Studies on CYP3A activity during the menstrual cycle as measured by urinary 6ß-hydroxycortisol/cortisol.

The 6ß-OH-cortisol/cortisol ratio (6ß-OHC/C) in urine is an endogenous marker of drug-metabolizing enzyme cytochrome P450 3A (CYP3A). The primary aim of this single center, prospective, non-interventional cohort study, was to investigate the variability of 6ß-OHC/C during the menstrual cycle. In addition, possible associations between the CYP3A activity and sex hormones, gut microbiota metabolite trimethylamine-N-Oxide (TMAO) and microRNA-27b, respectively, were investigated. Serum and urinary samples from healthy, regularly menstruating women followed for two menstrual cycles were analyzed. Twenty-six complete menstrual cycles including follicular, ovulatory, and luteal phase were defined based on hormone analyses in serum. 6ß-OHC/C were analyzed in urine and sex hormones, TMAO and miRNA-27b were analyzed in serum at the same time points. 6ß-OHC/C did not vary between the follicular, ovulatory, or luteal phases. There was a difference in the relative miRNA-27b expression between the follicular and ovulatory phase (p = .03). A significant association was found between 6ß-OHC/C and progesterone during the follicular (p = .005) and ovulatory (p = .01) phases (n = 26 for each phase). In addition, a significant association was found between the ratio and TMAO during the ovulatory (p = .02) and luteal (p = .002) phases. 6ß-OHC/C and gut microbiota TMAO were significantly associated (p = .003) when evaluating all values, for all phases (n = 78). Interestingly, the finding of an association between 6ß-OHC/C in urine and levels of TMAO in serum suggest that gut microbiota may affect CYP3A activity.

CYP3A Activity in End-of-Life Cancer Patients Measured by 4ß-Hydroxycholesterol/cholesterol Ratio, in Men and Women.

More than 50% of all drugs are metabolized by the cytochrome P450 3A enzyme (CYP3A). The aim of this study was to investigate if the CYP3A activity, measured by the endogenous marker 4ß-hydroxycholesterol/cholesterol ratio (4ß-OHC/C), is changed during the last weeks and days of life in men and women. To this end, serum samples from 137 deceased patients (median age 70 years) collected at a single time point 1-60 days before death, were analyzed and compared to 280 young (median 27 years), and 30 elderly (median age 70 years) non-cancer controls. There were no significant differences in the 4ß-OHC/C ratio between men and women in end-of-life patients (p < 0.25). The median 4ß-OHC/C was significantly higher in end-of-life male patients compared to both young (p < 0.0001) and elderly (p < 0.05) male controls. In a similar manner, 4ß-OHC/C in end-of-life female patients was significantly higher compared to young and elderly female controls, p < 0.0001 and p < 0.001, respectively. There was no significant correlation between 4ß-OHC/C and survival time. The results from this study suggest maintained CYP3A activity to the very last days of life and even a capacity of induction of the enzyme in end-of-life cancer patients.

Sex-Differences in Discontinuation of Statin Treatment in Cancer Patients the Year before Death.

Statin treatment is often terminated in patients with advanced cancer but guidelines for statin discontinuation are still lacking. The aim of this study was to investigate sex-differences in time-points of statin discontinuation in patients with advanced cancer. Medical records from 1535 deceased patients enrolled at a Palliative Home Care Unit were reviewed. A total of 149 patients (42 women and 107 men) who were diagnosed with cancer, and were treated with statins one year before death, were identified. Statin treatment was terminated earlier in women than in men, 3.0 months prior to death (IQR 0.88-7.25) as compared to 1.5 months (IQR 0.5-4.0) (p < 0.05), respectively. In a longitudinal analysis there was a significant difference between men and women still on statin treatment at all studied time-points, 9, 6, and 3 months before death (p < 0.05), where women terminated statin treatment earlier in the disease trajectory. Baseline demographics were similar between the sexes except that more men than women had a history of previous cardiovascular events (p < 0.01). However, neither the indication for statin treatment, i.e., primary prevention versus secondary prevention, nor age could explain the sex-difference in statin discontinuation. There was no difference in cardiovascular events or mortality between men and women after statin discontinuation.

Variations in biomarkers of dyslipidemia and dysbiosis during the menstrual cycle: a pilot study in healthy volunteers.

BACKGROUND: Dyslipidemia in metabolic syndrome may introduce an underestimation of the risk for cardiovascular disease (CVD) using Low-Density Lipoprotein-Cholesterol (LDL-C) as a surrogate marker. Recently, non-High-Density Lipoprotein-Cholesterol (non-HDL-C), Apolipoprotein B (ApoB) and remnant-Cholesterol (remnant-C) have been suggested as better biomarkers for dyslipidemia. In addition, the microbial metabolites trimethylamine-N-oxide (TMAO), betaine and choline have been associated with CVD and suggested as markers for dysbiosis. There is a lack of knowledge on potential alterations in these biomarkers during the menstrual cycle. The aim of this single center, prospective non-interventional study, was to investigate variations in biomarkers of dyslipidemia and dysbiosis in healthy volunteers during the menstrual cycle. METHOD: Serum samples were collected from 17 healthy, regularly menstruating women during two menstrual cycles, including the follicular, ovulatory and luteal phases. Levels of lipoproteins, lipoprotein ratios and microbial metabolites were analyzed in a total of 90 samples (30 complete menstrual cycles). RESULTS: ApoB, ApoB/HDL and non-HDL-C/HDL ratios were significantly higher in the follicular phase compared to the ovulatory and luteal phases (p < 0.05). Remnant-C were higher during the luteal phase (p < 0.05). TMAO did not vary during the different phases and did not correlate with estrogen levels. CONCLUSION: Our data support that biomarkers for dyslipidemia vary during the menstrual cycle. Thus, to avoid an underestimation of cardiovascular risk, sampling during the follicular phase, when levels of pro-atherogenic lipids are higher, may be considered.

Urinary steroid profile in relation to the menstrual cycle.

The interpretation of the steroidal module of the Athlete Biological Passport (ABP) in female athletes is complex due to the large variation of the endogenous urinary steroids. The menstrual cycle seems to be one of the largest confounders of the steroid profile. The duration of the different phases in the menstrual cycle differs between women and is difficult to predict only by counting days after menstruation. Here, we have determined the follicle, ovulation, and luteal phases, by assessing the menstrual hormones in serum samples collected from 17 healthy women with regular menses. Urine samples were collected three times per week during two consecutive cycles to measure the urinary steroid concentrations used in the ABP. The metabolite that was mostly affected by the menstrual phases was epitestosterone (E), where the median concentration was 133% higher in the ovulation phase compared to the follicle phase (p < 0.0001). The women with a large coefficient of variation (CV) in their first cycle also had a large CV in their second cycle and vice versa. The inter-individual difference was extensive with a range of 11%-230% difference between the lowest and the highest T/E ratio during a cycle. In conclusion, E and ratios with E as denominator are problematic biomarkers for doping in female athletes. The timing of the sample collection in the menstrual cycle will have a large influence on the steroid profile. The results of this study highlight the need to find additional biomarkers for T doping in females.

Fluctuations in hematological athlete biological passport biomarkers in relation to the menstrual cycle.

The interpretation of athlete biological passport (ABP) is strengthened by understanding the natural fluctuations in its biological parameters. Here we have assessed the influence of the menstrual cycle on the hematological module of the ABP. Seventeen women with regular menses were included. Blood samples were collected once a week for two consecutive cycles and analyzed for hematological parameters. Menstrual phases were hormonally determined. The intra-individual variation in the hematological parameters was similar between the two cycles. Reticulocyte percentage was significantly lower in the follicle phase (median 0.95%) than in the ovulatory (median 1.10%) and luteal phases (median 1.16%), P = 0.006, whereas no differences were found in hemoglobin concentration, hematocrit, red blood cell count, or red blood cell indices. When the values were entered into the ABP model, findings outside the program-calculated individual thresholds were identified in two participants. One woman showed an atypical low OFF-score in the last sample collected, mainly because of increased reticulocyte percentage. This was likely a response to treated insufficient iron stores. One woman displayed an atypical hemoglobin value at the lower limit 2 weeks after ovulation, which was likely due to fluctuations in plasma volume. In conclusion, the ABP parameters in general are stable throughout the menstrual cycle. Significant differences between the menstrual phases were found in reticulocytes; however, the variation was not related to findings outside the individual thresholds, except in one individual. Moreover, our results highlight the importance of having information about iron supplementation available when evaluating hematological passports.

Managing Implementation of a Parental Support Programme for Obesity Prevention in the School Context: The Importance of Creating Commitment in an Overburdened Work Situation, a Qualitative Study.

Health-related behaviours in children can be influenced by parental support programmes. The aim of this study was to explore barriers to and facilitators for the implementation of a parental support programme to promote physical activity and healthy dietary habits in a school context. We explored the views and experiences of 17 coordinating school nurses, non-coordinating school nurses, and school principals. We based the interview guide on the Consolidated Framework for Implementation Research. We held four focus group discussions with coordinating and non-coordinating school nurses, and conducted three individual interviews with school principals. We analysed data inductively using qualitative content analysis. We identified "Creating commitment in an overburdened work situation" as an overarching theme, emphasising the high workload in schools and the importance of creating commitment, by giving support to and including staff in the implementation process. We also identified barriers to and facilitators of implementation within four categories: (1) community and organisational factors, (2) a matter of priority, (3) implementation support, and (4) implementation process. When implementing a parental support programme to promote physical activity and healthy dietary habits for 5- to 7-year-old children in the school context, it is important to create commitment among school staff and school nurses. The implementation can be facilitated by political support and additional funding, external guidance, use of pre-existing resources, integration of the programme into school routines, a clearly structured manual, and appointment of a multidisciplinary team. The results of this study should provide useful guidance for the implementation of similar health promotion interventions in the school context.

Differences in discontinuation of statin treatment in women and men with advanced cancer disease.

BACKGROUND: Statins are often discontinued in patients with advanced cancer since the net effect of treatment is considered negative. However, guidelines concerning discontinuation of statin treatment are lacking. The aim of this study was to investigate any differences in time of discontinuation of statin treatment between men and women with advanced cancer disease. METHODS: Medical records from 195 deceased palliative cancer patients from a previous study cohort were reviewed. Patients treated with statins 2 years before death were identified as "statin users." The time of discontinuation of statin therapy was identified and correlated to time of death. Only patients that had incurable cancer disease at time of statin discontinuation were included in the analysis. RESULTS: Fifty-four patients were identified as statin users, 29 women and 25 men. The average time span between discontinuation of statin treatment and time of death was significantly longer in women than in men, 10 months compared to 4 months (p < 0.01), with a range of 1-24 months among women and 1-12 months for men. All patients died due to their cancer disease. More men than women had a history of stroke or cardiac infarction (p = 0.02). There were no differences in age, socioeconomic factors, or survival time from study inclusion between men and women. There was no difference in self-assessed quality of life (QoL) between statin users who had discontinued statin treatment and those who are still on treatment. Men generally assessed their QoL lower than women in this study (p = 0.03). CONCLUSION: Statin treatment was discontinued earlier in women than in men in patients with advanced cancer. The data suggest that statins may be discontinued earlier in men as well, since earlier discontinuation did not affect cardiovascular mortality.

Factors influencing the implementation of a school-based parental support programme to promote health-related behaviours--interviews with teachers and parents.

BACKGROUND: The 'Healthy School Start' programme was developed to promote healthy dietary habits and physical activity, targeting parents of 6-year-old children in pre-school class. Knowledge of barriers and facilitators of implementation is crucial before introducing this kind of programme on a larger scale. The aim of this study was to explore the views of teachers and parents regarding factors influencing the implementation of a school-based parental support programme to promote physical activity and healthy diet. METHODS: An inductive qualitative method was used to explore the experiences and views of teachers and parents involved in the programme. A group discussion was held with three teachers, and semi-structured interviews were conducted with 14 parents. Data were analysed using qualitative content analysis. RESULTS: Clear communication on roles and responsibilities was identified as an overarching theme, emphasising the importance of clear information and well-functioning cooperation between project management, schools and parents when implementing the programme in a school setting. Five categories at a manifest level described aspects influencing the implementation: 1) 'The programme' underlining the importance of flexibility and feed-back; 2) 'the school' referring to management and work routines; 3) 'family conditions', implying various life situations; 4) 'group dynamics' dealing with attitudes among children and parents; and 5) 'the surrounding community' including accessibility and attitudes within society. CONCLUSIONS: When implementing a parental support programme in a school setting it is important to facilitate communication and clearly define the division of responsibilities between project management, schools and parents. This emphasises the need for managerial support, and a professional prevention support system.

Understanding the Implementation Process of a Multi-Component Health Promotion Intervention for Adults with Intellectual Disabilities in Sweden.

BACKGROUND: There is a need to better understand implementation processes of health interventions. This study describes the implementation of a multicomponent intervention to improve diet and physical activity among adults with intellectual disabilities, viewed from the perspectives of staff and managers. MATERIALS AND METHODS: All health ambassadors (n = 12), appointed among staff and managers (n = 5) taking part of a health intervention in community residences in Sweden, were interviewed with a focus on barriers and facilitators regarding implementation of the intervention. Data were analysed using content analysis. RESULTS: The overarching theme describes the importance of supporting motivation for change among managers, caregivers and residents. The experiences of the implementation process are described in four main categories: intervention characteristics, individual commitment, organizational capacity and societal factors. CONCLUSION: The implementation can be facilitated by a programme meeting perceived needs, a flexible and participatory approach, external input and an extensive preparation phase.

Promoting health of people with intellectual disabilities: Views of professionals working in group homes.

Deinstitutionalisation has influenced the life situation for people with intellectual disabilities, whilst the experiences of health promotion in group homes now are limited. This study aimed to explore aspects important to consider when promoting health amongst persons with intellectual disabilities in group homes, from the perspective of professionals. Semi-structured interviews were conducted with seven professionals and were analysed with thematic analysis. The overarching theme 'sense of security' was identified as a prerequisite for health promotion, together with the sub-themes 'resources in the organisation', for example, respectful treatment of the residents, and `resources of the residents', for example, meaningfulness and social connectedness. Findings were discussed from the perspective of health assets which is defined as the factors contributing to maintain and sustain health. The importance of strengthening external assets, that is, resources in the society and the organisation, to promote internal assets, that is, residents' individual resources, and ultimately their health, is emphasised.

A multi-component universal intervention to improve diet and physical activity among adults with intellectual disabilities in community residences: a cluster randomised controlled trial.

People with ID have an increased risk for unhealthy diets, physical inactivity and weight disturbances. The aim of the current study was to investigate the effectiveness of a novel and complex intervention to improve diet and physical activity, targeting both caregivers and residents, in community residences for people with ID. A three component intervention based on Social Cognitive Theory was developed, including: (1) appointment of a health ambassador in each community residence attending network meetings, (2) a study circle for caregivers, and (3) a health course for the residents. The intervention lasted for 12-16 months and allowed for some local tailoring. A cluster randomised controlled trial, randomised at residence level, was conducted to evaluate the effects of the intervention. Thirty community residences for people with mild or moderate ID in Stockholm County, Sweden, were included. A total of 130 participants, 74 women and 56 men aged 20-66 years, entered, and 129 participants completed the study. The primary outcome was physical activity, measured by pedometry. Secondary outcomes were BMI, waist circumference, dietary quality measured by digital photography, satisfaction with life assessed with a scale, and work routines assessed with a questionnaire. Outcomes were related to intervention fidelity. A positive intervention effect was found on physical activity, with an average increase of 1608 steps/day among participants in the intervention group (P=0.045). The effect size was 0.29 (Cohen's d). The type of residence was found to be an effect moderator. A positive intervention effect was found as well on work routines, with an average increase of 7.1 percentage points on a self-assessment scale among residences in the intervention group (P=0.016). No significant effects were found on BMI, waist circumference, dietary quality, or satisfaction with life. In conclusion, this innovative intervention was effective in improving physical activity and work routines. It is likely that even greater effects could be achieved by improvements in implementation strategies, leading to higher fidelity.

Atorvastatin treatment induces uptake and efflux transporters in human liver.

The metabolism and disposition of statins are highly dependent on different cytochrome P450 enzymes, such as CYP3A4 and CYP2C9, as well as membrane transporters SLCO1B1, SLCO2B1, ABCB1, and ABCG2. Interindividual gene expression differences among these enzymes may explain part of the variability in tolerance and effect for statin treatment. The aim of the present study was to investigate the effect of statin treatment on these genes in human liver tissue. Levels of CYP3A4, CYP2C9, SLCO1B1, SLCO2B1, ABCB1, and ABCG2 mRNA in liver tissue from a previously performed clinical trial in 29 patients randomized to treatment with placebo, 80 mg/day of atorvastatin, or 20 mg/day of fluvastatin for 4 weeks were measured using quantitative polymerase chain reaction. Treatment with atorvastatin (n = 10), but not with fluvastatin (n = 10), resulted in 3-fold higher expression of SLCO2B1 compared with placebo-treated patients (n = 9) (P < 0.05). Atorvastatin increased the expression of both ABCB1 and ABCG2 by more than 2-fold (P < 0.05). No difference was found in CYP2C9, CYP3A4, or SLCO1B1 mRNA expression in patients administered statins or those administered placebo. Premenopausal women (n = 8) had higher expression of CYP3A4 (P < 0.05) and lower expression of CYP2C9 (P < 0.05) compared with postmenopausal women (n = 10) and men (n = 11), respectively. Here we show for the first time that atorvastatin treatment leads to increased expression of the membrane transporters SLCO2B1, ABCB1, and ABCG2 in human liver tissue, which potentially may counteract the efficacy of the treatment, and our findings may cast light on the mechanisms of clinical problems with adverse reactions and drug interactions in statin treatment.

The role of staff in health promotion in community residences for people with intellectual disabilities: variation in views among managers and caregivers.

Managers and caregivers in community residences for people with intellectual disabilities are expected both to promote residents' health and to support their autonomy. The aim of this article was to explore variation in views among managers and caregivers on the role of staff in health promotion. A qualitative study was conducted using semi-structured interviews with six managers and six caregivers. The analysis used a phenomenographic approach to categorize variation in views. We identified five qualitatively different main categories of roles staff play in health promotion: the parent, the manipulator, the coach, the educator and the libertarian. In addition lifestyle-related risk factors for ill-health and barriers to a healthy lifestyle were analysed and described using qualitative content analysis. The results highlight the ethical conflict that faces staff trying to support a healthy lifestyle as well as the autonomy of the residents.

Promoting a healthy diet and physical activity in adults with intellectual disabilities living in community residences: design and evaluation of a cluster-randomized intervention.

BACKGROUND: Many adults with intellectual disabilities have poor dietary habits, low physical activity and weight disturbances. This study protocol describes the design and evaluation of a health intervention aiming to improve diet and physical activity in this target group. In Sweden, adults with intellectual disabilities often live in community residences where the staff has insufficient education regarding the special health needs of residents. No published lifestyle interventions have simultaneously targeted both residents and staff. METHODS/DESIGN: The intervention is designed to suit the ordinary work routines of community residences. It is based on social cognitive theory and takes 12-15 months to complete. The intervention includes three components: 1) Ten health education sessions for residents in their homes; 2) the appointment of a health ambassador among the staff in each residence and formation of a network; and 3) a study circle for staff in each residence. The intervention is implemented by consultation with managers, training of health educators, and coaching of health ambassadors. Fidelity is assessed based on the participation of residents and staff in the intervention activities. The study design is a cluster-randomised trial with physical activity as primary outcome objectively assessed by pedometry. Secondary outcomes are dietary quality assessed by digital photography, measured weight, height and waist circumference, and quality of life assessed by a quality of life scale. Intermediate outcomes are changes in work routines in the residences assessed by a questionnaire to managers. Adults with mild to moderate intellectual disabilities living in community residences in Stockholm County are eligible for inclusion. Multilevel analysis is used to evaluate effects on primary and secondary outcomes. The impact of the intervention on work routines in community residences is analysed by ordinal regression analysis. Barriers and facilitators of implementation are identified in an explorative qualitative study through observations and semi-structured interviews. DISCUSSION: Despite several challenges it is our hope that the results from this intervention will lead to new and improved health promotion programs to the benefit of the target group. TRIAL REGISTRATION NUMBER: ISRCTN33749876.