Mechanistic and quantitative understanding of pharmacokinetics in zebrafish larvae through nanoscale blood sampling and metabolite modelling of paracetamol

Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically study and quantify pharmacokinetics in zebrafish larvae, and compare this to higher vertebrates, using paracetamol (acetaminophen) as paradigm compound. A method was developed to sample blood from zebrafish larvae at five days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulphate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analysed through non-linear mixed effects modelling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein with median volume (interquartile range) of 1.12 (0.676-1.66) nL per blood sample. Samples were pooled (n=15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulphate was the major metabolite and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well to reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development.Analytical BioSciencesPharmacolog

Older women, breast cancer, and social support

One in ten women over the age of 65 will develop breast cancer. Despite this high incidence of breast cancer among older women, social support for them is often inadequate. This paper describes a qualitative study of the impact of a breast cancer diagnosis on older women from racially/ethnically diverse populations and their subsequent need for social support. Forty-seven older African American, Asian American, Caucasian and Latina women between the ages of 65 to 83 participated in a larger study examining the impact of breast cancer on women from racially/ethnically diverse populations and the meaning and nature of social support. The women completed an in-depth qualitative interview on the psychosocial impact of breast cancer and the meaning and nature of social support. The results indicate that there are variations in reactions to a breast cancer diagnosis among older women, and that these reactions impact their experiences with seeking social support at diagnosis and during treatment. Respondents were concerned about their aging bodies, potential dependency on others, and loss of autonomy. At the same time, the severity of cancer treatment and existing co-morbidities often meant they needed to learn to receive support, and to reach out if they had no support. The implications of these findings underscore the older cancer patient’s need to strengthen her supportive networks at the time of diagnosis, during treatment, and post-treatment

The Impact of Thyroid Cancer and Post-Surgical Radioactive Iodine Treatment on the Lives of Thyroid Cancer Survivors: A Qualitative Study

BACKGROUND: Adjuvant treatment with radioactive iodine (RAI) is often considered in the treatment of well-differentiated thyroid carcinoma (WDTC). We explored the recollections of thyroid cancer survivors on the diagnosis of WDTC, adjuvant radioactive iodine (RAI) treatment, and decision-making related to RAI treatment. Participants provided recommendations for healthcare providers on counseling future patients on adjuvant RAI treatment. METHODS: We conducted three focus group sessions, including WDTC survivors recruited from two Canadian academic hospitals. Participants had a prior history of WDTC that was completely resected at primary surgery and had been offered adjuvant RAI treatment. Open-ended questions were used to generate discussion in the groups. Saturation of major themes was achieved among the groups. FINDINGS: There were 16 participants in the study, twelve of whom were women (75%). All but one participant had received RAI treatment (94%). Participants reported that a thyroid cancer diagnosis was life-changing, resulting in feelings of fear and uncertainty. Some participants felt dismissed as not having a serious disease. Some participants reported receiving conflicting messages from healthcare providers on the appropriateness of adjuvant RAI treatment or insufficient information. If RAI-related side effects occurred, their presence was not legitimized by some healthcare providers. CONCLUSIONS: The diagnosis and treatment of thyroid cancer significantly impacts the lives of survivors. Fear and uncertainty related to a cancer diagnosis, feelings of the diagnosis being dismissed as not serious, conflicting messages about adjuvant RAI treatment, and treatment-related side effects, have been raised as important concerns by thyroid cancer survivors

CFRP bonding pre-treatment with laser radiation of 3 μm wavelength: Laser/material interaction

Laser radiation of 3 μm wavelength was generated by frequency conversion of an industrial IR laser and applied in the context of CFRP bonding pre-treatment. Reinforced and non-reinforced epoxy resins were treated with this radiation varying the relevant parameters such as laser power or treatment time. The interaction between laser radiation of 3012 nm and 1064 nm wavelength and matrix resin was analyzed mechanically (e.g. ablation depth), optically (such as fiber exposure) and chemically (e.g. contamination removal). The results gathered show that, even with the small achievable pulse fluences, a sufficient treatment of the specimens and a sensitive removing of the contaminated layers are possible

Original Research Effects of Medicare Part D on drug affordability and use: Are seniors with prior high out-of-pocket drug spending affected more?

Abstract Background: Medicare Part D was expected to have differential impacts on patient drug expenditures and use based on beneficiaries' levels of pre-Part D patient drug spending, but it is unknown whether these projections have borne out. Objectives: We sought to evaluate whether and how the policy effect of Medicare Part D on drug expenditures and use was modified by levels of pre-Part D drug spending. Methods: A quasi-experimental, pretest-posttest, nonequivalent control group design was used. Data were obtained from a regional supermarket chain for all prescriptions dispensed between January 1, December 31, 2007 (n ¼ 1,230,612) to patients aged 60 years and older as of January 1, 2005 (n ¼ 51,305) to construct 12-month pre-Part D and post-Part D periods. Annual medication use was measured as the total number of pill days acquired. Annual drug expenditures were measured as total expenditures, patient outof-pocket expenditures, and the proportion of total expenditures paid out of pocket by the patient. Results: Part D resulted in significant reductions in out-of-pocket spending (17.6%) and significant increases in drug use (4.0%) for individuals in the highest pre-Part D drug-spending group relative to controls. The reduction in out-of-pocket spending for the highest pre-part D spending group was significantly greater compared with the moderate and lowest pre-Part D spending groups. Conclusions: Our findings suggest that, as expected, Part D facilitated access to medications for patients who previously experienced the greatest costs without adversely increasing use and costs among those with the lowest prior cost