Unraveling the Mechanisms of Cutaneous Graft-Versus-Host Disease

The skin is the most common target organ affected by graft-versus-host disease (GVHD), with severity and response to therapy representing important predictors of patient survival. Although many of the initiating events in GVHD pathogenesis have been defined, less is known about why treatment resistance occurs or why there is often a permanent failure to restore tissue homeostasis. Emerging data suggest that the unique immune microenvironment in the skin is responsible for defining location- and context-specific mechanisms of injury that are distinct from those involved in other target organs. In this review, we address recent advances in our understanding of GVHD biology in the skin and outline the new research themes that will ultimately enable design of precision therapies

Classifying Alarms: Seeking Durability, Credibility, Consistency, and Simplicity

Alongside the development and testing of new audible alarms intended to support International Electrotechnical Commission 60601-1-8, a global standard concerned with alarm safety, the categories of risk that the standard denotes require further thought and possible updating. In this article, we revisit the origins of the categories covered by the standard. These categories were based on the ways that tissue damage can be caused. We consider these categories from the varied professional perspectives of the authors: human factors, semiotics, clinical practice, and the patient or family (layperson). We conclude that while the categories possess many clinically applicable and defensible features from our range of perspectives, the advances in alarm design now available may allow a more flexible approach. We present a three-tier system with superordinate, basic, and subordinate levels that fit both within the thinking embodied in the current standard and possible new developments

Redefining the role of Langerhans cells as immune regulators within the skin

Langerhans cells (LC) are a unique population of tissue-resident macrophages that form a network of cells across the epidermis of the skin, but which have the ability to migrate from the epidermis to draining lymph nodes. Their location at the skin barrier suggests a key role as immune sentinels. However, despite decades of research, the role of LC in skin immunity is unclear; ablation of LC results in neither fatal susceptibility to skin infection nor overt autoimmunity due to lack of immune regulation. Our understanding of immune processes has traditionally been centered on secondary lymphoid organs as sites of lymphocyte priming and differentiation, which is exemplified by LC, initially defined as a paradigm for tissue dendritic cells that migrate to draining lymph nodes on maturation. But, more recently, an awareness of the importance of the tissue environment in shaping effector immunity has emerged. In this mini-review we discuss whether our lack of understanding of LC function stems from our lymph node-centric view of these cells, and question whether a focus on LC as immune regulators in situ in the skin may reveal clearer answers about their function in cutaneous immunology

Dendritic cells in tissues: in situ stimulation of immunity and immunopathology

Dendritic cells (DCs) prime and orchestrate naïve T cell immunity in lymphoid organs, but recent data also highlight the importance of DC–effector T cell interactions in tissues. These studies suggest that effector T cells require a second activating step in situ from tissue DCs to become fully competent for effector functions and/or proliferation and survival. DC stimulation of effector T cells within tissues has evolved as a mechanism to ensure that T cells are activated to their full potential only at the site of ongoing infection. Here, we propose that under conditions of uncontrolled inflammation and release of tissue antigens, the same DC-dependent checkpoint perpetuates a destructive response and immunopathology

Palliative care assessment of dry mouth: what matters most to patients with advanced disease?

Purpose: Dry mouth is a highly prevalent and significant symptom in patients with advanced progressive diseases. It is a poorly understood area of research, and currently, there is no standardised outcome measure or assessment tool for dry mouth. Methods: To assess responses to self-reported dry mouth questions, the impact of dry mouth, methods used to reduce symptoms and relevance of the questionnaire. A cross-sectional multisite study of 135 patients with advanced progressive disease experiencing dry mouth. Participants were located in the inpatient, day care, outpatient or community setting. Results: The majority (84.4%) of patients rated their dry mouth as moderate or severe using the verbal rating scale (VRS). Seventy-five percent (74.7%) had a numeric rating scale (NRS) score of 6 or more for dry mouth severity. Patients reported that dry mouth interfered most with talking and was the most important function to assess (median score 6 out of 10) followed by eating (median 5) and taste (median 5). Taking sips of drink was the most common and most effective self-management strategy. Over half of patients (54.6%) also reported impact on swallow and sleep and associated dryness of lips, throat and nasal passages. Conclusions: This study highlights the severity of dry mouth in advanced disease. Important factors when assessing patients with dry mouth should include the functional impact on day-to-day activities including talking, dysphagia and sleep. Simple considerations for patients include provision of drinks and reviewing medications. This study could be used to develop a standardised assessment tool for dry mouth to use in clinical practice

A correlation of the cosmic microwave sky with large scale structure

We cross correlate the large-scale cosmic microwave background (CMB) sky measured by WMAP with two probes of large-scale structure at z ~ 1. The hard X-ray background, measured by the HEAO-1 satellite, is positively correlated with the WMAP data at the 2.5-3.0 sigma level. The number counts of radio galaxies in the NVSS survey are also correlated at a slightly weaker level (2.-2.5 sigma). These correlations appear to arise from both hemispheres on the sky and are resilient to changes in the levels of masking of the Galaxy and point sources, suggesting that foregrounds are not responsible for the signal. The implication is that some of the observed CMB fluctuations arise at low redshifts. The level of the correlations is consistent with that expected for the cosmological constant (Omega_Lambda = 0.72) concordance model resulting from the integrated Sachs-Wolfe effect. Thus, we may be observing dark energy's effect on the growth of structure.Comment: 8 pages, 3 postscript figure

Is palliative care support associated with better quality end-of-life care indicators for patients with advanced cancer? A retrospective cohort study.

OBJECTIVES: This study aimed to establish the association between timing and provision of palliative care (PC) and quality of end-of-life care indicators in a population of patients dying of cancer. SETTING: This study uses linked cancer patient data from the National Cancer Registry, the electronic medical record system used in primary care (SystmOne) and the electronic medical record system used within a specialist regional cancer centre. The population resided in a single city in Northern England. PARTICIPANTS: Retrospective data from 2479 adult cancer decedents who died between January 2010 and February 2012 were registered with a primary care provider using the SystmOne electronic health record system, and cancer was certified as a cause of death, were included in the study. RESULTS: Linkage yielded data on 2479 cancer decedents, with 64.5% who received at least one PC event. Decedents who received PC were significantly more likely to die in a hospice (39.4% vs 14.5%, P<0.005) and less likely to die in hospital (23.3% vs 40.1%, P<0.05), and were more likely to receive an opioid (53% vs 25.2%, P<0.001). PC initiated more than 2 weeks before death was associated with avoiding a hospital death (≥2 weeks, P<0.001), more than 4 weeks before death was associated with avoiding emergency hospital admissions and increased access to an opioid (≥4 weeks, P<0.001), and more than 33 weeks before death was associated with avoiding late chemotherapy (≥33 weeks, no chemotherapy P=0.019, chemotherapy over 4 weeks P=0.007). CONCLUSION: For decedents with advanced cancer, access to PC and longer duration of PC were significantly associated with better end-of-life quality indicators