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Sharan K Rai,1 Alyssa Howren,1,2 Elizabeth S Wilcox,3 Anne F Townsend,1,4 Carlo A Marra,1,5 J Antonio Aviña-Zubieta,1,6 Mary A De Vera1,2 1Arthritis Research Canada, Vancouver, BC, Canada; 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; 3School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada; 4University of Exeter Medical School, Exeter, UK; 5School of Pharmacy, Otago University, Dunedin, New Zealand; 6Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada Objective: Medication non-adherence is a substantial problem among patients with inflammatory arthritis (IA). Our aim was to explore IA patients’ perspectives on strategies to support medication adherence.Methods: We collaborated with a leading arthritis patient group and conducted a qualitative study on individuals with IA who were taking at least one medication for their IA. An experienced facilitator led participants through a focus group exercise where participants were asked to design, and then discuss, strategies and/or tools supporting medication use. We applied thematic analysis using an iterative, constant comparative approach.Results: We studied six focus groups with 27 participants diagnosed with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and comparatively under-represented conditions in this research area such as Sjögren’s syndrome. Five themes emerged throughout the analysis. Two themes – 1) adapting to life with IA and 2) the complexities and dynamic nature of taking medications – describe learning to live with a chronic condition and the challenges encountered when using long-term medications. Three themes – 3) developing lifestyle strategies for medication use (eg, having physical reminders and prompts), 4) becoming informed about medications (eg, information at time of diagnosis, means of receiving information) and 5) receiving support (eg, from health care team members, from family) – offer perspectives on facilitators to medication use. From the relationship between the latter themes, a framework was developed that encompasses means of receiving information and support as actionable targets for patient-oriented adherence interventions for IA.Conclusion: This patient-oriented study highlights the importance of developing timely adherence interventions for IA. Our findings also led to a framework describing means of receiving information, such as through digital media and support, including from health care team members and family, as actionable targets for patient-oriented adherence interventions for IA. Keywords: inflammatory arthritis, medication adherence, concordance, facilitators, barriers, qualitative research, synthetic DMARDs, biologic DMARDs

Amir Khakban,1 Tima Mohammadi,2 Larry D Lynd,1 Don J Mabbott,3,4 Eric Bouffet,5,6 Louise Gastonguay,1 Zafar Zafari,7 David Malkin,5,6 Michael D Taylor,8,9 Carlo A Marra10 1Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada; 2Centre for Health Evaluation and Outcome Sciences, University of British Columbia, St Paul’s Hospital, Vancouver, BC, Canada; 3Department of Psychology, University of Toronto, Toronto, ON, Canada; 4Department of Psychology, The Hospital for Sick Children, Toronto, ON, Canada; 5Department of Pediatrics, University of Toronto, Toronto, ON, Canada; 6Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; 7Health Policy and Management, Mailman School of Public Health, Columbia University, New York, NY, USA; 8Departments of Surgery, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; 9Department of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; 10School of Pharmacy, University of Otago, Dunedin, New Zealand Objective: The aim of this study was to determine the preferences of parents with children with medulloblastoma and clinicians who manage this condition and their trade-offs between survival and disability using a best–worst scaling (BWS) choice experiment. Methods: Mixed methods were used to develop a BWS tool. Health professionals involved in the care of medulloblastoma patients were contacted through oncology networks in Canada. Parents of children diagnosed with brain tumors were recruited via two clinics in Vancouver and Toronto. The profile case BWS was used with each participant completing 12 choice profiles with the respondent indicating the best and worst features of each profile. Surveys were stratified into good, moderate, and poor prognosis based on the probability of survival presented. Paired model conditional logit analysis was used to generate quantitative preferences. Results: Fifty-four parents (80% female) and 176 providers (36% female, 79% oncologists) participated in this study. There were many similarities in the parents’ and providers’ preferences for treatment although the parents tended to value survival higher than disability while providers seemed to value the opposite. Specifically, providers were willing to take more risk of recurrence in a child with good prognosis compared to intermediate and poor prognosis. Also, parents were less willing to take more survival risks than providers when they had to trade-off between mild disability and survival rate. Conclusion: This study provides useful insights into the preferences of parents and health care providers, the stakeholders of a collaborative decision for the treatment of pediatric medulloblastoma, and compares their values and trade-offs between different levels of survival and disability. Keywords: best–worst scaling, BWS, preference, medulloblastoma, trade-off, cancer

Health state utility values (HSUV) are used as weightings to calculate quality-adjusted life years in economic evaluations. Evidence suggests that patients' perceptions of a new diagnosis for a chronic disease, while initially poor, may improve over time. The objective of this study was to examine the association between disease duration and direct HSUV scores in patients with systemic sclerosis (SSc).Our study included patients with SSc from a US SSc center. An interviewer administered direct HSUV techniques including the visual analog scale (VAS), time tradeoff (TTO), and standard gamble (SG). We calculated the Short Form 6D HSUV from the Medical Outcomes Study Short Form-36. Additional clinical and demographic variables were collected.The mean age of the SSc sample (n = 223) was 51 years (SD 16) with the majority being women (84%). Median disease duration was 5 years (interquartile range 1.5-9). Mean (SD) HSUV scores were 0.67 (0.19) for the VAS, 0.76 (0.28) for the TTO, 0.84 (0.22) for the SG, and 0.65 (0.13) for the SF-6D. In patients with early disease (defined as ≤ 2 yrs, n = 78), the mean HSUV values were 0.64 (VAS), 0.70 (TTO), 0.80 (SG), and 0.63 (SF-6D) versus for those with a longer disease duration: 0.69, 0.79, 0.87, and 0.67, respectively. In multivariate analysis, the SG measure showed a significant and positive association with disease duration measured as a continuous variable and using a threshold of 2 years (p = 0.047 and p = 0.023, respectively).Greater disease duration showed a positive association with a direct measure (SG) of utility elicitation after a period of 2 years.

The possible contribution of early changes in lipid composition, function, and antioxidant status of abdominal adipose tissue (AAT) induced by a fructose-rich diet (FRD) to the development of insulin resistance (IR) and oxidative stress (OS) was studied. Wistar rats were fed with a commercial diet with (FRD) or without 10% fructose in the drinking water for 3 weeks. The glucose (G), triglyceride (TG), and insulin (I) plasma levels, and the activity of antioxidant enzymes, lyposoluble antioxidants, total glutathione (GSH), lipid peroxidation as TBARS, fatty acid (FA) composition of AAT-TG as well as their release by incubated pieces of AAT were measured. Rats fed with a FRD have significantly higher plasma levels of G, TG, and I. Their AAT showed a marked increase in content and ratios of saturated to monounsaturated and polyunsaturated FAs, TBARS, and catalase, GSH-transferase and GSH-reductase, together with a decrease in superoxide dismutase and GSH-peroxidase activity, and total GSH, alpha-tocopherol, beta-carotene and lycopene content. Incubated AAT from FRD released in vitro higher amount of free fatty acids (FFAs) with higher ratios of saturated to monounsaturated and polyunsaturated FAs. Our data suggest that FRD induced an early prooxidative state and metabolic dysfunction in AAT that would favor the overall development of IR and OS and further development of pancreatic beta-cell failure; therefore, its early control would represent an appropriate strategy to prevent alterations such as the development of type 2 diabetes.

We have examined the incorporation and metabolism of [14C] stearic acid within the total lipids of HTC rat-hepatoma cells in suspension culture in presence and in absence of steroidal hormone stimulation. Both, glucocorticoids (dexamethasone, cortisol and corticosterone) and mineralocorticoids (deoxycorticosterone and aldosterone) as well as the estrogen beta-estradiol and the androgen testosterone enhanced the extent of delta 9 desaturation to oleic acid of the saturated precursors, whereas only the two mineralocorticoids affected the incorporation rate of the exogenous acid into total cellular lipids, thus promoting a little stimulation. Furthermore, all the hormones tested increased the radiolabelling of the total cellular phospholipids except deoxycorticosterone and testosterone, the former having no effect and the latter exerting a moderate inhibition. On the other hand, the incorporation of 14C into neutral lipids was stimulated by testosterone, in contrast to the inhibition of this parameter observed exclusively with either the mineralocorticoids or the estrogen. Within the phospholipid subclasses, the radiolabelling of phosphatidylcholine was augmented by means of all the steroids tested save deoxycorticosterone and testosterone, whereas phosphatidylethanolamine exhibited a decrease only in the presence of testosterone. In a similar fashion, within the neutral lipids, the predominating triglyceride fraction was preferentially labelled--at the expense of other subclasses of lesser abundance--upon treatment with the steroids except aldosterone, which exerted no effect. The results obtained were correlated with those changes observed in the mass distribution of the different lipid subclasses either with or without prior hormonal stimulation.

We report here a study of the incorporation and metabolism of various long chain fatty acids in SK-Hep-1 cultured hepatoma cells. Medium supplementation with radiolabelled palmitic, stearic, linoleic, alpha-linolenic and eicosa-8,11,14-trienoic acids (1 microM, 24 H) resulted in an active uptake of each of these precursors by the cultures. Subsequent analysis of the cellular lipids indicated that they exhibit almost all the enzymic activities of polyunsaturated fatty acid metabolism that are characteristic of normal hepatic cells. With respect to the desaturation capacities of this cell line, although alpha-linolenic acid reacted more extensively than did linoleic acid and the conversion of 8,11,14-eicosatrienoic acid by the delta 5 specific enzyme was more avid than had been previously seen in normal rat or human liver: the saturated fatty acids constituted relatively poor substrates, being preferentially chain-elongated rather than (mono) desaturated at the delta 9 position. Analysis of the fatty acid profiles of total cellular lipids and of various lipid subclasses, however, revealed a relative paucity of essential fatty acids when compared with the abundance of endogenous monoenoic acids (particularly oleic). Of the total cellular fatty acids, 58% were present in the form of phospholipids; with 33% of the remaining 42% (i.e., the neutral lipids) being associated with triacylglycerol fraction. Within the total lipids, phosphatidyl-choline and phosphatidyl-ethanolamine were the major sites for the incorporation of all metabolic products derived from the incubated radiolabelled 16- and 18-carbon fatty acid precursors, whereas the phosphatidyl-inositol fraction was the predominant recipient of nascent arachidonic acid when the eicosatrienoate was the substrate. The express purpose of this investigation was to characterize the biochemical routes involved in the anabolism of various essential fatty acids in the human hepatocyte, through the use of cultured human hepatoma cells as an experimental model system. In view of the similarities between certain aspects of the polyunsaturated fatty acid metabolism of these cells and the corresponding properties of other mammalian hepatic or liver-derived tissues, the data presented here would thus constitute a significant beginning alone those lines. Moreover, considering the extreme difficulty in obtaining for such investigation relevant tissue samples from normal human sources, we regard these results- and the availability for use of this particular human hepatoma cell line-as important new developments in the effort to characterize a useful experimental model both for gaining immediate information and for designing future experiments.

The incorporation and delta 9 desaturation of exogenous [14C]stearic acid were studied in HTC 7288c cells in suspension. We examined the uptake of the acid over a wide range of concentrations (0-160 microM) after incubating the cells for 6 h in a chemically-defined medium. Under this experimental condition, the uptake of the labeled acid was more extensive than that obtained from static cultures or from monolayer of isolated hepatocytes of rats. At an external concentration of 160 microM ca. 52 nmoles of acid per mg of cellular protein was taken up. The production of oleic acid from [14C]stearate (delta 9 desaturation) correlated well with the uptake curve between 0-80 microM concentration. For higher stearate concentrations, the biosynthesis of oleic acid declined substantially and a plateau of 22 nmoles/mg cellular protein was reached. The incorporation and desaturation of an initial exogeneous concentration of [14C]stearic acid (80 microM) was also studied from 0-6 h. The results obtained demonstrated that the uptake of the substrate into cellular lipids was fast and non saturable. Quantitative gas-liquid chromatography of total cellular lipids under the different experimental conditions demonstrated a negative correlation between the decrease in the palmitic and palmitoleic acids and the increase in the intracellular levels of stearic and oleic acids. These analytical modifications took place with no changes in the saturated/monoenoic fatty acid ratio. This work also demonstrated a significant contribution of the stearoyl-CoA desaturase system to the high levels of oleic acid present in this kind of hepatoma cells.

The effect of dexamethasone on the incorporation and conversion of [1-14C]eicosa-8,11,14-trienoic acid to arachidonic acid in isolated hepatocytes and in hepatoma tissue culture (HTC) cells was studied. In both kinds of cells, no changes in the exogenous acid incorporation were found when the hormone was added to the incubation media at 0.1 or 0.2 mM concentration, while the biosynthesis of arachidonic acid was significantly depressed. The effect on the biosynthesis was faster in isolated normal liver cells (60 min) than in tumoral cells (120 min) and reached an inhibition of ca. 50% after 3 hr of treatment. The addition of cycloheximide (10(-6) M) also caused a marked decrease in the biosynthesis of this polyunsaturated fatty acid, but when dexamethasone was added to the media simultaneously with cycloheximide, a synergistic action was not observed. The results obtained show that protein synthesis would be involved in the modulation of the biosynthesis of arachidonic acid by glucocorticoids. The changes in the delta 5 desaturation of labeled 20:3 omega 6 to arachidonic acid correlated with changes in the fatty acid composition in isolated cells.

The incorporation and conversion of eicosa-8,11,14-trienoic acid to arachidonic acid were studied in HTC cells (7288 c hepatoma cells) and isolated hepatocytes of rat. The cells were incubated at different concentrations of the acid during 0 to 6 hours. Both kinds of cells were able to take up the acid. However, the HTC cells have a greater avidity for the eicosatrienoic acid than normal liver cells. The incorporation of the acid modified the fatty acid composition of the cells and caused a decrease in the amount of saturated and monoenoic acid. In both cells eicosatrienoic acid was converted to arachidonic acid. However, in HTC cells arachidonic acid level was low and not correlated with the amount of the eicosatrienoic acid incorporated. This fact is apparently not due to an impairment in delta 5 desaturation activity since this enzyme is active in both cells. It would be possible that arachidonic acid production in malignant cells would be also interrupted in another metabolic pathway after delta 6 desaturation step. The strikingly low amount of arachidonic acid biosynthesized in HTC cells compared to normal hepatocytes could be interpreted as a consequence of a lower availability of eicosatrienoic acid for the microsomal desaturation system in malignant cells, in addition to the low delta 6 desaturase activity.

This report supports evidence for the existence of a dexamethasone-induced factor that modulates fatty acid desaturase activities. Dexamethasone at a dose of 1 mg/rat produced a significant decrease in microsomal delta 6 and delta 5 desaturation activity 12 h after the injection. Both desaturase activities were depressed by a soluble factor present in the cytosolic fraction of cells, since the supernatant of microsomes separated at 110,000 X g from hormonal-treated rat liver homogenates, added to crude or washed control microsomes, was able to inhibit in vitro linoleic and homo-gamma-linolenic conversion to gamma-linolenic and arachidonic acids, respectively. The inhibitory factor was loosely bound to microsomes, since it was also present in a soluble fraction obtained after washing crude microsomes from dexamethasone-treated rats with a low-ionic-strength solution. Besides, trypsin digestion deactivates the dexamethasone-induced factor. Therefore, the depressing effect of glucocorticoids on delta 6 and delta 5 desaturation capacity depends on an unchanged protein structure present in the cytosolic fraction of the cell and whose biosynthesis is brought about by hormonal induction.