substitutions SUBs and insertions/deletions INDELs), CNAs (including amplifications and homozygous deletions), genomic rearrangements, and select complex biomarkers. The assay validation of >30,000 test results comprises a considerable and increasing body of evidence that supports the clinical utility of F1CDx to match patients with solid tumors to targeted therapies or immunotherapies based on their tumor's genomic alterations and biomarkers. F1CDx meets the clinical needs of providers and patients to receive guideline-based biomarker testing, helping them keep pace with a rapidly evolving field of medicine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
493.
Life as a Process Dean C. T. Hurst
Bios (Madison, N.J.),
03/1945, Letnik:
16, Številka:
1
Journal Article
Recent years have seen increased interest in phylogenetic comparative analyses of multivariate data sets, but to date the varied proposed approaches have not been extensively examined. Here we review ...the mathematical properties required of any multivariate method, and specifically evaluate existing multivariate phylogenetic comparative methods in this context. Phylogenetic comparative methods based on the full multivariate likelihood are robust to levels of covariation among trait dimensions and are insensitive to the orientation of the data set, but display increasing model misspecification as the number of trait dimensions increases. This is because the expected evolutionary covariance matrix (V) used in the likelihood calculations becomes more ill-conditioned as trait dimensionality increases, and as evolutionary models become more complex. Thus, these approaches are only appropriate for data sets with few traits and many species. Methods that summarize patterns across trait dimensions treated separately (e.g., SURFACE) incorrectly assume independence among trait dimensions, resulting in nearly a 100% model misspecification rate. Methods using pairwise composite likelihood are highly sensitive to levels of trait covariation, the orientation of the data set, and the number of trait dimensions. The consequences of these debilitating deficiencies are that a user can arrive at differing statistical conclusions, and therefore biological inferences, simply from a dataspace rotation, like principal component analysis. By contrast, algebraic generalizations of the standard phylogenetic comparative toolkit that use the trace of covariance matrices are insensitive to levels of trait covariation, the number of trait dimensions, and the orientation of the data set. Further, when appropriate permutation tests are used, these approaches display acceptable Type I error and statistical power. We conclude that methods summarizing information across trait dimensions, as well as pairwise composite likelihood methods should be avoided, whereas algebraic generalizations of the phylogenetic comparative toolkit provide a useful means of assessing macroevolutionary patterns in multivariate data. Finally, we discuss areas in which multivariate phylogenetic comparative methods are still in need of future development; namely highly multivariate Ornstein–Uhlenbeck models and approaches for multivariate evolutionary model comparisons.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ascertainment of adrenal function assessing free rather that total cortisol may be beneficial for the diagnosis of critical illness-related cortisol insufficiency. We hypothesized that centrifugal ...ultrafiltration would provide timely free cortisol data that highly correlated with the gold standard, but logistically cumbersome, equilibrium dialysis technique when the free cortisol fractions were identically quantified by chemiluminescence immunoassay. We also hypothesized that free cortisol would correlate with illness severity in a large cohort of critically ill children.
Prospective, multi-institutional, observational cohort investigation.
Seven pediatric intensive care units within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.
One hundred sixty-five critically ill children across the spectrum of illness severity.
Blood sampling.
Time to derive plasma free cortisol concentrations after centrifugal ultrafiltration or equilibrium dialysis fractionation with chemiluminescence immunoassay was approximately 2 vs. approximately 24 hrs, respectively. Using centrifugal ultrafiltration, mean plasma free cortisol was 4.1 ± 6.7 μg/dL (median, 1.6 μg/dL; range, 0.2-43.6 μg/L), representing an average of 15.2 ± 9.4% of total cortisol. Nearly 60% of subjects exhibited free cortisol <2 and 30% <0.8 μg/dL, previously suggested threshold concentrations for defining critical illness-related cortisol insufficiency. Plasma-free cortisol concentrations comparing centrifugal ultrafiltration vs. equilibrium dialysis fractionation demonstrated a strong correlation (R2 = 0.97). For free cortisol <2 μg/dL, Bland-Altman analysis revealed minimal negative bias for the centrifugal ultrafiltration technique. Illness severity assessed by Pediatric Risk of Mortality III correlated moderately with free cortisol and percent total cortisol as free cortisol.
Determination of centrifugal ultrafiltration fractionated free cortisol was fast and results correlated highly with equilibrium dialysis fractionated free cortisol. Many children exhibited free cortisol <2 and <0.8 μg/dL but did not demonstrate clinical evidence of critical illness-related cortisol insufficiency. This study ascertains that real-time free cortisol quantification is feasible to potentially help guide clinical decision-making for cortisol replacement therapy in the pediatric intensive care unit.
Compared with thermoplastic polymers, thermoset polymers are difficult to recycle because they can not be remolded once cured and often do not decompose under mild conditions. Thermosets designed to ...be degradable afford a useful route to obtain thermoset recyclability and enable the recycling of valuable components that may be encapsulated in thermoset materials. In this review, the need for degradable thermosets as well as a summary of research progress is presented. Degradable thermosets are divided into different categories based on the different labile bonds or linkages studied such as esters, sulfur containing linkages (disulfide, sulfonate, 5-membered cyclic dithiocarbonate, trithiocarbonate, sulfite), nitrogen containing structures (acylhydrazone, alkoxyamine, azlactones, Schiff base, hindered ureas, aminal, carbamate), orthoester structures, carbonates, acetals, hemiacetals, olefinic bonds, D-A addition structures, vicinal tricarbonyl structures, peroxide bonds, phosphorus containing structures, tertiary ether bonds, and so on. The synthetic route, recycling methods, degradation mechanisms and progress in research of each approach to degradable thermosets is described. The efforts of the applicability of some degradable thermosets are also summarized. Finally, conclusions and trends of future work are highlighted.
Since its discovery in 1972 (ref. 1), the cranium KNM-ER 1470 has been at the centre of the debate over the number of species of early Homo present in the early Pleistocene epoch of eastern Africa. ...KNM-ER 1470 stands out among other specimens attributed to early Homo because of its larger size, and its flat and subnasally orthognathic face with anteriorly placed maxillary zygomatic roots. This singular morphology and the incomplete preservation of the fossil have led to different views as to whether KNM-ER 1470 can be accommodated within a single species of early Homo that is highly variable because of sexual, geographical and temporal factors, or whether it provides evidence of species diversity marked by differences in cranial size and facial or masticatory adaptation. Here we report on three newly discovered fossils, aged between 1.78 and 1.95 million years (Myr) old, that clarify the anatomy and taxonomic status of KNM-ER 1470. KNM-ER 62000, a well-preserved face of a late juvenile hominin, closely resembles KNM-ER 1470 but is notably smaller. It preserves previously unknown morphology, including moderately sized, mesiodistally long postcanine teeth. The nearly complete mandible KNM-ER 60000 and mandibular fragment KNM-ER 62003 have a dental arcade that is short anteroposteriorly and flat across the front, with small incisors; these features are consistent with the arcade morphology of KNM-ER 1470 and KNM-ER 62000. The new fossils confirm the presence of two contemporary species of early Homo, in addition to Homo erectus, in the early Pleistocene of eastern Africa.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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