Extensive metabolic consequences of human glycosyltransferase gene knockouts in prostate cancer.

BACKGROUND: Naturally occurring germline gene deletions (KO) represent a unique setting to interrogate gene functions. Complete deletions and differential expression of the human glycosyltransferase UGT2B17 and UGT2B28 genes are linked to prostate cancer (PCa) risk and progression, leukaemia, autoimmune and other diseases. METHODS: The systemic metabolic consequences of UGT deficiencies were examined using untargeted and targeted mass spectrometry-based metabolomics profiling of carefully matched, treatment-naive PCa cases. RESULTS: Each UGT KO differentially affected over 5% of the 1545 measured metabolites, with divergent metabolic perturbations influencing the same pathways. Several of the perturbed metabolites are known to promote PCa growth, invasion and metastasis, including steroids, ceramides and kynurenine. In UGT2B17 KO, reduced levels of inactive steroid-glucuronides were compensated by sulfated derivatives that constitute circulating steroid reservoirs. UGT2B28 KO presented remarkably lower levels of oxylipins paralleled by reduced inflammatory mediators, but higher ceramides unveiled as substrates of the enzyme in PCa cells. CONCLUSION: The distinctive and broad metabolic rewiring caused by UGT KO reinforces the need to examine their unique and divergent functions in PCa biology.

Extensive Alteration of Androgen Precursor Levels After Castration in Prostate Cancer Patients and Their Association With Active Androgen Level.

PURPOSE: Dihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids by castration and their association with dihydrotestosterone and testosterone levels. MATERIALS METHODS: A total of 116 serum samples were collected from 99 prostate cancer patients and categorized as eugonadal, castration-sensitive prostate cancer, castration-resistant prostate cancer, or castration-resistant prostate cancer under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using analysis of variance. Intrapatient association of steroid levels and the androgens testosterone and dihydrotestosterone were assessed using Pearson correlation and linear regression. RESULTS: Testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in castration-sensitive prostate cancer (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, dihydrotestosterone levels under androgen deprivation therapy were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant prostate cancer patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with dihydrotestosterone levels. CONCLUSIONS: Androgen deprivation therapy significantly reduces the levels of 13 circulating steroids. Upon androgen deprivation therapy initiation, the backdoor pathway metabolite androsterone are strongly associated with dihydrotestosterone levels. Under castration-resistant prostate cancer conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.

Prioritization of indicators of the quality of care provided to older adults with frailty by key stakeholders from five canadian provinces.

BACKGROUND: To meet the needs of older adults with frailty better, it is essential to understand which aspects of care are important from their perspective. We therefore sought to assess the importance of a set of quality indicators (QI) for monitoring outcomes in this population. METHODS: In this mixed-method study, key stakeholders completed a survey on the importance of 36 QIs, and then explained their ratings in a semi-structured interview. Stakeholders included older adults with frailty and their caregivers, healthcare providers (HCPs), and healthcare administrators or policy/decision makers (DMs). We conducted descriptive statistical analyses of quantitative variables, and deductive thematic qualitative analyses of interview transcripts. RESULTS: The 42 participants (8 older adults, 18 HCPs, and 16 DMs) rated six QIs as more important: increasing the patients' quality of life; increasing healthcare staff skills; decreasing patients' symptoms; decreasing family caregiver burden; increasing patients' satisfaction with care; and increasing family doctor continuity of care. CONCLUSIONS: Key stakeholders prioritized QIs that focus on outcomes targeted to patients and caregivers, whereas the current healthcare systems generally focus on processes of care. Quality improvement initiatives should therefore take better account of aspects of care that are important for older adults with frailty, such as having a chance to express their individual goals of care, receiving quality communications from HCPs, or monitoring symptoms that they might not spontaneously describe. Our results point to the need for patient-centred care that is oriented toward quality of life for older adults with frailty.

The challenges of ethical deliberation in palliative care settings: A descriptive study.

OBJECTIVE: Inadequate deliberation processes about ethical problems occurring in palliative care settings may negatively impact both patients and healthcare professionals. Better knowledge of the palliative care professionals' practices regarding such processes could help identify specific education needs to improve the quality of palliative care in the context of complex ethical situations. Therefore, this descriptive study aimed to (1) examine ethical deliberation processes in interprofessional teams in five palliative care settings; (2) identify organizational factors that constrain such processes; and (3) based on this knowledge, identify priority education needs for future and current palliative care professionals. METHOD: The study involved three data collection activities: (1) direct observation of simulated interprofessional ethical deliberations in various palliative care settings; (2) individual semi-structured interviews; and (3) deliberative dialogues. RESULTS: Thirty-six healthcare professionals took part in the simulated ethical deliberations and in the deliberative dialogue activities, and 13 were met in an individual interview. The study results revealed suboptimal interprofessional collaboration and ethical deliberation competencies, particularly regarding awareness of the ethical issue under consideration, clarification of conflicting values, reasonable decision making, and implementation planning. Participants also reported facing serious organizational constraints that challenged ethical deliberation processes. SIGNIFICANCE OF RESULTS: This study confirmed the need for professional education in interprofessional collaboration and ethical deliberation so that palliative care professionals can adequately face current and future ethical challenges. It also enabled the identification of educational priorities in this regard. Future research should focus on identifying promising educational activities, assessing their effectiveness, and measuring their impact on patient and family experience and the quality of palliative care.

Urinary oestrogen steroidome as an indicator of the risk of localised prostate cancer progression.

BACKGROUND: Prostate cancer (PCa) is the most common cancer in North American men. Beyond the established contribution of androgens to disease progression, growing evidence suggest that oestrogen-related pathways might also be of clinical importance. The aim of this study was to explore the association of urinary oestrogen levels with clinical outcomes. METHODS: Urine samples from the prospective multi-institutional PROCURE cohort were collected before RP for discovery (n = 259) and validation (n = 253). Urinary total oestrogens (unconjugated + conjugated), including oestrone and oestradiol, their bioactive and inactive catechol and methyl derivatives (n = 15), were measured using mass spectrometry (MS). RESULTS: The median follow-up time for the discovery and replication cohorts was 7.6 and 6.5 years, respectively. Highly significant correlations between urinary oestrogens were observed; however, correlations with circulating oestrogens were modest. Our findings indicate that higher levels of urinary oestriol and 16-ketoestradiol were associated with lower risk of BCR. In contrast, higher levels of 2-methoxyestrone were associated with an increased risk of development of metastasis/deaths. CONCLUSIONS: Our data suggest that urinary levels of oestriol and 16-ketoestradiol metabolites are associated with a more favourable outcome, whereas those of 2-methoxyestrone are associated with an elevated risk of metastasis after RP. Further studies are required to better understand the impact of oestrogens on disease biology and as easily accessible urine-based risk-stratification markers.

User experience with the Ask Your Pharmacist teleconsultation platform.

BACKGROUND: An increasing number of pharmacists use technology and social media to connect with patients. However, such means may pose confidentiality issues and legal problems. To correct this situation, a platform of teleconsultation services provided by pharmacists, titled "Ask Your Pharmacist," was created in Quebec, Canada. METHODS: A web-based satisfaction survey was carried out among patients and pharmacists who have used the Ask Your Pharmacist platform to describe their experience and satisfaction with the platform and explore the perceived usefulness of this service in the province of Quebec. RESULTS: A total of 53 patients and 27 pharmacists completed the survey. Most patients were satisfied or very satisfied with their experience with Ask Your Pharmacist (96.2%), said that it met their need (88.7%), and agreed they would not have to consult again about the matter discussed with the pharmacist (75.5%). The main motivation of pharmacists for volunteering on Ask Your Pharmacist was to meet the needs of patients (85.1%), promote their profession (55.6%), improve drug utilization in the population (55.6%) and increase accessibility to a pharmacist (51.9%). Most (81.5%) felt that providing written consultation (rather than oral) required more research on their part. DISCUSSION: Most patients judged they would not have to have another consultation about the matter discussed with the pharmacist, suggesting that Ask Your Pharmacist may avoid the need for physician and emergency department visits. CONCLUSION: Most patients and pharmacists were satisfied with their experience with Ask Your Pharmacist and perceived this service as useful. Further studies should assess the impact of this platform on the utilization of other health care services. Can Pharm J (Ott) 2021;154:xx-xx.

UGT2B17 modifies drug response in chronic lymphocytic leukaemia.

BACKGROUND: High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents. METHODS: Functional enzymatic assays and patients' plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels. RESULTS: High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub. CONCLUSIONS: Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.

Alternative promoters control UGT2B17-dependent androgen catabolism in prostate cancer and its influence on progression.

BACKGROUND: Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. The objective was to evaluate UGT2B17 protein expression in primary tumours in relation to hormone levels, disease characteristics and cancer evolution. METHODS: We conducted an analysis of a high-density prostate tumour tissue microarray consisting of 239 localised PCa cases treated by radical prostatectomy (RP). Cox proportional hazard ratio analysis was used to evaluate biochemical recurrence (BCR), and a linear regression model evaluated variations in circulating hormone levels measured by mass spectrometry. The transcriptome of UGT2B17 in PCa was established by using RNA-sequencing data. RESULTS: UGT2B17 expression in primary tumours was associated with node-positive disease at RP and linked to circulating levels of 3α-diol-17 glucuronide, a major circulating DHT metabolite produced by the UGT2B17 pathway. UGT2B17 was an independent prognostic factor linked to BCR after RP, and its overexpression was associated with development of metastasis. Finally, we demonstrated that distinctive alternative promoters dictate UGT2B17-dependent androgen catabolism in localised and metastatic PCa. CONCLUSIONS: The androgen-inactivating gene UGT2B17 is controlled by overlooked regulatory regions in PCa. UGT2B17 expression in primary tumours influences the steroidome, and is associated with relevant clinical outcomes, such as BCR and metastasis.

Glucuronidation of Abiraterone and Its Pharmacologically Active Metabolites by UGT1A4, Influence of Polymorphic Variants and Their Potential as Inhibitors of Steroid Glucuronidation.

Abiraterone (Abi) acetate (AA) is a prodrug of Abi, a CYP17A1 inhibitor used to treat patients with advanced prostate cancer. Abi is a selective steroidal inhibitor that blocks the biosynthesis of androgens. It undergoes extensive biotransformation by steroid pathways, leading to the formation of pharmacologically active Δ4-Abi (D4A) and 5α-Abi. This study aimed to characterize the glucuronidation pathway of Abi and its two active metabolites. We show that Abi, its metabolites, and another steroidal inhibitor galeterone (Gal) undergo secondary metabolism to form glucuronides (G) in human liver microsomes with minor formation by intestine and kidney microsomal preparations. The potential clinical relevance of this pathway is supported by the detection by liquid chromatography-tandem mass spectrometry of Abi-G, D4A-G, and 5α-Abi-G in patients under AA therapy. A screening of UGT enzymes reveals that UGT1A4 is the main enzyme involved. This is supported by inhibition experiments using a selective UGT1A4 inhibitor hecogenin. A number of common and rare nonsynonymous variants significantly abrogate the UGT1A4-mediated formation of Abi-G, D4A-G, and 5α-Abi-G in vitro. We also identify Gal, Abi, and its metabolites as highly potent inhibitors of steroid inactivation by the UGT pathway with submicromolar inhibitor constant values. They reduce the glucuronidation of both the adrenal precursors and potent androgens in human liver, prostate cancer cells, and by recombinant UGTs involved in their inactivation. In conclusion, tested CYP17A1 inhibitors are metabolized through UGT1A4, and germline variations affecting this metabolic pathway may also influence drug metabolism. SIGNIFICANCE STATEMENT: The antiandrogen abiraterone (Abi) is a selective steroidal inhibitor of the cytochrome P450 17α-hydroxy/17,20-lyase, an enzyme involved in the biosynthesis of androgens. Abi is metabolized to pharmacologically active metabolites by steroidogenic enzymes. We demonstrate that Abi and its metabolites are glucuronidated in the liver and that their glucuronide derivatives are detected at variable levels in circulation of treated prostate cancer patients. UDP-glucuronosyltransferase (UGT)1A4 is the primary enzyme involved, and nonsynonymous germline variations affect this metabolic pathway in vitro, suggesting a potential influence of drug metabolism and action in patients. Their inhibitory effect on drug and steroid glucuronidation raises the possibility that these pharmacological compounds might affect the UGT-associated drug-metabolizing system and pre-receptor control of androgen metabolism in patients.

Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients.

Chronic lymphocytic leukemia (CLL) is not considered a hormone-regulated cancer although sex is a recognized risk factor with men more frequently diagnosed and developing progressive disease. We hypothesized that variable hormonal exposure may have a sexually dimorphic influence on treatment-free survival (TFS). In 156 CLL cases, we quantitatively profiled 29 circulating steroids (progesterone, adrenal precursors, androgens, estrogens, and catechol estrogens) as well as luteinizing hormone (LH) and follicle-stimulating hormone. Median TFS was shorter for men than that for women (80.7 vs. 135.0 months, P = 0.033). Circulating hormone profiles in CLL patients were significantly different from those of healthy donors. In male CLL cases, higher LH levels were associated with shorter TFS (adjusted hazard ratio (HRadj) 2.11; P = 0.004). In female CLL cases, high levels of the potent androgens testosterone and dihydrotestosterone and the sum of methoxy estrogens were associated with an improved TFS with HRadj values of 0.24 (P = 0.007), 0.54 (P = 0.023), and 0.31 (P = 0.034), respectively. Reduced TFS was observed for women with CLL exhibiting high expression of the steroid-inactivating UGT2B17 enzyme. This study is the first to establish a link between the outcome of CLL patients, sex steroids, and pituitary hormones, revealing a sex-specific hormonal imbalance associated with disease progression.

Association between circulating levels of sex steroid hormones and Barrett's esophagus in men: a case-control analysis.

BACKGROUND & AIMS: Esophageal adenocarcinoma is believed to result from the progression of gastroesophageal reflux disease to erosive esophagitis and re-epithelialization of the esophagus with a columnar cell population termed Barrett's esophagus (BE). Men develop BE and esophageal adenocarcinoma more frequently than women, yet little is known about the mechanisms of this difference. We assessed whether sex steroid hormones were associated with BE in a male population. METHODS: We analyzed data from the Barrett's Esophagus Early Detection Case Control Study, based at the Walter Reed National Military Medical Center. Blood samples were collected from 174 men with BE and 213 men without BE (controls, based on endoscopic analysis); 13 sex steroid hormones were measured by mass spectrometry and sex hormone binding globulin was measured by enzyme-linked immunosorbent assay. We also calculated free estradiol, free testosterone, and free dihydrotestosterone (DHT). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, race, smoking status, alcohol consumption, body mass index, heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation). RESULTS: Levels of free testosterone and free DHT were associated positively with BE risk; patients in the highest quartile for these hormones were most likely to have BE (free testosterone: OR, 5.36; 95% CI, 2.21-13.03; P = .0002; free DHT: OR, 4.25; 95% CI, 1.87-9.66; P = .001). Level of estrone sulfate was associated inversely with BE risk (P for trend = .02). No other hormone was associated with BE risk. Relationships were not modified by age or BMI. CONCLUSIONS: In an analysis of men, levels of free testosterone and free DHT were significantly associated with BE.

Quantitative profiling of human renal UDP-glucuronosyltransferases and glucuronidation activity: a comparison of normal and tumoral kidney tissues.

Renal metabolism by UDP-glucuronosyltransferase (UGT) enzymes is central to the clearance of many drugs. However, significant discrepancies about the relative abundance and activity of individual UGT enzymes in the normal kidney prevail among reports, whereas glucuronidation in tumoral kidney has not been examined. In this study, we performed an extensive profiling of glucuronidation metabolism in normal (n = 12) and tumor (n = 14) kidneys using targeted mass spectrometry quantification of human UGTs. We then correlated UGT protein concentrations with mRNA levels assessed by quantitative polymerase chain reaction and with conjugation activity for the major renal UGTs. Beyond the wide interindividual variability in expression levels observed among kidney samples, UGT1A9, UGT2B7, and UGT1A6 are the most abundant renal UGTs in both normal and tumoral tissues based on protein quantification. In normal kidney tissues, only UGT1A9 protein levels correlated with mRNA levels, whereas UGT1A6, UGT1A9, and UGT2B7 quantification correlated significantly with their mRNA levels in tumor kidneys. Data support that posttranscriptional regulation of UGT2B7 and UGT1A6 expression is modulating glucuronidation in the kidney. Importantly, our study reveals a significant decreased glucuronidation capacity of neoplastic kidneys versus normal kidneys that is paralleled by drastically reduced UGT1A9 and UGT2B7 mRNA and protein expression. UGT2B7 activity is the most repressed in tumors relative to normal tissues, with a 96-fold decrease in zidovudine metabolism, whereas propofol and sorafenib glucuronidation is decreased by 7.6- and 5.2-fold, respectively. Findings demonstrate that renal drug metabolism is predominantly mediated by UGT1A9 and UGT2B7 and is greatly reduced in kidney tumors.

Palliative care costs in Canada: A descriptive comparison of studies of urban and rural patients near end of life.

BACKGROUND: Significant gaps in the evidence base on costs in rural communities in Canada and elsewhere are reported in the literature, particularly regarding costs to families. However, it remains unclear whether the costs related to all resources used by palliative care patients in rural areas differ to those resources used in urban areas. AIM: The study aimed to compare both the costs that occurred over 6 months of participation in a palliative care program and the sharing of these costs in rural areas compared with those in urban areas. DESIGN: Data were drawn from two prior studies performed in Canada, employing a longitudinal, prospective design with repeated measures. SETTING/PARTICIPANTS: The urban sample consisted of 125 patients and 127 informal caregivers. The rural sample consisted of 80 patients and 84 informal caregivers. Most patients in both samples had advanced cancer. RESULTS: The mean total cost per patient was CAD 26,652 in urban areas, while it was CAD 31,018 in rural areas. The family assumed 20.8% and 21.9% of costs in the rural and urban areas, respectively. The rural families faced more costs related to prescription medication, out-of-pocket costs, and transportation while the urban families faced more costs related to formal home care. CONCLUSION: Despite the fact that rural and urban families assumed a similar portion of costs, the distribution of these costs was somewhat different. Future studies would be needed to gain a better understanding of the dynamics of costs incurred by families taking care of a loved one at the end of life and the determinants of these costs in urban versus rural areas.

The use of palliative sedation: A comparison of attitudes of French-speaking physicians from Quebec and Switzerland.

OBJECTIVE: Previous literature has suggested that laws and regulations may impact the use of palliative sedation. Our present study compares the attitudes of French-speaking physicians practicing in the Quebec and Swiss environments, where different laws are in place regarding physician-assisted suicide. METHOD: Data were drawn from two prior studies, one by Blondeau and colleagues and another by Beauverd and coworkers, employing the same two-by-two experimental design with length of prognosis and type of suffering as independent variables. Both the effect of these variables and the effect of their interaction on Swiss and Quebec physicians' attitudes toward sedation were compared. The written comments of respondents were submitted to a qualitative content analysis and summarized in a comparative perspective. RESULTS: The analysis of variance showed that only the type of suffering had an effect on physicians' attitudes toward sedation. The results of the Wilcoxon test indicated that the attitudes of physicians from Quebec and Switzerland tended to be different for two vignettes: long-term prognosis with existential suffering (p = 0.0577) and short-term prognosis with physical suffering (p = 0.0914). In both cases, the Swiss physicians were less prone to palliative sedation. SIGNIFICANCE OF RESULTS: The attitudes of physicians from Quebec and Switzerland toward palliative sedation, particularly regarding prognosis and type of suffering, seem similar. However, the results suggest that physicians from Quebec could be slightly more open to palliative sedation, even though most were not in favor of this practice as an answer to end-of-life existential suffering.

Distribution and sharing of palliative care costs in rural areas of Canada.

Few data are available on the costs occurring during the palliative phase of care and on the sharing of these costs in rural areas. This study aimed to evaluate the costs related to all resources used by rural palliative care patients and to examine how these costs were shared between the public healthcare system (PHCS), patients' families, and not-for-profit organizations (NFPOs). A prospective longitudinal study was undertaken of 82 palliative care patients and their main informal caregivers in rural areas of four Canadian provinces. Telephone interviews were completed at two-week intervals. The mean total cost per patient for a six-month participation in a palliative care program was CA$31,678 +/- 1,160. A large part of this cost was attributable to inpatient hospital stays and was assumed by the PHCS. The patient's family contributed less than a quarter of the mean total cost per patient, and this was mainly attributable to caregiving time.

Pilot randomized controlled trial of a program to enhance experience and adherence with adjuvant endocrine therapy among women with non-metastatic breast cancer: 12-month quantitative results.

PURPOSE: Adjuvant endocrine therapy (AET) reduces recurrence risk after hormone receptor-positive breast cancer, but non-adherence is common. We pilot-tested SOIE, a program to enhance AET experience and adherence, to assess its acceptability, feasibility, and effects on psychosocial precursors of AET adherence. METHODS: We conducted a 12-month pilot randomized controlled trial among women who had a first AET prescription. Intervention group received SOIE while control group received usual care. Psychosocial factors from the Theory of Planned Behavior (TPB) (intention - primary outcome -, attitude, subjective norm, behavioral control), additional constructs (AET knowledge, social support, coping planning), impact of AET services received, and adherence were measured by questionnaires at baseline, 3-month, and 12-month endpoints. Group patterns were compared using repeated measures analyses with generalized estimating equations. RESULTS: A total of 106 women were randomized (participation = 54.9%; intervention n = 52; control n = 54; retention = 93.8%). Among SOIE women, ≥ 90% received the program components and were satisfied. Both groups scored high on adherence intentions and group patterns over time were not statistically different. In the intervention group, AET knowledge and coping planning with side effects increased (group-by-time p-value = .002 and .016), a higher proportion reported that AET services received helped them take their AET (p < .05) and have a consistent daily intake (p = .01). CONCLUSION: SOIE is feasible and acceptable for survivors with an AET. SOIE did not significantly impact adherence intentions but was beneficial for other program outcomes and daily intake. IMPLICATIONS FOR CANCER SURVIVORS: SOIE may represent an encouraging avenue to enhance supportive care and empower survivors with managing AET.

Multimorbidity Treatment Burden Questionnaire (MTBQ): Translation, Cultural Adaptation, and Validation in French-Canadian.

Reliable treatment burden measures are needed given the aging population and the associated increase in multimorbidity and polypharmacy. Treatment burden is defined as the effort to care for one's health and the resulting impact on one's daily life. This study aimed to translate the Multimorbidity Treatment Burden Questionnaire (MTBQ) for French-Canadians and assess its reliability and validity. The MTBQ was translated and tested with cognitive debriefing interviews, and the French version (MTBQ-F) was then administered 2 times among 105 participants. Reliability and validity were examined using the intra-class correlation coefficient (ICC), Cronbach's alpha, and Spearman's correlations. The median global MTBQ-F scores were 32.69 (interquartile range [IQR]: 21.15-48.08) and 30.77 (IQR: 21.15-46.15) for the first and second administrations, respectively. Test-retest (ICC: 0.73; 95% CI: 0.63-0.81) and internal consistency reliability (Cronbach's alpha: 0.80) were good. There was a moderate positive correlation between the MTBQ-F score and the number of self-reported conditions (rho: 0.28). This valid instrument could identify patients experiencing a high treatment burden and assess the impact of interventions among them.

Circulating adrenal 11-oxygenated androgens are associated with clinical outcome in endometrial cancer.

Context: Recent evidence support that androgens play an important role in the etiology of endometrial cancer (EC). Adrenal-derived 11-oxygenated androgens are highly potent agonists of the androgen receptor (AR), comparable to testosterone (T) and dihydrotestosterone (DHT) that have not been studied in the context of EC. Methodology: We studied a cohort of 272 newly diagnosed postmenopausal EC cases undergoing surgical treatment. Circulating concentrations of seven 11-oxygenated androgens including precursors, potent androgens and their metabolites were established in serum samples collected before and 1 month after surgery using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). Free (unconjugated) and total (free + sulfate and glucuronide conjugates following enzymatic hydrolysis) were analyzed in relation to clinicopathological features, recurrence and disease-free survival (DFS). Results: Levels of 11-oxygenated androgens were weakly correlated to those of canonical androgens such as testosterone (T) and dihydrotestosterone (DHT), with no evidence of their association with clinicopathological features. Levels of 11-oxygenated androgens declined after surgery but remained higher in overweight and obese compared to normal weight cases. Higher levels of preoperative free 11-ketoandrosterone (11KAST) were associated with an increased risk of recurrence (Hazard ratio (HR) of 2.99 (95%CI=1.09-8.18); P=0.03). Postoperative free 11ß-hydroxyandrosterone (11OHAST) levels were adversely associated with recurrence and DFS (HR = 3.23 (1.11-9.40); P=0.03 and 3.27 (1.34-8.00); P=0.009, respectively). Conclusion: 11-oxygenated androgen metabolites emerge as potential prognostic markers of EC.

Major involvement of mTOR in the PPARγ-induced stimulation of adipose tissue lipid uptake and fat accretion.

Evidence points to a role of the mammalian target of rapamycin (mTOR) signaling pathway as a regulator of adiposity, yet its involvement as a mediator of the positive actions of peroxisome proliferator-activated receptor (PPAR)γ agonism on lipemia, fat accretion, lipid uptake, and its major determinant lipoprotein lipase (LPL) remains to be elucidated. Herein we evaluated the plasma lipid profile, triacylglycerol (TAG) secretion rates, and adipose tissue LPL-dependent lipid uptake, LPL expression/activity, and expression profile of other lipid metabolism genes in rats treated with the PPARγ agonist rosiglitazone (15 mg/kg/day) in combination or not with the mTOR inhibitor rapamycin (2 mg/kg/day) for 15 days. Rosiglitazone stimulated adipose tissue mTOR complex 1 and AMPK and induced TAG-derived lipid uptake (136%), LPL mRNA/activity (2- to 6-fold), and fat accretion in subcutaneous (but not visceral) white adipose tissue (WAT; 50%) and in brown adipose tissue (BAT; 266%). Chronic mTOR inhibition attenuated the upregulation of lipid uptake, LPL expression/activity, and fat accretion induced by PPARγ activation in both subcutaneous WAT and BAT, which resulted in hyperlipidemia. In contrast, rapamycin did not affect most of the other WAT lipogenic genes upregulated by rosiglitazone. Together these findings demonstrate that mTOR is a major regulator of adipose tissue LPL-mediated lipid uptake and a critical mediator of the hypolipidemic and lipogenic actions of PPARγ activation.

Experience and Appreciation of Health Care Teams Regarding a New Model of Pharmaceutical Care in Long-Term Care Settings.

In long-term care (LTC) homes, the management of frail older residents' pharmacotherapy may be challenging for health care teams. A new pharmaceutical care model highlighting the recently expanded scope of pharmacists' practice in Quebec, Canada, was implemented in two LTC homes. This study aimed to evaluate health care providers' experience and satisfaction with this new practice model. Twenty-three semi-structured interviews were performed and analyzed thematically. Positive results of the model have been identified, such as increased timeliness of interventions. Barriers were encountered, such as lack of clarity regarding roles, and suboptimal communication. The increased involvement of pharmacists was perceived as useful in the context of scarce medical resources. Although requiring time and adjustments from health care teams, the new model seems to contribute to the health care providers' work satisfaction and to positively influence the timeliness and quality of care offered to LTC residents.