Increased cancer prevalence in peripartum cardiomyopathy

Objectives This study was designed to analyze the prevalence and potential genetic basis of cancer and heart failure in peripartum cardiomyopathy (PPCM). Background PPCM manifests as heart failure late in pregnancy or postpartum in women without previous heart disease. Methods Clinical history and cancer prevalence were evaluated in a cohort of 236 PPCM patients from Germany and Sweden. Exome sequencing assessed variants in 133 genes associated with cancer predisposition syndromes (CPS) and in 115 genes associated with dilated/hypertrophic cardiomyopathy (DCM/HCM) in 14 PPCM patients with a history of cancer, and in 6 PPCM patients without a history of cancer. Results The prevalence of cancer was 16-fold higher (8.9%, 21 of 236 patients) in PPCM patients compared to age-matched women (German cancer registry, Robert-Koch-Institute: 0.59%; p < 0.001). Cancer before PPCM occurred in 12 of 21 patients of whom 11 obtained cardiotoxic cancer therapies. Of those, 17% fully recovered cardiac function by 7 ± 2 months of follow-up compared to 55% of PPCM patients without cancer (p = 0.015). Cancer occurred after PPCM in 10 of 21 patients; 80% had left ventricular ejection fraction of ≥50% after cancer therapy. Whole-exome sequencing in 14 PPCM patients with cancer revealed that 43% (6 of 14 patients) carried likely pathogenic (Class IV) or pathogenic (Class V) gene variants associated with DCM/HCM in CPT2, DSP, MYH7, TTN, and/or with CPS in ATM, ERCC5, NBN, RECQL4, and SLX4. All CPS variants affected DNA damage response genes. Conclusions Cardiotoxic cancer therapy before PPCM is associated with delayed full recovery. The high cancer prevalence in PPCM is linked to likely pathogenic/pathogenic gene variants associated with DCM/HCM and/or CPS/DNA damage response–related cancer risk. This may warrant genetic testing and screening for heart failure in pregnant women with a cancer history and screening for cancer in PPCM patients

In peripartum cardiomyopathy plasminogen activator inhibitor-1 is a potential new biomarker with controversial roles

Aims Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously heart-healthy women. A common pathomechanism in PPCM involves the angiostatic 16 kDa-prolactin (16 kDa-PRL) fragment, which via NF-kappa B-mediated up-regulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyse whether the plasminogen activator inhibitor-1 (PAI-1) is involved in the pathophysiology of PPCM. Methods and results In healthy age-matched postpartum women (PP-Ctrl, n = 53, left ventricular ejection fraction, LVEF > 55%), PAI-1 plasma levels were within the normal range (21 +/- 10 ng/mL), but significantly elevated (64 +/- 38 ng/mL, P <0.01) in postpartum PPCM patients at baseline (BL, n = 64, mean LVEF: 23 +/- 8%). At 6-month follow-up (n = 23), PAI-1 levels decreased (36 +/- 14 ng/mL, P <0.01 vs. BL) and LVEF (49 +/- 11%) improved. Increased N-terminal pro-brain natriuretic peptide and Troponin T did not correlate with PAI-1. C-reactive protein, interleukin (IL)-6 and IL-1 beta did not differ between PPCM patients and PP-Ctrl. MiR-146a was 3.6-fold (P <0.001) higher in BL-PPCM plasma compared with PP-Ctrl and correlated positively with PAI-1. In BL-PPCM serum, 16 kDa-PRL coprecipitated with PAI-1, which was associated with higher (P <0.05) uPAR-mediated NF-kappa B activation in endothelial cells compared with PP-Ctrl serum. Cardiac biopsies and dermal fibroblasts from PPCM patients displayed higher PAI-1 mRNA levels (P <0.05) than healthy controls. In PPCM mice (due to a cardiomyocyte-specific-knockout for STAT3, CKO), cardiac PAI-1 expression was higher than in postpartum wild-type controls, whereas a systemic PAI-1-knockout in CKO mice accelerated peripartum cardiac fibrosis, inflammation, heart failure, and mortality. Conclusion In PPCM patients, circulating and cardiac PAI-1 expression are up-regulated. While circulating PAI-1 may add 16 kDa-PRL to induce vascular impairment via the uPAR/NF-kappa B/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-kappa B-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised

Catecholaminergic neuromodulation shapes intrinsic MRI functional connectivity in the human brain

The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity

Gradual caldera collapse at Bárdarbunga volcano, Iceland, regulated by lateral magma outflow

Large volcanic eruptions on Earth commonly occur with a collapse of the roof of a crustal magma reservoir, forming a caldera. Only a few such collapses occur per century, and the lack of detailed observations has obscured insight into the mechanical interplay between collapse and eruption.We usemultiparameter geophysical and geochemical data to show that the 110-squarekilometer and 65-meter-deep collapse of Bárdarbunga caldera in 2014-2015 was initiated through withdrawal of magma, and lateral migration through a 48-kilometers-long dike, from a 12-kilometers deep reservoir. Interaction between the pressure exerted by the subsiding reservoir roof and the physical properties of the subsurface flow path explain the gradual, nearexponential decline of both collapse rate and the intensity of the 180-day-long eruption.</p

Action planning and the timescale of evidence accumulation

Perceptual decisions are based on the temporal integration of sensory evidence for different states of the outside world. The timescale of this integration process varies widely across behavioral contexts and individuals, and it is diagnostic for the underlying neural mechanisms. In many situations, the decision-maker knows the required mapping between perceptual evidence and motor response (henceforth termed “sensory-motor contingency”) before decision formation. Here, the integrated evidence can be directly translated into a motor plan and, indeed, neural signatures of the integration process are evident as build-up activity in premotor brain regions. In other situations, however, the sensory-motor contingencies are unknown at the time of decision formation. We used behavioral psychophysics and computational modeling to test if knowledge about sensory-motor contingencies affects the timescale of perceptual evidence integration. We asked human observers to perform the same motion discrimination task, with or without trial-to-trial variations of the mapping between perceptual choice and motor response. When the mapping varied, it was either instructed before or after the stimulus presentation. We quantified the timescale of evidence integration under these different sensory-motor mapping conditions by means of two approaches. First, we analyzed subjects’ discrimination threshold as a function of stimulus duration. Second, we fitted a dynamical decision-making model to subjects’ choice behavior. The results from both approaches indicated that observers (i) integrated motion information for several hundred ms, (ii) used a shorter than optimal integration timescale, and (iii) used the same integration timescale under all sensory-motor mappings. We conclude that the mechanisms limiting the timescale of perceptual decisions are largely independent from long-term learning (under fixed mapping) or rapid acquisition (under variable mapping) of sensory-motor contingencies. This conclusion has implications for neurophysiological and neuroimaging studies of perceptual decision-making

Cognitive frames in corporate sustainability: managerial sensemaking with paradoxical and business case frames

Corporate sustainability confronts managers with tensions between complex economic, environmental, and social issues. Drawing on the literature on managerial cognition, corporate sustainability, and strategic paradoxes, we develop a cognitive framing perspective on corporate sustainability. We propose two cognitive frames—a business case frame and a paradoxical frame—and explore how differences between them in cognitive content and structure influence the three stages of the sensemaking process—that is, managerial scanning, interpreting, and responding with regard to sustainability issues. We explain how the two frames lead to differences in the breadth and depth of scanning, differences in issue interpretations in terms of sense of control and issue valence, and different types of responses that managers consider with regard to sustainability issues. By considering alternative cognitive frames, our argument contributes to a better understanding of managerial decision making regarding ambiguous sustainability issues, and it develops the underlying cognitive determinants of the stance that managers adopt on sustainability issues. This argument offers a cognitive explanation for why managers rarely push for radical change when faced with complex and ambiguous issues, such as sustainability, that are characterized by conflicting yet interrelated aspects

Practising an explosive eruption in Iceland: outcomes from a European exercise

A 3 day exercise simulating unrest and a large explosive eruption at Katla volcano, Iceland, was conducted in January 2016. A large volume of simulated data based on a complex, but realistic eruption scenario was compiled in advance and then transmitted to exercise participants in near-real time over the course of the exercise. The scenario was designed to test the expertise and procedures of the local institutions in charge of warning and responding to volcanic hazards, namely the volcano observatory, national civil protection, and the local university-science sector, as well as their interactions with the European science community and the London Volcanic Ash Advisory Centre. This exercise was the first of this magnitude and scope in Iceland and has revealed many successful developments introduced since the 2010 Eyjafjallajökull and 2011 Grímsvötn eruptions. Following the exercise, 90% of participants said that they felt better prepared for a future eruption. As with any exercise, it also identified areas where further development is required and improvements can be made to procedures. Seven key recommendations are made to further develop capability and enhance the collaboration between the volcano observatory, volcano research institutions and civil protection authorities. These recommendations cover topics including notification of responders, authoritative messaging, data sharing and media interaction, and are more broadly applicable to volcanic institutions elsewhere. Lessons and suggestions for how to run a large-scale volcanic exercise are given and could be adopted by those planning to rehearse their own response procedures.This work was funded by the European Community’s FP7 Programme grant 308377 (Project FUTUREVOLC).Peer Reviewe

Work-life balance, management practices and productivity

Do “Anglo-Saxon” management practices generate higher productivity only at the expense of lousy work-life balance (WLB) for workers? Many critics of “neo-libéralisme sauvage” have argued that increased competition from globalisation is damaging employees’ quality of life. Others have argued the opposite that improving work-life balance is actually a competitive tool that companies can use to raise productivity. We try to shed some empirical light on these issues using an innovative survey tool to collect new data on management and work-life balance practices from 732 medium sized manufacturing firms in the US, France, Germany and the UK. First, we show that our measure of work-life balance is a useful summary of a range of policies in the firm – family-friendly policies, flexible working, shorter hours, more holidays, subsidised childcare, etc. We show that this worklife balance measure is significantly associated with better management. Firms in environments that are more competitive and/or who are more productive, however, do not have significantly worse work-life balance for their workers. These findings are inconsistent with the view that competition, globalisation and “Anglo-Saxon” management practices are intrinsically bad for the work-life balance of workers. On the other hand, neither are these findings supportive of the optimistic “winwin” view that work-life balance improves productivity in its own right. Rather we find support for a “hybrid” theory that work-life balance is a choice for managers that is compatible with low or high productivity