Agreement between Youth Self-Report and Biospecimen-Confirmed Substance Use: A Systematic Review.

ContextBiospecimen analysis may enhance confidence in the accuracy of self-reported substance use among adolescents and transitional age youth (TAY). Associations between biospecimen types and self-reported use, however, are poorly characterized in the existing literature. Objective: We performed a systematic review of associations between biospecimen-confirmed and self-reported substance use. Data sources: PubMed, Embase, and Web of Science. Study selection: We included studies documenting associations between self-reported and biospecimen-confirmed substance use among adolescents (12-18 years) and TAY (19-26 years) published 1990-2020. Data extraction: Three authors extracted relevant data using a template and assessed bias risk using a modified JBI Critical Appraisal Tool. Results: We screened 1523 titles and abstracts, evaluated 73 full texts for eligibility, and included 28 studies. Most studies examined urine (71.4%) and hair (32.1%) samples. Self-report retrospective recall period varied from past 24 h to lifetime use. Agreement between self-report and biospecimen results were low to moderate and were higher with rapidly metabolized substances (e.g., amphetamines) and when shorter retrospective recall periods were applied. Frequently encountered sources of potential bias included use of non-validated self-report measures and failure to account for confounding factors in the association between self-reported and biospecimen-confirmed use. Limitations: Study heterogeneity prevented a quantitative meta-analysis. Studies varied in retrospective recall periods, biospecimen processing, and use of validated self-report measures. Conclusions: Associations between self-reported and biospecimen-confirmed substance use are low to moderate and are higher for shorter recall periods and for substances with rapid metabolism. Future studies should employ validated self-report measures and include demographically diverse samples.

Greenhouse gas fluxes from turfgrass systems: Species, growth rate, clipping management, and environmental effects.

Turfgrass systems can be an important source or sink for greenhouse gases (GHG), including carbon dioxide (CO2 ), nitrous oxide (N2 O), and methane (CH4 ). Further research is required in turfgrass systems; therefore, our objectives were to evaluate the effects of turfgrass species, growth rate, clipping management, and environmental conditions on GHG emissions. Greenhouse gas fluxes were measured in two separate field experiments in West Lafayette, IN. Experiment 1 investigated GHG flux in three cool-season (C3 ) and two warm-season (C4 ) turfgrass species during two growing seasons. Experiment 2 investigated fluxes in two C3 cultivars with varying growth rates and under different clipping management regimes. The C3 turfgrasses had the highest mean CO2 flux rates ranging from 0.373 to 0.431 g CO2 -C m-2 h-1 compared with 0.273 to 0.361 g CO2 -C m-2 h-1 for C4 turfgrasses. Mean hourly N2 O flux rates ranged from 43.3 to 50.9 µg N2 O-N m-2 h-1 for C3 compared with 11.1 to 14.4 µg N2 O-N m-2 h-1 for C4 turfgrasses. Methane flux was more variable across time, but overall C4 turfgrasses were more likely to be a CH4 source, whereas C3 turfgrasses were often a CH4 sink. Growth rate and grass clipping management treatments had negligible impact on measured GHG flux. The differences in management practices specific to C3 and C4 turfgrasses had the largest impact on GHG flux. Results indicate the impact and importance of turfgrass species selection on GHG flux and also provide more information on our overall understanding on carbon and nitrogen cycling in urban soils.

Provider perceptions of the electronic health record incentive programs: a survey of eligible professionals who have and have not attested to meaningful use.

BACKGROUND: The HITECH Act of 2009 enabled the Centers for Medicare & Medicaid Services (CMS) to provide financial incentives to health care providers who demonstrate "meaningful use" (MU) of their electronic health records (EHRs). Despite stakeholder involvement in the rule-making phase, formal input about the MU program from a cross section of providers has not been reported since incentive payments began. OBJECTIVE: To examine the perspectives and experiences of a random sample of health care professionals eligible for financial incentives (eligible professionals or EPs) for demonstrating meaningful use of their EHRs. It was hypothesized that EPs actively participating in the MU program would generally view the purported benefits of MU more positively than EPs not yet participating in the incentive program. DESIGN: Survey data were collected by mail from a random sample of EPs in Washington State and Idaho. Two follow-up mailings were made to non-respondents. PARTICIPANTS: The sample included EPs who had registered for incentive payments or attested to MU (MU-Active) and EPs not yet participating in the incentive program (MU-Inactive). MAIN MEASURES: The survey assessed perceptions of general realities and influences of MU on health care; views on the influence of MU on clinics; and personal views about MU. EP opinions were assessed with close- and open-ended items. KEY RESULTS: Close-ended responses indicated that MU-Active providers were generally more positive about the program than MU-Inactive providers. However, the majority of respondents in both groups felt that MU would not reduce care disparities or improve the accuracy of patient information. The additional workload on EPs and their staff was viewed as too great a burden on productivity relative to the level of reimbursement for achieving MU goals. The majority of open-ended responses in each group reinforced the general perception that the MU program diverted attention from treating patients by imposing greater reporting requirements. CONCLUSIONS: Survey results indicate the need by CMS to step up engagement with EPs in future planning for the MU program, while also providing support for achieving MU standards.

Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures.

The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid ß-peptide (Aß), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APP(swe)/PS1(L166P))-green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type γ-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.

The Cryptococcus neoformans catalase gene family and its role in antioxidant defense.

In the present study, we sought to elucidate the contribution of the Cryptococcus neoformans catalase gene family to antioxidant defense. We employed bioinformatics techniques to identify four members of the C. neoformans catalase gene family and created mutants lacking single or multiple catalase genes. Based on a phylogenetic analysis, CAT1 and CAT3 encode putative spore-specific catalases, CAT2 encodes a putative peroxisomal catalase, and CAT4 encodes a putative cytosolic catalase. Only Cat1 exhibited detectable biochemical activity in vitro, and Cat1 activity was constitutive in the yeast form of this organism. Although they were predicted to be important in spores, neither CAT1 nor CAT3 was essential for mating or spore viability. Consistent with previous studies of Saccharomyces cerevisiae, the single (cat1, cat2, cat3, and cat4) and quadruple (cat1 cat2 cat3 cat4) catalase mutant strains exhibited no oxidative-stress phenotypes under conditions in which either exogenous or endogenous levels of reactive oxygen species were elevated. In addition, there were no significant differences in the mean times to mortality between groups of mice infected with C. neoformans catalase mutant strains (the cat1 and cat1 cat2 cat3 cat4 mutants) and those infected with wild-type strain H99. We conclude from the results of this study that C. neoformans possesses a robust antioxidant system, composed of functionally overlapping and compensatory components that provide protection against endogenous and exogenous oxidative stresses.

Transcription factor Nrg1 mediates capsule formation, stress response, and pathogenesis in Cryptococcus neoformans.

The Cryptococcus neoformans NRG1 gene was identified using gene microarrays to define putative transcription factor genes regulated by the cyclic AMP (cAMP) signal transduction pathway. Disruption of NRG1 results in delayed capsule formation and mating, two phenotypes that are directly controlled by cAMP signaling. Putative targets of the Nrg1 transcription factor were identified using a second genome microarray to define differences in the transcriptomes of the wild-type and nrg1 mutant strains. These experiments implicate Nrg1 in the transcriptional control of multiple genes involved in carbohydrate metabolism and substrate oxidation, as well as the UGD1 gene encoding a UDP-glucose dehydrogenase required for polysaccharide capsule production and cell wall integrity. In addition to being under transcriptional control of the cAMP pathway, Nrg1 contains a putative protein kinase A phosphorylation site; mutation of this motif results in reduced Nrg1 activity. Consistent with prior studies in hypocapsular mutants, the nrg1 mutant strain is attenuated in an animal model of disseminated cryptococcal disease.

Transcriptional network of multiple capsule and melanin genes governed by the Cryptococcus neoformans cyclic AMP cascade.

Cryptococcus neoformans is an opportunistic human fungal pathogen that elaborates several virulence attributes, including a polysaccharide capsule and melanin pigments. A conserved Galpha protein/cyclic AMP (cAMP) pathway controls melanin and capsule production. To identify targets of this pathway, we used an expression profiling approach to define genes that are transcriptionally regulated by the Galpha protein Gpa1. This approach revealed that Gpa1 transcriptionally regulates multiple genes involved in capsule assembly and identified two additional genes with a marked dependence on Gpa1 for transcription. The first is the LAC1 gene, encoding the laccase enzyme that catalyzes a rate-limiting step in diphenol oxidation and melanin production. The second gene identified (LAC2) is adjacent to the LAC1 gene and encodes a second laccase that shares 75% nucleotide identity with LAC1. Similar to the LAC1 gene, LAC2 is induced in response to glucose deprivation. However, LAC2 basal transcript levels are much lower than those for LAC1. Accordingly, a lac2 mutation results in only a modest delay in melanin formation. LAC2 overexpression suppresses the melanin defects of gpa1 and lac1 mutants and partially restores virulence of these strains. These studies provide mechanistic insights into the regulation of capsule and melanin production by the C. neoformans cAMP pathway and demonstrate that multiple laccases contribute to C. neoformans melanin production and pathogenesis.

In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B.

Halichondrin B is a highly potent anticancer agent originally found in marine sponges. Although scarcity of the natural product has hampered efforts to develop halichondrin B as a new anticancer drug, the existence of a complete synthetic route has allowed synthesis of structurally simpler analogues that retain the remarkable potency of the parent compound. In this study, we show that two macrocyclic ketone analogues of halichondrir B, ER-076349 and ER-086526, have sub-nM growth inhibitory activities in vitro against numerous human cancer cell lines as well as marked in vivo activities at 0.1-1 mg/kg against four human xenografts: MDA-MB-435 breast cancer, COLO 205 colon cancer, LOX melanoma, and NIH: OVCAR-3 ovarian cancer. ER-076349 and ER-086526 induce G2-M cell cycle arrest and disruption of mitotic spindles, consistent with the tubulin-based antimitotic mechanism of halichondrin B. This is supported further by direct binding of the biotinylated analogue ER-040798 to tubulin and inhibition of tubulin polymerization in vitro by ER-076349 and ER-086526. Retention of the extraordinary in vitro and in vivo activity off halichondrin B in structurally simplified, fully synthetic analogues establishes the feasibility of developing halichondrin B-based agents as highly effective, novel anticancer drugs.

Structure-function studies in a series of carboxyl-terminal octapeptide analogues of anaphylatoxin C5a.

The synthesis and structure-activity relationships of C-terminal octapeptide analogues of anaphylatoxin C5a have been studied. The introduction of hydrophobic amino acids into the N-acetylated native octapeptide (N-Ac-His-Lys-Asp-Met-Gln-Leu-Gly-Arg-OH) (1) has led to an analogue with 100 times more activity than the native octapeptide in inhibiting the binding of 125I-labeled anaphylatoxin C5a to human neutrophil membrane receptors. The observed apparent binding Ki's for the compounds (8-10) are in the range of 1-3 microM, and they possess nearly full agonist activity, despite the fact that these analogues are one-eighth or -ninth the size of the natural ligand anaphylatoxin C5a.

Identification and synthesis of a receptor binding site of human anaphylatoxin C5a.

C5a is a 74 amino acid polypeptide that likely plays an important role in the pathogenesis of a number of inflammatory diseases. Therefore, the discovery of a C5a antagonist is of considerable therapeutic interest. A series of peptides designed to survey various regions of the molecule was synthesized by solid-phase peptide synthesis and evaluated for receptor-binding activity with polymorphonuclear leukocyte membranes. The C-terminal octapeptide (Ac-His-Lys-Asp-Met-Gln-Leu-Gly-Arg-OH) was identified as the smallest fragment which possessed reasonable C5a receptor binding activity.

Structure of ethyl 2-chloro-4-methyl-6-(1-pyrrolidinyl)benzoate.

C14H18ClNO2, Mr = 267.7, orthorhombic, Pbca, a = 10.571 (3), b = 12.081 (5), c = 21.384 (6) A, V = 2731 A3, Z = 8, Dx = 1.30 g cm-3, Mo K alpha, lambda = 0.71069 A, mu = 3.59 cm-1, F(000) = 1136, T = 293 K, R = 0.0357 for 716 observed reflections. In molecules of the title compound the ester substituent is forced from conjugation with the aromatic ring and nitrogen long pair by steric interaction with the adjacent chlorine.