Transesterification of Poly(ethyl glyoxylate): A Route to Structurally Diverse Polyglyoxylates

Polyglyoxylates are a class of self-immolative polymers that depolymerize in solution and the solid state. The glyoxylic acid degradation product is a metabolite in the glyoxylate cycle and can also be processed in the liver in humans, making polyglyoxylates attractive for applications in the environment and in medicine. Although expanding the scope of available polyglyoxylates would enable new properties and applications, highly pure glyoxylate monomers are required for polymerization, and this level of purity is difficult to achieve for many potential monomers. To address this challenge, we report here the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed post-polymerization transesterification of poly(ethyl glyoxylate) (PEtG) as a general method for the synthesis of directly inaccessible polyglyoxylates. Using a new end-capping strategy, PEtG compatible with the transesterification reaction was developed. n-Propanol, i-propanol, n-butanol, t-butanol, n-pentanol, n-hexanol, n-octanol, and benzyl alcohol were employed and the reactivities of these different alcohols were investigated. The resulting polyglyoxylates were characterized chemically and their thermal properties were compared. In all cases, the transesterified polyglyoxylates retained the stimuli-responsive depolymerization properties of the parent PEtG. In addition, functional polyglyoxylates based on allyl, propargyl, and furfuryl esters, which are suitable for subsequent click reactions, were prepared. The propargyl-functionalized polyglyoxylate was used to conjugate pyrene, and the resulting molecules underwent a change in fluorescence properties upon depolymerization

Tuning the hydrophobic cores of self-immolative polyglyoxylate assemblies

Polyglyoxylates are a recently-introduced class of self-immolative polymers, that depolymerize to small molecules upon the cleavage of a stimuli-responsive end-cap from the polymer terminus. The incorporation of different pendant ester groups or other aldehyde monomers offers the potential to tune the polymer properties, but this remains largely unexplored. With the goal of tuning the self-assembly and drug-loading properties of polyglyoxylate block copolymers, we explored the polymerization and copolymerization of n-butyl glyoxylate, L-menthyl glyoxylate, and chloral with ethyl glyoxylate to form UV light-responsive polyglyoxylates. The resulting polymers were coupled to poly(ethylene glycol) to afford amphiphilic block copolymers. Self-assembly of the different copolymers was studied and although each system formed solid particles, the cores of the assemblies differed in their stability, hydrophobicity, and their ability to load the hydrophobic drug celecoxib. All systems depolymerized and released the drug in response to UV light. The toxicity profiles for the assemblies were also evaluated using MDA-MB-231 cells. Overall, this work demonstrates that the properties of polyglyoxylates and their assemblies can be readily tuned through the incorporation of new monomers, thereby providing a promising platform for drug delivery and other applications

Examining the effectiveness of general practitioner and nurse promotion of electronic cigarettes versus standard care for smoking reduction and abstinence in hardcore smokers with smoking-related chronic disease:protocol for a randomised controlled trial

BACKGROUND: Despite the clear harm associated with smoking tobacco, many people with smoking-related chronic diseases or serious mental illnesses (SMI) are unwilling or unable to stop smoking. In many cases, these smokers have tried and exhausted all methods to stop smoking and yet clinicians are repeatedly mandated to offer them during routine consultations. Providing nicotine through electronic cigarettes (e-cigarettes) may reduce the adverse health consequences associated with tobacco smoking, but these are not currently offered. The aim of this study is to examine the feasibility, acceptability and effectiveness of general practitioners (GPs) and nurses delivering a brief advice intervention on e-cigarettes and offering an e-cigarette starter pack and patient support resources compared with standard care in smokers with smoking-related chronic diseases or SMI who are unwilling to stop smoking. METHODS/DESIGN: This is an individually randomised, blinded, two-arm trial. Smokers with a smoking-related chronic condition or SMI with no intention of stopping smoking will be recruited through primary care registers. Eligible participants will be randomised to one of two groups if they decline standard care for stopping smoking: a control group who will receive no additional support beyond standard care; or an intervention group who will receive GP or nurse-led brief advice about e-cigarettes, an e-cigarette starter pack with accompanying practical support booklet, and telephone support from experienced vapers and online video tutorials. The primary outcome measures will be smoking reduction, measured through changes in cigarettes per day and 7-day point-prevalence abstinence at 2 months. Secondary outcomes include smoking reduction, 7-day point-prevalence abstinence and prolonged abstinence at 8 months. Other outcomes include patient recruitment and follow-up, patient uptake and use of e-cigarettes, nicotine intake, contamination of randomisation and practitioner adherence to the delivery of the intervention. Qualitative interviews will be conducted in a subsample of practitioners, patients and the vape team to garner their reactions to the programme. DISCUSSION: This is the first randomised controlled trial to investigate whether e-cigarette provision alongside a brief intervention delivered by practitioners leads to reduced smoking and abstinence among smokers with smoking-related chronic diseases or SMI. TRIAL REGISTRATION: ISRCTN registry, ISRCTN59404712. Registered 28/11/17

A mixed methods process evaluation of a person-centred falls prevention program

Background RESPOND is a telephone-based falls prevention program for older people who present to a hospital emergency department (ED) with a fall. A randomised controlled trial (RCT) found RESPOND to be effective at reducing the rate of falls and fractures, compared with usual care, but not fall injuries or hospitalisations. This process evaluation aimed to determine whether RESPOND was implemented as planned, and identify implementation barriers and facilitators. Methods A mixed-methods evaluation was conducted alongside the RCT. Evaluation participants were the RESPOND intervention group (n=263) and the clinicians delivering RESPOND (n=7). Evaluation data were collected from participant recruitment and intervention records, hospital administrative records, audio-recordings of intervention sessions, and participant questionnaires. The Rochester Participatory Decision-Making scale (RPAD) was used to evaluate person-centredness (score range 0 (worst) - 9 (best)). Process factors were compared with pre-specified criteria to determine implementation fidelity. Six focus groups were held with participants (n=41), and interviews were conducted with RESPOND clinicians (n=6). Quantitative data were analysed descriptively and qualitative data thematically. Barriers and facilitators to implementation were mapped to the ‘Capability, Opportunity, Motivation – Behaviour’ (COM-B) behaviour change framework. Results RESPOND was implemented at a lower dose than the planned 10 hours over six months, with a median (IQR) of 2.9 hours (2.1, 4). The majority (76%) of participants received their first intervention session within one month of hospital discharge. Clinicians delivered the program in a person-centred manner with a median (IQR) RPAD score of 7 (6.5, 7.5) and 87% of questionnaire respondents were satisfied with the program. The reports from participants and clinicians suggested that implementation was facilitated by the use of positive and personally relevant health messages. Complex health and social issues were the main barriers to implementation. Conclusions RESPOND was person-centred and reduced falls and fractures at a substantially lower dose, using fewer resources, than anticipated. However, the low dose delivered may account for the lack of effect on falls injuries and hospitalisations. The results from this evaluation provide detailed information to guide future implementation of RESPOND of similar programs. Trial registration: This study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614000336684 (27 March 2014)

Triggering Depolymerization: Progress and Opportunities for Self-Immolative Polymers

© 2019 American Chemical Society. Polymers that depolymerize end-to-end upon cleavage of their backbones or end-caps, often termed self-immolative polymers (SIPs), have garnered significant interest in recent years. They can be distinguished from other degradable and stimuli-responsive polymers by their ability to provide amplified responses to stimuli, as a single bond cleavage event is translated into the release of many small molecules through a cascade of reactions. Here, the synthesis and properties of the major classes of SIPs including poly(benzyl carbamate)s, poly(benzyl carbonate)s, poly(benzyl ether)s polyphthalaldehydes, polyglyoxylates, polyglyoxylamides, and poly(olefin sulfone)s are presented. In addition, their advantages and limitations as well as their recent applications in areas including sensors, drug delivery, micro- and nanopatterning, transient devices and composites, coatings, antibacterial, and recyclable plastics are described. Finally, the challenges associated with the development of new SIP backbones and their translation into commercial products are discussed

Vigorous intensity exercise for glycemic control in patients with type 1 diabetes

Regular physical activity has substantial health benefits in persons with type 1 diabetes, including reduced risk of complications and cardiovascular mortality as well as improved self-rated quality of life. Despite these benefits, individuals with type 1 diabetes are often less active than their peers without diabetes. When factors such as time constraints, work pressure and environmental conditions are often cited as barriers to physical activity in the general population, 2 additional major factors may also explain the low rates of physical activity in young people with type 1 diabetes: (1) fear of hypoglycemia both during and after (particularly overnight) exercise and (2) a lack of empiric evidence for the efficacy of physical activity for achieving optimal glycemic control. A number of acute exercise trials recently showed that the inclusion of vigorous intensity physical activity in conventional moderate intensity (i.e. walking and light cycling) exercise sessions may overcome these barriers. No studies have tested the efficacy of high-intensity physical activity on glycemic control (A1C) or post-exercise hypoglycemia in a randomized controlled trial. This article summarizes the literature related to the role of physical activity for the management of blood glucose levels in individuals with type 1 diabetes and provides a rationale for the need of a randomized controlled trial examining the effects of vigorous-intensity physical activity on blood glucose control

EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-Expressing Breast Cancer

PURPOSE: Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS: Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator\u27s choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS: Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION: Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway

Minimal effect of walking before dinner on glycemic responses in type 2 diabetes: outcomes from the multi-site E-PAraDiGM study

Aim To examine the effect of walking before dinner on 24-h glycemic control in individuals with type 2 diabetes using the standardized multi-site Exercise-Physical Activity and Diabetes Glucose Monitoring (E-PAraDiGM) Protocol. Methods Eighty participants were studied under two conditions (exercise vs. non-exercise control) separated by 72 h in a randomized crossover design. Each condition lasted 2 days during which standardized meals were provided. Exercise consisted of 50 min of treadmill walking at 5.0 km/h before the evening meal, while control involved 50 min of sitting. The primary outcome measure was mean glucose during the 24-h period following exercise (or sitting) measured by continuous glucose monitoring. Results Of the 80 participants who were initially randomized, 73 completed both exercise and control. Sixty-three participants [29 males, 34 females; age = 64 ± 8 years, body mass index = 30.5 ± 6.5 kg/m2 and HbA1c = 51 ± 8 mmol/mol (6.8 ± 0.7%), mean ± SD] complied with the standardized diets and had complete continuous glucose monitoring data. Exercise did not affect mean 24-h glucose compared to control (0.03 mmol/L; 95% CI − 0.17, 0.22, P = 0.778) but individual differences between conditions ranged from − 2.8 to +1.8 mmol/L. Exercise did not affect fasting glucose, postprandial glucose or glucose variability. Glucose concentrations measured by continuous glucose monitoring were reduced during the 50 min of walking in exercise compared to sitting in control (− 1.56 mmol/L; 95% CI − 2.18, − 0.95, p ˂ 0.001). Conclusion Contrary to previous acute exercise studies, 50 min of walking before dinner in the E-PAraDiGM protocol did not affect 24-h glucose profiles. However, highly heterogeneous responses to exercise were observed.</p