Shared decision-making related to treatment of haemophilia: A scoping review of influential factors and available support tools.

INTRODUCTION: Treatment selection in haemophilia is increasingly challenging given evolving therapeutic options and the need for individualization. Shared decision-making (SDM) approaches have recently gained interest, though a synthesis of available studies is lacking. AIM: A scoping review was conducted to summarize literature reporting on factors impacting treatment SDM in haemophilia and tools or models available to support such decisions. METHODS: PubMed, Embase, the Cochrane Library, Web of Science and grey literature were searched for studies published through August 2023. Original studies reporting on facilitators and barriers to haemophilia SDM and SDM tools were included and analyzed for themes, characteristics and gaps. RESULTS: A total of 625 records were identified and 14 unique studies were selected (factors influencing treatment SDM, n = 7; SDM tools, n = 7). The studies typically included input from persons with haemophilia, caregivers and healthcare practitioners (HCPs). Thematic organization of factors influencing SDM revealed three main categories: knowledge, patient characteristics and HCP-patient interactions. Availability of information was a commonly reported facilitator of SDM, while poor HCP-patient engagement was a commonly reported barrier. Tools varied in focus, with some facilitating general treatment SDM while others supported selection of certain therapy types. The studies underscored additional factors critical for SDM, such as alignment of HCP-patient perceptions, shared language and tailoring of tools to specific subpopulations. CONCLUSION: Few studies report on treatment SDM factors and tools in haemophilia; available tools vary considerably. It remains unclear whether published tools have been successfully implemented into clinical practice. Additional research is warranted.

The link between environmental toxicant exposure and endometriosis.

Endometriosis is an estrogen-dependent disease characterized by the growth of endometrial cells in ectopic locations. Although the etiology of endometriosis is unknown, several hypotheses have been proposed to explain its origin. Retrograde menstruation of endometrial cells into the peritoneum is the most widely accepted theory, however, this phenomenon occurs in approximately 90% of women while the prevalence of endometriosis is much lower. Hence, other factors are thought to contribute to the development of this disease, including exposure to environmental toxicants. Although the epidemiological evidence is equivocal, animal and experimental investigations provide a basis for the proposed association between dioxin and dioxin-like chemical exposure and endometriosis. However, the mechanism(s) underlying this potential association are poorly understood. Development of novel animal models that more reliably recapitulate the pathogenesis and pathophysiology of this disease provide exciting opportunities to further test the link between exposure to these chemicals and endometriosis. Moreover, differential expression of several novel genes that may be important in the disease provides new targets to test the actions of environmental toxicants in the pathobiology of endometriosis.

Spontaneous appearance of uterine tumors in vehicle and 3-methylcholanthrene-treated Wistar rats.

During the conduct of a study designed to determine the effect of 3-methylcholanthrene (3-MC), a synthetic polycyclic aromatic hydrocarbon (PAH) that acts through the aryl hydrocarbon receptor (AhR), on uterine contractility in Wistar rats, uterine tumors were identified in both vehicle and 3-MC-treated animals. The objective of the current study was to describe the histological characteristics of these tumors. Sexually mature female rats (110 days old) were treated with 70 micro mol/kg 3-MC or vehicle (olive oil) for 4 days and euthanized by exsanguination. At necropsy uterine tumors were unexpected findings in two vehicle and four 3-MC-treated rats. The tumors appeared as multiple unilateral or bilateral subserosal nodes. No tumors were found in other tissues on gross inspection. Prior to necropsy, tumor-presenting animals were acyclic and arrested in a state of persistent proestrus. Haematoxylin and eosin staining of tumor sections revealed nests of acidophilic granule-containing cells within a highly vascular stroma of the uterine wall below the muscularis. Positive periodic acid Schiff (PAS) staining suggested the presence of glycogen or glycophospholipids within these granules, however, negative PAS diastase staining indicated that the acidophilic bodies were not composed of glycogen. The tumors are histologically similar to human dysgerminomas. We conclude that these tumors are unrelated to treatment and are of a granular type not previously documented in Wistar rats.

Targeting improved patient outcomes using innovative product listing agreements: a survey of Canadian and international key opinion leaders.

OBJECTIVES: To address the uncertainty associated with procuring pharmaceutical products, product listing agreements (PLAs) are increasingly being used to support responsible funding decisions in Canada and elsewhere. These agreements typically involve financial-based rebating initiatives or, less frequently, outcome-based contracts. A qualitative survey was conducted to improve the understanding of outcome-based and more innovative PLAs (IPLAs) based on input from Canadian and international key opinion leaders in the areas of drug manufacturing and reimbursement. METHODS: Results from a structured literature review were used to inform survey development. Potential participants were invited via email to partake in the survey, which was conducted over phone or in person. Responses were compiled anonymously for review and reporting. RESULTS: Twenty-one individuals participated in the survey, including health technology assessment (HTA) key opinion leaders (38%), pharmaceutical industry chief executive officers/vice presidents (29%), ex-payers (19%), and current payers/drug plan managers/HTA (14%). The participants suggested that ~80%-95% of Canadian PLAs are financial-based rather than outcomes-based. They indicated that IPLAs offer important benefits to patients, payers, and manufacturers; however, several challenges limit their use (eg, administrative burden, lack of agreed-upon endpoint). They noted that IPLAs are useful in rapidly evolving therapeutic areas and those associated with high unmet need, a quantifiable endpoint, and/or robust data systems. The Canadian Agency for Drugs and Technologies in Health, the pan-Canadian Pharmaceutical Alliance, and other arms-length organizations could play important roles in identifying uncertainty and endpoints and brokering pan-Canadian PLAs. Industry should work collaboratively with payers to identify uncertainty and develop innovative mechanisms to address it. CONCLUSION: The survey results indicated that while challenging, use of IPLAs may be associated with various benefits. Collaboration among stakeholders remains key: Canadian agencies could play an important role in the success of these agreements, while industry should be proactive in offering solutions that will help improve outcomes across the entire health care system.

Heteroactivation of cytochrome P450 1A1 by teas and tea polyphenols.

We studied 7-ethoxyresorufin deethylase as an index of cytochrome P4501A1 (CYP1A1) activity in liver microsomes from rats pretreated with 3-methylcholanthrene. The enzyme had complex kinetics compatible with a multisite model. At 1 microM substrate, brewed black, green and white teas had complex effects on enzyme activity consisting of activation at low concentrations and inhibition at higher concentrations. Data fit well to a two-site model that allowed us to determine maximal activation (% increase above control), pEC(50) for activation (g ml(-1)) and pIC(50) for inhibition (g ml(-1)). These parameters were 190+/-40, 5.9+/-0.1 and 4.51+/-0.09 for green tea, 350+/-40, 5.43+/-0.05 and 5.43+/-0.05 for black tea and 230+/-80, 5.3+/-0.3 and 4.7+/-0.2 for white tea, respectively. The effects of the brewed teas were mimicked to different degrees by the green tea polyphenols. Maximal activation, pEC(50) (M) and pIC(50) (M) were: (-)-epicatechin, 55+/-9, 5.4+/-0.3, 2+/-1; (-)-epicatechin gallate, 160+/-60, 6.2+/-0.3, 5.28+/-0.06; (-)-epigallocatechin 30+/-10, 6.5+/-0.5, 3.37+/-0.08; and (-)-epigallocatechin gallate 130+/-40, 6.7+/-0.3, 5.0+/-0.1. A crude extract of black tea polyphenols inhibited 7-ethoxyresorufin deethylase, but did not cause enzyme activation consistently. Enzyme activation was dependent upon substrate concentration. Heteroactivation of CYP1A1 may partially explain the lack of agreement between biological and epidemiological evidence of a role for tea in cancer prevention.

Tyrosine receptor kinase B (TrkB) protein expression in the human endometrium.

Tyrosine kinase receptor B (TrkB) gene expression, a neurotrophic factor receptor expressed in the brain and ovary, has recently been identified in deep infiltrating endometriosis by gene array. TrkB is thought to be important in resistance to anchorage independent apoptosis (ANOIKIS) and thus could be important in the pathogenesis of endometriosis. However, TrkB protein expression in the eutopic endometrium of women with and without endometriosis is unknown. Therefore, we examined TrKB protein expression in the endometrium by Western blot (n = 50) and immunohistochemistry (n = 17). Immunoblots of endometrial biopsies were prepared from women with endometriosis (n = 21) vs. healthy controls (n = 29) undergoing benign gynecological surgery at McMaster University Medical Centre. TrkB protein expression was significantly higher in immunoblots from women with endometriosis compared to women without endometriosis. In samples of archived paraffin-embedded endometrial tissue TrkB was localized to the cytoplasm of epithelial cells of the eutopic endometrium from women with endometriosis (n = 7) and without endometriosis (n = 10). We conclude that TrkB protein is expressed in human endometrium. Our results also suggest that TrkB expression may be greater in women with endometriosis compared to women without endometriosis.