Search

Marco Boeri,1 Boglarka Szegvari,2 Brett Hauber,3 Brennan Mange,3 Irina Mountian,2 Michael Schiff,4 Nikolaos Maniadakis51RTI Health Solutions, Belfast, UK; 2UCB Pharma, Brussels, Belgium; 3RTI Health Solutions, Research Triangle Park, NC, USA; 4Rheumatology Division, University of Colorado School of Medicine, Denver, CO, USA; 5Health Services Management, National School of Public Health, Athens, GreecePurpose: To quantify rheumatology patient preferences and willingness to pay (WTP) for features differentiating enhanced from standard self-injection devices and to investigate differences among subgroups.Patients and methods: Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) were recruited in the UK. A discrete-choice experiment was used to elicit preferences; respondents were presented with 10 choices between 3 different devices: a free standard disposable device, and 2 hypothetical reusable devices characterized by presence/absence of skin sensor, injection speed control, on-screen instructions, injection reminders, electronic log, and large grip. Every hypothetical device included a cost component to assess WTP for each enhanced feature. A random-parameters logit model was used to estimate preference weights and WTP.Results: Data were collected from 323 respondents by electronic survey (15/11/2017–15/02/2018; RA: 108; PsA: 103; axSpA: 112). On average, the skin sensor was the most preferred feature (£30), followed by injection speed control, injection reminders, electronic log (∼£20 each), on-screen instructions (∼£12), and a device with a small, rather than large grip (∼£7). Similar preferences for attributes were observed across condition subgroups except for grip size: axSpA patients preferred small grip (∼£27); PsA patients preferred large grip (∼£19). Overall, respondents preferred reusable devices with all enhanced features (WTP value: £85) over the standard device. RA patients exhibited a higher WTP (£145) than PsA (£102) or axSpA (£62) for the same enhanced device.Conclusion: Patients positively valued reusable self-injection devices with enhanced features, which may improve patient experience, potentially improving treatment adherence, clinical, and economic outcomes.Keywords: rheumatology, subcutaneous injection, self-administration, patient preference, discrete-choice experiment

Globally, ocean dumping of chemical waste is a common method of disposal and relies on the assumption that dilution, diffusion, and dispersion at ocean scales will mitigate human exposure and ecosystem impacts. In southern California, extensive dumping of agrochemical waste, particularly chlorinated hydrocarbon contaminants such as DDT, via sewage outfalls and permitted offshore barging occurred for most of the last century. This study compiled a database of existing sediment and fish DDT measurements to examine how this unique legacy of regional ocean disposal translates into the contemporary contamination of the coastal ocean. We used spatiotemporal modeling to derive continuous estimates of sediment DDT contamination and show that the spatial signature of disposal (i.e., high loadings near historic dumping sites) is highly conserved in sediments. Moreover, we demonstrate that the proximity of fish to areas of high sediment loadings explained over half of the variation in fish DDT concentrations. The relationship between sediment and fish contamination was mediated by ecological predictors (e.g., species, trophic ecology, habitat use), and the relative influence of each predictor was context-dependent, with habitat exhibiting greater importance in heavily contaminated areas. Thus, despite more than half a century since the cessation of industrial dumping in the region, local ecosystem contamination continues to mirror the spatial legacy of dumping, suggesting that sediment can serve as a robust predictor of fish contamination, and general ecological characteristics offer a predictive framework for unmeasured species or locations.

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.