Prognostic significance of nonfatal reinfarction during 3-year follow-up: Results of the thrombolysis in myocardial infarction (TIMI) phase II clinical trial

Objectives.This study sought to assess the independent contribution of nonfatal reinfarction to the risk of subsequent death in patients with acute myocardial infarction undergoing thrombolytic therapy.Background.A composite of “unsatisfactory outcomes” as an end point has increased statistical power and facilitated evaluation of evolving treatment regimens in acute myocardial infarction. The significance of nonfatal reinfarction as a component of a composite end point has not been evaluated in the thrombolytic era.Methods.Event rate of nonfatal reinfarction over 3-year follow-up was evaluated in patients with acute myocardial infarction entered into the Thrombolysis in Myocardial Infarction Phase II trial. The independent risk of nonfatal reinfarction for subsequent death within various time intervals of follow-up was determined. The mortality rate after nonfatal reinfarction was compared with that of a matched control group.Results.During 3-year follow-up, 349 of 3,339 patients had a nonfatal reinfarction. Univariate predictors were history (antedating the index event) of angina (p = 0.01), hypertension (p = 0.01), multivessel disease (p = 0.007) and not a current smoker (p = 0.003); the latter was an independent predictor (relative risk [RR] 1.3, 99% confidence interval [CI]1.0 to 1.8). Forty-three of the 349 patients with a nonfatal reinfarction died: RR for death (vs. patients without a nonfatal reinfarction) was 1.9 (99% CI 1.1 to 3.2) if reinfarction occurred within 42 days of study entry, 6.2 (99% CI 3.0 to 12.9) if reinfarction occurred between 43 and 365 days and 2.9 (99% CI 0.6 to 13.4) if reinfarction occurred between 366 days and 3 years. The cumulative 3-year death rate was 14.1% in patients with a nonfatal reinfarction compared with 7.9% (p < 0.01) in a matched control group. Univariate predictors of death after nonfatal reinfarction were age ≥65 years (p < 0.001), not low risk category (p = 0.015) and history of heart failure before the index event (p < 0.001). Age ≥65 years was the only independent predictor (RR 5.4, 99% CI 2.3 to 12.4).Conclusions.Nonfatal reinfarction is a strong and independent predictor for subsequent death. It represents a powerful component for a composite end point in patients who received thrombolytic therapy after acute myocardial infarction

Detecting coevolution without phylogenetic trees? Tree-ignorant metrics of coevolution perform as well as tree-aware metrics

<p>Abstract</p> <p>Background</p> <p>Identifying coevolving positions in protein sequences has myriad applications, ranging from understanding and predicting the structure of single molecules to generating proteome-wide predictions of interactions. Algorithms for detecting coevolving positions can be classified into two categories: tree-aware, which incorporate knowledge of phylogeny, and tree-ignorant, which do not. Tree-ignorant methods are frequently orders of magnitude faster, but are widely held to be insufficiently accurate because of a confounding of shared ancestry with coevolution. We conjectured that by using a null distribution that appropriately controls for the shared-ancestry signal, tree-ignorant methods would exhibit equivalent statistical power to tree-aware methods. Using a novel t-test transformation of coevolution metrics, we systematically compared four tree-aware and five tree-ignorant coevolution algorithms, applying them to myoglobin and myosin. We further considered the influence of sequence recoding using reduced-state amino acid alphabets, a common tactic employed in coevolutionary analyses to improve both statistical and computational performance.</p> <p>Results</p> <p>Consistent with our conjecture, the transformed tree-ignorant metrics (particularly Mutual Information) often outperformed the tree-aware metrics. Our examination of the effect of recoding suggested that charge-based alphabets were generally superior for identifying the stabilizing interactions in alpha helices. Performance was not always improved by recoding however, indicating that the choice of alphabet is critical.</p> <p>Conclusion</p> <p>The results suggest that t-test transformation of tree-ignorant metrics can be sufficient to control for patterns arising from shared ancestry.</p

Course-based Science Research Promotes Learning in Diverse Students at Diverse Institutions

Course-based research experiences (CREs) are powerful strategies for spreading learning and improving persistence for all students, both science majors and nonscience majors. Here we address the crucial components of CREs (context, discovery, ownership, iteration, communication, presentation) found across a broad range of such courses at a variety of academic institutions. We also address how the design of a CRE should vary according to the background of student participants; no single CRE format is perfect. We provide a framework for implementing CREs across multiple institutional types and several disciplines throughout the typical four years of undergraduate work, designed to a variety of student backgrounds. Our experiences implementing CREs also provide guidance on overcoming barriers to their implementation

Pharmacokinetic Properties of Single- and Repeated-dose Sufentanil Sublingual Tablets in Healthy Volunteers

AbstractPurposeSufentanil is a μ-opioid agonist with a high therapeutic index in preclinical studies and no active metabolites, and it is highly lipophilic, thereby enabling a transmucosal route of administration. Rapid distribution from the plasma after IV sufentanil administration results in a short duration of action requiring excessive repeated dosing if used for postoperative analgesia. The sufentanil sublingual tablet system (SSTS) is a handheld, preprogrammed, patient-controlled analgesia system designed to allow patients to self-administer sufentanil 15-μg tablets under their tongue with a 20-minute lockout. The pharmacokinetic (PK) characteristics of sufentanil, administered by different routes of delivery and after single and repeated sublingual (SL) administration, were examined in 2 studies.MethodsA randomized, open-label, crossover study in healthy subjects evaluated the PK profile of sufentanil 15 μg administered by different routes: IV, SL, buccal (BU), and PO. A second open-label, crossover study in healthy subjects evaluated the PK parameters after single and repeated doses (full SSTS drug cartridge of 40 consecutive SL doses administered every 20 minutes) of a sufentanil 15-μg SL tablet. Doses were self-administered using the SSTS.FindingsIn the route of administration study (n = 25), mean Cmax values were highest with IV administration, and bioavailability values were: SL, 59%; BU, 78%; and PO, 9%. The absorption across the oral mucosa was associated with a median plasma half-time (time from Cmax to 50% of Cmax) that was 25-fold longer (2.5 hours) with SL versus IV administration (0.1 hours). In the single- and repeated-dose study (n = 38), mean AUC0–∞ was 125.5 h · pg/mL, and Cmax was 35.0 pg/mL, with a median Tmax of 0.8 hours after the administration of a single sufentanil SL tablet. With 40 consecutive doses, Cmax was 8-fold higher compared with that of a single dose, and steady state was achieved after the 13th dose. Median plasma half-time after the 40th dose was not statistically longer than that after a single dose (2.7 vs 2.2 hours, respectively), and the median Tmax was 0.3 hours after the last repeated dose.ImplicationsThese study results support the viability of the SSTS for use in patient-controlled analgesia. The wide range of mean drug concentrations achieved after repeated dosing at 20-minute intervals compared with those with a single dose suggests the flexibility of patient-controlled dosing to meet individual analgesic requirements. The prolonged plasma half-time with SL administration is expected to provide a more appropriate duration of analgesia compared with that of IV administration, and the PK properties of repeated-dose administration support a 20-minute lockout interval

The Four Distal Tyrosines Are Required for LAT-dependent Signaling in FcɛRI-mediated Mast Cell Activation

The linker for activation of T cells (LAT) is an adaptor protein critical for FcɛRI-mediated mast cell activation. LAT is a substrate of the tyrosine kinases activated after TCR and FcɛRI engagement. After phosphorylation of the cytosolic domain of LAT, multiple signaling molecules such as phospholipase C–γ1, Grb2, and Gads associate with phosphorylated LAT via their SH2 domains. The essential role of the four distal tyrosines in TCR-mediated signaling and T cell development has been demonstrated by experiments using LAT-deficient cell lines and genetically modified mice. To investigate the role of these four tyrosines of LAT in FcɛRI-mediated mast cell activation, bone marrow–derived mast cells from LAT-deficient mice were infected with retroviral vectors designed to express wild-type or mutant LAT. Examination of bone marrow–derived mast cells expressing various tyrosine to phenylalanine mutants in LAT demonstrates a differential requirement for these different binding sites. In these studies, assays of biochemical pathways, degranulation, and cytokine and chemokine release were performed. Finally, the role of these tyrosines was also evaluated in vivo using genetically modified animals. Deletion of all four distal tyrosines, and in particular, loss of the primary phospholipase C–γ-binding tyrosine had a significant effect on antigen-induced histamine release

Combining genomics and epidemiology to track mumps virus transmission in the United States.

Unusually large outbreaks of mumps across the United States in 2016 and 2017 raised questions about the extent of mumps circulation and the relationship between these and prior outbreaks. We paired epidemiological data from public health investigations with analysis of mumps virus whole genome sequences from 201 infected individuals, focusing on Massachusetts university communities. Our analysis suggests continuous, undetected circulation of mumps locally and nationally, including multiple independent introductions into Massachusetts and into individual communities. Despite the presence of these multiple mumps virus lineages, the genomic data show that one lineage has dominated in the US since at least 2006. Widespread transmission was surprising given high vaccination rates, but we found no genetic evidence that variants arising during this outbreak contributed to vaccine escape. Viral genomic data allowed us to reconstruct mumps transmission links not evident from epidemiological data or standard single-gene surveillance efforts and also revealed connections between apparently unrelated mumps outbreaks

Glubodies: randomized libraries of glutathione transferase enzymes

AbstractBackground: The immunoglobulin framework has been mutagenized to engineer recombinant libraries of proteins as potential diagnostics and novel catalysts, although the often shallow binding cleft may limit the utility of this framework for binding diverse small organic molecules. By contrast, the glutathione S-transferase (GST) family of enzymes contains a deep binding cleft, which has evolved to accommodate a broad range of hydrophobic xenobiotics. We set out to determine whether GST molecules with novel ligand-binding characteristics could be produced by random mutagenesis of segments of the binding cleft.Results: We have identified two ligand-recognition segments (LRSs) in human GST P1, which are near the active site in the folded protein, but have characteristics indicating that the integrity of their sequence is not essential for the overall structure or activity of the protein. Libraries of GST P1-derived proteins were produced by substituting randomized sequences for an LRS or inserting random sequences into an LRS. The recombinant proteins in the libraries, collectively designated as ‘glubodies,’ generally retain enzymatic activity but differ markedly both from each other and from the parent enzyme in sensitivity to inhibition by diverse small organic compounds. In some instances, a glubody is inhibited by completely novel structures.Conclusions: We have shown that a non-antibody framework can be used to create large libraries of proteins with a wide range of binding specificities for small organic molecules. The glubodies provide a rich source of data for correlating the structural and functional features of proteins relevant to ligand binding. The criteria applied for identifying an LRS in GST P1 are generally applicable to other protein frameworks

Somatic Symptoms Among US Adolescent Females: Associations with Sexual and Physical Violence Exposure

To examine the association between physical and sexual violence exposure and somatic symptoms among female adolescents