Long term adjuvant endocrine therapy and risk of cardiovascular disease in female breast cancer survivors: systematic review

OBJECTIVE: To investigate the effect of endocrine therapies on a wide range of specific clinical cardiovascular disease outcomes in women with a history of non-metastatic breast cancer. DESIGN: Systematic review and meta-analysis of randomised controlled trials and observational studies. DATA SOURCES: Medline and Embase up until June 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they investigated the risk of a specific cardiovascular disease outcome associated with use of either tamoxifen or an aromatase inhibitor, or compared the two treatments, in women with a history of non-metastatic breast cancer. APPRAISAL AND DATA EXTRACTION: Relevant studies were originally identified and results extracted by one researcher, with a full replication of the study identification process by a combination of two other researchers. The Cochrane Collaboration's tool for assessing risk of bias was used to assess risk of bias in randomised controlled trials, and this tool was adapted to assess risk of bias in observational studies. RESULTS: 26 studies were identified, with results for seven specific cardiovascular disease outcomes (venous thromboembolism, myocardial infarction, stroke, angina, heart failure, arrhythmia, and peripheral vascular disease). Results suggested an increased risk of venous thromboembolism in tamoxifen users compared with both non-users and aromatase inhibitor users. Results were also consistent with a higher risk of the vascular diseases myocardial infarction and angina in aromatase inhibitor users compared with tamoxifen users, but there was also a suggestion that this may be partly driven by a protective effect of tamoxifen on these outcomes. Data were limited, and evidence was generally inconsistent for all other cardiovascular disease outcomes. CONCLUSION: This review has collated substantial randomised controlled trial and observational evidence on the effect of endocrine therapies on several specific cardiovascular disease outcomes including venous thromboembolism and myocardial infarction, progressing knowledge. Although the choice of aromatase inhibitor or tamoxifen will primarily be based on the effectiveness against the recurrence of breast cancer, this review shows that the individual patient's risk of venous or arterial vascular disease should be an important secondary consideration. SYSTEMATIC REVIEW REGISTRATION: Prospero CRD42017065944

Ultrahigh energy cosmic rays from shocks in the lobes of powerful radio galaxies

The origin of ultrahigh energy cosmic rays (UHECRs) has been an open question for decades. Here, we use a combination of hydrodynamic simulations and general physical arguments to demonstrate that UHECRs can in principle be produced by diffusive shock acceleration (DSA) in shocks in the backflowing material of radio galaxy lobes. These shocks occur after the jet material has passed through the relativistic termination shock. Recently, several authors have demonstrated that highly relativistic shocks are not effective in accelerating UHECRs. The shocks in our proposed model have a range of non-relativistic or mildly relativistic shock velocities more conducive to UHECR acceleration, with shock sizes in the range 1-10 kpc. Approximately 10 per cent of jet's energy flux is focused through a shock in the backflow of M > 3. Although the shock velocities can be low enough that acceleration to high energy via DSA is still efficient, they are also high enough for the Hillas energy to approach 1019-20 eV, particularly for heavier CR composition and in cases where fluid elements pass through multiple shocks. We discuss some of the more general considerations for acceleration of particles to ultrahigh energy with reference to giant-lobed radio galaxies such as Centaurus A and Fornax A, a class of sources which may be responsible for the observed anisotropies from UHECR observatories

Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour

Microglial immunophenotype in dementia with Alzheimer's pathology.

BACKGROUND: Genetic risk factors for Alzheimer's disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. METHODS: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer's pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I). RESULTS: The presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0.007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer's pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer's pathology was negative or not significant, and positive in participants with dementia and Alzheimer's pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001). CONCLUSIONS: Our findings raise the possibility that in dementia with Alzheimer's pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer's pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aβ and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses

Soliton pair dynamics in patterned ferromagnetic ellipses

Confinement alters the energy landscape of nanoscale magnets, leading to the appearance of unusual magnetic states, such as vortices, for example. Many basic questions concerning dynamical and interaction effects remain unanswered, and nanomagnets are convenient model systems for studying these fundamental physical phenomena. A single vortex in restricted geometry, also known as a non-localized soliton, possesses a characteristic translational excitation mode that corresponds to spiral-like motion of the vortex core around its equilibrium position. Here, we investigate, by a microwave reflection technique, the dynamics of magnetic soliton pairs confined in lithographically defined, ferromagnetic Permalloy ellipses. Through a comparison with micromagnetic simulations, the observed strong resonances in the subgigahertz frequency range can be assigned to the translational modes of vortex pairs with parallel or antiparallel core polarizations. Vortex polarizations play a negligible role in the static interaction between two vortices, but their effect dominates the dynamics.Comment: supplemental movies on http://www.nature.com/nphys/journal/v1/n3/suppinfo/nphys173_S1.htm

Maximum levels of hepatitis C virus lipoviral particles are associated with early and persistent infection

Background & Aims: Hepatitis C virus (HCV) is bound to plasma lipoproteins and circulates as an infectious lipoviral particle (LVP). Experimental evidence indicates that LVPs have decreased susceptibility to antibody-mediated neutralisation and higher infectivity. This study tested the hypothesis that LVPs are required to establish persistent infection, and conversely, low levels of LVP in recent HCV infection increase the probability of spontaneous HCV clearance. Methods: LVP in non-fasting plasma was measured using the concentration of HCV RNA bound to large >100 nm sized lipoproteins after ex vivo addition of a lipid emulsion, that represented the maximum concentration of LVP (maxi-LVP). This method correlated with LVP in fasting plasma measured using iodixanol density gradient ultracentrifugation. Maxi-LVP was measured in a cohort of 180 HCV participants with recent HCV infection and detectable HCV RNA from the Australian Trial in Acute Hepatitis C (ATAHC) and Hepatitis C Incidence and Transmission Study in prison (HITS-p) cohorts. Results: Spontaneous clearance occurred in 15% (27 of 180) of individuals. In adjusted analyses, low plasma maxi-LVP level was independently associated with spontaneous HCV clearance (≤827 IU/ml; adjusted odds ratio 3.98, 95% CI: 1.02, 15.51, P = 0.047), after adjusting for interferon lambda-3 rs8099917 genotype, estimated duration of HCV infection and total HCV RNA level. Conclusions: Maxi-LVP is a biomarker for the maximum concentration of LVP in non-fasting samples. Low maxi-LVP level is an independent predictor of spontaneous clearance of acute HCV

Cyclic Force Applied to FAs Induces Actin Recruitment Depending on the Dynamic Loading Pattern

Mechanical forces acting on focal adhesions (FAs) are believed to be an important determinant for cytoskeletal reorganization. However, the effect of the temporal pattern of forces on cellular responses has not been elucidated. In the present study, we examined the responses of FAs to locally-applied cyclic forces. Magnetic micro beads coated with fibronectin were attached to the apical surface of endothelial cells and continuous or cyclic forces at frequencies of 0.1-10 Hz with duty cycles of 0-100% were applied to the beads using a newly developed electromagnetic tweezer. A significant increase in actin recruitment around the beads was observed when cyclic forces at 1-2 Hz and 25-50% duty cycles were applied. This tendency disappeared upon modification of myosin activity. These results indicate that the sensitivity to temporal patterns of forces is detemined by the viscoelastic properes of FAs and depends on myosin activity

Making a HIIT: study protocol for assessing the feasibility and effects of co-designing high-intensity interval training workouts with students and teachers

This is the final version. Available on open access from BMC via the DOI in this recordBACKGROUND: High-intensity interval training (HIIT) is an effective strategy for improving a variety of health outcomes within the school setting. However, there is limited research on the implementation of school-based HIIT interventions and the integration of HIIT within the Health and Physical Education (HPE) curriculum. The aims of the Making a HIIT study are to: 1) describe the methodology and evaluate the feasibility of co-designing HIIT workouts with students and teachers in HPE; 2) determine the effect of co-designed HIIT workouts on cardiorespiratory and muscular fitness, and executive function; 3) understand the effect of co-design on students' motivation, enjoyment, and self-efficacy towards the workouts; and 4) evaluate the implementation of the intervention. METHODS: Three schools will participate. Within each school, three different groups will be formed from Year 7 and 8 classes: 1) Co-Designers; 2) HIIT Only; and 3) Control. The study will include two phases. In phase one, Group 1 will co-design HIIT workouts as part of the HPE curriculum using an iterative process with the researcher, teacher, and students as collaborators. This process will be evaluated using student discussions, student surveys, and teacher interviews. In phase two, Groups 1 and 2 will use the co-designed 10-minute HIIT workouts in HPE for 8-weeks. Group 3 (control) will continue their regular HPE lessons. All students will participate in cardiorespiratory fitness, muscular fitness, and executive function assessments before and after the HIIT program or control period. Students will complete questionnaires on their motivation, enjoyment, and self-efficacy of the workouts. Differences between groups will be assessed using linear regressions to account for covariates. Heart rate and rating of perceived exertion will be collected during each HIIT session. The implementation will be evaluated using the Framework for Effective Implementation. Ethical approval was granted by the University of Queensland Human Research Ethics Committee and other relevant bodies. DISCUSSION: This study will be the first to co-design HIIT workouts with teachers and students within the HPE curriculum. As this study relies on co-design, each HIIT workout will differ, which will add variability between HIIT workouts but increase the ecological validity of the study. TRIAL REGISTRATION: ACTRN, ACTRN12622000534785, Registered 5 April 2022 - Retrospectively registered, https://www.anzctr.org.au/ACTRN12622000534785.aspx.QUEX Institute for Global ExcellenceSports Medicine Australia

Current sample size conventions: Flaws, harms, and alternatives

<p>Abstract</p> <p>Background</p> <p>The belief remains widespread that medical research studies must have statistical power of at least 80% in order to be scientifically sound, and peer reviewers often question whether power is high enough.</p> <p>Discussion</p> <p>This requirement and the methods for meeting it have severe flaws. Notably, the true nature of how sample size influences a study's projected scientific or practical value precludes any meaningful blanket designation of <80% power as "inadequate". In addition, standard calculations are inherently unreliable, and focusing only on power neglects a completed study's most important results: estimates and confidence intervals. Current conventions harm the research process in many ways: promoting misinterpretation of completed studies, eroding scientific integrity, giving reviewers arbitrary power, inhibiting innovation, perverting ethical standards, wasting effort, and wasting money. Medical research would benefit from alternative approaches, including established <it>value of information </it>methods, simple choices based on cost or feasibility that have recently been justified, sensitivity analyses that examine a meaningful array of possible findings, and following previous analogous studies. To promote more rational approaches, research training should cover the issues presented here, peer reviewers should be extremely careful before raising issues of "inadequate" sample size, and reports of completed studies should not discuss power.</p> <p>Summary</p> <p>Common conventions and expectations concerning sample size are deeply flawed, cause serious harm to the research process, and should be replaced by more rational alternatives.</p