Search

Many advances in health care fail to reach patients. Implementation science is the study of novel approaches to mitigate this evidence-to-practice gap.The American Thoracic Society (ATS) created a multidisciplinary ad hoc committee to develop a research statement on implementation science in pulmonary, critical care, and sleep medicine. The committee used an iterative consensus process to define implementation science and review the use of conceptual frameworks to guide implementation science for the pulmonary, critical care, and sleep community and to explore how professional medical societies such as the ATS can promote implementation science.The committee defined implementation science as the study of the mechanisms by which effective health care interventions are either adopted or not adopted in clinical and community settings. The committee also distinguished implementation science from the act of implementation. Ideally, implementation science should include early and continuous stakeholder involvement and the use of conceptual frameworks (i.e., models to systematize the conduct of studies and standardize the communication of findings). Multiple conceptual frameworks are available, and we suggest the selection of one or more frameworks on the basis of the specific research question and setting. Professional medical societies such as the ATS can have an important role in promoting implementation science. Recommendations for professional societies to consider include: unifying implementation science activities through a single organizational structure, linking front-line clinicians with implementation scientists, seeking collaborations to prioritize and conduct implementation science studies, supporting implementation science projects through funding opportunities, working with research funding bodies to set the research agenda in the field, collaborating with external bodies responsible for health care delivery, disseminating results of implementation science through scientific journals and conferences, and teaching the next generation about implementation science through courses and other media.Implementation science plays an increasingly important role in health care. Through support of implementation science, the ATS and other professional medical societies can work with other stakeholders to lead this effort.

More than 1.5 million adults in the United States use supplemental oxygen for a variety of respiratory disorders to improve their quality of life and prolong survival. This document describes recommendations from a multidisciplinary workshop convened at the ATS International Conference in 2017 with the goal of optimizing home oxygen therapy for adults. Ideal supplemental oxygen therapy is patient-specific, provided by a qualified clinician, includes an individualized prescription and therapeutic education program, and offers oxygen systems that are safe, promote mobility, and treat hypoxemia. Recently, patients and clinicians report a growing number of problems with home oxygen in the United States. Oxygen users experience significant functional, mechanical, and financial problems and a lack of education related to their oxygen equipment-problems that impact their quality of life. Health care providers report a lack of readily accessible resources needed to prescribe oxygen systems correctly and efficiently. Patients with certain lung diseases are affected more than others because of physically unmanageable or inadequate portable systems. Analysis is needed to quantify the unintended impact that the Centers for Medicare and Medicaid Services Competitive Bidding Program has had on patients receiving supplemental oxygen from durable medical equipment providers. Studies using effectiveness and implementation research designs are needed to develop and evaluate new models for patient education, identify effective ways for stakeholders to interface, determine the economic benefit of having respiratory therapists perform in-home education and follow-up testing, and collaborate with technology companies to improve portable oxygen devices. Generation of additional evidence of the benefit of supplemental oxygen across the spectrum of advanced lung diseases and the development of clinical practice guidelines should both be prioritized.

Active-learning pedagogies have been repeatedly demonstrated to produce superior learning gains with large effect sizes compared with lecture-based pedagogies. Shifting large numbers of college science, technology, engineering, and mathematics (STEM) faculty to include any active learning in their teaching may retain and more effectively educate far more students than having a few faculty completely transform their teaching, but the extent to which STEM faculty are changing their teaching methods is unclear. Here, we describe the development and application of the machine-learning-derived algorithm Decibel Analysis for Research in Teaching (DART), which can analyze thousands of hours of STEM course audio recordings quickly, with minimal costs, and without need for human observers. DART analyzes the volume and variance of classroom recordings to predict the quantity of time spent on single voice (e.g., lecture), multiple voice (e.g., pair discussion), and no voice (e.g., clicker question thinking) activities. Applying DART to 1,486 recordings of class sessions from 67 courses, a total of 1,720 h of audio, revealed varied patterns of lecture (single voice) and nonlecture activity (multiple and no voice) use. We also found that there was significantly more use of multiple and no voice strategies in courses for STEM majors compared with courses for non-STEM majors, indicating that DART can be used to compare teaching strategies in different types of courses. Therefore, DART has the potential to systematically inventory the presence of active learning with ∼90% accuracy across thousands of courses in diverse settings with minimal effort.

Instructor Talk—noncontent language used by instructors in classrooms—is a recently defined and promising variable for better understanding classroom dynamics. Having previously characterized the Instructor Talk framework within the context of a single course, we present here our results surrounding the applicability of the Instructor Talk framework to noncontent language used by instructors in novel course contexts. We analyzed Instructor Talk in eight additional biology courses in their entirety and in 61 biology courses using an emergent sampling strategy. We observed widespread use of Instructor Talk with variation in the amount and category type used. The vast majority of Instructor Talk could be characterized using the originally published Instructor Talk framework, suggesting the robustness of this framework. Additionally, a new form of Instructor Talk—Negatively Phrased Instructor Talk, language that may discourage students or distract from the learning process—was detected in these novel course contexts. Finally, the emergent sampling strategy described here may allow investigation of Instructor Talk in even larger numbers of courses across institutions and disciplines. Given its widespread use, potential influence on students in learning environments, and ability to be sampled, Instructor Talk may be a key variable to consider in future research on teaching and learning in higher education.

The unusual base-induced ring-enlargement of halomethylenecyclobutanes to 1-halocyclopentenes was examined with unsymmetrical and (13)C-labeled substrates to study regio- and stereochemical characteristics. Migration of a ring carbon atom (single migration) or simultaneous migration of a ring carbon atom and the halide (double migration) gives the ring-enlarged products. (13)C-labeling experiments established that both rearrangements occur with retention of configuration at the migrating center. These systems are suggested as models for the Fritsch-Buttenberg-Wiechell (FBW) rearrangement.

The synthesis of a simple analogue of salicylihalamide A with a truncated lactone ring (+/- 2) was achieved in 10 steps. Its cytotoxicity profile in the NCI 60-cell-line human tumor assay differed significantly from that of salicylihalamide A in both level and specificity.

A new proline-rich cyclodecapeptide, designated stylopeptide 2, has been isolated from a cytotoxic extract of the Papua New Guinea marine sponge Stylotella sp. and found to correspond to structure 1. The structural assignment was based on HRMS collision-induced dissociation tandem mass spectrometry (CID MS/MS), NMR spectroscopic data, and amino acid analysis, which led to assignment of the absolute configuration.

Clavosolides A-D (1-4), dimeric macrolides incorporating cyclopropyl, tetrahydropyranyl, and glycosidic ring systems, were isolated from the cytotoxic extract of a Philippines collection of the marine sponge Myriastra clavosa. The structures of the clavosolides, which occurred as only trace metabolites, were elucidated through extensive NMR spectroscopic analyses. Clavosolides A (1) and B (2) were recently reported metabolites from M. clavosa, while the unsymmetrical dimers clavosolides C (3) and D (4) had new structures.

Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E’s more specific mechanism of action suggests minimal toxic side effects.

The carbanionic ring enlargement of (halomethylene)cyclobutanes to 1-halocyclopentenes has been extended to the fluoro analogues. At 180 °C, 3-hexyl-1-(fluoromethylene)cyclobutane provides better yields of rearranged product than the corresponding chloride, bromide, or iodide. At temperatures Br > Cl, and the fluoride does not react. Experiments with labeled substrates show that, in general, the larger the halide and the higher the reaction temperature, the greater the preference for double migration over single migration as a mechanistic pathway. The trifluormethyl group is ineffective in promoting anionic rearrangement.

A sevised regiochemistry and the absolute configuration are established for cartilagineol (formerly allo-isoobtusol). This revised structure renders cartilagineol the first example of the fourth stereochemical type of Laurencia-derived polyhalogenated chamigrene in support of current biogenetic theory. Earlier misassigned NMR data for ma'ilione is corrected.

Summary Rottnestol, a new hemiketal, was isolated from an Australian collection of the marine sponge Haliclona sp. Its structure was deduced as 3 from 1H, 13C, COSY, HMQC, HMBC and nOe NMR studies. Hemiketal 3 was readily converted to its epimer, 4, and the methyl ketal of 4.

A sevised regiochemistry and the absolute configuration are established for cartilagineol (formerly allo-isoobtusol). This revised structure renders cartilagineol the first example of the fourth stereochemical type of Laurencia-derived polyhalogenated chamigrene in support of current biogenetic theory. Earlier misassigned NMR data for ma'ilione is corrected.

A new cell growth inhibitory (P388 lymphocytic leukemia ED 50 0.8 μg/mL) cycloheptapeptide designated stylostatin 1 (1) has been isolated from the south Pacific Ocean sponge Stylotella aurantium Kelly-Borges and Bergquist. Structural determination was accomplished primarily by utilizing high-field 1 H-NMR (500 MHz) with appropriate 2D-NMR experiments and was confirmed by X-ray crystallographic analysis. The absolute configuration (established by chiral gas chromatographic analysis) and crystal structure conformation (with hydrogen bonding) for stylostatin 1 (1) were determined

Withanolide E (WE), a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to TRAIL-mediated apoptosis. WE, the most potent and least toxic of 5 TRAIL sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling via a rapid decline in the levels of both cFLIPL and cFLIPS proteins. Normal non-transformed human renal epithelial cells were completely resistant to the WE plus TRAIL combination. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in various pro-and anti-apoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIPL and cFLIPS was predominantly due to destabilization and/or aggregation of the proteins subsequently leading to their proteasomal degradation. Since cFLIPL and cFLIPS are reported to be HSP90 client proteins, and WE can inhibit HSP90 activity, the effect of WE on various other HSP90 client proteins was assessed. WE treatment of ACHN renal carcinoma cells altered the stability of a limited number of HSP90 client proteins when compared to the well-known HSP90 inhibitor geldanamycin. The destabilization of cFLIP proteins provides a potentially novel mechanism for sensitizing cancer cells to TRAIL mediated apoptosis. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by WE and its lack of toxicity were confirmed in animal studies, in which a combination treatment of WE with an agonist antibody to TRAIL death receptor 5 (DR5) provided a significant therapeutic benefit compared to either agent alone in a renal cancer xenograft model. Due to its novel activity, WE is a promising reagent for analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. Various structural analogs of WE are currently being tested for their TRAIL-sensitizing activity to provide more insight into Structure Activity Relationships (SAR) for these compounds. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, WE's more specific mechanism of action suggests minimal toxic side effects might accompany its combination with TRAIL death receptor agonists for cancer therapy. Citation Format: Brooks D. Alan, Curtis J. Henrich, Karen L. Erickson, Cheryl L. Thomas, Heidi R. Bokesch, Poonam Tewary, Candace R. Thompson, Richard J. Pompei, Kirk R. Gustafson, James B. McMahon, Thomas J. Sayers. Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2928. doi:10.1158/1538-7445.AM2015-2928

Chemical investigation of the Philippines marine sponge Myriastra clavosa has resulted in the isolation of three new cyclic octapeptides, myriastramides A ( 1 ), B ( 2 ), and C ( 3 ). The structures of compounds 1–3 were assigned based on extensive NMR spectroscopic analyses and a series of degradation and derivatization studies.

CD2 is a pan-T cell marker, while CD19 and CD21 are important molecules in signal transduction of B lymphocytes. CD19 and CD21 are both present on mature B cells, while CD19 is also present in developing B cells and plasma cells. Monoclonal antibodies (mAbs) against cetacean lymphocyte putative homologues to CD2 (two different antibodies), CD19 and CD21 were characterized. The proteins immunoprecipitated were as follows: F21.I (putative anti-CD2), 43 and 59 kDa; F21.B (putative anti-CD19), 83 and 127 kDa; F21.F (putative anti-CD21), 144 kDa. The second putative anti-CD2 (F21.C) selectively inhibited the binding of F21.I. Both the putative anti-CD2 (T cell markers) stained T-cell zones on lymph node sections, while both the B cell markers (putative CD19 and CD21) stained B-cell zones. F21.B and F21.F were absent from thymus single cell suspension but labeled 63 and 65% mesenteric lymph node lymphocytes, respectively, while both F21.C and F21.F were present on 100% thymocytes and fewer lymph node lymphocytes. B and T cell markers were mutually exclusive on double labeling using flow cytometry. These mAbs are foreseen as possible valuable diagnostic and research tools to assess immune functions of captive and wild cetaceans.

Two novel, highly potent, cytotoxic macrolides, salicylihalamides A (1) and B (2), were isolated from the sponge Haliclona sp. This new macrolide class incorporates salicylic acid, a 12-membered lactone ring, and an enamide side chain. COMPARE pattern-recognition analyses of the NCI 60-cell mean graph screening profiles of 1 did not reveal any significant correlations to the profiles of known antitumor compounds in the NCI's “standard agent database”, thus supporting the conclusion that the salicylihalamides represent a potentially important new class for antitumor lead optimization and in vivo investigations.

A cyclic depsipeptide, georgamide (1), was isolated from an Australian cyanobacterium and characterized by spectroscopic means. The constituent units were five amino acid residues, one each of L-Thr, L-Pro, L-Val, N-Me-L-Val, and N-Me-L-Phe, and two hydroxy carboxylic acids, 2(S)-hydroxy-3(R)-methylpentanoic acid and the unusual 2,2-dimethyl-3-hydroxy-7-octynoic acid. The stereochemistry was determined by hydrolysis of the peptide followed by derivatization and HPLC comparison with standard samples.

Several new compounds were isolated from the organic extract of the cyanobacterium Microcoleus lyngbyaceus, and their structures were determined by spectroscopic means. Polychlorinated acetamidoalkynes and alkanes were the major metabolites. 6-Acetamido-1,1,1-trichloroundecane, a positional isomer of the naturally occurring 5-acetamido-1,1,1-trichloroundecane, was synthesized in six steps from delta-decanolactone.

Serinol derivatives 4a and 4b were isolated from an Australian blue-green alga and characterized by spectroscopic means. Their absolute stereochemistry was established by chemical methods.

The yellow pigment observed in older axanthic (ax/ax) mutant Mexican axolotls (Ambystoma mexicanum) was analyzed by thin layer chromatography and by spectrofluorometry of its acetyl derivative. Ethanol extracts from the skin of axanthic animals were acetylated and the chloroform-soluble portion of the product mixture was compared with a chloroform solution of an authentic riboflavin tetraacetate standard prepared in the same manner. The pigment in these two solutions behaved identically on thin layer chromatograms and in fluorescent emission spectroscopy. This confirms that the yellow pigment seen in these genetically axanthic animals is riboflavin and, since it cannot be synthesized by the animal, must be derived from the diet.

Seven new sesquiterpenes, majapolenes A [1] and B [2], majapolone [3], and majapols A [4], B [5], C [6], and D [7], were isolated from a Philippine collection of Laurencia majuscula. With the exception of majapolene B [2], all compounds were isolated as inseparable diastereomeric mixtures. Structure elucidation was achieved by spectroscopic methods. Majapolene A [1], a dioxabicyclo[2.2.2]-alkene, displayed modest activity in the NCI 60-cell line cytotoxicity screen. Majapolene A was also found as a major component of a Philippine collection of Laurencia caraibica.

The novel phorbol ester 12-deoxyphorbol 13-(3E,5E-decadienoate) [1] was isolated as the anti-HIV principle of Excoecaria agallocha leaves and stems collected in northwest Australia. The structure was determined by spectral means. Compound 1 was also a potent displacer of [3H]-phorbol dibutyrate from rat brain membranes.

Two in vitro functional assays were developed to evaluate mitogen-induced responses of peripheral blood mononuclear leukocytes (PBML) from free-ranging harbor seals, Phoca vitulina. Lymphocyte proliferation was measured by a standard blastogenesis assay following optimization of culture conditions including mitogen concentration, cell density, and incubation time. These optimized parameters, with the exception of incubation time, were subsequently employed to measure lymphocyte activation by analytical flow cytometry using fluorochrome-based identification of cell surface interleukin-2 receptor (IL-2r) expression. Baseline values established for free-ranging harbor seals had extensive animal variability; there was evidence that the samples were derived from a group of animals with a normal distribution. Positive correlations were observed between blastogenesis assays, and between blastogenesis and activation assays, when using pokeweed or concanavalin A as the stimulus. However, no relationship was found in the expression of the IL-2r induced by these mitogens. This result supports the contention that the two mitogens stimulate different lymphocyte subpopulations. This was observed only with the IL-2r expression assay because of its unique ability to measure the number of T lymphocytes initially activated rather than the ultimate number of progeny cells identified by blastogenesis. Both assays, used concurrently, should provide a more comprehensive representation of lymphocyte competence and serve as a measure of animal health.

Kahukuenes A [4] and B [5], new diterpenoids possessing an unprecedented prenylated chamigrene structure as part of a decalin ring, were isolated from the Hawaiian marine alga Laurencia majuscula. Spectroscopic methods, including extensive 1D and 2D nmr studies, were used to establish the structure and relative stereochemistry of these two secondary metabolites.

A new cytotoxic tribrominated chamigrene with a dibromohydrin functionality was isolated from an undetermined species of red alga, Laurencia sp. Its structure was determined by spectroscopic methods.

The syn and anti stereoisomers of 3-ethoxy-2-methyl-2-vinylcyclobutanone were prepared. Reinterpretation of the literature 13C spectra led to an inversion of the original structure assignments. Confirmation of relative stereochemistry was provided by NOE difference experiments. Copyright © 2001 John Wiley & Sons, Ltd.

An procedure that uses smaller volumes of "safer" solvents in performing the extraction and allows the use of simultaneous spectrophotometric analysis in the determination.

The prototypic kappa opiate ketocyclazocine produced robust analgesia in 10-day-old rats in the tail-flick nociceptive test. The kappa-opiate behavioral response coincided with the onset of a rapid rise to adult levels in brain kappa receptor site density. In contrast, morphine (prototypic mu opiate) was without marked effect until 14 days of age. The period of rapid mu receptor increase did not take place until days 14-16, which was after kappa receptor levels had already plateaued. Further, there was no or incomplete cross-tolerance between ketocyclazocine and morphine at 14 days of age. The present study, therefore, establishes a role for the kappa binding site in thermal analgesia in the tail flick test and differentiates its ontogenetic pattern from that of the mu receptor.

Two new sesquiterpenoid metabolites have been characterized from a Jamaican variety of the marine alga Laurencia obtusa. These are 2-chloro-3-hydroxy-α-chamigren-9-one, with an unusual cis-relationship of the heteroatoms at the 2,3-positions, and its intramolecular conjugate addition derivative possessing a cineole moiety fused to a cyclohexane ring.

Enyne 1 was isolated from the marine red alga Laurencia majuscula , and its structure was elucidated by spectroscopic means. 1 is the first 2,2′- bis -tetrahydrofuran lauroxane to be found as a Laurencia metabolite.

3-(13-Methylhexadecyloxy)-1,2-(S)-propanediol ( 6 ) and 3-(15-methyloctadecyloxy)-1,2-(S)-propanediol ( 7 ) were isolated from an Aaptos species of marine sponge from Taiwanese waters and characterized by spectroscopic methods. Homolog 6 was independently synthesized.

Possible mechanisms by which the C2-unit of the tryptamine bridge of condylocarpine-type alkaloids can be lost to give the uleine skeleton are considered. A terminally-oxidized β-C2 substituent on an α-methyleneindoline system could not be cleaved, but a β-C3 acid unit fragmented readily.