Liminality as a Dimension of the Experience of Living with Terminal Cancer

Objectives: This paper is concerned with the phenomenology of death awareness within the context of being diagnosed with terminal cancer. The objective of the research presented in this paper is to provide a deeper insight into terminally ill cancer patients’ engagement with their mortality. Methods: The analysis presented here forms part of a wider project which involved conducting a metasynthesis of 23 phenomenological studies of the experience of living with the awareness of having terminal cancer published between 2011 and 2016. Results: The metasynthesis identified four master themes which represent distinct experiential dimensions of living with terminal cancer. This paper focuses on one of these themes, liminality, in order to provide novel insights into the structure of death awareness whilst living with terminal cancer. Significance of Results: The results suggest that liminality describes an experiential space from within which terminal cancer patients encounter a new relationship with their existence. Liminality offers opportunities for both connection (e.g. with the natural world) as well as disconnection (e.g. from loved ones and others who still have a future) and therefore contains the potential for suffering and distress as well as for joy and a sense of fulfilment. This understanding of liminality can help health care professionals provide psychological support for this client group

Examining the effect of Early Life Stress on autonomic and endocrine indicators of individual stress reactivity

Early life stress (ELS) is associated with altered stress reactivity and an increased risk for the development of psychopathological conditions in later life. However, depending on whether autonomic or endocrine measures were used as indicators of stress reactivity, previous studies reported conflicting findings of either increased or decreased stress reactivity after ELS experience. In the present study we therefore aimed to investigate the effect of ELS on both autonomic and endocrine indicators (heart rate and salivary cortisol) of individual stress reactivity and applied a psychosocial stress task in a sample of healthy participants with and without exposure to mild to moderate ELS. Results showed no significant effects of ELS on autonomic and endocrine indicators of individual stress reactivity. Importantly though, heart rate proved as more sensitive than salivary cortisol with regard to differentiating between stress and control conditions and thereby as a more feasible indicator of an individual's stress reactivity. Accordingly, our data suggest that sole reliance on salivary cortisol as an indicator of stress reactivity might lead to an oversight of more subtle effects of psychosocial stress

Examining the effect of Early Life Stress on autonomic and endocrine indicators of individual stress reactivity

Early life stress (ELS) is associated with altered stress reactivity and an increased risk for the development of psychopathological conditions in later life. However, depending on whether autonomic or endocrine measures were used as indicators of stress reactivity, previous studies reported conflicting findings of either increased or decreased stress reactivity after ELS experience. In the present study we therefore aimed to investigate the effect of ELS on both autonomic and endocrine indicators (heart rate and salivary cortisol) of individual stress reactivity and applied a psychosocial stress task in a sample of healthy participants with and without exposure to mild to moderate ELS. Results showed no significant effects of ELS on autonomic and endocrine indicators of individual stress reactivity. Importantly though, heart rate proved as more sensitive than salivary cortisol with regard to differentiating between stress and control conditions and thereby as a more feasible indicator of an individual's stress reactivity. Accordingly, our data suggest that sole reliance on salivary cortisol as an indicator of stress reactivity might lead to an oversight of more subtle effects of psychosocial stress

Immune Cell Profiling During Switching from Natalizumab to Fingolimod Reveals Differential Effects on Systemic Immune-Regulatory Networks and on Trafficking of Non-T Cell Populations into the Cerebrospinal Fluid—Results from the ToFingo Successor Study

Leukocyte sequestration is an established therapeutic concept in multiple sclerosis (MS) as represented by the trafficking drugs natalizumab (NAT) and fingolimod (FTY). However, the precise consequences of targeting immune cell trafficking for immunoregulatory network functions are only incompletely understood. In the present study, we performed an in-depth longitudinal characterization of functional and phenotypic immune signatures in peripheral blood (PB) and cerebrospinal fluid (CSF) of 15 MS patients during switching from long-term NAT to FTY treatment after a defined 8-week washout period within a clinical trial (ToFingo successor study; ClinicalTrials.gov: NCT02325440). Unbiased visualization and analysis of high-dimensional single cell flow-cytometry data revealed that switching resulted in a profound alteration of more than 80% of investigated innate and adaptive immune cell subpopulations in the PB, revealing an unexpectedly broad effect of trafficking drugs on peripheral immune signatures. Longitudinal CSF analysis demonstrated that NAT and FTY both reduced T cell subset counts and proportions in the CSF of MS patients with equal potency; NAT however was superior with regard to sequestering non-T cell populations out of the CSF, including B cells, natural killer cells and inflammatory monocytes, suggesting that disease exacerbation in the context of switching might be driven by non-T cell populations. Finally, correlation of our immunological data with signs of disease exacerbation in this small cohort suggested that both (i) CD49d expression levels under NAT at the time of treatment cessation and (ii) swiftness of FTY-mediated effects on immune cell subsets in the PB together may predict stability during switching later on

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

International audienceInterference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity

ATLAS pixel detector electronics and sensors

The silicon pixel tracking system for the ATLAS experiment at the Large Hadron Collider is described and the performance requirements are summarized. Detailed descriptions of the pixel detector electronics and the silicon sensors are given. The design, fabrication, assembly and performance of the pixel detector modules are presented. Data obtained from test beams as well as studies using cosmic rays are also discussed

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Rate of venous thromboembolism in a prospective all-comers cohort with COVID-19

Abstract COVID-19 is associated with a variety of clinical complications including coagulopathy, which frequently results in venous thromboembolism (VTE). Retrospective analyses reported a markedly increased rate of VTEs in COVID-19. However, most recent studies on coagulopathy in COVID-19 were only focused on critically ill patients, and without suitable control groups. We aimed to evaluate the rate of VTEs in an all-comers cohort with suspected COVID-19 during a 30-days follow-up period. We also studied the level of D-dimers and their association with the course of disease. In our prospective single-center study (DRKS00021206, 03/30/2020), we analyzed 190 patients with suspected COVID-19 admitted to the emergency department between March and April 2020. Forty-nine patients were SARS-CoV-2 positive (25.8%). The 141 SARS-CoV-2-negative patients served as control group. After completion of a 30-days follow-up, VTE was diagnosed in 3 patients of the SARS-CoV-2-positive group (6.1%, amongst these 2 ICU cases) versus 5 patients in the SARS-CoV-2-negative group (3.5%), however the difference was not statistically significant (p = 0.427). 30-days mortality was similar in both groups (6.1% vs. 5%, p = 0.720). Disease severity correlated with the maximum level of D-dimers during follow-up in COVID-19. The rate of VTE was numerically higher in SARS-CoV-2 positive all-comers presenting with suspected COVID-19 as compared to well-matched controls suffering from similar symptoms. VTEs in the COVID-19 group predominantly occurred in ICU courses. The maximum level of D-dimers during follow-up was associated with disease severity in COVID-19, whereas the level of D-dimers at admission was not

Early-Life stress modulates neural networks associated with habitual use of reappraisal

Recent evidence shows that early life stress (ELS) is associated with altered resting-state functional connectivity (RSFC) between amygdala and the prefrontal cortex, as well as with maladaptive emotion regulation strategies and negative mood. However, the relation between ELS and maladaptive emotion regulation is not deterministic. Adaptive emotion regulation strategies such as reappraisal can also ensue from experience and learning in adulthood and can prevent negative mood. The present study aims to investigate the joint influence of ELS, in particular early-life emotional abuse (EA), and habitual use of reappraisal on amygdala-centered RSFC and mood. We examined amygdala-centered RSFC using functional magnetic resonance imaging (fMRI) in 28 healthy adults with varied exposure to early-life emotional abuse. We found that in subjects with high early-life emotional abuse, reappraisal was predominantly associated with RSFC between left centromedial amygdala (CMA) and the ventrolateral prefrontal cortex (VLPFC), whereas in subjects with low early-life EA reappraisal predominantly involved RSFC between right CMA, premotor and supplementary motor regions. For subjects with high EA, reappraisal use was associated with a decrease in negative mood whereas it was associated with an increase in positive mood for subjects with low EA. The general findings of the study suggest that reappraisal use might act as a protective factor, notably for individuals who were exposed to ELS, and that this is mediated by alteration of amygdala-centered RSFC

Attenuation of immune activation in patients with multiple sclerosis on a wheat-reduced diet: a pilot crossover trial

Background: Western lifestyle has been associated with an increase in relapsing–remitting multiple sclerosis (RRMS). In mice, dietary wheat amylase–trypsin inhibitors (ATIs) activate intestinal myeloid cells and augment T cell-mediated systemic inflammation. Objective: The aim of this study was to assess whether a wheat- and thus ATI-reduced diet might exert beneficial effects in RRMS patients with modest disease activity. Methods: In this 6-month, crossover, open-label, bicentric proof-of-concept trial, 16 RRMS patients with stable disease course were randomized to either 3 months of a standard wheat-containing diet with consecutive switch to a > 90% wheat-reduced diet, or vice versa. Results: The primary endpoint was negative, as the frequency of circulating pro-inflammatory T cells did not decrease during the ATI-reduced diet. We did, however, observe decreased frequencies of CD14 + CD16 ++ monocytes and a concomitant increase in CD14 ++ CD16 − monocytes during the wheat-reduced diet interval. This was accompanied by an improvement in pain-related quality of life in health-related quality of life assessed (SF-36). Conclusion: Our results suggest that the wheat- and thus ATI-reduced diet was associated with changes in monocyte subsets and improved pain-related quality of life in RRMS patients. Thus, a wheat (ATI)-reduced diet might be a complementary approach accompanying immunotherapy for some patients. Registration: German Clinical Trial Register (No. DRKS00027967)