Delay Discounting is Associated with Treatment Response among Cocaine-Dependent Outpatients

Rationale—Delay discounting (DD) describes the rate at which reinforcers lose value as the temporal delay to their receipt increases. Steeper discounting has been positively associated with vulnerability to substance use disorders, including cocaine use disorders. Objectives—In the present study, we examined whether DD of hypothetical monetary reinforcers is associated with the duration of cocaine abstinence achieved among cocainedependent outpatients. Methods—Participants were 36 adults who were participating in a randomized controlled trial examining the efficacy of voucher-based contingency management (CM) using low-magnitude (N = 18) or high-magnitude (N = 18) voucher monetary values. Results—DD was associated with the number of continuous weeks of cocaine abstinence achieved, even after adjusting for treatment condition during the initial 12-week (t(33) = 2.48, p = .045) and entire recommended 24-week of treatment (t(33) = 2.40, p = .022). Participants who exhibited steeper discounting functions achieved shorter periods of abstinence in the Lowmagnitude voucher condition (12-week: t(16) = 2.48, p = .025; 24-week: t(16) = 2.68, p = .017), but not in the High-magnitude voucher condition (12-week: t(16) = 0.51, p = .618; 24-week: t(16) = 1.08, p = .298), although the interaction between DD and treatment condition was not significant (12-week: t(32) = −1.12, p = .271; 24-week: t(32) = −0.37, p = .712). Conclusions—These results provide further evidence on associations between DD and treatment response and extend those observations to a new clinical population (i.e., cocainedependent outpatients), while also suggesting that a more intensive intervention like the Highmagnitude CM condition may diminish this negative relationship between DD and treatment response

Absence of neutralizing antibodies against influenza A/H5N1 virus among children in Kamphaeng Phet, Thailand

Background: Influenza A/H5N1 actively circulated in Kamphaeng Phet (KPP), Thailand from 2004 to 2006. A prospective longitudinal cohort study of influenza virus infection in 800 adults conducted during 2008–2010 in KPP suggested that subclinical or mild H5N1 infections had occurred among this adult cohort. However, this study was conducted after the peak of H5N1 activity in KPP. Coincidentally, banked serum samples were available from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses from 2004 to 2007 and lived in the same district of KPP as the adult cohort. Objectives: We sought to investigate whether subclinical or mild H5N1 infections had occurred among KPP residents during the peak of H5N1 activity from 2004 to 2006. Study design: H5N1 microneutralization (MN) assay was performed on banked serum samples from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses in KPP. Annual blood samples collected from 2004 to 2006 from 251 children were selected based on the criteria that they lived in villages with documented H5N1 infection. Result: No H5N1 neutralizing antibodies were detected in 753 annual blood samples from 251 children. Conclusion: During 2004–2006, very few subclinical or mild H5N1 infections occurred in KPP. Elevated H5N1 MN titers found in the adult cohort in 2008 were likely due to cross-reactivity from other influenza virus subtypes highlighting the complexities in interpreting influenza serological data

Characterization of the Raf Kinase Inhibitory Protein (RKIP) Binding Pocket: NMR-Based Screening Identifies Small-Molecule Ligands

Raf kinase inhibitory protein (RKIP), also known as phoshaptidylethanolamine binding protein (PEBP), has been shown to inhibit Raf and thereby negatively regulate growth factor signaling by the Raf/MAP kinase pathway. RKIP has also been shown to suppress metastasis. We have previously demonstrated that RKIP/Raf interaction is regulated by two mechanisms: phosphorylation of RKIP at Ser-153, and occupation of RKIP's conserved ligand binding domain with a phospholipid (2-dihexanoyl-sn-glycero-3-phosphoethanolamine; DHPE). In addition to phospholipids, other ligands have been reported to bind this domain; however their binding properties remain uncharacterized.In this study, we used high-resolution heteronuclear NMR spectroscopy to screen a chemical library and assay a number of potential RKIP ligands for binding to the protein. Surprisingly, many compounds previously postulated as RKIP ligands showed no detectable binding in near-physiological solution conditions even at millimolar concentrations. In contrast, we found three novel ligands for RKIP that specifically bind to the RKIP pocket. Interestingly, unlike the phospholipid, DHPE, these newly identified ligands did not affect RKIP binding to Raf-1 or RKIP phosphorylation. One out of the three ligands displayed off target biological effects, impairing EGF-induced MAPK and metabolic activity.This work defines the binding properties of RKIP ligands under near physiological conditions, establishing RKIP's affinity for hydrophobic ligands and the importance of bulky aliphatic chains for inhibiting its function. The common structural elements of these compounds defines a minimal requirement for RKIP binding and thus they can be used as lead compounds for future design of RKIP ligands with therapeutic potential

Assessment of Antimicrobial Pharmacokinetics Curricula Across Schools and Colleges of Pharmacy in the United States

Introduction Advances in technology and understanding of pharmacokinetic/pharmacodynamic relationships have prompted guideline updates and advances in precision dosing, but the role of clinical pharmacokinetics (PK) in pharmacy education remains inconsistent. Previous surveys of pharmacy school PK curricula revealed large variations in content, integration, and teaching tools but did not focus on antimicrobials or details of andragogy used. Objective Identify how antimicrobial PK is taught in pharmacy curricula across the United States, as well as instructor perceptions of current practices. Methods An online survey was distributed to 118 pharmacy programs across the United States in 2018. This 30-minute questionnaire covered curriculum content, teaching strategies, assessment modalities, and perceptions. Results Completed surveys were received from 53 programs (45% response rate) via relevant course coordinators. Among 35 traditional progressive curriculum programs (TPC), antimicrobial PK was taught in basic science (33, 94%), clinical PK (15, 43%), pharmacology (8, 23%), therapeutics (28, 80%), and skills lab courses (21, 65%). Among 18 integrated block curriculum programs (IBC), it was taught in foundations/principles (17, 94%), organ systems (12, 67%), and skills lab courses (9, 50%). On average, TPC programs had more courses with antimicrobial PK than IBC programs. Vancomycin and aminoglycosides were the most common antimicrobials taught (100%), while didactic lecturing was the predominant andragogy. Multiple choice was the primary assessment modality, being frequently used in 64% of TPC and 68% of IBC courses, respectively. Among respondents, 72% believed more time was needed to teach PK and 53% believed students were adequately prepared at the start of APPEs. Conclusion Antimicrobial PK instruction remains highly inconsistent in U.S. pharmacy schools and colleges. IBC programs may provide less opportunity for antimicrobial PK instruction, which conflicts with the desire for more instruction time. As clinical applications of antimicrobial PK change and expand, it is crucial that pharmacy education prioritizes PK education appropriately

ACCESS-OM2 v1.0: a global ocean-sea ice model at three resolutions

We introduce ACCESS-OM2, a new version of the ocean–sea ice model of the Australian Community Climate and Earth System Simulator. ACCESS-OM2 is driven by a prescribed atmosphere (JRA55-do) but has been designed to form the ocean–sea ice component of the fully coupled (atmosphere–land–ocean–sea ice) ACCESS-CM2 model. Importantly, the model is available at three different horizontal resolutions: a coarse resolution (nominally 1∘ horizontal grid spacing), an eddy-permitting resolution (nominally 0.25∘), and an eddy-rich resolution (0.1∘ with 75 vertical levels); the eddy-rich model is designed to be incorporated into the Bluelink operational ocean prediction and reanalysis system. The different resolutions have been developed simultaneously, both to allow for testing at lower resolutions and to permit comparison across resolutions. In this paper, the model is introduced and the individual components are documented. The model performance is evaluated across the three different resolutions, highlighting the relative advantages and disadvantages of running ocean–sea ice models at higher resolution. We find that higher resolution is an advantage in resolving flow through small straits, the structure of western boundary currents, and the abyssal overturning cell but that there is scope for improvements in sub-grid-scale parameterizations at the highest resolution

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Brevetoxin persistence in sediments and seagrass epiphytes of east Florida coastal waters

► A Karenia brevis bloom developed in the Intracoastal Waterway along the east Florida coast in summer 2007. ► In summer 2008 brevetoxins were found in sediments of the northern Intracoastal Waterway. ► Brevetoxins were also found in summer 2008 within seagrass epiphytes in the southern Intracoastal Waterway. ► Generally, brevetoxins were present in either sediments or seagrass epiphytes at any station. A bloom of Karenia brevis Davis developed in September 2007 near Jacksonville, Florida and subsequently progressed south through east Florida coastal waters and the Atlantic Intracoastal Waterway (ICW). Maximum cell abundances exceeded 10 6 cells L −1 through October in the northern ICW between Jacksonville and the Indian River Lagoon. The bloom progressed further south during November, and terminated in December 2007 at densities of 10 4 cells L −1 in the ICW south of Jupiter Inlet, Florida. Brevetoxins were subsequently sampled in sediments and seagrass epiphytes in July and August 2008 in the ICW. Sediment brevetoxins occurred at concentrations of 11–15 ng PbTx-3 equivalents (g dry wt sediment) −1 in three of five basins in the northern ICW during summer 2008. Seagrass beds occur south of the Mosquito Lagoon in the ICW. Brevetoxins were detected in six of the nine seagrass beds sampled between the Mosquito Lagoon and Jupiter Inlet at concentrations of 6–18 ng (g dry wt epiphytes) −1. The highest brevetoxins concentrations were found in sediments near Patrick Air Force Base at 89 ng (g dry wt sediment) −1. In general, brevetoxins occurred in either seagrass epiphytes or sediments. Blades of the resident seagrass species have a maximum life span of less than six months, so it is postulated that brevetoxins could be transferred between epibenthic communities of individual blades in seagrass beds. The occurrence of brevetoxins in east Florida coast sediments and seagrass epiphytes up to eight months after bloom termination supports observations from the Florida west coast that brevetoxins can persist in marine ecosystems in the absence of sustained blooms. Furthermore, our observations show that brevetoxins can persist in sediments where seagrass communities are absent

Characterization of the Raf Kinase Inhibitory Protein (RKIP) Binding Pocket: NMR-Based Screening Identifies Small-Molecule Ligands

Background: Raf kinase inhibitory protein (RKIP), also known as phoshaptidylethanolamine binding protein (PEBP), has been shown to inhibit Raf and thereby negatively regulate growth factor signaling by the Raf/MAP kinase pathway. RKIP has also been shown to suppress metastasis. We have previously demonstrated that RKIP/Raf interaction is regulated by two mechanisms: phosphorylation of RKIP at Ser-153, and occupation of RKIP's conserved ligand binding domain with a phospholipid (2-dihexanoyl-sn-glycero-3-phosphoethanolamine; DHPE). In addition to phospholipids, other ligands have been reported to bind this domain; however their binding properties remain uncharacterized.Methods/Findings: In this study, we used high-resolution heteronuclear NMR spectroscopy to screen a chemical library and assay a number of potential RKIP ligands for binding to the protein. Surprisingly, many compounds previously postulated as RKIP ligands showed no detectable binding in near-physiological solution conditions even at millimolar concentrations. In contrast, we found three novel ligands for RKIP that specifically bind to the RKIP pocket. Interestingly, unlike the phospholipid, DHPE, these newly identified ligands did not affect RKIP binding to Raf-1 or RKIP phosphorylation. One out of the three ligands displayed off target biological effects, impairing EGF-induced MAPK and metabolic activity.Conclusions/Significance: This work defines the binding properties of RKIP ligands under near physiological conditions, establishing RKIP's affinity for hydrophobic ligands and the importance of bulky aliphatic chains for inhibiting its function. The common structural elements of these compounds defines a minimal requirement for RKIP binding and thus they can be used as lead compounds for future design of RKIP ligands with therapeutic potential.</p

Little evidence of avian or equine influenza virus infection among a cohort of Mongolian adults with animal exposures, 2010-2011.

Avian (AIV) and equine influenza virus (EIV) have been repeatedly shown to circulate among Mongolia's migrating birds or domestic horses. In 2009, 439 Mongolian adults, many with occupational exposure to animals, were enrolled in a prospective cohort study of zoonotic influenza transmission. Sera were drawn upon enrollment and again at 12 and 24 months. Participants were contacted monthly for 24 months and queried regarding episodes of acute influenza-like illnesses (ILI). Cohort members confirmed to have acute influenza A infections, permitted respiratory swab collections which were studied with rRT-PCR for influenza A. Serologic assays were performed against equine, avian, and human influenza viruses. Over the 2 yrs of follow-up, 100 ILI investigations in the cohort were conducted. Thirty-six ILI cases (36%) were identified as influenza A infections by rRT-PCR; none yielded evidence for AIV or EIV. Serological examination of 12 mo and 24 mo annual sera revealed 37 participants had detectable antibody titers (≥1∶10) against studied viruses during the course of study follow-up: 21 against A/Equine/Mongolia/01/2008(H3N8); 4 against an avian A/Teal/Hong Kong/w3129(H6N1), 11 against an avian-like A/Hong Kong/1073/1999(H9N2), and 1 against an avian A/Migrating duck/Hong Kong/MPD268/2007(H10N4) virus. However, all such titers were <1∶80 and none were statistically associated with avian or horse exposures. A number of subjects had evidence of seroconversion to zoonotic viruses, but the 4-fold titer changes were again not associated with avian or horse exposures. As elevated antibodies against seasonal influenza viruses were high during the study period, it seems likely that cross-reacting antibodies against seasonal human influenza viruses were a cause of the low-level seroreactivity against AIV or EIV. Despite the presence of AIV and EIV circulating among wild birds and horses in Mongolia, there was little evidence of AIV or EIV infection in this prospective study of Mongolians with animal exposures