Short-term and medium-term survival of critically ill patients with solid tumours admitted to the intensive care unit:A retrospective analysis

OBJECTIVES: Patients with cancer frequently require unplanned admission to the intensive care unit (ICU). Our objectives were to assess hospital and 180-day mortality in patients with a non-haematological malignancy and unplanned ICU admission and to identify which factors present on admission were the best predictors of mortality. DESIGN: Retrospective review of all patients with a diagnosis of solid tumours following unplanned admission to the ICU between 1 August 2008 and 31 July 2012. SETTING: Single centre tertiary care hospital in London (UK). PARTICIPANTS: 300 adult patients with non-haematological solid tumours requiring unplanned admission to the ICU. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOMES: Hospital and 180-day survival. RESULTS: 300 patients were admitted to the ICU (median age 66.5 years; 61.7% men). Survival to hospital discharge and 180 days were 69% and 47.8%, respectively. Greater number of failed organ systems on admission was associated with significantly worse hospital survival (p<0.001) but not with 180-day survival (p=0.24). In multivariate analysis, predictors of hospital mortality were the presence of metastases (OR 1.97, 95% CI 1.08 to 3.59), Acute Physiology and Chronic Health Evaluation II (APACHE II) Score (OR 1.07, 95% CI 1.01 to 1.13) and a Glasgow Coma Scale Score <7 on admission to ICU (OR 5.21, 95% CI 1.65 to 16.43). Predictors of worse 180-day survival were the presence of metastases (OR 2.82, 95% CI 1.57 to 5.06), APACHE II Score (OR 1.07, 95% CI 1.01 to 1.13) and sepsis (OR 1.92, 95% CI 1.09 to 3.38). CONCLUSIONS: Short-term and medium-term survival in patients with solid tumours admitted to ICU is better than previously reported, suggesting that the presence of cancer alone should not be a barrier to ICU admission

Microfluidic synthesis of protein-loaded nanogels in a coaxial flow reactor using a design of experiments approach

Ionic gelation is commonly used to generate nanogels but often results in poor control over size and polydispersity. In this work we present a novel approach to the continuous manufacture of protein-loaded chitosan nanogels using microfluidics whereby we demonstrate high control and uniformity of the product characteristics. Specifically, a coaxial flow reactor (CFR) was employed to control the synthesis of the nanogels, comprising an inner microcapillary of internal diameter (ID) 0.595 mm and a larger outer glass tube of ID 1.6 mm. The CFR successfully facilitated the ionic gelation process via chitosan and lysozyme flowing through the inner microcapillary, while cross-linkers sodium tripolyphosphate (TPP) and 1-ethyl-2-(3-dimethylaminopropyl)-carbodiimide (EDC) flowed through the larger outer tube. In conjunction with the CFR, a four-factor three-level face-centered central composite design (CCD) was used to ascertain the relationship between various factors involved in nanogel production and their responses. Specifically, four factors including chitosan concentration, TPP concentration, flow ratio and lysozyme concentration were investigated for their effects on three responses (size, polydispersity index (PDI) and encapsulation efficiency (% EE)). A desirability function was applied to identify the optimum parameters to formulate nanogels in the CFR with ideal characteristics. Nanogels prepared using the optimal parameters were successfully produced in the nanoparticle range at 84 ± 4 nm, showing a high encapsulation efficiency of 94.6 ± 2.9% and a high monodispersity of 0.26 ± 0.01. The lysis activity of the protein lysozyme was significantly enhanced in the nanogels at 157.6% in comparison to lysozyme alone. Overall, the study has demonstrated that the CFR is a viable method for the synthesis of functional nanogels containing bioactive molecules

Microfluidic production of nanogels as alternative triple transfection reagents for the manufacture of adeno-associated virus vectors

Adeno-associated viral vectors (AAVs) have proved a mainstay in gene therapy, owing to their remarkable transduction efficiency and safety profile. Their production, however, remains challenging in terms of yield, the cost-effectiveness of manufacturing procedures and large-scale production. In this work, we present nanogels produced by microfluidics as a novel alternative to standard transfection reagents such as polyethylenimine-MAX (PEI-MAX) for the production of AAV vectors with comparable yields. Nanogels were formed at pDNA weight ratios of 1 : 1 : 2 and 1 : 1 : 3, of pAAV cis-plasmid, pDG9 capsid trans-plasmid and pHGTI helper plasmid respectively, where vector yields at a small scale showed no significant difference to those of PEI-MAX. Weight ratios of 1 : 1 : 2 showed overall higher titers than 1 : 1 : 3, where nanogels with nitrogen/phosphate ratios of 5 and 10 produced yields of ≈8.8 × 10^{8} vg mL^{-1} and ≈8.1 × 10^{8} vg mL^{-1} respectively compared to ≈1.1 × 10^{9} vg mL^{-1} for PEI-MAX. In larger scale production, optimised nanogels produced AAV at a titer of ≈7.4 × 10^{11} vg mL^{-1}, showing no statistical difference from that of PEI-MAX at ≈1.2 × 10^{12} vg mL^{-1}, indicating that equivalent titers can be achieved with easy-to-implement microfluidic technology at comparably lower costs than traditional reagents

Advances in restoration ecology: rising to the challenges of the coming decades

Simultaneous environmental changes challenge biodiversity persistence and human wellbeing. The science and practice of restoration ecology, in collaboration with other disciplines, can contribute to overcoming these challenges. This endeavor requires a solid conceptual foundation based in empirical research which confronts, tests and influences theoretical developments. We review conceptual developments in restoration ecology over the last 30 years. We frame our review in the context of changing restoration goals which reflect increased societal awareness of the scale of environmental degradation and the recognition that inter-disciplinary approaches are needed to tackle environmental problems. Restoration ecology now encompasses facilitative interactions and network dynamics, trophic cascades, and above- and below ground linkages. It operates in a non-equilibrium, alternative states framework, at the landscape scale, and in response to changing environmental, economic and social conditions. Progress has been marked by conceptual advances in the fields of trait-environment relationships, community assembly, and understanding the links between biodiversity and ecosystem functioning. Conceptual and practical advances have been enhanced by applying evolving technologies, including treatments to increase seed germination and overcome recruitment bottlenecks, high throughput DNA sequencing to elucidate soil community structure and function, and advances in satellite technology and GPS tracking to monitor habitat use. The synthesis of these technologies with systematic reviews of context dependencies in restoration success, model based analyses and consideration of complex socio-ecological systems will allow generalizations to inform evidence based interventions. Ongoing challenges include setting realistic, socially acceptable goals for restoration under changing environmental conditions, and prioritizing actions in an increasingly space-competitive world. Ethical questions also surround the use of genetically modified material, translocations, taxon substitutions, and de-extinction, in restoration ecology. Addressing these issues, as the Ecological Society of America looks to its next century, will require current and future generations of researchers and practitioners, including economists, engineers, philosophers, landscape architects, social scientists and restoration ecologists, to work together with communities and governments to rise to the environmental challenges of the coming decades

The evolutionary legacy of size-selective harvesting extends from genes to populations

Size-selective harvesting is assumed to alter life histories of exploited fish populations, thereby negatively affecting population productivity, recovery, and yield. However, demonstrating that fisheries-induced phenotypic changes in the wild are at least partly genetically determined has proved notoriously difficult. Moreover, the population-level consequences of fisheries-induced evolution are still being controversially discussed. Using an experimental approach, we found that five generations of size-selective harvesting altered the life histories and behavior, but not the metabolic rate, of wild-origin zebrafish (Danio rerio). Fish adapted to high positively size selective fishing pressure invested more in reproduction, reached a smaller adult body size, and were less explorative and bold. Phenotypic changes seemed subtle but were accompanied by genetic changes in functional loci. Thus, our results provided unambiguous evidence for rapid, harvest-induced phenotypic and evolutionary change when harvesting is intensive and size selective. According to a life-history model, the observed life-history changes elevated population growth rate in harvested conditions, but slowed population recovery under a simulated moratorium. Hence, the evolutionary legacy of size-selective harvesting includes populations that are productive under exploited conditions, but selectively disadvantaged to cope with natural selection pressures that often favor large body size.Peer reviewe

Big data and data repurposing – using existing data to answer new questions in vascular dementia research

Introduction: Traditional approaches to clinical research have, as yet, failed to provide effective treatments for vascular dementia (VaD). Novel approaches to collation and synthesis of data may allow for time and cost efficient hypothesis generating and testing. These approaches may have particular utility in helping us understand and treat a complex condition such as VaD. Methods: We present an overview of new uses for existing data to progress VaD research. The overview is the result of consultation with various stakeholders, focused literature review and learning from the group’s experience of successful approaches to data repurposing. In particular, we benefitted from the expert discussion and input of delegates at the 9th International Congress on Vascular Dementia (Ljubljana, 16-18th October 2015). Results: We agreed on key areas that could be of relevance to VaD research: systematic review of existing studies; individual patient level analyses of existing trials and cohorts and linking electronic health record data to other datasets. We illustrated each theme with a case-study of an existing project that has utilised this approach. Conclusions: There are many opportunities for the VaD research community to make better use of existing data. The volume of potentially available data is increasing and the opportunities for using these resources to progress the VaD research agenda are exciting. Of course, these approaches come with inherent limitations and biases, as bigger datasets are not necessarily better datasets and maintaining rigour and critical analysis will be key to optimising data use

Geophysical monitoring of moisture‐induced landslides: a review

Geophysical monitoring of landslides can provide insights into spatial and temporal variations of subsurface properties associated with slope failure. Recent improvements in equipment, data analysis, and field operations have led to a significant increase in the use of such techniques in monitoring. Geophysical methods complement intrusive approaches, which sample only a very small proportion of the subsurface, and walk-over or remotely sensed data, which principally provide information only at the ground surface. In particular, recent studies show that advances in geophysical instrumentation, data processing, modeling, and interpretation in the context of landslide monitoring are significantly improving the characterization of hillslope hydrology and soil and rock hydrology and strength and their dynamics over time. This review appraises the state of the art of geophysical monitoring, as applied to moisture-induced landslides. Here we focus on technical and practical uses of time-lapse methods in geophysics applied to monitoring moisture-induced landslide. The case studies identified in this review show that several geophysical techniques are currently used in the monitoring of subsurface landslide processes. These geophysical contributions to monitoring and predicting the evolution of landslide processes are currently underrealized. Hence, the further integration of multiple-parametric and geotechnically coupled geophysical monitoring systems has considerable potential. The complementary nature of certain methods to map the distribution of subsurface moisture and elastic moduli will greatly increase the predictive and monitoring capacity of early warning systems in moisture-induced landslide settings

Structural Basis for Type VI Secretion Effector Recognition by a Cognate Immunity Protein

The type VI secretion system (T6SS) has emerged as an important mediator of interbacterial interactions. A T6SS from Pseudomonas aeruginosa targets at least three effector proteins, type VI secretion exported 1–3 (Tse1–3), to recipient Gram-negative cells. The Tse2 protein is a cytoplasmic effector that acts as a potent inhibitor of target cell proliferation, thus providing a pronounced fitness advantage for P. aeruginosa donor cells. P. aeruginosa utilizes a dedicated immunity protein, type VI secretion immunity 2 (Tsi2), to protect against endogenous and intercellularly-transferred Tse2. Here we show that Tse2 delivered by the T6SS efficiently induces quiescence, not death, within recipient cells. We demonstrate that despite direct interaction of Tsi2 and Tse2 in the cytoplasm, Tsi2 is dispensable for targeting the toxin to the secretory apparatus. To gain insights into the molecular basis of Tse2 immunity, we solved the 1.00 Å X-ray crystal structure of Tsi2. The structure shows that Tsi2 assembles as a dimer that does not resemble previously characterized immunity or antitoxin proteins. A genetic screen for Tsi2 mutants deficient in Tse2 interaction revealed an acidic patch distal to the Tsi2 homodimer interface that mediates toxin interaction and immunity. Consistent with this finding, we observed that destabilization of the Tsi2 dimer does not impact Tse2 interaction. The molecular insights into Tsi2 structure and function garnered from this study shed light on the mechanisms of T6 effector secretion, and indicate that the Tse2–Tsi2 effector–immunity pair has features distinguishing it from previously characterized toxin–immunity and toxin–antitoxin systems

METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: an initiative of the Joint Programme for Neurodegenerative Disease Research

Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically “silent” cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular-related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention