Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Electronic health records and support for primary care teamwork

Objective Consensus that enhanced teamwork is necessary for efficient and effective primary care delivery is growing. We sought to identify how electronic health records (EHRs) facilitate and pose challenges to primary care teams as well as how practices are overcoming these challenges.Methods Practices in this qualitative study were selected from those recognized as patient-centered medical homes via the National Committee for Quality Assurance 2011 tool, which included a section on practice teamwork. We interviewed 63 respondents, ranging from physicians to front-desk staff, from 27 primary care practices ranging in size, type, geography, and population size.Results EHRs were found to facilitate communication and task delegation in primary care teams through instant messaging, task management software, and the ability to create evidence-based templates for symptom-specific data collection from patients by medical assistants and nurses (which can offload work from physicians). Areas where respondents felt that electronic medical record EHR functionalities were weakest and posed challenges to teamwork included the lack of integrated care manager software and care plans in EHRs, poor practice registry functionality and interoperability, and inadequate ease of tracking patient data in the EHR over time.Discussion Practices developed solutions for some of the challenges they faced when attempting to use EHRs to support teamwork but wanted more permanent vendor and policy solutions for other challenges.Conclusions EHR vendors in the United States need to work alongside practicing primary care teams to create more clinically useful EHRs that support dynamic care plans, integrated care management software, more functional and interoperable practice registries, and greater ease of data tracking over time.     

Multidimensionality of the PROMIS self-efficacy measure for managing chronic conditions

Quality of Life Research - This study investigated the PROMIS Self-Efficacy Measure for Managing Chronic Conditions (PROMIS-SE) domain distributions and examined the factor structure of the...     

Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression

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Continuous passive motion following total knee replacement: a prospective randomized trial with follow-up to 1 year

We have carried out a prospective randomised, single blind clinical trial to investigate the effect of continuous passive motion on range of knee flexion, lack of extension, pain levels and analgesic use after total knee replacement surgery. 85 subjects were randomly allocated to control or study group. All subjects followed the existing rehabilitation protocol, which permits immediate active range of motion exercises and mobilisation with the study group using continuous passive motion for 1 h, twice a day. Outcome measures employed were range of motion, pain assessed on a visual analogue scale and analgesic use according to the WHO ladder. Blinded evaluation was carried out preoperatively, at time of discharge from hospital, 6 weeks, 6 and 12 months postoperation. No significant difference was observed between groups at all time intervals for each outcome variable using Wilcoxon Rank sum tests. The results substantiate previous findings that short duration continuous passive motion following total knee arthroplasty does not influence outcome of range of motion or reported pain.