Search

Objective Despite evidence-based Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations, outcomes are poor. GOLD uses chronic obstructive pulmonary disease (COPD) assessment test (CAT) scores with exacerbation history to categorize COPD severity into A, B, C, and D severity groups. Therapy is group-specific; monotherapy/dual long-acting bronchodilators (LABDs) therapy is preferred to inhaled corticosteroids (ICS). Pharmacist-accessible data could be used to identify evidence-based interventions to improve outcomes. The primary objective was to analyze previously collected data to compare the consistency of patient-described COPD regimens with GOLD therapeutic recommendations to identify potential pharmacist interventions. Methods Cross-sectional, nonrandomized design using a written questionnaire and CAT scores. Dispensing data from 35 Missouri community pharmacies initially identified participants aged 40 years or older with 1 or more COPD medications dispensed in the past year. Those self-reporting COPD, emphysema, or chronic bronchitis completed a demographic survey with medication history, including oral corticosteroid and antibiotic use, and CAT scores. Proportion of days covered (PDC) was calculated for any COPD maintenance medication dispensed over 1 year. The participants' COPD was categorized into A, B, C, and D severity groups. The reported medication regimens were categorized into consistent with, escalated from, or less than initial first-line/alternative recommended therapy for the A, B, C, and D severity groups. Results The participants totaled 709 (group A: 6%; group B: 35%; group C: 4%; group D: 55%). Of the regimens, 41% were consistent with, 34% were escalated from, and 24% were less than initial first-line/alternative GOLD recommendations. Most (96%) of the participants were highly symptomatic. Regimens containing ICS: (67.5%); ICS plus LABD (37.2%) exceeded dual LABD (4.2%). The average PDC was 0.43 ± 0.37; only 28.7% were adherent (PDC ≥ 0.80). Conclusions Participants with self-reported COPD were highly symptomatic and nonadherent; undertreatment was noted. Community pharmacists could provide therapeutic interventions consistent with GOLD A, B, C, and D severity groups, promote dual LABD versus ICS therapies, and optimize adherence.

Background Body image dissatisfaction (BID) is prevalent in patients with Inflammatory Bowel Disease (IBD). Historically female sex, previous IBD surgery, impaired QoL have been associated with negative body image. The introduction of biologic therapies and modern IBD care in Australia in 2007 has improved disease control and endoscopic outcomes, but it is unclear if body image has improved in parallel with this. We aimed to determine whether body image and QoL have improved amongst IBD patients with modern IBD car Methods Tertiary IBD service patients were offered inclusion in the study in 2006 by postal survey (pre-biologic era), and in 2021 by electronic survey (biologic era). Surveys included demographics and history of IBD surgery. In the pre-biologic era (PBE) body image dissatisfaction (BID) and QoL were assessed using a patient reported yes/no question, followed by an open question about how IBD or treatment has changed the way they view their body’s appearance. In the biologic era (BE) the validated modified Body Image Scale and Short Inflammatory Bowel Disease Questionnaire were used. Results The BE included 135 patients, 59% female, mean age 45.9. The PBE included 215 patients, 66% female and mean age 35.5. PBE had 40% reporting IBD surgery vs 36% in BE (P=0.489). BID was observed in 67% vs 39% of the PBE and BE respectively (p Conclusion Whilst the rate of BID has decreased with modern IBD treatment; it remains highly prevalent and is associated with impaired QoL. Whilst females remain disproportionately affected, the historically observed association between IBD surgery and impaired body image was not demonstrated in the BE. This may reflect improved surgical techniques and biologic down staging prior to surgery. However, body image remains an important Patient Reported Outcome in IBD and warrants further attention.

Understanding types and frequency of medication taking discrepancies could help design pharmacist interventions to improve adherence, outcomes, and prescribing.This study aimed to assess concordance between participants' descriptions of chronic obstructive pulmonary disease (COPD) medication taking behaviors and prescription instructions.Continued analysis of previously collected data. Dispensing data from 35 community pharmacies identified participants at the age of ≥ 40 years, with ≥ 1 COPD maintenance medication in the past year and self-reported COPD. Participants completed a survey of demographics, corticosteroid/antibiotic drug use, and symptom scores. Participants listed each medication and described medication taking behavior. COPD severity was classified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) ABCD categories from exacerbation history and symptoms. Aggregate proportion days covered (PDC) for any 1 maintenance medicine was calculated using 12-month dispensing data. Discrepancies between medication taking and instructions were classified: (1) overuse, (2) underuse, or (3) discontinued by participant (without prescriber knowledge). Descriptive statistics summarized survey results. Chi-square compared discrepancies among long-acting bronchodilators (LABDs), inhaled corticosteroids (ICS), and short-acting bronchodilators (SABDs).Most participants (N = 709; 27.6% urban, 70.5% rural) were highly symptomatic (GOLD groups B/D = 89.9%) and high risk (groups C/D = 59.2%). Median medication number was 4. Concordance of ICS and LABD taking behavior with prescriber instructions was 80.6% and 81.8%, respectively (P0.05). PDC averaged 0.46 ± 0.37; only 28.7% were adherent (i.e., PDC ≥ 0.80). ICS underuse (11.8%) exceeded LABD (5.5%). LABD discontinuation (7.4%) exceeded ICS (2.7%) or SABD (0.6%). SABD overuse (9.3%) exceeded ICS (3.4%) or LABD (4.3%) (P0.5 all comparisons).Although most were highly symptomatic, high risk, and frequently described correct medication taking behavior, overall adherence was very low. Discrepancies included overuse, underuse, and self-discontinuation. Nonadherence and medication taking discrepancies may increase symptoms, exacerbations, and additional medication prescribing. Potential pharmacist strategies include regularly assessing adherence and differentiating intentional versus nonintentional nonadherence to identify and implement patient-specific interventions to encourage medication taking as prescribed.

The chemokine receptor CXCR4 plays an integral role in the development of highly metastatic breast cancer and in the pathogenesis of chronic HIV infection. In this study, we compared the effects of CXCR4 antagonists on apoptosis induction in hematopoietic cells and in tumor cells. We incubated cells expressing CXCR4 with a series of CXCR4 antagonists and subsequently exposed the cultures to a pro-apoptotic peptide derived from the HIV-1 Nef protein (NefM1). The NefM1 peptide contains residues 50–60 of Nef and was previously shown to be the sequence necessary for Nef to initiate the apoptotic program through CXCR4 signaling. We found that several of the compounds studied potently blocked Nef-induced apoptosis in Jurkat T-lymphocyte cells. Interestingly, many of the same compounds selectively triggered apoptosis in MDA-MB-231 breast cancer cells, in some cases at sub-nanomolar concentrations. None of the compounds were toxic to lymphocyte, monocyte or macrophage cells, suggesting that aggressive breast cancer carcinomas may be selectively targeted and eliminated using CXCR4-based therapies without additional cytotoxic agents. Our results also demonstrate that not all CXCR4 antagonists are alike and that the observed anti-Nef and pro-apoptotic effects are chemically tunable. Collectively, these findings suggest our CXCR4 antagonists have promising clinical utility for HIV or breast cancer therapies as well as being useful probes to examine the link between CXCR4 and apoptosis.

[Image: see text] The rationale for the structural and mechanistic basis of a tetrahydroisoquinoline (THIQ) based series of CXCR4 antagonists is presented. Using the previously reported crystal structures which reveal two distinct binding sites of CXCR4 defined as the small molecule (IT1t or minor) binding pocket and peptide (CVX15 or major) binding pocket, we hypothesized our THIQ small molecule series could bind like either molecule in these respective receptor configurations (IT1t versus CVX15 based poses). To this end, a thorough investigation was performed through a combination of receptor mutation studies, medicinal chemistry, biological testing, conformational analysis, and flexible docking. Our findings showed that the CVX15 peptide-based CXCR4 receptor complexes (red pose) were consistently favored over the small molecule IT1t based CXCR4 receptor configurations (blue pose) to correctly explain the computational and mutational studies as well as key structural components of activity for these small molecules.

Objectives Data on symptom burden or medication adherence in patients with chronic obstructive pulmonary disease (COPD) within a community pharmacy setting are limited. This study assessed symptom burden and adherence to respiratory medications in individuals reporting COPD, chronic bronchitis, or emphysema diagnoses visiting community pharmacies. Design This cross-sectional study enrolled participants visiting 35 community pharmacies in Missouri (October 2016 to April 2017). Participants Eligible participants (aged 40 years or more with a self-reported history of COPD, prescription for at least 1 COPD maintenance medication during the previous 12 months, and able to complete an English questionnaire) were identified from pharmacy dispensing records. Main outcome measures Participants completed a questionnaire assessing demographics, clinical characteristics, health literacy, COPD Assessment Test (CAT) modified Medical Research Council (mMRC) dyspnea scale scores, and exacerbation history. Recent spirometry data were obtained, if available, from participants’ physicians. COPD was classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 criteria. Medication adherence was assessed as proportion of days covered (PDC) from dispensing records. Results Of 682 participants (mean age 63.0 years; 57% female) with available pharmacy data, 251 (36.8%) had available spirometry data. Most participants had mMRC scores ≥ 2 (60.9%) and CAT scores ≥ 10 (90.2%); 57.2% reported at least 2 moderate or 1 or more severe exacerbations within the previous 12 months. GOLD classifications varied depending on the scale used (mMRC vs. CAT); more participants were classified as group C/D than group A/B, with the highest proportion classified as group D (higher symptom burden and exacerbation risk). Mean PDC was 0.46 ± 0.37; only 28.7% of participants were adherent (PDC ≥ 80%) to at least 1 COPD maintenance medication. Conclusion Individuals self-reporting a COPD diagnosis receiving respiratory medications from community pharmacies in Missouri have a high symptom burden and low medication adherence. Further research should determine reasons for low adherence and ways to reduce COPD symptoms.

Endothelial dysfunction is a known consequence of bone morphogenetic protein type II receptor (BMPR2) mutations seen in pulmonary arterial hypertension (PAH). However, standard 2D cell culture models fail to mimic the mechanical environment seen in the pulmonary vasculature. Hydrogels have emerged as promising platforms for 3D disease modeling due to their tunable physical and biochemical properties. In order to recreate the mechanical stimuli seen in the pulmonary vasculature, we have created a novel 3D hydrogel-based pulmonary vasculature model (&ldquo, artificial arteriole&rdquo, ) that reproduces the pulsatile flow rates and pressures seen in the human lung. Using this platform, we studied both Bmpr2R899X and WT endothelial cells to better understand how the addition of oscillatory flow and physiological pressure influenced gene expression, cell morphology, and cell permeability. The addition of oscillatory flow and pressure resulted in several gene expression changes in both WT and Bmpr2R899X cells. However, for many pathways with relevance to PAH etiology, Bmpr2R899X cells responded differently when compared to the WT cells. Bmpr2R899X cells were also found not to elongate in the direction of flow, and instead remained stagnant in morphology despite mechanical stimuli. The increased permeability of the Bmpr2R899X layer was successfully reproduced in our artificial arteriole, with the addition of flow and pressure not leading to significant changes in permeability. Our artificial arteriole is the first to model many mechanical properties seen in the lung. Its tunability enables several new opportunities to study the endothelium in pulmonary vascular disease with increased control over environmental parameters.

Objective. To develop a comprehensive instrument specific to student pharmacist-patient communication skills, and to determine face, content, construct, concurrent, and predictive validity and reliability of the instrument.Methods. A multi-step approach was used to create and validate an instrument, including the use of external experts for face and content validity, students for construct validity, comparisons to other rubrics for concurrent validity, comparisons to other coursework for predictive validity, and extensive reliability and inter-rater reliability testing with trained faculty assessors.Results. Patient-centered Communication Tools (PaCT) achieved face and content validity and performed well with multiple correlation tests with significant findings for reliability testing and when compared to an alternate rubric.Conclusion. PaCT is a useful instrument for assessing student pharmacist communication skills with patients.

We report novel anti-HIV-1 agents with combined dual host-pathogen pharmacology. Lead compound 3, composed of a pyrazole-piperidine core, exhibits three concurrent mechanisms of action: (1) non-nucleoside reverse transcriptase inhibition, (2) CCR5-mediated M-tropic viral entry inhibition, and (3) CXCR4-based T-tropic viral entry inhibition that maintains native chemokine ligand binding. This discovery identifies important tool compounds for studying viral infectivity and prototype agents that block HIV-1 entry through dual chemokine receptor ligation.

The NMDA receptor mediates a slow component of excitatory synaptic transmission, and NMDA receptor dysfunction has been implicated in numerous neurological disorders. Thus, interest in developing modulators that are capable of regulating the channel continues to be strong. Recent research has led to the discovery of a number of compounds that hold therapeutic and clinical value. Deeper insight into the NMDA intersubunit interactions and structural motifs gleaned from the recently solved crystal structures of the NMDA receptor should facilitate a deeper understanding of how these compounds modulate the receptor.This article discusses the known pharmacology of NMDA receptors. A discussion of the patent literature since 2012 is also included, with an emphasis on those that claimed new chemical entities as regulators of the NMDA receptor.The number of patents involving novel NMDA receptor modulators suggests a renewed interest in the NMDA receptor as a therapeutic target. Subunit-selective modulators continue to show promise, and the development of new subunit-selective NMDA receptor modulators appears poised for continued growth. Although a modest number of channel blocker patents were published, successful clinical outcomes involving ketamine have led to a resurgent interest in low-affinity channel blockers as therapeutics.

A convenient, single-pot protocol for the transformation of esters into analytically pure ketones is described herein. This method circumvents the need for purification and affords near quantitative yields for all substrates investigated. As a test of its utility, the method is used to improve the yields of a process for preparing a pharmacologically relevant anti-HIV intermediate by nearly 10 fold.

Objective To assess whether student pharmacists’ communication skills improved using the Four Habits Model (FHM) at the St. Louis College of Pharmacy. Methods During the Fall of 2009 and 2010, student pharmacists in the third professional year learned and practiced the FHM. They were given feedback by faculty on three of the four Habits, used the FHM for self and peer assessment, and were formally evaluated on all four Habits during a standardized patient encounter. Results Student pharmacist performance significantly improved from baseline during both Fall 2009 and Fall 2010 in the majority of the Habits assessed. Conclusion Use of the FHM in pharmacy education can improve a student pharmacists’ ability to display the four Habits of communicating and developing relationships with patients. Tailoring of the FHM to pharmacy encounters will further enhance the utility of this communication framework. Practice implications Use of the FHM enhances the measurement and assessment of the relational aspects of student pharmacist–patient communication skills. Consistent use of the FHM over time is likely necessary to fully develop and retain communication skills. The overall goal is to improve patient's health literacy and appropriate medication use by improving communication and the pharmacist–patient relationship.

Background and purpose To develop and implement a system for junior clinical faculty to become successful course coordinators with the use of a mentoring program and ensure that student performance and satisfaction are maintained at a high level. Educational activity and setting For five years, first-time faculty discussion group leaders in a required large (>225 students) multi-instructor pathophysiology course opted into a structured mentoring program for course coordination in the subsequent year. Program categories included course material development, exam and quiz management, discussion group management, and communication among students, faculty, and staff. Findings Mentors’ previous coordination experience ranged from a few years to over a decade. Faculty participants included three second-year faculty. Each participant successfully undertook a full co-coordinator role the following year. Subsequently, each then became a lead mentor the following year for new participants. Exam quality/reliability statistics were sustained at a high level, course evaluations and student performance improved throughout the program, and all mentor/mentee reflections demonstrated a positive and impactful experience. Discussion and summary Course coordination can be a small percentage of clinical faculty workload, yet is a significant time commitment. Pharmacy resident certificate or new faculty academy programs often do not include course coordination, which is a vital, higher level function/role. Structured mentoring early in professional career of junior faculty aids in the assumption of pedagogical leadership roles, while also developing mentoring skills of mid-level faculty.

Objective Fluticasone furoate (FF), an inhaled corticosteroid (ICS), and vilanterol (VI), a long-acting beta2 receptor agonist (LABA), is a new combination used in an Ellipta® device. This article compares FF–VI to other ICS–LABA combinations available, particularly emphasizing product selection from the patient perspective. Data sources A PubMED and EMBASE search completed in October 2015 identified trials using the MeSH terms “fluticasone”, “vilanterol”, and “asthma”. Additional information was gathered from references cited in the identified publications, the manufacturer, package insert, and ClinicalTrials.gov registry. Study selection/data extraction Preference was given to randomized controlled clinical trials. Animal trials, trials for COPD, and non-English sources were excluded. Data synthesis Seven efficacy trials of FF–VI in asthma were identified. Only one (24 weeks) trial compared FF–VI to another ICS–LABA combination (fluticasone propionate–salmeterol). Primary outcomes (usually lung function) and secondary outcomes (eg, quality of life and symptom scores) were comparable. In three FF–VI safety trials, the type and frequency of common adverse reactions (ie, thrush and dysphonia) were similar to those in clinical trials. Over 90% of subjects rated the Ellipta® device as “easy to use” and demonstrated correct device technique initially and at 4 weeks. Conclusion Individuals may have drug- and device-specific preferences that should be incorporated into therapeutic decision making. Limited data indicate that clinical and patient-oriented efficacy/safety outcomes of FF–VI are likely comparable to other available combinations for adults with asthma. Patient-friendly features include once-daily dosing, flexibility of dose timing, and design/ease of the use of the device. Additional larger and long-term comparative studies are needed to determine whether these features translate into greater efficacy, safety, patient preference, or adherence versus other ICS–LABA combinations. In the next few years, the availability of less expensive generic ICS–LABA products may strongly influence patient preference.

A chemo- and diastereoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides with secondary amides is described. This method allows for convergent and highly selective synthesis of trans-β-aminocyclopropane carboxylic acid derivatives.

A new, general, and chemoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides is described. A wide range of alcohols and phenols can be employed as pronucleophiles in this transformation, providing expeditious access to trans-cyclopropanol ethers. A new mode of the selectivity control through a thermodynamic equilibrium is realized, alternative to the previously described steric and directing modes.

The robust and scalable title method is based on the reaction between methyl 1-benzylpiperidine-4-carboxylate and primary Grignard reagents, but fails using secondary Grignard reagents.

A novel series of CXCR4 antagonists with substituted piperazines as benzimidazole replacements is described. These compounds showed micromolar to nanomolar potency in CXCR4-mediated functional and HIV assays, namely inhibition of X4 HIV-1(IIIB) virus in MAGI-CCR5/CXCR4 cells and inhibition of SDF-1 induced calcium release in Chem-1 cells. Preliminary SAR investigations led to the identification of a series of N-aryl piperazines as the most potent compounds. Results show SAR that indicates type and position of the aromatic ring, as well as type of linker and stereochemistry are significant for activity. Profiling of several lead compounds showed that one (49b) reduced susceptibility towards CYP450 and hERG, and the best overall profile when considering both SDF-1 and HIV potencies (6-20 nM).

We used data collected over 3 years at two study sites to quantify the rates and consequences of multiple paternity and to determine the opportunity for selection on male and female northern water snakes (Nerodia sipedon). We sampled litters from 45 females that gave birth to 811 offspring. Using eight microsatellite DNA loci (probability of exclusion of nonparental males 0.99), we assigned paternity to 93% of neonates from one study population and 69% of neonates from the other population. Observations of participation in mating aggregations predicted individual reproductive success poorly for two reasons. First, males regularly courted nonreproductive females. Second, more than half of all sexually mature males obtained no reproductive success each year, despite the fact that many of them participated in mating aggregations. The number of sires per litter ranged from one to five, with 58% of all litters sired by more than one male. Multiple paternity increased with female size, apparently both because bigger females mated with more males and because the larger litters of big females provide paternity opportunities to more males. Multiple paternity was also more prevalent in years with shorter mating seasons. We detected no advantage to multiple paternity in reducing either the number of unfertilized ovules or stillborn young. Despite the majority of males siring no young each year, some males fathered young with as many as three different females in one year. Male reproductive success increased by more than 10 offspring for each additional mate, whereas female success increased by fewer than 2 offspring for each additional mate. The opportunity for sexual selection was more than five times higher in males than females. Key words: mating system, microsatellites, multiple paternity, Nerodia sipedon, paternity analysis, sexual selection, snakes. [Behav Ecol 13: 800–807 (2002)]

Male northern water snakes (Nerodia sipedon) have high variance in reproductive success relative to females. We used DNAbased paternity analyses from a 3-year study of two marsh populations of water snakes to investigate the factors that contribute to variation in male success. Male traits investigated included body size, condition, tail length, home range size, activity during the mating season, and genetic profile (genetic similarity to females, heterozygosity, and genetic variability [d 2 ]). We successfully assigned 80% of offspring to sires from a sample of 811 offspring from 45 litters. Male reproductive success did not vary significantly with body size, tail length, condition, home range size, or the number of microsatellite loci at which males were heterozygous, nor with other features of their genetic profiles. However, we found evidence of positive assortative mating by size in the marsh in which receptive females were not spatially clumped. Also, males that were most active during the mating season were more successful, particularly where females were not clumped. We failed to find evidence of selection acting on male size through variance in reproductive success, indicating that sexual selection does not have an important influence on sexual size dimorphism in this species (males are smaller than females). We propose that males are smaller than females because the lack of advantage to large size allows males to adopt a low-energy, low-growth strategy that reduces their risk of predation outside the mating season. Key words: assortative mating, DNA loci, heterozygosity, microsatellites, Nerodia sipedon, northern water snake, paternity analysis, sexual selection, sexual size dimorphism. [Behav Ecol 13:808–815 (2002)]

Male northern water snakes (Nerodia sipedon) have high variance in reproductive success relative to females. We used DNA-based paternity analyses from a 3-year study of two marsh populations of water snakes to investigate the factors that contribute to variation in male success. Male traits investigated included body size, condition, tail length, home range size, activity during the mating season, and genetic profile (genetic similarity to females, heterozygosity, and genetic variability [d-super-2]). We successfully assigned > 80% of offspring to sires from a sample of 811 offspring from 45 litters. Male reproductive success did not vary significantly with body size, tail length, condition, home range size, or the number of microsatellite loci at which males were heterozygous, nor with other features of their genetic profiles. However, we found evidence of positive assortative mating by size in the marsh in which receptive females were not spatially clumped. Also, males that were most active during the mating season were more successful, particularly where females were not clumped. We failed to find evidence of selection acting on male size through variance in reproductive success, indicating that sexual selection does not have an important influence on sexual size dimorphism in this species (males are smaller than females). We propose that males are smaller than females because the lack of advantage to large size allows males to adopt a low-energy, low-growth strategy that reduces their risk of predation outside the mating season. Copyright 2002.

We used data collected over 3 years at two study sites to quantify the rates and consequences of multiple paternity and to determine the opportunity for selection on male and female northern water snakes (Nerodia sipedon). We sampled litters from 45 females that gave birth to 811 offspring. Using eight microsatellite DNA loci (probability of exclusion of nonparental males > 0.99), we assigned paternity to 93% of neonates from one study population and 69% of neonates from the other population. Observations of participation in mating aggregations predicted individual reproductive success poorly for two reasons. First, males regularly courted nonreproductive females. Second, more than half of all sexually mature males obtained no reproductive success each year, despite the fact that many of them participated in mating aggregations. The number of sires per litter ranged from one to five, with 58% of all litters sired by more than one male. Multiple paternity increased with female size, apparently both because bigger females mated with more males and because the larger litters of big females provide paternity opportunities to more males. Multiple paternity was also more prevalent in years with shorter mating seasons. We detected no advantage to multiple paternity in reducing either the number of unfertilized ovules or stillborn young. Despite the majority of males siring no young each year, some males fathered young with as many as three different females in one year. Male reproductive success increased by more than 10 offspring for each additional mate, whereas female success increased by fewer than 2 offspring for each additional mate. The opportunity for sexual selection was more than five times higher in males than females. Copyright 2002.

The CXC chemokine receptor 4 (CXCR4) is involved in chemotaxis and serves as a coreceptor for T-tropic HIV-1 viral entry, thus making this receptor an attractive drug target. Recently, crystal structures of CXCR4 were reported as complexes with the small molecule IT1t and the CVX15 peptide. Follow-up efforts to model different antagonists into the small molecule CXCR4:IT1t crystal structure did not generate poses consistent with either the X-ray crystal structure or site-directed mutagenesis (SDM). Here, we compare the binding pockets of the two CXCR4 crystal structures, revealing differences in helices IV, V, VI, and VII, with major differences for the His203 residue buried in the binding pocket. The small molecule antagonist AMD11070 was docked into both CXCR4 crystal structures. An AMD11070 pose identified from the CXCR4:CVX15 model presented interactions with Asp171, Glu288, Trp94, and Asp97, consistent with published SDM data, thus suggesting it is the bioactive pose. A CXCR4 receptor model was optimized around this pose of AMD11070, and the resulting model correlated HIV-1 inhibition with MM-GBSA docking scores for a congeneric AMD11070-like series. Subsequent NAMFIS NMR results successfully linked the proposed binding pose to an independent experimental structure. These results strongly suggest that not all small molecules will bind to CXCR4 in a similar manner as IT1t. Instead, the CXCR4:CVX15 crystal structure may provide a binding locus for small organic molecules that is more suitable than the secondary IT1t site. This work is expected to provide modeling insights useful for future CXCR4 antagonist and X4-tropic HIV-1 based drug design efforts.

Objective Evaluate curricular changes related to health literacy and determine impact on independent-living senior residents as part of an introductory pharmacy practice experience for third-year student pharmacists. Design Students were randomly assigned a resident whom they visited multiple times to conduct assessments and provide various services using three methods: Ask Me 3™ Four Habits Model, and Teach-back. Setting The study was conducted at independent-living apartments within a 24-mile radius from the St. Louis College of Pharmacy, St. Louis, Missouri. Patients, participants Participants (n = 147 to 173, across all three years) were volunteer, elderly residents, living at a facility that collaborated with the research. Interventions Within one academic year, students collected medical and medication histories, conducted household safety checks, performed screening assessments, assessed adherence, and provided general recommendations to a resident. Main outcome measure(s) Outcomes included resident satisfaction, student satisfaction, and correlations between student use of health literacy tools and resident satisfaction. Results Exit surveys indicated resident overall satisfaction with the program, increased understanding of health-related information, increased confidence in asking health care professionals questions about their health, and greater commitment to medication adherence as a result of the experience. Students were highly satisfied with the program. Analyses reveal some correlations between a previously determined performance level of student communication and resident satisfaction. Conclusions Students' use of health literacy communication tools during encounters with independent-living senior residents can result in greater patient understanding and empowerment, which may in turn help improve medication adherence.

Reductions in red meat and increases in cereals in the diet may compromise the intake and bioavailability of Zn. In this cross-sectional study of 330 premenopausal New Zealand women aged 18–40 years, we have assessed the inter-relationships among dietary intakes (via computer-administered food-frequency questionnaire), biochemical Zn status, and anthropometric indices, and compared our results with earlier data. Fasting serum (12·00 (SD 1·36) ΜMOL/L) AND HAIR ZN (2·71 (sd 0·36) μmol/g) were lower than those for young Dunedin, New Zealand, women in 1973 (non-fasting serum Zn 18·6 (sd 4·6) μmol/l, hair Zn 2·99 (sd 0·35) μmol/g). Further, our mean serum Zn was at the 25th percentile of the US National Health and Nutrition Examination Survey (NHANES) (1976–1980) reference sample for women aged 20–44 years. Meat–poultry–fish contributed only 28 % total Zn in the present study, a level comparable with that from cereals–nuts–legumes (27 %), compared to about 40 % in 1989. Significant negative correlations existed between serum Zn and dietary [phytate]:[Zn] molar ratios (r-0·163, P15, a level said to compromise Zn status. Mean serum Zn of a subgroup of non-oral contraceptive users free of infection was higher in the red-meat eaters (n149) compared with non-red-meat eaters (n48) (12·2v.11·8 μmol/g, P15v.v.12·3 μmol/l, P=0·04). We postulate that the lower biochemical Zn status of these New Zealand women may be associated in part with changes in food selection patterns, which have led to a reduction in the bioavailability of dietary Zn.

Incomplete knowledge of pedigrees sometimes limits the methods of estimating quantitative genetic parameters (heritability, genetic correlation) in nature and may result in estimates that are inflated by nongenetic sources of variation. North American garter snakes and their allies provide a model system for investigating evolutionary quantitative genetics, but estimates of quantitative genetic parameters in these snakes are mostly based on offspring-dam regression and full-sib analysis, methods that fail to discriminate between maternal genetic, maternal environmental, and direct genetic effects on traits of interest. Using data from the garter snake Thamnophis sirtalis, we demonstrate that microsatellite DNA markers can be used to identify full-sib sireships within litters in species that produce large numbers of offspring and in which multiple paternity is common. This allows estimation of quantitative genetic parameters using a maternal half-sib analysis in which sires are nested within dams. Six microsatellite DNA loci were scored for four wild-caught dams and their 73 offspring and revealed two full-sib sireships within each litter. Maternal half-sib analyses of scalation and behavior suggest that heritability may be lower and maternal effects larger than was previously thought.

The formation of cyclopropanes catalyzed by 18-crown-6 gives products with high diastereoselectivity.

Objective: To evaluate the efficacy and safety of the combination of fluticasone furoate/vilanterol (FF/VI) and compare it with other inhaled combination corticosteroid/long-acting β2-receptor agonists for maintenance treatment of chronic obstructive pulmonary disease (COPD). Data Sources: A PubMed and EMBASE search in June 2013 using the MeSH terms fluticasone and vilanterol identified trials using this combination for COPD. Additional information was gathered from references cited in the identified publications, the manufacturer, and package insert as well as the ClinicalTrials.gov registry. Study Selection/Data Extraction: Preference was given to randomized controlled clinical trials. Data from animal trials, clinical trials for asthma, and non-English sources were excluded. Data Synthesis: Given once daily, FF/VI improves trough forced expiratory volume at 1 s by about 230 mL in a 28-day trial versus placebo. However, a more modest increase (100-130 mL) was seen in 2 longer 28-week trials. In the longest trial of 1 year, a slight but significant decrease in the yearly rate of moderate plus severe exacerbations, the time to first moderate or severe exacerbation, and the frequency of exacerbations requiring systemic corticosteroids was seen. There was no difference in the rate of exacerbations requiring hospitalization. The product appears to have the adverse effect profile typical of its class. Conclusions: Of the inhaled corticosteroid/long-acting β2 receptor agonist combinations, VI/FF is the first allowing once-daily dosing. Similar to the other combination products, it may slightly decrease the incidence of COPD exacerbations in the patient subset with Global Initiative for Chronic Obstructive Lung Disease risk category C or D. There are no direct safety or efficacy data comparing this with other available inhaled combination products. The once-daily dosing might improve adherence in select patients. The Ellipta delivery device may assist some who are unable to use other devices correctly.

We used data from 88 litters of northern water snakes (Nerodia sipedon) to test predictions about how mothers would adaptively vary the sex ratios of their offspring. Larger mothers produced significantly more daughters (r2 = 0.04, P = 0.05), and mothers producing larger offspring produced significantly more daughters (r2 = 0.06, P = 0.02). Because neonate size did not vary with maternal size, these sex-ratio patterns were independent of each other. These patterns were more pronounced for wild females than for females maintained in captivity while gravid, but rearing conditions did not have a significant effect on sex ratio. Also, because sex ratios were similar between captive and free-living females despite captive females giving birth 16 days earlier, on average, and because sex ratios did not vary with birth date within the two groups of females, gestation appeared not to affect sex ratio. If females vary sex ratios adaptively, only the relationship between sex ratio and neonate size was consistent with our predictions. Limited evidence from other snake species also indicates variation in neonatal sex ratios that is nonrandom but not necessarily adaptive. A better understanding of these patterns will require information on the factors that affect the fitness of male and female neonates differently. An unexpected sex-ratio pattern that we found was that 14 of 19 stillborn young were male. We speculate that this pattern could be a result of male embryonic sensitivity to temperature. Thus, the need for gravid females to maintain a high body temperature so that their young are born with enough time to find hibernation sites may conflict with the need for embryos to develop at a safe temperature.

The influence of age on variation in female phonontaxis in the field cricket,Gryllus integer, was investigated using a Kugel treadmill-type device. Synthetic male calling songs, with different pulse rates, were presented in both single-stimulus and three-stimulus designs. Females were either 11–14 or 25–28 days postecdysis. Females varied in motivation, or the degree of reproductive effort they exhibited, but only in single-stimulus trials: older females achieved higher scores than younger females. Females varied in selectivity, or the extent to which they discriminated among potential mates, in both presentation designs. All females discriminated against atypical pulse rates. In multiple-stimulus trials with normal range pulse rates, younger females were discriminatory; older females were not. Mated females showed reduced phonotaxis and selectivity irrespective of mating interval.

Surveillance for colorectal neoplasia in inflammatory bowel disease (IBD) is widely practised despite a lack of convincing mortality reduction. The psychological impact of this approach is largely unexplored.To examine psychological well-being among IBD subjects undergoing colonoscopic surveillance for colorectal cancer (CRC).A cross-sectional study was performed by interrogating an IBD database for subjects currently enrolled in colonoscopic surveillance programmes. Identified surveillance subjects were age- and gender-matched with IBD control subjects not meeting surveillance criteria. Subjects were mailed a questionnaire including demographic details, the Short Form 36 (SF-36) survey to assess quality of life, the Spielberger State-Trait Personality Inventory, the Multidimensional Health Locus of Control, and a Risk Perception Questionnaire.One hundred and thirty-nine of 286 (49%) subjects responded, 53% male, 46% Crohn disease. Fifty-six per cent respondents were in the surveillance group. Surveillance subjects were older (55.4 vs 51.1 years; P = .048) with longer disease duration, but otherwise had comparable demographics with controls. Overall, quality of life was not significantly different between cohorts (mean SF-36 63.82 vs 65.48; P = 0.70). Groups did not differ on any locus of control classification (P = 0.52), nor was there any difference between mean scores on 'state' subscales of the Spielberger State-Trait Personality Inventory: anxiety (P = 0.91), curiosity (P = 0.12), anger (P = 0.81) or depression (P = 0.70). Both groups grossly overestimated their perceived lifetime risk of CRC at 50%, with no difference between surveillance and control subjects (P = 1.0).Enrolment in colonoscopic colon cancer surveillance does not appear to impair psychological well-being in individuals with IBD despite longer disease duration. IBD patients overestimate their risk of CRC.

A highly chemo- and diastereoselective protocol toward amino-substituted donor−acceptor cyclopropanes via the formal nucleophilic displacement in bromocyclopropanes is described. A wide range of N-nucleophiles, including carboxamides, sulfonamides, azoles, and anilines, can be efficiently employed in this transformation, providing expeditious access to stereochemically defined and densely functionalized cyclopropylamine derivatives.