Adjuvant endocrine therapy after breast cancer: a qualitative study of factors associated with adherence.

INTRODUCTION: Despite evidence of the efficacy of adjuvant endocrine therapy (AET) in reducing the risk of recurrence and mortality after treatment for primary breast cancer, adherence to AET is suboptimal. This study aimed to explore factors that influence adherence and nonadherence to AET following breast cancer to inform the development of supportive interventions. METHODS: Interviews were conducted with 32 women who had been prescribed AET, 2-4 years following their diagnosis of breast cancer. Both adherers (n=19) and nonadherers (n=13) were recruited. The analysis was conducted using the Framework approach. RESULTS: Factors associated with adherence were as follows: managing side effects including information and advice on side effects and taking control of side effects, supportive relationships, and personal influences. Factors associated with nonadherence were as follows: burden of side effects, feeling unsupported, concerns about long-term AET use, regaining normality, including valuing the quality of life over length of life, and risk perception. CONCLUSION: Provision of timely information to prepare women for the potential side effects of AET and education on medication management strategies are needed, including provision of timely and accurate information on the efficacy of AET in reducing breast cancer recurrence and on potential side effects and ways to manage these should they arise. Trust in the doctor-patient relationship and clear patient pathways for bothersome side effects and concerns with AET are important. Training and education on AET for GPs should be considered alongside novel care pathways such as primary care nurse cancer care review and community pharmacist follow-up

Observational and theoretical evidence for frictional-viscous flow at shallow crustal levels

Along the Hikurangi Subduction Margin, accretionary prism uplift has exposed the Hungaroa fault zone, an inactive thrust developed within the Middle to Late Eocene Wanstead Formation. Within the ~33 m-wide fault core, deformation of the smectitic, calcareous mudstone matrix produced a penetrative foliation that locally wraps around clasts. Deformation occurred at temperatures constrained by syntectonic calcite vein clumped isotope thermometry, which yielded a narrow range of Δ47 values between 0.445 ± 0.024‰ and 0.482 ± 0.013‰, corresponding to a mean calcite precipitation temperature of 82−12+13 °C. Optical and scanning electron microscopy analyses reveal that calcite underwent: dissolution along stylolites and clast, vein, and microlithon margins; precipitation in foliation-parallel and foliation-perpendicular extension veins; and precipitation in hybrid veins and strain fringes. Maximum differential stress estimates obtained from calcite twin densities (44.1 ± 13.9 to 96.6 ± 20.8 MPa) are consistent with those sustainable by a cohesionless fault at ~3 km depth with a friction coefficient in the range measured for two calcareous mudstones (μ = 0.38 to 0.50) and a micrite clast (μ = 0.61 and 0.64). Marlstone clasts within the foliated calcareous mudstone matrix contain mutually cross-cutting shear fractures and extension veins with crack-seal textures, providing evidence for temporal fluctuations in shear strength resulting from pore fluid overpressure transients. At strain rates imposed during laboratory experiments, frictional sliding involves granular flow processes. Yet, calcite microstructures indicate that diffusive mass transfer played an important role in accommodating deformation. We model the fault zone rheology assuming diffusion-controlled frictional-viscous flow, with deformation at strain rates γ˙≤ 10−9 s−1 able to have taken place at very low shear stresses (τ < 10 MPa) given sufficiently short diffusion distances (d < 0.1 mm), even in the absence of pore fluid overpressures. However, if grain-scale and fracture-scale processes change the diffusion distance, fault zones deforming via frictional-viscous flow can exhibit temporally variable strain rates. Thus, our results suggest that the shallow (up-dip) limit of the seismogenic zone is not a simple function of temperature in fault zones governed by a frictional-viscous flow rheology

Adjuvant endocrine therapy after breast cancer: A qualitative study of factors associated with adherence

Introduction : Despite evidence of the efficacy of Adjuvant Endocrine Therapy (AET) in reducing the risk of recurrence and mortality after treatment for primary breast cancer, adherence to AET is suboptimal. This study aimed to explore factors that influence adherence and non-adherence to adjuvant endocrine therapy (AET) following breast cancer to inform the development of supportive interventions. Methods: Interviews were conducted with 32 women who had been prescribed AET, 2-4 years following their diagnosis of breast cancer,. Both adherers (n=19) and non-adherers (n=13) were recruited. The analysis was conducted using the Framework approach. Results: Factors associated with adherence were: Managing side effects including information and advice on side effects, and taking control of side effects, Supportive relationships, and Personal influences. Factors associated with non-adherence were: Burden of side effects, Feeling unsupported, Concerns about long term AET use, Re-gaining normality, including valuing quality of life over length of life, and Risk perception Conclusions: Provision of timely information to prepare women for the potential side effects of AET and education on medication management strategies are needed, including provision of timely and accurate information on the efficacy of AET in reducing breast cancer recurrence, and on potential side effects and ways to manage these should they arise. . Trust in the doctor-patient relationship and clear patient pathways for bothersome side effects and concerns with AET are important. Training and education around AET for GPs should be considered alongside novel care pathways such as primary care nurse cancer care review, and community pharmacist follow-up

Petrophysical, Geochemical, and Hydrological Evidence for Extensive Fracture-Mediated Fluid and Heat Transport in the Alpine Fault's Hanging-Wall Damage Zone

International audienceFault rock assemblages reflect interaction between deformation, stress, temperature, fluid, and chemical regimes on distinct spatial and temporal scales at various positions in the crust. Here we interpret measurements made in the hanging‐wall of the Alpine Fault during the second stage of the Deep Fault Drilling Project (DFDP‐2). We present observational evidence for extensive fracturing and high hanging‐wall hydraulic conductivity (∼10−9 to 10−7 m/s, corresponding to permeability of ∼10−16 to 10−14 m2) extending several hundred meters from the fault's principal slip zone. Mud losses, gas chemistry anomalies, and petrophysical data indicate that a subset of fractures intersected by the borehole are capable of transmitting fluid volumes of several cubic meters on time scales of hours. DFDP‐2 observations and other data suggest that this hydrogeologically active portion of the fault zone in the hanging‐wall is several kilometers wide in the uppermost crust. This finding is consistent with numerical models of earthquake rupture and off‐fault damage. We conclude that the mechanically and hydrogeologically active part of the Alpine Fault is a more dynamic and extensive feature than commonly described in models based on exhumed faults. We propose that the hydrogeologically active damage zone of the Alpine Fault and other large active faults in areas of high topographic relief can be subdivided into an inner zone in which damage is controlled principally by earthquake rupture processes and an outer zone in which damage reflects coseismic shaking, strain accumulation and release on interseismic timescales, and inherited fracturing related to exhumation

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist