Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

Association Between Patient and Physician Sex and Physician-Estimated Stroke and Bleeding Risks in Atrial Fibrillation

Background

Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain.

The Dangerous Middle: Situational Awareness and Worker Perception of Beetle Kill

ABSTRACT

Forest workers, including loggers, foresters, and wildland firefighters, are regularly exposed to some of the most fatal occupational environments in the United States. These hazardous work environments may become even more complex and dynamic when subject to bark beetle outbreaks that have resulted in significant tree mortality. The impacts of tree death from bark beetles are significant, with the cumulative 17-year (2000–2016) footprint for bark beetle caused tree mortality estimated at 54 million acres. However, how workers think about and act in these environments is understudied. This study, therefore, approaches the issue of beetle kill and forest worker safety by examining the perspectives or workers themselves. Its contribution is to leverage ethnographic research to provide insights that can generate new research questions, better inform outreach, and ultimately improve worker safety outcomes. The resulting insights show that beetle kill was understood by workers as a hazard that increased the complexity and dynamism of the work environment, making situational awareness both more necessary and more difficult to maintain. While much research about situational awareness focuses on hazardous situations, it is suggested that building adequate situational awareness should also include broader considerations of organizational communication, as well as training and experience considered over the course of entire careers.     

Contextualizing the lived experience of quality of life for persons with spinal cord injury: A mixed-methods application of the response shift model

Objective: The objective of this study was to gain greater insight into individuals’ quality of life (QOL) definitions, appraisals, and adaptations following spinal cord injury (SCI).

Design: A mixed-methods design, applying the Schwartz and Sprangers response shift (RS) model. RS is a cognitive process wherein, in response to a change in health status, individuals change internal standards, values, or conceptualization of QOL

Setting: Community-dwelling participants who receive medical treatment at a major Midwestern medical system and nearby Veterans’ Affairs hospital.

Participants: A purposive sample of participants with SCI (N?=?40) completed semi-structured interviews and accompanying quantitative measures.

Interventions: Not applicable.

Outcome Measures: Qualitative data were analyzed using content analysis to identify themes. Analysis of variance were performed to detect differences based on themes and QOL, well-being, and demographic and injury characteristics.

Results: Four RS themes were identified, capturing the range of participant perceptions of QOL. The themes ranged from complete RS, indicating active engagement in maintaining QOL, to awareness and comparisons redefining QOL, to a relative lack of RS. Average QOL ratings differed as a function of response shift themes. PROMIS Global Health, Anxiety, and Depression also differed as a function of RS themes.

Conclusion: The RS model contextualizes differences in QOL definitions, appraisals, and adaptations in a way standardized QOL measures alone do not.     

Endothelial function,regulation of angiogenesis and embryonic central hemodynamics in ART-conceived pregnancies

Abstract

This study was undertaken to compare the concentrations of pro- and anti-angiogenic growth factors, nitric oxide (NO) stable metabolites in maternal serum and embryonic left ventricular (LV) isovolumic relaxation time (IRT, ms) during the first trimester in two groups of women: with pregnancy conceived by assisted reproductive technologies (ART, n?=?39) and normally conceived (control group, n?=?68) pregnancy. The concentration of vasoconstrictor endothelin 1 was 45.5 times more in ART than in control group. On the contrary, the concentrations of NO stable metabolites in ART were 1.9 times less than in control women. The assessment of angiogenic suppressors in ART women demonstrates the decrease in s-endoglin concentration was 1.6 times and in soluble receptor to vascular endothelial growth factor concentration was 2.0 times in comparison with control group. There was a significant increase in LV IRT in ART embryos in comparison to control ones. These data suggest significant changes in pro- anti-angiogenic factors balance and increase in vascular impedance in ART-conceived embryos.     

A process evaluation of implementing a vocational enablement protocol for employees with hearing difficulties in clinical practice

Objective: A multidisciplinary vocational rehabilitation programme, the Vocational Enablement Protocol (VEP) was developed to address the specific needs of employees with hearing difficulties. In the current study we evaluated the process of implementing the VEP in audiologic care among employees with hearing impairment. Design: In conjunction with a randomized controlled trial, we collected and analysed data on seven process parameters: recruitment, reach, fidelity, dose delivered, dose received and implemented, satisfaction, and perceived benefit. Study sample: Sixty-six employees with hearing impairment participated in the VEP. The multidisciplinary team providing the VEP comprised six professionals. Results: The professionals performed the VEP according to the protocol. Of the recommendations delivered by the professionals, 31% were perceived as implemented by the employees. Compliance rate was highest for hearing-aid uptake (51%). Both employees and professionals were highly satisfied with the VEP. Participants rated good perceived benefit from it. Conclusions: Our results indicate that the VEP could be a useful treatment for employees with hearing difficulties from a process evaluation perspective. Implementation research in the audiological setting should be encouraged in order to further provide insight into parameters facilitating or hindering successful implementation of an intervention and to improve its quality and efficacy.     

Interpersonal Counseling in the Treatment of Adolescent Depression: A Randomized Controlled Effectiveness and Feasibility Study in School Health and Welfare Services

In order to offer early and accessible treatment for adolescents with depression, brief and effective treatments in adolescents’ everyday surroundings are needed. This randomized controlled trial studied the preliminary effectiveness, feasibility, and acceptability of interpersonal counseling (IPC) and brief psychosocial support (BPS) in school health and welfare services. The study was conducted in the 28 lower secondary schools of a large city in Southern Finland, randomized to provide either IPC or BPS. Help-seeking 12–16-year-old adolescents with mild-to-moderate depression, with and without comorbid anxiety, were included in the study. Fifty-five adolescents received either 6 weekly sessions of IPC or BPS and two follow-up sessions. Outcome measures included self- and clinician-rated measures of depression, global functioning, and psychological distress/well-being. To assess feasibility and acceptability of the treatments, adolescents’ and counselors’ treatment compliance and satisfaction with treatment were assessed. Both treatments were effective in reducing depressive disorders and improving adolescents’ overall functioning and well-being. At post-treatment, in both groups, over 50% of adolescents achieved recovery based on self-report and over 70% based on observer report. Effect sizes for change were medium or large in both groups at post-treatment and increased at 6-month follow-up. A trend indicating greater baseline symptom severity among adolescents treated in the IPC-providing schools was observed. Adolescents and counselors in both groups were satisfied with the treatment, and 89% of the adolescents completed the treatments and follow-ups. This trial suggests that both IPC and BPS are feasible, acceptable, and effective treatments for mild-to-moderate depression in the school setting. In addition, IPC seems effective even if comorbid anxiety exists. Our study shows that brief, structured interventions, such as IPC and BPS, are beneficial in treating mild-to-moderate depression in school settings and can be administered by professionals working at school.

Trial registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT03001245.

     

Effect of Tropicamide on Laser Flare Meter Measurements in Patients with Pseudoexfoliation

ABSTRACT

Purpose

To investigate the effect of 1% tropicamide on anterior chamber aqueous flare (ACAF) measurements acquired with laser flare meter in patients with pseudoexfoliation.