Non-Surgical Site Pain in Women following Breast Cancer Surgery: A Systematic Review and Meta-Analysis.

Background: Chronic pain after breast cancer surgery affects up to 60% of patients. Evidence supports the fact that pain outwith the surgical site is a significant issue. This systematic review and meta-analysis sought to evaluate the prevalence of non-surgical site pain (NSSP) in women after breast cancer surgery at 6 months post-operatively. Methods: Adult women with a confirmed breast cancer diagnosis who had undergone breast cancer surgery were identified. The outcome pursued was pain outwith the surgical site measured on either NRS/VRS or VAS rating scale. CENTRAL, Embase, PubMed, MEDLINE, CINAHL, PsycInfo, Web of Science, and Scopus were searched to identify studies that examined NSSP after breast cancer surgery at 6 months. Data were gathered via pre-piloted Excel forms and analysed both quantitively and qualitatively. Meta-analysis was carried out using a random-effects model to assess risk difference with 95% confidence interval (CI). Results: A total of sixteen studies were identified for inclusion. Eleven studies failed to provide sufficient data and consequently were analysed qualitatively. Five studies were adequate for quantitative analysis, including a total of 995 patients. Meta-analysis identified a risk difference of 18% (95% CI: 5-31%) between patients who had breast cancer surgery and a reference, however, this is low-quality evidence. Conclusion: This review has highlighted that breast cancer surgery increases the risk of pain outwith the surgical site postoperatively. It was additionally identified that NSSP data are often gathered in research yet rarely presented in results or highlighted as a primary outcome. As the quality of evidence was low, research specifying NSSP as a primary outcome is required to provide more certainty.

Regional variation in the antibacterial activity of a wild plant, wild garlic (Allium ursinum L.).

Antibacterial activity is a common and highly studied property of plant secondary metabolites. Despite the extensive literature focusing on identifying novel antibacterial metabolites, little work has been undertaken to examine variation in levels of antibacterial activity in any plant species. Here, we used large-scale sampling of leaves of the antibacterial plant, wild garlic (Allium ursinum L.), assembling a set of tissue extracts from 168 plants, with 504 leaves collected and analysed. We assayed extracts for antibacterial activity against Bacillus subtilis and used LC-MS to carry out a chemometric analysis examining variation in individual metabolites, comparing them with several ecological parameters. We found that allicin was the only metabolite which was positively related to antibacterial activity. Soil temperature was a key determinant of variability in the concentrations of many foliar metabolites, however, neither allicin concentrations nor antibacterial activity was related to any of our measured ecological parameters, other than roadside proximity. We suggest that the synthesis of allicin precursors may be largely independent of growing conditions. This may be to ensure that allicin is synthesised rapidly and in sufficiently high concentrations to effectively prevent herbivory and pest damage. This finding contrasts with flavonoids which were found to vary greatly between plants and across sites. Our findings suggest that key biologically active metabolites are constrained in their concentration range compared to other compounds in the metabolome. This has important implications for the development of wild garlic as a health supplement or animal feed additive.

New Constraints on Dark Photon Dark Matter with Superconducting Nanowire Detectors in an Optical Haloscope.

Uncovering the nature of dark matter is one of the most important goals of particle physics. Light bosonic particles, such as the dark photon, are well-motivated candidates: they are generally long-lived, weakly interacting, and naturally produced in the early universe. In this work, we report on Light A^{'} Multilayer Periodic Optical SNSPD Target, a proof-of-concept experiment searching for dark photon dark matter in the eV mass range, via coherent absorption in a multilayer dielectric haloscope. Using a superconducting nanowire single-photon detector (SNSPD), we achieve efficient photon detection with a dark count rate of ∼6×10^{-6} counts/s. We find no evidence for dark photon dark matter in the mass range of ∼0.7-0.8 eV with kinetic mixing ε≳10^{-12}, improving existing limits in ε by up to a factor of 2. With future improvements to SNSPDs, our architecture could probe significant new parameter space for dark photon and axion dark matter in the meV to 10 eV mass range.

Physician Support for Non-Physician Advanced Practice Providers for Persons With Cardiopulmonary Disease.

BACKGROUND: The use of non-physician advanced practice providers (NPAPP) has increased in the United States to offset shortages in the physician workforce. Yet there are still gaps in some locations where there is little to no access to quality health care. This study sought to identify whether physicians perceived a workforce gap and their level of interest in hiring an NPAPP with cardiopulmonary expertise to fill the perceived gap. METHODS: An American Association for Respiratory Care (AARC)-led workgroup surveyed 1,401 physicians in 6 different specialties. The survey instrument contained 32 closed-ended questions and 4 open-ended questions. RESULTS: 74% of the 1,401 physician respondents agreed or strongly agreed that there will be a future need for an NPAPP with cardiopulmonary expertise. Respondents from sleep, pediatrics, pulmonary, and critical care were most likely to indicate that there is a current need for an NPAPP. A majority of respondents perceived that the specialized NPAPP would improve efficiency and productivity (74%), patient experience (73%), and patient outcomes (72%). Interest in adding this NPAPP did not increase when participants were told to presume authority for hiring, budget, and reimbursement. CONCLUSIONS: These results indicate that there is both a need for and an interest in hiring an NPAPP with cardiopulmonary expertise. Having an NPAPP would boost physician efficiency and productivity, improve the patient care experience, and provide benefits that other clinicians are not trained to provide to persons with cardiopulmonary disease. Results suggest there should be continued efforts to develop the NPAPP role to add value for physicians and patients alike.

Orientation mapping with Kikuchi patterns generated from a focused STEM probe and indexing with commercially available EDAX software.

Relating a crystal's microscopic structure-such as orientation and size-to a material's macroscopic properties is of great importance in materials science. Although most crystal orientation microscopy is performed in the scanning electron microscope (SEM), transmission electron microscopy (TEM)-based methods have a number of benefits, including higher spatial resolution. Current TEM orientation methods have either specific hardware requirements or use software that has limited scope, utility, or availability. In this article, a technique is described for orientation mapping using Kikuchi diffraction patterns generated from a focused STEM probe. One key advantage is that indexing and analysis of the patterns and maps occurs in the robust OIM Analysis software, currently widely used for electron backscatter diffraction (EBSD) and transmission Kikuchi diffraction (TKD) analysis. It was found that with minimal to no image processing and by changing only a few software parameters, reliable indexing of Kikuchi patterns is possible. Three samples, a deformed ß-Titanium (Ti), a medium carbon heat-treated steel, and BaCe0.8Y0.2O3-δ were tested to determine the effectiveness of the approach. In all three measurements the algorithms effectively and reliably determined the phases and the crystal orientations of the features measured. For the two orientation maps produced, less than 5% of the patterns were misindexed including boundary areas where overlapping patterns existed. An angular resolution of 0.15° was achieved while features <25 nm were able to be spatially resolved.

Predictors of the Perception of Smoking Health Risks in Smokers With or Without Schizophrenia.

OBJECTIVE: This study sought to examine the predictors of health risk perception in smokers with or without schizophrenia. METHODS: The health risk subscale from the Smoking Consequences Questionnaire was dichotomized and used to measure health risk perception in smokers with (n = 67) and without schizophrenia (n = 100). A backward stepwise logistic regression was conducted using variables associated at the bivariate level to determine multivariate predictors. RESULTS: Overall, 62.5% of smokers without schizophrenia and 40.3% of smokers with schizophrenia completely recognize the health risks of smoking (p ≤ .01). Multivariate predictors for smokers without schizophrenia included: sex (Exp (B) = .3; p < .05), Smoking Consequences Questionnaire state enhancement (Exp (B) = .69; p < .01), and craving relief (Exp (B) = 1.8; p < .01). Among smokers with schizophrenia, predictors were education (Exp (B) = .7; p < .05), nicotine dependence (Exp (B) = .5; p < .01), motivation to quit (Exp (B) = 1.8; p < .01), and Smoking Consequences Questionnaire craving relief (Exp (B) = 1.8; p < .01). CONCLUSIONS: There was overlap and differences between predictors in smokers with and without schizophrenia. Commonly used techniques for education on the health consequences of cigarettes may work in smokers with schizophrenia, but intervention efforts specifically tailored to smokers with schizophrenia might be more efficacious.

Rheology and dynamics of colloidal superballs.

Recent advances in colloidal synthesis make it possible to generate a wide array of precisely controlled, non-spherical particles. This provides a unique opportunity to probe the role that particle shape plays in the dynamics of colloidal suspensions, particularly at higher volume fractions, where particle interactions are important. We examine the role of particle shape by characterizing both the bulk rheology and micro-scale diffusion in a suspension of pseudo-cubic silica superballs. Working with these well-characterized shaped colloids, we can disentangle shape effects in the hydrodynamics of isolated particles from shape-mediated particle interactions. We find that the hydrodynamic properties of isolated superballs are marginally different from comparably sized hard spheres. However, shape-mediated interactions modify the suspension microstructure, leading to significant differences in the self-diffusion of the superballs. While this excluded volume interaction can be captured with a rescaling of the superball volume fraction, we observe qualitative differences in the shear thickening behavior of moderately concentrated superball suspensions that defy simple rescaling onto hard sphere results. This study helps to define the unknowns associated with the effects of shape on the rheology and dynamics of colloidal solutions.

Structure-guided optimization of small molecule c-Abl activators.

c-Abl kinase is maintained in its normal inactive state in the cell through an assembled, compact conformation. We describe two chemical series that bind to the myristoyl site of the c-Abl kinase domain and stimulate c-Abl activation. We hypothesize that these molecules activate c-Abl either by blocking the C-terminal helix from adopting a bent conformation that is critical for the formation of the autoinhibited conformation or by simply providing no stabilizing interactions to the bent conformation of this helix. Structure-based molecular modeling guided the optimization of binding and activation of c-Abl of these two chemical series and led to the discovery of c-Abl activators with nanomolar potency. The small molecule c-Abl activators reported herein could be used as molecular tools to investigate the biological functions of c-Abl and therapeutic implications of its activation.

Physiological and medical findings in insomnia: implications for diagnosis and care.

This review will examine objective physiological abnormalities and medical comorbidities associated with insomnia and assess the need to measure parameters associated with these abnormalities for diagnosis and to monitor treatment outcomes. Findings are used to develop a decision tree for the work-up of insomnia patients. Currently available measures and those with possible future predictive value will be discussed. Costs, advantages, and the development of screening laboratory tests will be presented. It is concluded that there is a need to differentially evaluate insomnia patients based upon their comorbidities and the presence of objectively decreased total sleep time to direct optimal treatment. The development of objective diagnostic criteria and treatment outcome goals beyond subjective symptomatic relief will establish insomnia as a true medical problem and improve patient care.

Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.

c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

The characterization of a novel V1b antagonist lead series.

The SAR around a V1b antagonist HTS hit 3 was explored to produce a series of thiazole sulfonamides as a lead series with selectivity over the related V1 and oxytocin receptors.

Facile synthesis of 6-aryl 5-N-substituted pyridazinones: microwave-assisted Suzuki-Miyaura cross coupling of 6-chloropyridazinones.

A facile synthesis of 5-dialkylamino-6-aryl-(2H)-pyridazin-3-one from 5,6-dichloropyridazinone was carried out by using a palladium-catalyzed Suzuki-Miyaura cross coupling of 6-chloro-5-dialkylaminopyridazinone 1 with various arylboronic acids (3 equiv) as the key transformation. The Suzuki-Miyaura cross-coupling reaction proceeded smoothly under microwave irradiation at 135-140 degrees C for 30 min with 5 mol % of Pd catalyst in moderate to good isolated yields. The use of a CombiPhos Pd6 mixture catalyst system and a single Pd-SPhos catalyst system was evaluated.

Real-time MR imaging-guided laser atrial septal puncture in swine.

PURPOSE: The authors performed this study to report their initial preclinical experience with real-time magnetic resonance (MR) imaging-guided atrial septal puncture by using a MR imaging-conspicuous blunt laser catheter that perforates only when energized. MATERIALS AND METHODS: The authors customized a 0.9-mm clinical excimer laser catheter with a receiver coil to impart MR imaging visibility at 1.5 T. Seven swine underwent laser transseptal puncture under real-time MR imaging. MR imaging signal-to-noise ratio profiles of the device were obtained in vitro. Tissue traversal force was tested with a calibrated meter. Position was corroborated with pressure measurements, oximetry, angiography, and necropsy. Intentional non-target perforation simulated serious complication. RESULTS: Embedded MR imaging antennae accurately reflected the position of the laser catheter tip and profile in vitro and in vivo. Despite having an increased profile from the microcoil, the 0.9-mm laser catheter traversed in vitro targets with similar force (0.22 N +/- 0.03) compared with the unmodified laser. Laser puncture of the atrial septum was successful and accurate in all animals. The laser was activated an average of 3.8 seconds +/- 0.4 before traversal. There were no sequelae after 6 hours of observation. Necropsy revealed 0.9-mm holes in the fossa ovalis in all animals. Intentional perforation of the aorta and atrial free wall was evident immediately. CONCLUSIONS: MR imaging-guided laser puncture of the interatrial septum is feasible in swine and offers controlled delivery of perforation energy by using an otherwise blunt catheter. Instantaneous soft tissue imaging provides immediate feedback on safety.

Studies on acyl pyrrolidine inhibitors of HCV RNA-dependent RNA polymerase to identify a molecule with replicon antiviral activity.

The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon).

Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate.

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.

An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.

An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available chiral Fmoc-protected alpha-amino acids loaded onto Wang resin, Fmoc removal, reductive amination followed by amide bond formation, and base-catalyzed cyclization with simultaneous cleavage from the resin provided the desired products. Compounds described are potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.

Identification of small molecule inhibitors of the hepatitis C virus RNA-dependent RNA polymerase from a pyrrolidine combinatorial mixture.

HTS of the compound collection for inhibition of the HCV RNA dependent RNA polymerase identified two 168 member N-acyl pyrrolidine combinatorial mixture hits. Deconvolution and expansion of these mixtures by solid phase synthesis to establish initial SAR and identify a potent inhibitor is reported.

Palladium-catalyzed intermolecular coupling of aryl chlorides and sulfonamides under microwave irradiation.

[reaction: see text] An efficient intermolecular N-arylation of sulfonamides with aryl chlorides is realized using palladium catalysis. The reaction proceeds under microwave irradiation at 180-200 degrees C for 10 min with 2-10 mol % of Pd catalyst in 32-85% isolated yields.