A Modular Fluorescent Probe for Viscosity and Polarity Sensing in DNA Hybrid Mesostructures

here exists a critical need in biomedical molecular imaging and diagnostics for molecular sensors that report on slight changes to their local microenvironment with high spatial fidelity. Herein, a modular fluorescent probe, termed StyPy, is rationally designed which features i) an enormous and tunable Stokes shift based on twisted intramolecular charge transfer (TICT) processes with no overlap, a broad emission in the far‐red/near‐infrared (NIR) region of light and extraordinary quantum yields of fluorescence, ii) a modular applicability via facile para‐fluoro‐thiol reaction (PFTR), and iii) a polarity‐ and viscosity‐dependent emission. This renders StyPy as a particularly promising molecular sensor. Based on the thorough characterization on the molecular level, StyPy reports on the viscosity change in all‐DNA microspheres and indicates the hydrophilic and hydrophobic compartments of hybrid DNA‐based mesostructures consisting of latex beads embedded in DNA microspheres. Moreover, the enormous Stokes shift of StyPy enables one to detect multiple fluorophores, while using only a single laser line for excitation in DNA protocells. The authors anticipate that the presented results for multiplexing information are of direct importance for advanced imaging in complex soft matter and biological systems

Self-reporting visible light-induced polymer chain collapse

We introduce a facile photoinduced self-reporting crosslinking methodology for the compaction of polymer chains in highly diluted solution. The chain compaction, which is readily monitored via the change in optical properties due to the release of the chromophore, is achieved via mild visible light irradiation (430-435 nm) of statistically distributed pyrene-substituted oxime ester derivatives. In-depth characterization via size exclusion chromatography (SEC), UV/Vis and fluorescence spectroscopy, as well as NMR measurements including diffusion ordered spectroscopy (DOSY), reveals an efficient system, which may serve as a blueprint for reading out the state of SCNPs in more complex scenarios.</p

DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality

AIMS/HYPOTHESIS: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. RESULTS: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. CONCLUSIONS/INTERPRETATION: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529

Effectiveness of Compounded Bioidentical Hormone Replacement Therapy: An Observational Cohort Study

<p>Abstract</p> <p>Background</p> <p>Bioidentical Hormone Replacement Therapy (BHRT) is believed it to be a safer and equally effective alternative to Conventional Hormone Therapy for the relief of menopausal symptoms; however, data are needed to support these claims. The objective of this study is to evaluate the effectiveness of compounded BHRT provided in six community pharmacies.</p> <p>Methods</p> <p>This was an observational cohort study of women between the ages of 18-89 who received a compounded BHRT product from January 1, 2003 to April 30, 2010 in six community pharmacies. Data included patient demographics, comorbidities, therapeutic outcomes, and hormone therapies. Women self-rated menopausal symptoms as absent, mild, moderate, or severe. Descriptive statistics were used to characterize the patient population, BHRT use, and adverse events. Patient symptom severity was compared at baseline and 3 to 6 months follow-up using the Wilcoxon signed-rank test.</p> <p>Results</p> <p>Women (n = 296) receiving BHRT at Oakdell Pharmacy had a mean (standard deviation) age of 52 (9) years. The most common BHRT dosage forms utilized were topical (71%) and oral (43%). Compounded BHRT regimens were generally initiated at low doses regardless of route. Women experienced a 25% decrease in emotional lability (p < 0.01), a 25% decrease in irritability (p < 0.01), and a 22% reduction in anxiety (p = 0.01) within 3 to 6 months. These women also experienced a 14% reduction in night sweats (p = 0.09) and a 6% reduction in hot flashes (p = 0.50).</p> <p>Conclusions</p> <p>This study demonstrates that compounded BHRT improves mood symptoms. Larger studies are needed to examine the impact on vasomotor symptoms, myocardial infarction and breast cancer.</p

Biodegradable core crosslinked star polymer nanoparticles as 19F MRI contrast agents for selective imaging

With the aim of developing stimuli-responsive imaging agents, we report here the synthesis of core crosslinked star (CCS) polymers and their evaluation as pH-sensitive 19F magnetic resonance imaging (19F MRI) contrast agents. Block copolymers consisting of poly(ethylene glycol)methyl ether methacrylate (PPEGMA) as the first block and a copolymer of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,2-trifluoroethyl methacrylate (TFEMA) as the second block were synthesised using RAFT polymerisation. The polymerisation kinetics were studied in detail. The block copolymers were then used as arm precursors for the arm-first synthesis of CCS polymers through RAFT dispersion polymerisation. The synthetic conditions were investigated and optimised. CCS polymers with a degradable core were also synthesised and evaluated as 19F MRI contrast agents. The degradation of the core was confirmed by treatment with various reducing agents. The particle size, 19F NMR signal and relaxation times as well as 19F MRI imaging performance of the CCS polymers were studied at a range of value of solution pH. Significant enhancement of the image intensity was observed when the pH was decreased from 8 to 5, indicating that the CCS nanoparticles could be used as 19F MRI contrast agents for the detection of the acidic environment within tumour tissue

Boundary Capabilities in MNCs: Knowledge Transformation for Creative Solution Development

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The management of knowledge across country units is critical to multinational corporations (MNCs). Building on the argument that boundary spanning leads to the development of creative problem solving outcomes, this study advances the concept of MNC knowledge transformation and examines its relationship with solution creativity. Using questionnaire data on 67 problem solving projects, we find that opportunity formation is an underlying mechanism linking MNC knowledge transformation to the development of creative solutions. These insights contribute to our understanding of boundary spanning in global organizations by substantiating MNC knowledge transformation and elaborating the relationship between boundary spanning and creative solution development. If successful at knowledge transformation, collaborators from across the MNC can construct previously unimagined opportunities for the generation of creative outcomes.This study was funded by the Irish Research Council with co-funding from the European Commission (Marie-Curie Fellowship). We are very grateful for the insightful comments of Phillip C. Nell, the three reviewers, editors and participants at the paper development workshop at Ivey Business School

Learning to represent exact numbers

This article focuses on how young children acquire concepts for exact, cardinal numbers (e.g., three, seven, two hundred, etc.). I believe that exact numbers are a conceptual structure that was invented by people, and that most children acquire gradually, over a period of months or years during early childhood. This article reviews studies that explore children’s number knowledge at various points during this acquisition process. Most of these studies were done in my own lab, and assume the theoretical framework proposed by Carey (2009). In this framework, the counting list (‘one,’ ‘two,’ ‘three,’ etc.) and the counting routine (i.e., reciting the list and pointing to objects, one at a time) form a placeholder structure. Over time, the placeholder structure is gradually filled in with meaning to become a conceptual structure that allows the child to represent exact numbers (e.g., There are 24 children in my class, so I need to bring 24 cupcakes for the party.) A number system is a socially shared, structured set of symbols that pose a learning challenge for children. But once children have acquired a number system, it allows them to represent information (i.e., large, exact cardinal values) that they had no way of representing before

Recent advances in glycopolypeptide synthesis

Glycosylated peptides and proteins are ubiquitous in nature and display a wide range of biological functions including mediation of recognition events, protection from proteases, and lubrication in eyes and joints. Similarly, synthetic glycopolypeptides are also expected to show great potential as biomedical materials (e.g. scaffolds for tissue repair and drug carriers), as well as serve as valuable tools for probing carbohydrate-protein interactions. Although block copolypeptides and other complex polypeptide architectures have been known for some time, the synthesis of complex and well-defined glycopolypeptide materials, until recently, has been challenging. This article reviews the many advances and accomplishments made in the past few years toward development of strategies and methods for the preparation of synthetic glycopolypeptides via ring opening polymerization. © 2014 The Royal Society of Chemistry