Utilities associated with subcutaneous injections and intravenous infusions for treatment of patients with bone metastases

Introduction: Although cost−utility models are often used to estimate the value of treatments for metastatic cancer, limited information is available on the utility of common treatment modalities. Bisphosphonate treatment for bone metastases is frequently administered via intravenous infusion, while a newer treatment is administered as a subcutaneous injection. This study estimated the impact of these treatment modalities on health state preference. Methods: Participants from the UK general population completed time trade-off interviews to assess the utility of health state vignettes. Respondents first rated a health state representing cancer with bone metastases. Subsequent health states added descriptions of treatment modalities (ie, injection or infusion) to this basic health state. The two treatment modalities were presented with and without chemotherapy, and infusion characteristics were varied by duration (30 minutes or 2 hours) and renal monitoring. Results: A total of 121 participants completed the interviews (52.1% female, 76.9% white). Cancer with bone metastases had a mean utility of 0.40 on a standard utility scale (1 = full health; 0 = dead). The injection, 30-minute infusion, and 2-hour infusion had mean disutilities of −0.004, −0.02, and −0.04, respectively. The mean disutility of the 30-minute infusion was greater with renal monitoring than without. Chemotherapy was associated with substantial disutility (−0.17). When added to health states with chemotherapy, the mean disutilities of injection, 30-minute infusion, and 2-hour infusion were −0.02, −0.03, and −0.04, respectively. The disutility associated with injection was significantly lower than the disutility of the 30-minute and 2-hour infusions (P , 0.05), regardless of chemotherapy status. Conclusion: Respondents perceived an inconvenience with each type of treatment modality, but injections were preferred over infusions. The resulting utilities may be used in cost−utility models examining the value of treatments for the prevention of skeletal-related events in patients with bone metastases

Combining capture-recapture data and known ages allows estimation of age-dependent survival rates

In many animal populations, demographic parameters such as survival and recruitment vary markedly with age, as do parameters related to sampling, such as capture probability. Failing to account for such variation can result in biased estimates of population-level rates. However, estimating age-dependent survival rates can be challenging because ages of individuals are rarely known unless tagging is done at birth. For many species, it is possible to infer age based on size. In capture-recapture studies of such species, it is possible to use a growth model to infer the age at first capture of individuals. We show how to build estimates of age-dependent survival into a capture-mark-recapture model based on data obtained in a capture-recapture study. We first show how estimates of age based on length increments closely match those based on definitive aging methods. In simulated analyses, we show that both individual ages and age-dependent survival rates estimated from simulated data closely match true values. With our approach, we are able to estimate the age-specific apparent survival rates of Murray and trout cod in the Murray River, Australia. Our model structure provides a flexible framework within which to investigate various aspects of how survival varies with age and will have extensions within a wide range of ecological studies of animals where age can be estimated based on size

Health and mortality consequences of abdominal obesity : evidence from the AusDiab study

Objective: To provide an estimate of the morbidity and mortality resulting from abdominal overweight and obesity in the Australian population.Design and setting: Prospective, national, population-based study (the Australian Diabetes, Obesity and Lifestyle [AusDiab] study).Participants: 6072 men and women aged ≥ 25 years at study entry between May 1999 and December 2000, and aged ≤ 75 years, not pregnant and for whom there were waist circumference data at the follow-up survey between June 2004 and December 2005.Main outcome measures: Incident health outcomes (type 2 diabetes, hypertension, dyslipidaemia, the metabolic syndrome and cardiovascular diseases) at 5 years and mortality at 8 years. Comparison of outcome measures between those classified as abdominally overweight or obese and those with a normal waist circumference at baseline, and across quintiles of waist circumference, and (for mortality only) waist-to-hip ratio.Results: Abdominal obesity was associated with odds ratios of between 2 and 5 for incident type 2 diabetes, dyslipidaemia, hypertension and the metabolic syndrome. The risk of myocardial infarction among obese participants was similarly increased in men (hazard ratio [HR], 2.75; 95% CI, 1.08–7.03), but not women (HR, 1.43; 95% CI, 0.37–5.50). Abdominal obesity-related population attributable fractions for these outcomes ranged from 13% to 47%, and were highest for type 2 diabetes. No significant associations were observed between all-cause mortality and increasing quintiles of abdominal obesity.Conclusions: Our findings confirm that abdominal obesity confers a considerably heightened risk for type 2 diabetes, the metabolic syndrome (as well as its components) and cardiovascular disease, and they provide important information that enables a more precise estimate of the burden of disease attributable to obesity in Australia

Population demographics of golden perch (Macquaria ambigua) in the Darling River prior to a major fish kill: A guide for rehabilitation

An understanding of population demographics and life history processes is integral to the rehabilitation of fish populations. In Australia's highly modified Murray-Darling Basin, native fish are imperilled and fish deaths in the Darling River in 2018-19 highlighted their vulnerability. Golden perch (Macquaria ambigua) is a long-lived percichthyid that was conspicuous in the fish kills. To guide population rehabilitation in the Darling River, pre-fish kill age structure, provenance and movement of golden perch were explored using otolith microstructure and chemistry (87Sr/86Sr). Across the Lower and Mid-Darling River, recruitment was episodic, with dominant cohorts associated with years characterised by elevated discharge. There was substantial variability in age structure, recruitment source and movement patterns between the Lower and Mid-Darling River. In the Mid-Darling River, tributaries were an important recruitment source, whereas in the Lower Darling fish predominantly originated in the Darling River itself. Downstream movement of juveniles, upstream migration of adults and return movements to natal locations were important drivers of population structure. Restoring resilient golden perch populations in the Darling River will be reliant on mitigating barriers to movement, promoting a connected mosaic of recruitment sources and reinstating the hydrological and hydraulic factors associated with spawning, recruitment and dispersal. Globally, increasing water resource development and climate change will necessitate such integrated approaches to the management of long-lived migratory riverine fishes. © 2022 Journal Compilatio

Mobile Consumer Behavior in Fashion m-Retail: An Eye Tracking Study to Understand Gender Differences

© 2020 ACM. With exponential adoption of mobile devices, consumers increasingly use them for shopping. There is a need to understand the gender differences in mobile consumer behavior. This study used mobile eye tracking technology and mixed-method approach to analyze and compare how male and female mobile fashion consumers browse and shop on smartphones. Mobile eye tracking glasses recorded fashion consumers' shopping experiences using smartphones for browsing and shopping on the actual fashion retailer's website. 14 participants successfully completed this study, half of them were males and half females. Two different data analysis approaches were employed, namely a novel framework of the shopping journey, and semantic gaze mapping with 31 Areas of Interest (AOI) representing the elements of the shopping journey. The results showed that male and female users exhibited significantly different behavior patterns, which have implications for mobile website design and fashion m-retail. The shopping journey map framework proves useful for further application in market research

Binding Site Turnover Produces Pervasive Quantitative Changes in Transcription Factor Binding between Closely Related Drosophila Species

Genome-wide comparison of transcription factor binding between related Drosophila species highlights how sequence changes affect the biochemical events that underlie animal development

Cut-points for waist circumference in Europids and South Asians

There is little strong evidence that currently recommended higher waist circumference cut-points for Europids compared with South Asians are associated with similar risk for type 2 diabetes. This study was designed to provide such evidence. Longitudinal studies over 5 years were conducted among 5,515 Europid and 2,214 ethnically South Asian participants. Age-standardized diabetes incidence at different levels of waist circumference and incidence difference relative to a reference value were calculated. The Youden Index was used to determine waist circumference cut-points. At currently recommended cut-points, estimated annual diabetes incidence for a 50-year-old Europid was &lt;0.6% for both sexes, and for a 50-year-old South Asian, 5.8% for men and 2.1% for women. Annual diabetes incidence of 1% was observed for a 50 year old at a waist circumference 35&ndash;40 cm greater in Europid compared to South Asian men and women. Incidence difference between recommended cut-points and a reference value (80 cm in men, 70 cm in women) was 0.3 and 4.4% per year for Europid and South Asian men, and 0.2 and 0.8% per year for Europid and South Asian women, respectively. Waist circumference cut-points chosen using the Youden Index were shown to be dependent on obesity levels in the population. The much higher observed risk of diabetes in South Asians compared to Europids at the respective recommended waist circumference cut-points suggests that differences between them should be greater. Approaches that use the Youden Index to select waist circumference cut-points are inappropriate and should not be used for this purpose.<br /

Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Cornelia de Lange syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers it does not affect transcription of the pluripotency network in mouse embryonic stem cells. Rather, it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange syndrome

Comparative Gene Expression Profiling of P. falciparum Malaria Parasites Exposed to Three Different Histone Deacetylase Inhibitors

Histone deacetylase (HDAC) inhibitors are being intensively pursued as potential new drugs for a range of diseases, including malaria. HDAC inhibitors are also important tools for the study of epigenetic mechanisms, transcriptional control, and other important cellular processes. In this study the effects of three structurally related antimalarial HDAC inhibitors on P. falciparum malaria parasite gene expression were compared. The three hydroxamate-based compounds, trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA; Vorinostat®) and a 2-aminosuberic acid derivative (2-ASA-9), all caused profound transcriptional effects, with ∼2–21% of genes having >2-fold altered expression following 2 h exposure to the compounds. Only two genes, alpha tubulin II and a hydrolase, were up-regulated by all three compounds after 2 h exposure in all biological replicates examined. The transcriptional changes observed after 2 h exposure to HDAC inhibitors were found to be largely transitory, with only 1–5% of genes being regulated after removing the compounds and culturing for a further 2 h. Despite some structural similarity, the three inhibitors caused quite diverse transcriptional effects, possibly reflecting subtle differences in mode of action or cellular distribution. This dataset represents an important contribution to our understanding of how HDAC inhibitors act on malaria parasites and identifies alpha tubulin II as a potential transcriptional marker of HDAC inhibition in malaria parasites that may be able to be exploited for future development of HDAC inhibitors as new antimalarial agents

Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics

Published: April 13, 2023With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.Madeline G. Dans, Henni Piirainen, William Nguyen, Sachin Khurana, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Aurelie T. Dawson, Sujaan Das, Molly Parkyn Schneider, Thorey K. Jonsdottir, Mikha Gabriela, Maria R. Gancheva, Christopher J. Tonkin, Vanessa Mollard, Christopher Dean Goodman, Geoffrey I. McFadden, Danny W. Wilson, Kelly L. Rogers, Alyssa E. Barry, Brendan S. Crabb, Tania F. de Koning-Ward, Brad E. Sleebs, Inari Kursula, Paul R. Gilso