Blurring disciplinary boundaries in the design studio: Bringing architecture, business, and arts students together to prototype new solutions for palliative care

As complex global problems increasingly require the knowledge and skills of a broad array of disciplines, existing pedagogical approaches need to shift to support graduates to develop the skills necessary for innovation. This article reports on an experimental design studio that asked students from the disciplines of architecture, business and arts to work collaboratively to propose innovative solutions to complex real-world problems. While bringing other disciplines into the design studio is not new, in previously reported examples students were provided well defined parameters for assessment tasks, alongside clear expectations for how disciplines should work together. The studio reported here provided students with the agency to define their own artefacts in response to the problems facing palliative care, and to decide how they would work together in the process of that production. Within this context, students were forced to examine their own disciplinary limitations and to find strategies for working beyond those, and in doing so, move beyond the recognized limitations of inter- and multi-disciplinary approaches to problem solving. To understand the value of this learning experience, extensive data were gathered from students in addition to educator observations. This article provides advice for design educators wanting to augment the studio learning environment through transdisciplinary collaboration, as well as those beyond the design disciplines who may be interested in utilizing this learning approach

After the teleconsultation : getting medicines to patients when pharmacy services are not available

Peer reviewe

Sex and outcrossing in a sessile freshwater invertebrate

SUMMARY1. The freshwater bryozoan Cristatella mucedo, in common with other sessile, benthic freshwater taxa, has an unusual life history: sex occurs during a relatively brief period near the start of the growing season, and overwintering occurs in the form of asexually produced dormant propagules (statoblasts). Consistent observed heterozygosity (Ho) deficits in C. mucedo populations have previously suggested that inbreeding is common, although a possible contribution of a Wahlund effect to low Ho could not be discounted. 2. We have used microsatellite data in the first study based on codominant markers to genetically characterise maternal colonies and larval offspring of C. mucedo. The 'population' represented by the larvae was in Hardy–Weinberg equilibrium, which has previously been found in only one of 39 populations of C. mucedo. At least 64% of larvae were the products of outcrossing. We suggest that the unusual early timing of sex may be a strategy to maximise rates of outcrossing within populations of sessile freshwater invertebrate

Predicting survival in malignant pleural mesothelioma using routine clinical and laboratory characteristics

Introduction The prognosis of malignant pleural mesothelioma (MPM) is poor, with a median survival of 8–12 months. The ability to predict prognosis in MPM would help clinicians to make informed decisions regarding treatment and identify appropriate research opportunities for patients. The aims of this study were to examine associations between clinical and pathological information gathered during routine care, and prognosis of patients with MPM, and to develop a 6-month mortality risk prediction model.Methods A retrospective cohort study of patients diagnosed with MPM at Queen Alexandra Hospital, Portsmouth, UK between December 2009 and September 2013. Multivariate analysis was performed on routinely available histological, clinical and laboratory data to assess the association between different factors and 6-month survival, with significant associations used to create a model to predict the risk of death within 6 months of diagnosis with MPM.Results 100 patients were included in the analysis. Variables significantly associated with patient survival in multivariate analysis were age (HR 1.31, 95% CI 1.09 to 1.56), smoking status (current smoker HR 3.42, 95% CI 1.11 to 4.20), chest pain (HR 2.14, 95% CI 1.23 to 3.72), weight loss (HR 2.13, 95% CI 1.18 to 3.72), platelet count (HR 1.05, 95% CI 1.00 to 1.10), urea (HR 2.73, 95% CI 1.31 to 5.69) and adjusted calcium (HR 1.47, 95% CI 1.10 to 1.94). The resulting risk model had a c-statistic value of 0.76. A Hosmer-Lemeshow test confirmed good calibration of the model against the original dataset.Conclusion Risk of death at 6 months in patients with a confirmed diagnosis of MPM can be predicted using variables readily available in clinical practice. The risk prediction model we have developed may be used to influence treatment decisions in patients with MPM. Further validation of the model requires evaluation of its performance on a separate dataset

The m.13051G>A mitochondrial DNA mutation results in variable neurology and activated mitophagy.

Maternally inherited mitochondrial DNA (mtDNA) mutations cause symptoms of Leber hereditary optic neuropathy (LHON) in -1 in 30,000 individuals. Most of the affected individuals lack respiratory chain defects1 and there is no proven prophylactic treatment

THERAPEUTIC EFFECTS OF HYPOXIC AND PRO-INFLAMMATORY PRIMING OF MESENCHYMAL STEM CELL-DERIVED EXTRACELLULAR VESICLES IN INFLAMMATORY ARTHRITIS

AbstractNovel biological therapies have revolutionised the management of Rheumatoid Arthritis (RA) but no cure currently exists. Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA).EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA.All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Th17:Treg homeostatic balance.Priming of MSCs in EV production can be applied to alter the therapeutic efficacy however normoxic EVs present the optimal strategy for broad therapeutic benefit. The varied outcomes observed in MSCs priming may promote EVs optimised for therapies targeted for specific therapeutic priorities. EVs present an effective novel technology with potential for cell-free therapeutic translation.</jats:p

Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

Leishmania infantum Amastigotes Enhance HIV-1 Production in Cocultures of Human Dendritic Cells and CD4+ T Cells by Inducing Secretion of IL-6 and TNF-α

Visceral leishmaniasis (VL) is a potentially deadly parasitic disease afflicting millions worldwide. Although itself an important infectious illness, VL has also emerged as an opportunistic disease among patients infected with HIV-1. This is partly due to the increasing overlap between urban regions of high HIV-1 transmission and areas where Leishmania is endemic. Furthermore, VL increases the development and clinical progression of AIDS-related diseases. Conversely, HIV-1-infected individuals are at greater risk of developing VL or suffering relapse. Finally, HIV-1 and Leishmania can both productively infect cells of the macrophage-dendritic cell lineage, resulting in a cumulative deficiency of the immune response. We therefore studied the effect of Leishmania infantum on HIV-1 production when dendritic cells (DCs) are cocultured with autologous CD4+ T cells. We show that amastigotes promote virus replication in both DCs and lymphocytes, due to a parasite-mediated production of soluble factors by DCs. Micro-beads array analyses indicate that Leishmania infantum amastigotes infection induces a higher secretion of several cytokines in these cells, and use of specific neutralizing antibodies revealed that the Leishmania-induced increase in HIV-1 replication is due to IL-6 and TNF-α. These findings suggest that Leishmania's presence within DC/T-cell conjugates leads to an enhanced HIV-1 production

A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation

BACKGROUND: To identify the best possible outcomes in liver transplantation from donation after circulatory death donors (DCD) and to propose outcome values, which serve as reference for individual liver recipients or patient groups. METHODS: Based on 2219 controlled DCD liver transplantations, collected from 17 centres in North America and Europe, we identified 1012 low-risk, primary, adult liver transplantations with a laboratory MELD of ≤20points, receiving a DCD liver with a total donor warm ischemia time of ≤30minutes and asystolic donor warm ischemia time of ≤15minutes. Clinically relevant outcomes were selected and complications were reported according to the Clavien-Dindo-Grading and the Comprehensive Complication Index (CCI). Corresponding benchmark cut-offs were based on median values of each centre, where the 75(th)-percentile was considered. RESULTS: Benchmark cases represented between 19.7% and 75% of DCD transplantations in participating centers. The one-year retransplant and mortality rate was 5.23% and 9.01%, respectively. Within the first year of follow-up, 51.1% of recipients developed at least one major complication (≥Clavien-Dindo-Grade-III). Benchmark cut-offs were ≤3days and ≤16days for ICU and hospital stay, ≤66% for severe recipient complications (≥Grade-III), ≤16.8% for ischemic cholangiopathy, and ≤38.9CCI points at one-year posttransplant. Comparisons with higher risk groups showed more complications and impaired graft survival, outside the benchmark cut-offs. Organ perfusion techniques reduced the complications to values below benchmark cut-offs, despite higher graft risk. CONCLUSIONS: Despite excellent 1-year survival, morbidity in benchmark cases remains high with more than half of recipients developing severe complications during 1-year follow-up. Benchmark cut-offs targeting morbidity parameters offer a valid tool to assess the protective value of new preservation technologies in higher risk groups, and provide a valid comparator cohort for future clinical trials. LAY SUMMARY: The best possible outcomes after liver transplantation of grafts donated after circulatory death (DCD) were defined using the concept of benchmarking. These were based on 2219 liver transplantations following controlled DCD donation in 17 centres worldwide. The following benchmark cut-offs for the most relevant outcome parameters were developed: ICU and hospital stay: ≤3 and ≤16 days; primary non function: ≤2.5%; renal replacement therapy: ≤9.6%; ischemic cholangiopathy: ≤16.8% and anastomotic strictures ≤28.4%. One-year graft loss and mortality were defined as ≤14.4% and 9.6%, respectively. Donor and recipient combinations with higher risk had significantly worse outcomes. The use of novel organ perfusion technology achieved similar, good results in this high-risk group with prolonged donor warm ischemia time, when compared to the benchmark cohort