Regulation of Myofilament Contractile Function in Human Donor and Failing Hearts

Heart failure (HF) often includes changes in myocardial contractile function. This study addressed the myofibrillar basis for contractile dysfunction in failing human myocardium. Regulation of contractile properties was measured in cardiac myocyte preparations isolated from frozen, left ventricular mid-wall biopsies of donor (n = 7) and failing human hearts (n = 8). Permeabilized cardiac myocyte preparations were attached between a force transducer and a position motor, and both the Ca2+ dependence and sarcomere length (SL) dependence of force, rate of force, loaded shortening, and power output were measured at 15 ± 1°C. The myocyte preparation size was similar between groups (donor: length 148 ± 10 μm, width 21 ± 2 μm, n = 13; HF: length 131 ± 9 μm, width 23 ± 1 μm, n = 16). The maximal Ca2+-activated isometric force was also similar between groups (donor: 47 ± 4 kN⋅m–2; HF: 44 ± 5 kN⋅m–2), which implicates that previously reported force declines in multi-cellular preparations reflect, at least in part, tissue remodeling. Maximal force development rates were also similar between groups (donor: ktr = 0.60 ± 0.05 s–1; HF: ktr = 0.55 ± 0.04 s–1), and both groups exhibited similar Ca2+ activation dependence of ktr values. Human cardiac myocyte preparations exhibited a Ca2+ activation dependence of loaded shortening and power output. The peak power output normalized to isometric force (PNPO) decreased by ∼12% from maximal Ca2+ to half-maximal Ca2+ activations in both groups. Interestingly, the SL dependence of PNPO was diminished in failing myocyte preparations. During sub-maximal Ca2+ activation, a reduction in SL from ∼2.25 to ∼1.95 μm caused a ∼26% decline in PNPO in donor myocytes but only an ∼11% change in failing myocytes. These results suggest that altered length-dependent regulation of myofilament function impairs ventricular performance in failing human hearts

Natural Categorization: Electrophysiological Responses to Viewing Natural Versus Built Environments

Environments are unique in terms of structural composition and evoked human experience. Previous studies suggest that natural compared to built environments may increase positive emotions. Humans in natural environments also demonstrate greater performance on attention-based tasks. Few studies have investigated cortical mechanisms underlying these phenomena or probed these differences from a neural perspective. Using a temporally sensitive electrophysiological approach, we employ an event-related, implicit passive viewing task to demonstrate that in humans, a greater late positive potential (LPP) occurs with exposure to built than natural environments, resulting in a faster return of activation to pre-stimulus baseline levels when viewing natural environments. Our research thus provides new evidence suggesting natural environments are perceived differently from built environments, converging with previous behavioral findings and theoretical assumptions from environmental psychology

Cluster randomised trials in the medical literature: two bibliometric surveys

Background: Several reviews of published cluster randomised trials have reported that about half did not take clustering into account in the analysis, which was thus incorrect and potentially misleading. In this paper I ask whether cluster randomised trials are increasing in both number and quality of reporting. Methods: Computer search for papers on cluster randomised trials since 1980, hand search of trial reports published in selected volumes of the British Medical Journal over 20 years. Results: There has been a large increase in the numbers of methodological papers and of trial reports using the term 'cluster random' in recent years, with about equal numbers of each type of paper. The British Medical Journal contained more such reports than any other journal. In this journal there was a corresponding increase over time in the number of trials where subjects were randomised in clusters. In 2003 all reports showed awareness of the need to allow for clustering in the analysis. In 1993 and before clustering was ignored in most such trials. Conclusion: Cluster trials are becoming more frequent and reporting is of higher quality. Perhaps statistician pressure works

Correlates of exercise motivation and behavior in a population-based sample of endometrial cancer survivors: an application of the Theory of Planned Behavior

<p>Abstract</p> <p>Background</p> <p>Despite evidence of the benefits of exercise in cancer survivors, exercise participation rates tend to decline after treatments. Few studies have examined the determinants of exercise in less common cancer sites. In this study, we examined medical, demographic, and social cognitive correlates of exercise in endometrial cancer survivors using the Theory of Planned Behavior (TPB).</p> <p>Methods</p> <p>A mailed survey was completed by 354 endometrial cancer survivors (1 to 10 years postdiagnosis) residing in Alberta, Canada. The study was cross-sectional. Exercise behavior was assessed using the Godin Leisure Time Exercise Questionnaire and the TPB constructs were assessed with standard self-report scales. Multiple regression analyses were used to determine the independent associations of the TPB constructs with intention and behavior.</p> <p>Results</p> <p>Chi-square analyses indicated that marital status (<it>p </it>= .003), income level (<it>p </it>= .013), and body mass index (BMI) (<it>p </it>= .020) were associated with exercise. The TPB explained 34.1% of the variance in exercise behavior with intention (<it>β </it>= .38, <it>p </it>< .001) and self-efficacy (<it>β </it>= .18, <it>p </it>= .029) being independent correlates. For intention, 38.3% of the variance was explained by the TPB with self-efficacy (<it>β </it>= .34, <it>p </it>< .001) and affective attitude (<it>β </it>= .30, <it>p </it>< .001) being the independent correlates. The TPB mediated the associations of marital status and BMI with exercise but not income level. Age and BMI moderated the associations of the TPB with intention and behavior.</p> <p>Conclusion</p> <p>The TPB may be a useful framework for understanding exercise in endometrial cancer survivors. Exercise behavior change interventions based on the TPB should be tested in this growing population.</p

The comprehensive cohort model in a pilot trial in orthopaedic trauma

Background: The primary aim of this study was to provide an estimate of effect size for the functional outcome of operative versus non-operative treatment for patients with an acute rupture of the Achilles tendon using accelerated rehabilitation for both groups of patients. The secondary aim was to assess the use of a comprehensive cohort research design (i.e. a parallel patient-preference group alongside a randomised group) in improving the accuracy of this estimate within an orthopaedic trauma setting. Methods: Pragmatic randomised controlled trial and comprehensive cohort study within a level 1 trauma centre. Twenty randomised participants (10 operative and 10 non-operative) and 29 preference participants (3 operative and 26 non-operative). The ge range was 22-72 years and 37 of the 52 patients were men. All participants had an acute rupture of their Achilles tendon and no other injuries. All of the patients in the operative group had a simple end-to-end repair of the tendon with no augmentation. Both groups then followed the same eight-week immediate weight-bearing rehabilitation programme using an off-the-shelf orthotic. The disability rating index (DRI; primary outcome), EQ-5D, Achilles Total Rupture Score and complications were assessed ed at two weeks, six weeks, three months, six months and nine months after initial injury. Results: At nine months, there was no significant difference in DRI between patients randomised to operative or non-operative management. There was no difference in DRI between the randomised group and the parallel patient preference group. The use of a comprehensive cohort of patients did not provide useful additional information as to the treatment effect size because the majority of patients chose non-operative management. Conclusions: Recruitment to clinical trials that compare operative and non-operative interventions is notoriously difficult; especially within the trauma setting. Including a parallel patient preference group to create a comprehensive cohort of patients has been suggested as a way of increasing the power of such trials. In our study, the comprehensive cohort model doubled the number of patients involved in the study. However, a strong preference for non-operative treatment meant that the increased number of patients did not significantly increase the ability of the trial to detect a difference between the two interventions

In vitro Evidence That Combination Therapy With CD16-Bearing NK-92 Cells and FDA-Approved Alefacept Can Selectively Target the Latent HIV Reservoir in CD4+ CD2hi Memory T Cells

Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be distinguishable from uninfected cells. CD2 was recently identified as a potential marker enriched in the HIV-1 reservoir on CD4+ T cells, the largest, longest-lived and best-characterized constituent of the HIV reservoir. We previously proposed to repurpose FDA-approved alefacept, a humanized α-CD2 fusion protein, to reduce the HIV reservoir in CD2hi CD4+ memory T cells. Here, we show the first evidence that alefacept can specifically target and reduce CD2hi HIV infected cells in vitro. We explore a variety of natural killer (NK) cells as mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) including primary NK cells, expanded NK cells as well as the CD16 transduced NK-92 cell line which is currently under study in clinical trials as a treatment for cancer. We demonstrate that CD16.NK-92 has a natural preference to kill CD2hi CD45RA– memory T cells, specifically CD45RA– CD27+ central memory/transitional memory (TCM/TM) subset in both healthy and HIV+ patient samples as well as to reduce HIV DNA from HIV+ samples from donors well controlled on antiretroviral therapy. Lastly, alefacept can combine with CD16.NK-92 to decrease HIV DNA in some patient samples and thus may yield value as part of a strategy toward sustained HIV remission

Survey and scoping of wildcat priority areas

This report summarises the findings of three complementary projects commissioned by SNH to inform the selection of Priority Areas for wildcat conservation; as proposed in the Scottish Wildcat Conservation Action Plan 2013. The scoping projects combined field surveys, taxonomic and genetic assessments, population modelling and a questionnaire survey of public attitudes to wildcat conservation measures. The report makes a recommendations for six wildcat Priority Areas from the nine areas pre-selected by SNH for survey. The sites recommended as Priority Areas all had evidence of cats that were classified as wildcats based on their appearance. However, domestic cats or hybrids (between domestic cats and wildcats) were also found, highlighting the need for conservation actions to reduce the risks they pose to wildcats from hybridisation and disease

Design effect in multicenter studies: gain or loss of power?

<p>Abstract</p> <p>Background</p> <p>In a multicenter trial, responses for subjects belonging to a common center are correlated. Such a clustering is usually assessed through the design effect, defined as a ratio of two variances. The aim of this work was to describe and understand situations where the design effect involves a gain or a loss of power.</p> <p>Methods</p> <p>We developed a design effect formula for a multicenter study aimed at testing the effect of a binary factor (which thus defines two groups) on a continuous outcome, and explored this design effect for several designs (from individually stratified randomized trials to cluster randomized trials, and for other designs such as matched pair designs or observational multicenter studies).</p> <p>Results</p> <p>The design effect depends on the intraclass correlation coefficient (ICC) (which assesses the correlation between data for two subjects from the same center) but also on a statistic <it>S</it>, which quantifies the heterogeneity of the group distributions among centers (thus the level of association between the binary factor and the center) and on the degree of global imbalance (the number of subjects are then different) between the two groups. This design effect may induce either a loss or a gain in power, depending on whether the <it>S </it>statistic is respectively higher or lower than 1.</p> <p>Conclusion</p> <p>We provided a global design effect formula applying for any multicenter study and allowing identifying factors – the ICC and the distribution of the group proportions among centers – that are associated with a gain or a loss of power in such studies.</p

A priori postulated and real power in cluster randomized trials: mind the gap

BACKGROUND: Cluster randomization design is increasingly used for the evaluation of health-care, screening or educational interventions. The intraclass correlation coefficient (ICC) defines the clustering effect and be specified during planning. The aim of this work is to study the influence of the ICC on power in cluster randomized trials. METHODS: Power contour graphs were drawn to illustrate the loss in power induced by an underestimation of the ICC when planning trials. We also derived the maximum achievable power given a specified ICC. RESULTS: The magnitude of the ICC can have a major impact on power, and with low numbers of clusters, 80% power may not be achievable. CONCLUSION: Underestimating the ICC during planning cluster randomized trials can lead to a seriously underpowered trial. Publication of a priori postulated and a posteriori estimated ICCs is necessary for a more objective reading: negative trial results may be the consequence of a loss of power due to a mis-specification of the ICC