Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKa Polar Moiety

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Influence of Shared Medical Appointments on Patient Satisfaction: A Retrospective 3-Year Study

PURPOSE

Shared medical appointments (SMAs) are becoming popular, but little is known about their association with patient experience in primary care. We performed an exploratory analysis examining overall satisfaction and patient-centered care experiences across key domains of the patient-centered medical home among patients attending SMAs vs usual care appointments.

METHODS

We undertook a cross-sectional study using a mailed questionnaire measuring levels of patient satisfaction and other indicators of patient-centered care among 921 SMA and 921 usual care patients between 2008 and 2010. Propensity scores adjusted for potential case mix differences between the groups. Multivariate logistic regression assessed propensity-matched patients’ ratings of care. Generalized estimating equations accounted for physician-level clustering.

RESULTS

A total of 40% of SMA patients and 31% of usual care patients responded. In adjusted analyses, SMA patients were more likely to rate their overall satisfaction with care as “very good” when compared with usual care counterparts (odds ratio = 1.26; 95% CI, 1.05–1.52). In the analysis of patient-centered medical home elements, SMA patients rated their care as more accessible and more sensitive to their needs, whereas usual care patients reported greater satisfaction with physician communication and time spent during their appointment.

CONCLUSIONS

Overall, SMA patients appear more satisfied with their care relative to patients receiving usual care. SMAs may also improve access to care and deliver care that patients find to be sensitive to their needs. Further research should focus on enhancing patient-clinician communication within an SMA as this model of care becomes more widely adopted.     

Immune function in patients with β thalassaemia receiving the orally active iron-chelating agent deferiprone

Short-term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immunosuppression or immunodeficiency are observed during deferiprone therapy.     

Rate limit of protein elastic response is tether dependent

The elastic restoring force of tissues must be able to operate over the very wide range of loading rates experienced by living organisms. It is surprising that even the fastest events involving animal muscle tissues do not surpass a few hundred hertz. We propose that this limit is set in part by the elastic dynamics of tethered proteins extending and relaxing under a changing load. Here we study the elastic dynamics of tethered proteins using a fast force spectrometer with sub-millisecond time resolution, combined with Brownian and Molecular Dynamics simulations. We show that the act of tethering a polypeptide to an object, an inseparable part of protein elasticity in vivo and in experimental setups, greatly reduces the attempt frequency with which the protein samples its free energy. Indeed, our data shows that a tethered polypeptide can traverse its free-energy landscape with a surprisingly low effective diffusion coefficient D_eff ∼ 1,200 nm²/s. By contrast, our Molecular Dynamics simulations show that diffusion of an isolated protein under force occurs at D_eff ∼ 10⁸ nm²/s. This discrepancy is attributed to the drag force caused by the tethering object. From the physiological time scales of tissue elasticity, we calculate that tethered elastic proteins equilibrate in vivo with D_eff ∼ 10⁴–10⁶ nm²/s which is two to four orders magnitude smaller than the values measured for untethered proteins in bulk.     

Stone tool production and utilization by bonobo-chimpanzees (Pan paniscus)

Using direct percussion, language-competent bonobo-chimpanzees Kanzi and Pan-Banisha produced a significantly wider variety of flint tool types than hitherto reported, and used them task-specifically to break wooden logs or to dig underground for food retrieval. For log breaking, small flakes were rotated drill-like or used as scrapers, whereas thick cortical flakes were used as axes or wedges, leaving consistent wear patterns along the glued slits, the weakest areas of the log. For digging underground, a variety of modified stone tools, as well as unmodified flint nodules, were used as shovels. Such tool production and utilization competencies reported here in Pan indicate that present-day Pan exhibits Homo-like technological competencies.     

Area–heterogeneity tradeoff and the diversity of ecological communities

For more than 50 y ecologists have believed that spatial heterogeneity in habitat conditions promotes species richness by increasing opportunities for niche partitioning. However, a recent stochastic model combining the main elements of niche theory and island biogeography theory suggests that environmental heterogeneity has a general unimodal rather than a positive effect on species richness. This result was explained by an inherent tradeoff between environmental heterogeneity and the amount of suitable area available for individual species: for a given area, as heterogeneity increases, the amount of effective area available for individual species decreases, thereby reducing population sizes and increasing the likelihood of stochastic extinctions. Here we provide a comprehensive evaluation of this hypothesis. First we analyze an extensive database of breeding bird distribution in Catalonia and show that patterns of species richness, species abundance, and extinction rates are consistent with the predictions of the area–heterogeneity tradeoff and its proposed mechanisms. We then perform a metaanalysis of heterogeneity–diversity relationships in 54 published datasets and show that empirical data better fit the unimodal pattern predicted by the area–heterogeneity tradeoff than the positive pattern predicted by classic niche theory. Simulations in which species may have variable niche widths along a continuous environmental gradient are consistent with all empirical findings. The area–heterogeneity tradeoff brings a unique perspective to current theories of species diversity and has important implications for biodiversity conservation.     

An Ex Vivo Bacteriologic Study Comparing Antiseptic Techniques for Natural Orifice Translumenal Endoscopic Surgery (NOTES) via the Gastrointestinal Tract

Background

NOTES via the gastrointestinal tract raises the specter of intra-peritoneal infection. Various anti-microbial techniques have been employed in animal and human survival studies, including saline lavage, intravenous and topical antibiotics, and povidone-iodine, although there is a paucity of data regarding their general effectiveness.

Aim

To assess the effectiveness of existing sterilization techniques for NOTES by quantifying and speciating colony-forming units (CFUs) before and after treatment.

Design

Ex vivo animal studies; bacteriological study.

Methods

Stomachs and distal colons were harvested en bloc from ten fasted adult white pigs following euthanasia. Half received cefazolin 1 g intravenously prior to killing. Multiple tissue samples were obtained from each resected organ. Each tissue sample was then assigned to one of five treatment arms: (1) normal saline, (2) Betadine, (3) cefazolin/metronidazole suspension, (4) chlorhexidine, (5) no treatment. Fifteen samples were used per arm. After treatment, the mucosal surface of each sample was swabbed and inoculated in normal saline, followed by serial dilutions, which were then plated onto sheep’s blood agar plates and incubated under aerobic and anaerobic conditions. CFUs were quantified and speciated.

Results

Median bacterial density was estimated to be 8.0 × 10⁵ CFUs/ml (stomach) and 1.9 × 10⁶ CFUs/ml (colon). The predominant organisms were Escherichia coli (stomach) and both E. coli and Enterococcus sp. (colon). Saline and antibiotic suspension lavages caused a 1-log reduction in stomach and colon. Betadine/chlorhexidine lavage resulted in a 4-log reduction. Intravenous antibiotics alone resulted in a 4-log reduction. Combining intravenous antibiotics and either Betadine or chlorhexidine decreased counts to the 10¹ level. By Kruskal–Wallis method, differences were statistically significant (p = 0.001).

Conclusions

The use of intravenous antibiotics in addition to topical Betadine or chlorhexidine effectively reduced microbial burden in both gastric and colonic mucosa in this porcine model to the 10¹ level.     

Double jeopardy: balance between bleeding and stent thrombosis with prolonged dual antiplatelet therapy after drug-eluting stent implantation

Prolonged dual antiplatelet therapy with aspirin and clopidogrel is mandatory after drug-eluting stent (DES) implantation because of potential increase risk of stent thrombosis compared to bare-metal stents. As more DES are being implanted, many of these patients will undergo non-cardiac surgery whilst on antiplatelet therapy. The optimal management of perioperative antiplatelet therapy is not well established. The risk of excessive bleeding associated with antiplatelet therapy needs to be balanced against the risk of stent thrombosis with interruption of antiplatelet therapy on a case-to-case basis.     

Expansive remodeling in venous bypass grafts: novel implications for vein graft disease

ObjectiveTo date, intimal hyperplasia has been regarded as the principle mechanism responsible for subsequent vein graft disease. Lumen remodeling has not been previously considered as an additional mechanism. The objectives of this study were to determine changes in lumen remodeling in arterialized vein grafts, the accompanying cellular and extracellular matrix events contributing to remodeling, and the effects of a high cholesterol diet.Methods and resultsReversed jugular vein-to-common carotid artery interposition grafts were constructed in 70 normocholesterolemic and 11 hypercholesterolemic male New Zealand white rabbits. The lumen area initially remained unchanged between 1 and 4 weeks but significantly increased by 40% at 12 weeks. This phase of expansive positive remodeling was accompanied by significantly increased cell apoptosis, collagen synthesis (1.7-fold), collagen content (3.7-fold), gelatinase (MMP-2 and MMP-9) levels and decreased tissue inhibitor of metalloproteinase (TIMP) levels. Expansive remodeling temporally corresponded to high macrophage infiltration and increased low density lipoprotein (LDL) retention (fourfold) in the vein grafts. A high cholesterol diet stimulated early macrophage infiltration and increased MMP-12 (metalloelastase) levels, which was associated with earlier onset of expansive remodeling.ConclusionExpansive lumenal remodeling is a novel mechanism of vein graft response to the arterial circulation, which is accelerated by a high cholesterol diet.